Podcasts about 5fu

In this episode of The Common Sense MD, Dr. Rogers is joined by his daughter and Performance Medicine's lead esthetician, Kelli Rogers. With her years of experience, Kelli shares expert tips for rejuvenating sun-damaged skin. Discover effective treatments like the combined use of 5FU and calcipetriene, and learn about innovative methods such as the CO2 CoolPeel and chemical peels. Kelli also discusses prevention strategies and the advantages of non-toxic sunscreens. From winter skincare advice to body contouring technologies, this episode offers practical, actionable tips for maintaining beautiful skin all year round. Check out our brand new online vitamin store: ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠https://performancemedicine.net/shop/⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ What did you think of this episode of the podcast? Let us know by leaving a review! Connect with Performance Medicine! Sign up for our weekly newsletter: ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠https://performancemedicine.net/doctors-note-sign-up/⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ Facebook: ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠@PMedicine⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ Instagram: ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠@PerformancemedicineTN⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ YouTube: ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠Performance Medicine⁠

Drs. Vamsi Velcheti, Taofeek Owonikoko, and Janakiraman Subramanian discuss their experiences navigating the cancer drug shortage in the United States, the impact on patients and clinical trial enrollment, lessons learned, and proactive strategies to mitigate future crises. TRANSCRIPT  Dr. Vamsi Velcheti: Hello, I'm Dr. Vamsi Velcheti, your guest host for the ASCO Daily News Podcast today. I'm a professor of medicine and director of thoracic oncology at the Perlmutter Cancer Center at NYU Langone. On today's episode, we'll be discussing the impact of the shortage of cancer chemotherapy drugs across the United States. This has been affecting several thousands of patients with adult and pediatric cancers and hampering enrollment in clinical trials. Among the shortages are very commonly used drugs like cisplatin, carboplatin, methotrexate, and fludarabine. Some of these shortages have persisted since the time of the pandemic in 2020.   So today, to discuss this really troubling scenario, I have two outstanding colleagues, Dr. Janakiraman Subramanian, the director of thoracic oncology at Inova Schar Cancer Institute in Virginia, and Dr. Taofeek Owonikoko, a professor of medicine and the chief of the Division of Hematology and Oncology at the University of Pittsburgh Hillman Cancer Center in Pittsburgh.   Our full disclosures are available in the transcript of this episode, and disclosures relating to all episodes of the podcast are available at asco.org/DNpod.  So, a recent survey by the NCCN found that 90% of the nation's largest cancer centers have experienced a shortage in carboplatin, and 70% of the centers have reported a shortage in cisplatin. These are platinum-based chemotherapies we use frequently in patients with cancer, and these are often curative intent treatments for several cancers, and these are used in several tumor types, both solid tumors and hematologic malignancies. So, the scale of the problem is immense.   Dr. Owonikoko, I'd like to hear your take on this situation and how are you dealing with this at the UPMC Cancer Center.  Dr. Taofeek Owonikoko: Yeah, thank you, Dr. Velcheti, and happy to be part of this panel. As you rightly surmised, the chemotherapy drug shortage is what we've all experienced across the length and breadth of the United States. Our cancer center here in Pittsburgh is not an exception. We've had to be proactive as well as think outside the box to be able to manage the challenge. Just like every other cancer center across the country, maybe to varying degrees, we've had to look at patients in need of chemotherapy with these standard-of-care agents such as cisplatin or carboplatin, and to some degree docetaxel, during this past episode of drug shortage that we all went through. And while we did not have to, fortunately, cancel any patient treatment, we all went through it with bated breath; not sure of where the next batch of chemotherapy drugs will come through, but I would say in the past couple of weeks, we've actually seen some improvement in drug availability.   But before then, we've had to have contingency plans where, on a weekly basis, we review our patient list and the drug regimens that they're going to need, and must make sure that we have enough drug on hand for those patients. And in situations where we thought we might not have enough drug; we also had a plan to use alternative regimens. We were proactive in having guiding principles that are consistent with ASCO's recommendations in terms of quality care delivery for cancer patients. So, I'm sure that this is more or less the same approach adopted by other leading cancer centers across the country.   Dr. Vamsi Velcheti: Thank you, Dr. Owonikoko. And Dr. Subramanian, you're in a community setting, a large cancer center that serves a lot of patients in the state of Virginia. So, what is the scale of the problem at your institution and how are you handling it?   Dr. Janakiraman Subramanian: First of all, Dr. Velcheti, thanks for having me here on this panel. And as you rightly said, this is a significant problem, and it is across the country like Dr. Owonikoko said. And as medical oncologists, we are not always thinking of drug shortages. Our focus is on taking care of our patients. So, this is one more issue that we need to keep in mind now as we manage our patients with cancer. When this shortage started, the biggest problem, as you know, was when we became aware of this was primarily in cisplatin and we had some of our patients who were getting curative treatment and we had to make a decision - can they get cisplatin or can they get carboplatin. And one of the things we did was to have an ethics committee that will review each patient that is being planned to receive cisplatin-based chemotherapy and come to a decision on how best we can support them.   The template for some of this was based upon some of the triage mechanisms we used during COVID, as well as the ASCO guideline document for managing this chemotherapy shortage, which was one of the blueprints we used. And they have reviewed all cases, all patients that are being planned for cisplatin or carboplatin for that matter, and we come to a decision based on that. And we also have another committee that constantly monitors drug availability on a weekly basis and tries to forecast where the next problem would be as we take care of our patients.   And particularly as a lung cancer doctor, we've had situations where we had to use carboplatin instead of cisplatin and even we also have carboplatin shortage. And so, the committee usually approves two cycles at a time, but thankfully so far we have not had a situation where we could not offer our patients the chemotherapy treatment. But we are very carefully monitoring the situation, hoping that this will improve.   The other aspect of the shortage has been in 5FU. A lot of our GI colleagues; I treat esophageal cancer patients as well, where we've had to forego the bolus 5FU and have a 10% reduction on all 5FU infusions. And we've been using some of that dose reduction to ensure that we can have 5FU available for all our patients. And that's how we've been trying to manage this shortage situation here at Inova Schar.   Dr. Vamsi Velcheti: Dr. Subramanian and Dr. Owonikoko, we are oncologists, we are treating patients, and the toughest part really is telling a patient that we don't have access to certain drugs and we have to switch treatments to perhaps another treatment regimen that may be suboptimal. And it's always a very anxiety-provoking discussion, and especially for patients with metastatic cancer, they're already under a lot of stress and it's a really difficult conversation. How do you handle that, Dr. Owonikoko?  Dr. Taofeek Owonikoko: That's a conversation we all hope we don't have to have. And fortunately, with this current crisis, I've actually not had such misfortune of having to inform a patient that we don't have drugs to treat them or that we have to switch to something inferior. But conceptually, it's possible that could have happened and that would have been very difficult. But the one thing that we did, though, as part of our mitigation strategy was actually to inform the patient ahead of time because the way we handled this was to look at our inventory on a week-by-week basis. And if there are patients where we felt maybe they will be coming in towards the end of the week and we may not have enough drugs for them, to let them know the possibility exists that we might have to switch them to something different. While we did not have to do that for any patient, yes, there are patients that we had to give that heads up to, to say, “We're having this shortage. We're doing everything we can to make sure it's available. But just in case it's not available…” I think what is most important for most patients is to be aware of that decision ahead of time, to be able to process it, and to be transparent.   The other challenge that we face was, if you have to choose between patients, what should be your guiding principles as to who gets the drug and who doesn't get it? I think it's very easy for all of us to say, “Oh, if it's curative intent, we do it. If it's not curative intent, we don't do it.” It's a little more complicated than that because if we put the equity hat on, curative intent doesn't actually mean that that life is more valuable than somebody who cannot be cured. And this is where really, I think having people with expertise in ethics of care delivery and disaster management will be very important for us to proactively anticipate that, should this become a recurrent problem in the future that we actually have a well-vetted approach, just like we did during COVID where you have to ration resources that we have those people with expertise to help us as oncologists because not all of us, at least personally I can speak for myself, that is not my area of expertise and comfort.  Dr. Vamsi Velcheti: Excellent points. Dr. Subramanian, anything to add?  Dr. Janakiraman Subramanian: Oh, absolutely. I echo what Dr. Owonikoko said. These are conversations that we would like to hopefully never have with our patients. But this is a crisis that we are facing now. And personally, I can tell you two situations where we ran into this problem. But overall, though, we never had to stop a treatment or cancel a treatment for our patient. In the first situation, we had a young man with a rare germ cell tumor in the hospital for whom cisplatin was key. He was already in the ICU and sometimes the treatment start dates are not perfect, unlike what we do in the outpatient setting, depending on how well he's doing or the treatment start dates might move by a day or so. So we basically had to hold a certain dose of cisplatin for him.   This brings the next question, which is how do we decide who gets cisplatin versus who can go for an alternative option? And I think Dr. Owonikoko made a great point where, just because it is a curative disease does not mean their life is more valuable. This is where I think trying to make that decision at an individual level, as an individual treating physician can be extremely hard. And that's why at our institution we have this ethics committee where we have oncologists, pharmacists, and ethicists that review these chemotherapy orders, particularly for cisplatin, and try to use some guiding principles that we learned from COVID as well as ASCO's guidance to decide how we assign our resources. That's one option, one way we have done it.    And then in another situation that was faced by one of my GI oncology colleagues was a patient that was originally planned to go on a clinical trial where the chemotherapy backbone was FOLFOX and because we had the 5FU shortage, we could not offer that patient clinical trial enrollment. And that was a tough conversation where they had to tell them that they could not go on a clinical trial that they were looking forward to. And this then brings the next question, which is by foregoing the bolus 5FU and by the 10% reduction in the infusional 5FU, are we providing them inferior treatment? And it's a conversation that's had at a very individual level. I don't envy my colleague who had to have that conversation. It's a challenge and we try to do our best to communicate to our patients that we are trying to provide care without trying to compromise the effectiveness of treatment for them.  Dr. Vamsi Velcheti: Thank you so much both of you. And we had the same issues here at NYU in New York City as well. It appears, you know, the degree of shortage and the drugs that are in shortage has been somewhat different at different locations across the United States. But the theme has been that we are having to ration treatments for our patients. And of course, there are some tumor types where there's really no adequate substitution, for example, GU cancers. I mean, you can't really not give them cisplatin. A lot of these are situations which have curative intent and young patients. So, it's really troubling.   And I think one of the things that really came out of this is there's been a lot of push from professional societies that actually ASCO has been spearheading and some intense discussions with CMS and legislators to kind of provide more long-term fix for these things. And I think all of us have to be more engaged in those discussions with our professional societies like ASCO to kind of help promote awareness. So if you kind of think about it, these drugs are not that expensive. These are generic drugs that we've all been using for such a long time. And the fact that we can't provide these drugs for various reasons is kind of really concerning. We spend so much money on research and more expensive drugs and not being able to manufacture these drugs within the country and kind of having to rely on complex supply chains is troubling, and I hope the situation improves very soon.    So, I know both of you are at large cancer centers that enroll patients on clinical trials. Of course, these drugs, especially carboplatin, for lung cancer, especially, are like core treatments that are used in managing cancer patients with lung cancer. So how is this affecting your clinical trial accrual? Are you prioritizing patients on clinical trials for these drugs? Have you had to make any decisions to hold clinical trial accrual for certain trials? Kind of curious to hear.  Dr. Taofeek Owonikoko: Yeah, so I can maybe weigh in a little bit on that in terms of what we've had to do for patients receiving treatment as standard of care versus those going on clinical trials. As we all recognize that when a patient goes on a clinical trial, even if they are going to receive a standard-of-care regimen as part of that trial, it still has to be administered in line with the protocol. So, during the extreme period of shortage anxiety, we actually had consideration for perhaps not putting patients on trial if we're not sure that they will be able to continue to receive the protocol-mandated treatment, whether it's a control intervention or the experimental intervention.   The good thing to come out of this is at least here at UPMC, we actually did not have any instance where we had to deny a patient clinical trial participation. But there were anxious periods when we already had patients enrolled and they were scheduled to receive a platinum-containing regimen and we were not sure whether or not we were going to have adequate supply of the drug for them while on trial. I think this really raises an important consideration going forward as we come out of this current shortage. I don't by any stretch of the imagination assume that this is going to be the last one we experience, but I think the lessons learned here, we have to also carry that forward both in the design of the trial as well as in the regulatory environment surrounding clinical trial conduct, to say, should another incidence of drug shortage are to happen, how do we actually operationalize that with respect to patients on trial, whether starting or already on trial?   I think it's much more challenging when the patient is already on the trial, they've already started. It's less challenging if you just have to make a decision about somebody starting newly on the trial. But equally important is that by not allowing new patients to go on trial is denying something that potentially could be of benefit to them, albeit it is still a trial, it's not an established treatment option yet.  Dr. Janakiraman Subramanian : I completely agree with Dr. Owonikoko. Those were very key points and issues that we face as well. In terms of my patients with lung cancer, we haven't had a problem in getting them on clinical trials. Even though we have had carboplatin shortage patients who are already on treatment, they were able to get the carboplatin. For new patients, we were still able to provide them carboplatin as well. The biggest problem for clinical trials has been primarily with my GI colleagues who have to use 5FU. And there, as I said before, we are unable to give bolus 5FU and there is a 10% reduction of the infusional 5FU. So, we can't have any of these patients go on clinical trials.    And as a result, anything that has to do with 5FU has come to a screeching halt in terms of clinical trials for our patients. And I think I echo the point of Dr. Owonikoko that by no means this is the last drug shortage we're going to be dealing with and we are here today discussing this, also because this shortage has not ended. It's been ongoing. It's one of the longest drug shortages in my memory as a medical oncologist, and that's concerning. We still see that there is some improvement, but we haven't gotten past it yet.     And therefore, as we develop clinical trials and we need to have methods to address drug shortages and how we manage patient enrollment as well as how do we manage existing patients who are already on a clinical trial and, if possible, what might be their options in that situation. We may not have all the answers, but it is definitely an issue that we need to think about in the future as we develop and implement newer clinical trials for our patients.  Dr. Vamsi Velcheti: I completely agree and great points, both of you. And we've had the same issues with clinical trials at NYU Langone as well due to the shortage. It's been a challenge, and I think this is a problem that's so complex because of supply chain issues and the way the drugs are priced and incentives for manufacturing these drugs in the United States are not lucrative enough to actually onshore a lot of the production of these drugs.   I think at the end of the day, I think we have to come up with some creative, innovative, reimbursement structures for these generic chemotherapy drugs. I think this would require a very complex economic solution that perhaps ASCO and other organizations should kind of really foster an environment of innovation to kind of help facilitate onshoring some of the manufacturing of these key drugs within the United States. I think ASCO is already trying to do that, trying to collaborate with all the stakeholders to kind of address this problem is very critical, and I think all of us have to be engaged in some of the advocacy efforts that are ongoing to kind of address these drug shortages. And this is not a short-term problem.  So, Dr. Owonikoko and Dr. Subramanian, any final thoughts before we wrap up the podcast today?  Dr. Janakiraman Subramanian: So, Vamsi, you mentioned the whole complex supply chain and the fact that we rely primarily on overseas manufacturers to get these drugs that are off-patent but still a key backbone of our cancer treatment. I think those are all key issues that policymakers and leaders in the field have to keep in mind. As an institution at Inova, one of the key mechanisms that have helped us to sort of stay ahead of the shortage was to have this inventory management team that monitors the inventory out there. And in fact, the inventory management team does have access to what the inventory is in some of their main suppliers in terms of the drugs. And they also have an idea of how many patients are going through treatment, what is the weekly usage of a specific drug like carboplatin. And they try to forecast what is coming down the road and try to prepare for it.   And as we try to look for solutions, maybe a forecasting mechanism in a larger scale like either spearheaded by ASCO or by policymakers level that can, for the overall country, try to see where some of the inventory is for some of these critical drugs and try to prepare for it ahead of time, rather than wait till we hit the shortage and then try to find alternative suppliers to get the drug, which obviously doesn't happen quick enough. It takes months or even longer to catch up and get the inventory back to the level where we can comfortably take care of our patients.  I think that is something we should be advocating for that as well as the professional societies should take a handle on that and see if they can support something like that as well as letting the institutions know ahead of time what's coming might be very helpful.  Dr. Vamsi Velcheti: Yeah, very good point, Janakiraman, and I think that's a key takeaway here. I think we have to learn from other industries and try to– I mean this is not unique to healthcare by any means. I mean these chronic shortages due to supply chain issues, inventory management, there might be some learnings from other industries here that we probably should also focus on inventory management and improve supply chain logistics.   Dr. Owonikoko, any closing thoughts?   Dr. Taofeek Owonikoko: Yeah, I agree as well with all the points made by Dr. Subramanian and yourself. This is a chronic problem that requires a long-term strategy. I think it's both an economic problem as well as a regulatory problem. As we all know, part of the reason why we went through this current crisis is the regulatory decision by the FDA regarding safety of one of the manufacturers. So being proactive in terms of how these audits are conducted and giving people lead time I think will help avoid similar situations in the future.    It's an economic problem. There's a reason why a lot of the big pharma companies are not producing these drugs. And if the cost of production is such that the amount of money you get paid is enough to cover your price, I think there is an economic issue there to be addressed. That is unfortunately not within the scope of what any one of us can do individually, but as advocates in terms of the structure of incentivizing new drug versus old drug, some of these newer drugs are quite expensive, but oftentimes they are used along with standard drugs that are not as expensive. So, where do we strike that balance where we do not stifle innovation but at the same time, we don't create a perverse incentive system where everybody just wants to come up with the newest, most expensive drug and nobody is interested in really producing the backbone chemotherapy and other agents that will make those new drugs work well.   So, I think we have to pay attention. We have to advocate for our patients through our different institutions and organizations, and I hope that society as a whole that we've learned a lot of lessons from this crisis and that will help us craft some long-term strategies.   Dr. Vamsi Velcheti: Thank you both Dr. Owonikoko and Dr. Subramanian for your time today to speak with me and our listeners and for sharing your insights with us on the ASCO Daily News podcast.   Dr. Taofeek Owonikoko: Thank you.   Dr. Janakiraman Subramanian: Thank you.  Dr. Vamsi Velcheti: And thank you to our listeners for your time today. If you value the insights that you hear on ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcast. Thank you so much.  Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  ASCO Resources Related to Drug Shortages are available here.     Follow today's speakers:    Dr. Vamsidhar Velcheti    @VamsiVelcheti    Dr. Janakiraman Subramanian  @RamSubraMD  Dr. Taofeek Owonikoko  @teekayowo    Follow ASCO on social media:     @ASCO on X (formerly Twitter)    ASCO on Facebook    ASCO on LinkedIn      Disclosures:     Dr. Vamsidhar Velcheti:     Honoraria: ITeos Therapeutics    Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen, Elevation Oncology, Taiho Oncology, Merus    Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline      Dr. Janakiraman Subramanian:  Consulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, Daichi, G1 Therapeutics, Jazz Pharmaceuticals, Janssen Oncology, Lilly, Blueprint Medicines, Axcess, BeiGene, Cardinal Health, Takeda, OncoCyte  Speakers' Bureau: AstraZeneca, Boehringer Ingelheim, G1 Therapeutics, Jazz Pharmaceuticals, Janssen Oncology  Research Funding (Inst.): G1 Therapeutics, Tesaro/GSK, Novartis, Genentech, Novocure, Merck   Dr. Taofeek Owonikoko:  Stocks and Other Ownership Interests: Cambium Oncology, GenCart, Coherus Biosciences  Consulting or Advisory Role: Novartis, Celgene, Abbvie, Eisai, GI Therapeutics, Takeda, Bristol-Myers Squibb, MedImmune, BerGenBio, Lilly, Amgen, AstraZeneca, PharmaMar, Boehringer Ingelheim, EMD Serono, Xcovery, Bayer, Merck, Jazz Pharmaceuticals, Zentalis, Wells Fargo, Ipsen, Roche/Genentech, Janssen, Exelixis, BeiGene, Triptych Health Partners, Daichi, Coherus Biosciences  Speakers Bureau: Abbvie  Research Funding (Inst.): Novartis, Astellas Pharma, Bayer, Regeneron, AstraZenece/MedImmune, Abbvie, G1Therapeutics, Bristol-Myers Squibb, United Therapeutics, Amgen, Loxo/Lilly, Fujifilm, Pfizer, Aeglea Biotherapeutics, Incyte, Merck, Oncorus, Ispen, GlaxoSmithKline, Calithera Biosciences, Eisai, WindMIL, Turning Point Therapeutics, Roche/Genentech, Mersana, Meryx, Boehringer Ingelheim  Patents, Royalties, Other Intellectual Property (Inst.):   Overcoming Acquired Resistance to Chemotherapy Treatments Through Suppression of STAT3  Selective Chemotherapy Treatments and Diagnostic Methods Related Thereto  DR4 Modulation and Its Implications in EGFR-Target Cancer Therapy Ref: 18089 PROV (CSP) United States Patent Application No. 62/670,210 June 26, 2018 (Co-Inventor)  Soluble FAS ligand as a biomarker of recurrence in thyroid cancer; provisional patent 61/727,519 (Inventor)  Other Relationship: Roche/Genentech, EMD Serono, Novartis  Uncompensated Relationships: Reflexion Medical           

DYPD is a gene that provides instructions for making an enzyme called dihydropyrimidine dehydrogenase (DPD). This enzyme plays very important in breaking down a substance called uracil, which is found in our DNA and RNA. Mutations in the DYPD gene can lead to decreased or absent DPD activity, which if you think about it can cause a buildup of uracil in the body.  If someone is DPD deficiency it can make it difficult for the body to process certain chemotherapy drugs and can lead to severe side effects, such as nerve damage, GI problems, and even death. Genetic testing before being placed on a chemo agent, to see if there is a DPD deficiency is vital.  According to Advocates for Universal DPD/DPYD Testing (AUDT), Europe is becoming the standard of care for testing for this gene and only in some selected institutions in the US the testing it being done.  AUDT is made up of a group of patient advocates and medical professionals who are seeking to improve treatment outcomes for patients that are preparing to receive chemotherapy based on fluoropyrimidine drugs. One of the founders of this non-profit organization, AUDT, Karen Merritt is our guest today. She lost her mother in 2014 due to being DPD deficient and after getting her first infusion of 5FU. Karen dedicated herself to advocating and raising awareness about pre-testing for DPD deficiency before fluoropyrimidine chemotherapy administration to reduce unnecessary suffering. Resources: https://test4dpd.org/about-us/ Disclaimer: These are my personal views and opinions, and I am not speaking on behalf of Castle Biosciences, Inc.

DYPD is a gene that provides instructions for making an enzyme called dihydropyrimidine dehydrogenase (DPD). This enzyme plays very important in breaking down a substance called uracil, which is found in our DNA and RNA. Mutations in the DYPD gene can lead to decreased or absent DPD activity, which if you think about it can cause a buildup of uracil in the body.  If someone is DPD deficiency it can make it difficult for the body to process certain chemotherapy drugs and can lead to severe side effects, such as nerve damage, GI problems, and even death. Genetic testing before being placed on a chemo agent, to see if there is a DPD deficiency is vital.  According to Advocates for Universal DPD/DPYD Testing (AUDT), Europe is becoming the standard of care for testing for this gene and only in some selected institutions in the US the testing it being done.  AUDT is made up of a group of patient advocates and medical professionals who are seeking to improve treatment outcomes for patients that are preparing to receive chemotherapy based on fluoropyrimidine drugs. One of the founders of this non-profit organization, AUDT, Karen Merritt is our guest today. She lost her mother in 2014 due to being DPD deficient and after getting her first infusion of 5FU. Karen dedicated herself to advocating and raising awareness about pre-testing for DPD deficiency before fluoropyrimidine chemotherapy administration to reduce unnecessary suffering. Disclaimer: These are my personal views and opinions, and I am not speaking on behalf of Castle Biosciences, Inc. Resources: https://test4dpd.org/about-us/

Oncology is a rapidly evolving medical field. So how do you keep up with all the advances and updates that are delivered through publications, conferences, and social media? This ASCO Education podcast explores how three oncologists in various settings and stages of their career manage this issue. Our moderator Dr. Adriana Alvarez, a medical oncologist at Cleveland Clinic in Ohio is joined by Dr. Sharad Goyal, a professor and division chief of Radiation Oncology at George Washington University in Washington, DC; Dr. Shruti Patel, an oncology fellow at Stanford University in California; and Dr. Banu Symington, a medical oncologist at Memorial Hospital of Sweetwater County in Wyoming, and adjunct professor in the University of Utah College of Nursing. Each will describe what they do to keep up to date on research advances and guidelines (3:25), how they find time to stay current in their field (7:25) and how they follow developments outside of their area of concentration (13:57).  The speakers have no relevant disclosures.  Resources: Podcast: Cancer Topics - Burned Out? Here's What You Can Do About It (Part 1)  Podcast: Cancer Topics - Burned Out? Here's What You Can Do About It (Part 2)  Podcast: Cancer Topics - Burnout in Oncology: Trainee Perspective  If you liked this episode, please follow the show. To explore other educational content, including courses, visit education.asco.org. Contact us at education@asco.org. TRANSCRIPT Disclosures for this podcast are listed on the podcast page.  Dr. Adriana Alvarez: An oncologist recently described that while sitting on a couch to write an article, by the time he finished his first paragraph, he received six notifications on his iPhone from WhatsApp, Twitter, and other messages. He knows what the dilemma is; you can shut down your phone, but you become worried about missing an urgent call or important update. The oncologist knows that social media is a place to follow friends and colleagues, to discover new presentations, and even debate about them. However, he understands the overload of information that is part of the rapidly evolving field of oncology. On any given day or week, there are research advances and updates in the management of cancer being shared through journal publications, conference presentations, newsletters, social media, and other methods. How does one keep up to date with these advances in oncology?  I'm Dr. Adriana Alvarez, a medical oncologist at Cleveland Clinic in Ohio. In this ASCO Education Podcast, we will examine what various oncology professionals at different stages in their careers and working in different practice settings, namely academic versus community and urban versus rural, are doing to manage the large amount of information influx regarding advances in oncology.  Joining me are Dr. Sharad Goyal, a professor and division chief of radiation oncology at George Washington University in Washington, DC; Dr. Shruti Patel, an oncology fellow at Stanford University; and Dr. Banu Symington, a medical oncologist at Memorial Hospital of Sweetwater County in Wyoming, and adjunct professor in the University of Utah College of Nursing.  Let's start. One of the first questions I have here is how you can describe your current field of focus in oncology. Dr. Patel? Dr. Shruti Patel: My current clinical focus in oncology is in thoracic and gastrointestinal malignancies, while my research interests include clinical trials, liquid biopsy, and diversity, and equity and inclusion.  Dr. Sharad Goyal: My current clinical and research focus is on breast cancer, radiation therapy, as well as radiation therapy with respect to neuro-oncology in the neuro-oncology space. Dr. Adriana Alvarez: What about you, Dr. Symington? Dr. Banu Symington: I'm a general oncologist, medical oncologist, in an extreme rural, I'm considered a frontier practice. I have a special interest in eliminating the social disparity that is represented by rurality, and I'm interested in clinical trials. We are the only Wyoming Cancer Center that opened clinical trials. Dr. Adriana Alvarez: Well, it's all wonderful to hear about you and know a little bit about what your focus of work is, and we come from a variety of backgrounds. How do you feel like you keep up to date with the clinical practice, the research parts with new drugs approval in oncology? You are still in training Dr. Patel. How do you do that? Dr. Shruti Patel: As a millennial, it may come as no surprise that I primarily stay up to date on clinical practice guidelines via Twitter on my phone. I find Twitter to be the best place to learn new information. Just because you don't just get information about the new approvals, but typically experts in the field will weigh in on the trial design, their thoughts on whether it truly will replace the current standard of care or what situations they might use the new approval for, which can really be helpful, especially as a fellow in training. It's helpful context beyond just the information that you get from the approval itself. And then, I also learn about the applications of these new guidelines in the clinic with my mentors, because I am, of course, lucky enough to still be in training where I can gather that information from my attendings. Dr. Adriana Alvarez: Dr. Goyal, what is your preferred method of keeping up to date and learning more about the new treatments and research in your area of interest?  Dr. Sharad Goyal: As opposed to Dr. Patel, I am not part of social media in medicine. Actually, I'm not a part of any social media, whether it's personal or work-related. So I tend to be a little more “old school” with respect to how I ingest information. So, in terms of clinical practice guidelines and new drug approvals, which is somewhat peripheral to my field in radiation oncology, I tend to rely on NCCN guidelines and attendance at tumor boards to receive that information from my colleagues in medical oncology. I believe that with any patient that I see with a malignancy, I do tend to refer to the NCCN guidelines on a regular basis. And if it's a malignancy that I do not see, I have to reference PubMed, UpToDate, and the NCCN guidelines to determine the best course of treatment for that patient. Dr. Adriana Alvarez: What about you, Dr. Symington? Being in the rural area, I can see that you have a variety of situations. How do you keep up to date? Dr. Banu Symington: I guess I'm midway between Doctors Patel and Goyal. I do not follow Twitter, but I belong to a 5000-member online hematology/oncology support group, and we post questions, and local thought leaders will reply. I am in such an isolated location. I don't get the stimulation or the benefit of walking down the hall to a colleague to say ‘What would you do?' So I am affiliated with the Huntsman and the University of Utah. I've made an effort to join every organ-specific tumor board so that I can hear discussions by disease thought leaders about how they're going to take care of each type of cancer and hearing that week after week, I do absorb it.  Medical oncology is a challenging field because things move so rapidly. I took an 18-month, mostly Sabbatical, as I functioned as a chief of staff at a larger hospital. And in that 18-month period, where I volunteered in a clinic, immune checkpoint therapy arose, and targeted therapies for lung cancer arose and I felt like Sleeping Beauty. I went to sleep in one world, and I woke up in a completely different world of oncology. And it was hard to get back into the drift until I connected with colleagues. I'm an avid reader. I don't sleep much. So I am a member of AMA, ASCO, and ACP, so I get all the print journals. And I have a disorder, an obsessive-compulsive disorder, that makes me have to look through every single journal I get. So print and tumor boards and colleagues.  Dr. Adriana Alvarez: So we are very busy, and the work that we do, the clinical work, trying to keep up to date and training and all that, how do you schedule time to do this, to learn about the research advances and to keep going? Dr. Goyal, how do you find the time? Dr. Sharad Goyal: In general, I do think that in my realm, in my head, I think that there are three processes that have to occur when I incorporate research into my practice. So number one, I have to learn about it. Number two, I have to determine if that's going to help change my practice. And then number three, if I do end up changing practice, I have to implement it. And that involves dealing with my staff. So I'm going to delve into each of those in a little bit more detail. So learning about the advance typically, I learn about things through CME activities. So in one of my roles in our cancer center, I help organize our grand rounds and some oncology-specific courses. Being involved in the organization, helping find speakers really keeps me engaged not only in the organization process, but also in the learning process because I have a vested interest in making sure that the trainees and other faculty that attend my courses are learning and are happy.  Dr. Adriana Alvarez: To organize all these, do you schedule time during your job, outside work hours? Dr. Sharad Goyal: Yes, that is part of my job, which extends outside of work hours. Dr. Adriana Alvarez: Sounds good. Dr. Symington, well, you mentioned that you don't sleep much, you keep up to date, looks more at night. But do you find the time in between patients or during your workday to keep up to date, or is more like a solitude type of time?  Dr. Banu Symington: I forgot to mention a resource that I feel like people should know about, MedNet, which is presented daily with three clinical cases and thought leaders mentioning what they would do. They often introduce research ideas that are not adopted into practice. Since I read, I read about new innovative treatments, but I am not an early adopter, so I wait until they become an NCCN guideline before I would adopt it. So that might be different from Dr. Goyal, who's in an academic center. But I see patients five days a week, 10 hours a day, so it has to be all scheduled outside of those hours. It's fortunate that my kids are grown, and I don't sleep much.  Dr. Adriana Alvarez: What about you, Dr. Patel? On the go, I can imagine. I remember not long ago, being fellow and a millennial, so I guess on your iPhone. Dr. Shruti Patel: Even though I'm a fellow, I do like sleep. And now that I'm in my research years, I actually get sleep, which is lovely. I can't say that I schedule time to learn about research advances, but rather it's– Usually, I take the train to work, and so I'm scrolling on my Twitter on the Caltrain down to Palo Alto, monitoring for medical news or updates. Really, that's how I gather information. I also partake in CME activity, creating CME educational materials on Twitter as well. And so that's another way in which I learn because if I'm creating the information, then I have to go through the trials and go through all of these things, side effects. And so it's a really great way, additionally, for me to learn. But none of that stuff is really scheduled. It's kind of really when I have time, on my to-do list, usually outside of business hours. Part of the job is staying up to date with things outside of business hours. And I think we all knew that when we signed up for the job. And it's only gotten more as all of these advances are kind of coming out at us like drinking out of a fire hydrant. Dr. Adriana Alvarez: The most recent moment that you found new information related to your practice, how did you learn about it? Not about everything that you do, but the last time, the most recent one that you did that. Dr. Goyal? Dr. Sharad Goyal: I recently referenced the NCCN guidelines. I was treating a gentleman with male breast cancer, and he told me he had some half-brothers and that they were going to get tested, but he was inquiring about the screening guidelines for men with BRCA mutations, and I had to look that up. I knew what they were for women, but I actually did not know what they were for men. Dr. Adriana Alvarez: What about you, Dr. Symington? Dr. Banu Symington: So last Thursday morning at 7:00, I joined the Huntsman Tumor Board for Breast. And one of the breast-specific oncologists actually said something that defies the NCCN guidelines, but it sounded like it made sense. He said he regularly gets PET scans for staging lymph node-positive HER2-positive breast cancer because he finds, and apparently the breast cancer community finds, that other scans can give you a false-negative result. And there are enough patients with metastatic disease in the lymph node-positive setting that he recommended PET scans for staging of HER2-positive breast cancer patients but not for ER-positive breast cancer patients. So that was just five days ago. Dr. Adriana Alvarez: Wow. And what about you, Dr. Patel? When was the most recent time that you found something that was good information for your practice?  Dr. Shruti Patel: Yeah, as a fellow, I love learning about new information when I'm able to learn how to integrate it into the practice with someone that's more experienced than I am. So, of course, I've already mentioned that Twitter can be a great place. But also a few weeks ago, I was attending GI ASCO up in San Francisco, and they presented the latest results from NAPOLI-3, which was a phase 3 study looking at first-line liposomal irinotecan 5FU and oxaliplatin versus gem-Abraxane. And they presented that it was shown to improve overall survival compared to gem-Abraxane in first-line metastatic pancreatic cancer. And I was actually sitting next to my clinic mentor at the time, and during the break, I got to hear about his thoughts on whether this is going to be integrated into clinical practice, given that the control arm was gem-Abraxane, and not FOLFOXIRI. And we ended up discussing it again during our weekly GI trials meetings, just when we're thinking about opening new trials and what the control arm should be. And so I just thought that was like a new piece of information. Thought about it in the clinic, thought about it in the trial meeting, and it was pretty cool. Dr. Adriana Alvarez: Great. So different settings, different ways to gain information. So, Dr. Symington, you have to see a little bit of everything. So you have to be an expert in everything. And I wonder how you, Dr. Goyal, and Dr. Patel, that you are kind of more subspecialized. How do you usually follow advances in other cancers that are not in your particular area of interest or just focus on your disease group? I'm going to let Dr. Goyal go first. Dr. Sharad Goyal: Thank you. So I find that I tend to go to conferences to learn about advances outside of my disease focus. I prefer going to the educational sessions at major conferences like ASTRO or ASCO to keep up on things. On a more local level, I do find when I cover tumor boards for my colleagues that I do have to prep their patients and learn about different treatment paradigms within those disease sites. And in doing so, I feel like I'm able to gain really a deeper understanding about oncology in general, and I do very much appreciate that. Dr. Adriana Alvarez: And Dr. Patel, well, you're in training, so you have to see a little bit of everything, even though you have the focus of your specialty that you are looking forward to do. But do you follow those too, as well? Other areas that might not take your interest right away but you want to be updated? Dr. Shruti Patel: That's exactly it. I have to have a working knowledge of all the areas of oncology that are not my focus area. But really, for the most up-to-date information, the reality is that there are so many new advances in all of these disease types that I find myself leaning on my colleagues. If I come across a lymphoma patient on consults, I'll usually reach out to my lymphoma specialized colleagues, whether that's my co-fellows or attendings, just to kind of run the patient by them, get their insight, get their input, because they're just a lot more up to date on those things than I am. But really, regardless of the subspecialty within oncology, I do think that understanding the basics of all the oncology subspecialties is important in medical oncology. Because most of us will, or are, will for me because I'm a fellow, will be spending time on the inpatient service, which is not tumor type specific, and you really do have to make decisions for patients. And while, of course, you always have your colleagues to rely on and call on, some of those decisions are being made in the middle of the night. And so having a working knowledge of all of them, I think, is important. Dr. Adriana Alvarez: We are lucky to live in a time that we have so many options, right? As a practicing oncologist myself, I rely also on all the resources that you're mentioning. The fear I have sometimes is, okay, I'm relying on the NCCN guidelines, but what if I'm missing something? The fear of missing something, right? It's like if I'm not on Twitter or in another social media; I'm missing the most recent data, that may affect my patient care or things like that. But if I have to ask one of you, if you have to pick one, what would be your preferred method or format of receiving updated information if you have to decide where you could go for it? What about you, Dr. Symington? Dr. Banu Symington: So, although I have made the case that I love reading, I actually absorb information better if someone is talking to me. So if I had the freedom to take time off, I would prefer to hear it at one-day specialty seminars where a thought leader is describing their work. That is not what I do in practice, but that would be my preferred way of getting new information.  Dr. Adriana Alvarez: Dr. Goyal? Dr. Sharad Goyal: I'm very much aligned with Dr. Symington in that. I prefer a less active role in the learning process, and I prefer to be spoken to. My preferred method is via podcast, but I also do prefer the in-person or virtual learning through a conference as well. Dr. Adriana Alvarez: What about you, Dr. Patel? Dr. Shruti Patel: I promise you that Elon Musk is not paying me to say all of this because I've probably mentioned Twitter in every single answer. But my preferred method, as you guys probably can guess, is Twitter. It doesn't require too much dedicated time. Information is delivered in small doses. Like I said, I do it on my commute, so it makes me feel like my commute is actually part of my work, which is just wonderful. I do like to attend these smaller meetings to be kind of, like both Dr. Symington and Dr. Goyal said, to be spoken to and really learn additional information. I would say that I don't necessarily always get that experience at the bigger meetings where the focus is more networking. But ‘Best of ASCO', those are kind of some types of meetings where the information is kind of told to you. It's distilled down into bite-sized pieces and really understandable. Dr. Adriana Alvarez: Well, all amazing experiences. And I'm glad that we have different points of view, different settings, different career paths. Someone mentioned before is that we're always learning. I feel like here; everybody's very humble to recognize that we're on the learning curve all the time and that we have a real interest in our patient care. Because we are trying to catch the moment, try to make sure that we deliver the best care to our patients, like keeping up to date and listening to the new information. Dr. Goyal, any advice for your colleagues in terms of how to best keep up to date? Dr. Sharad Goyal: My personal philosophy is that as a physician, the learning never stops. And if you do stop learning, maybe you should find a different field. During the pandemic, I started scheduling time with colleagues, friends in my field, and I would set up a meeting with them via our assistants every two or three months. And we would not only socialize but we would kind of catch up on the current state of affairs in our field. And it was an opportunity to also network, and it was very helpful, especially during COVID. It really helped me gain some normalcy and kind of keep me attached to the field of radiation oncology during that time. Dr. Adriana Alvarez: How do you navigate clinic work, keeping up to date, and work-life balance? Dr. Goyal? Dr. Sharad Goyal: Like Dr. Symington, I probably work about 50 hours a week in the office, so I tend to work from 7:00 to 5:00, and I'm out of the office at 5:00 on the dot. I have two small children at home, and I want to see them at least for two hours in the evening before they go to bed. As a radiation oncologist, we take HomeCall, and there are very few emergencies, so I have the weekends to not only spend time with my family but also catch up on any work that needs to be done.  Dr. Adriana Alvarez: I'm so glad to hear that. Congratulations on your family.  Dr. Symington? Dr. Banu Symington: Well, I rescue small dogs, so at the moment, I have five small dogs, and they get a walk a day when weather permits. We're in the middle of a blizzard in Wyoming, so weather hasn't been permitting for the past four days, so the love and attention of those dogs keep me grounded. I also regularly go to the gym. I dread it every time I go, but I go at least four times a week, and I leave the gym and leave some of my problems behind. When I was younger, people would comment on the fact that I was slender and didn't need to go to the gym and would ask me why I did it, and I would say it's so I don't beat my children. That was obviously a joke, but I could shed the problems of the day by running on the treadmill or using the StairMaster. So I guess that's how I keep work-life balance.  Dr. Adriana Alvarez: What about you, Dr. Patel? Dr. Shruti Patel: I would say that my work-life balance has improved greatly in the last eight months since I started the research portion of my fellowship. I'm not writing papers at 2:00 a.m. anymore, so that's like a huge upgrade. But really, I think, prioritizing when you're at work, you're at work, but then when you're at home, really trying to prioritize the things that are important to you. I am currently in my parents' home, while I'm recording this podcast, I get to spend time with them. I get to spend time with my family, my friends. I like to make time for those things because they provide me joy. I think a huge part of our work is being there for people in really, really tough times in their life, and that can be extremely emotionally draining, even though it's exactly what we want to do. And I think making sure that you have things outside of work that really provide you a lot of joy is extremely important. And so I think now that I have the time to do it, I really am trying to capitalize on it. Dr. Adriana Alvarez: Well, I really want to thank you, all of you, Dr. Goyal, Dr. Patel, and Dr. Symington, for a lively discussion. I learned a lot from you and a little bit about your personal life. Thank you for sharing that and sharing how you navigate to be a physician in oncology.  So this ASCO Education Podcast is where we explore topics ranging from implementing new cancer treatments and improving patient care to oncology well-being and professional development. If you have an idea for a topic or guest you would like to see on the show, please email us at education@asco.org. To stay up to date with the latest episodes and explore other educational content, visit education.asco.org. Thank you very much.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.              

Dr. Filip Ionescu (hematology-oncology fellow at Moffitt Cancer Center in Tampa, FL), Dr. Teodora Donisan (cardiology fellow at the Mayo Clinic in Rochester, MN and CardioNerds House Thomas chief), Dr. Sarah Waliany (internal medicine chief resident at Stanford University in Palo Alto, CA), Dr. Dinu Balanescu (internal medicine chief resident at Beaumont Hospital in Royal Oak, MI) and Dr. Amit Goyal (structural interventional cardiology fellow at the Cleveland Clinic, in Cleveland, OH and CardioNerds Co-Founder), discuss the cardiotoxicities of common cancer treatments with Dr. Susan Dent, a medical oncologist and one of the founders of the field of Cardio-Oncology. Using the recently published ESC Guidelines on cardio-oncology, they cover cardiovascular risk stratification in oncology patients, pretreatment testing, as well as prevention and management of established cardiotoxicity resulting from anthracyclines, trastuzumab, and fluoropyrimidines. They touch on the unique aspects of cardio-oncology encountered in patients with breast cancer, rectal cancer, and lung cancer, who are frequently the recipients of multiple cardiotoxic treatments. Audio editing by CardioNerds Academy Intern, student doctor Chelsea Amo Tweneboah. Access the CardioNerds Cardiac Amyloidosis Series for a deep dive into this important topic. This episode is supported by a grant from Pfizer Inc. This CardioNerds Cardio-Oncology series is a multi-institutional collaboration made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Giselle Suero Abreu, Dr. Dinu Balanescu, and Dr. Teodora Donisan.  Pearls • Notes • References • Production Team CardioNerds Cardio-Oncology PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Pearls and Quotes - Cancer Therapy-Related Cardiac Dysfunction (CTRCD) – The Oncologist Perspective with Dr. Susan Dent Formal cardiovascular risk stratification must be performed prior to initiating a potentially cardiotoxic anticancer treatment regimen. Considering both drug toxicity and patient-related factors (e.g., age, smoking, hypertension etc) is important.  Anthracyclines affect the cardiomyocyte in complex ways which lead to a largely irreversible cardiomyopathy. All patients should have a pretreatment echocardiogram and ECG.  Trastuzumab cardiotoxicity, by contrast, is more like stunning the myocardium, which manifests as a reversible decrease in left ventricular ejection fraction which generally normalizes upon discontinuation of the drug.  The treatment of chemotherapy-induced cardiomyopathy should involve interdisciplinary discussions and shared decision making with the patient. Beyond guideline-directed medical therapy of heart failure with reduced ejection fraction, management can include temporarily holding or permanently discontinuing the offending agent.  Fluoropyrimidine-associated cardiotoxicity manifests as cardiac ischemia from coronary vasospasm. A 5FU infusion is essentially a stress test as it tends to unmask clinically silent atherosclerosis.  Show notes What is the basic pretreatment assessment of any oncology patient who is to receive a potentially cardiotoxic regimen?  Awareness and management of the cardiovascular toxicity of oncology treatments are of paramount importance to be able to deliver treatment safely and to achieve maximal efficacy guided by an expert multidisciplinary team. Thanks to Dr. Dent and her colleagues' work, this year we have seen the publication of the first Cardio-Oncology guideline (1). Perhaps the most important recommendation is that cancer patients about to start a cardiotoxic regimen should undergo formal cardiovascular risk stratification by considering both the adverse profile of the planned treatment...

El Dr. Iván Romarico González Espinoza, oncólogo médico adscrito al Hospital Ángeles en Puebla, México, nos habla sobre lo más destacado en el día 4 del Congreso Anual de la Sociedad Europea de Oncología Médica 2022, resaltando los siguientes estudios: Carcinoma de células renales: COSMIC-313: Estudio fase III, que evaluó cabozantinib en combinación con nivolumab e ipilimumab en carcinoma avanzado de células renales no tratado previamente de riesgo intermedio o bajo de IMDC (Resumen LBA8). Cáncer de pulmón: IPSOS: Estudio fase III, que evaluó atezolizumab de 1L vs. quimioterapia de agente único en pacientes con cáncer de pulmón de células no pequeñas (CPCNP) no elegibles para un régimen que contenga platino (Resumen LBA11). CodeBreak 200: Estudio fase III, que evaluó sotorasib vs. docetaxel para el CPCNP previamente tratado con mutación KRAS G12C (Resumen LBA10). Cáncer de tiroides: DIRECTION: Estudio fase III, multicéntrico, aleatorizado, doble ciego, y controlado con placebo, que evaluó donafenib en cáncer diferenciado de tiroides localmente avanzado/metastásico, refractario al yodo radiactivo (Resumen 1644O). Tumores neuroendocrinos pancreáticos: SEQTOR (GETNE 1206): Estudio fase III, aleatorizado y abierto, que comparó la eficacia y la seguridad de everolimus seguido de quimioterapia con estreptozotocina-5FU en progresión o secuencia inversa, en tumores neuroendocrinos pancreáticos progresivos avanzados (Resumen LBA45). Cáncer de próstata: RADICALS-HD (ISRCTN40814031): Primeros resultados del estudio fase III, el cual evaluó la duración de la terapia de deprivación androgénica + radioterapia postoperatoria para el cáncer de próstata (Resumen LBA9). Fecha de grabación: 12 de septiembre de 2022. Todos los comentarios emitidos por los participantes son a título personal y no reflejan la opinión de ScienceLink u otros. Se deberá revisar las indicaciones aprobadas en el país para cada uno de los tratamientos y medicamentos comentados. Las opiniones vertidas en este programa son responsabilidad de los participantes o entrevistados, ScienceLink las ha incluido con fines educativos. Este material está dirigido a profesionales de la salud exclusivamente.

Dr. Rachna Shroff, of the University of Arizona Cancer Center, tells guest host, Dr. Shaalan Beg, of UT Southwestern's Harold C. Simmons Comprehensive Cancer Center and Science 37, about advances in precision medicine for pancreatic cancer featured at the 2022 ASCO Annual Meeting. She also highlights compelling new data from the FOLFOX, FOENIX-CCA2, and HERB trials in hepatocellular carcinoma, cholangiocarcinoma, and biliary tract cancer.   TRANSCRIPT Dr. Shaalan Beg: Hello and welcome to the ASCO Daily News podcast. I'm Dr. Shaalan Beg, your guest host of the ASCO Daily News podcast today. I'm an adjunct associate professor at UT Southwestern Simmons Comprehensive Cancer Center and vice president of oncology at Science 37. I'm delighted to welcome Dr. Rachna Shroff, the associate dean for clinical and translational research and the chief of gastrointestinal (GI) medical oncology at the University of Arizona Cancer Center where she's also the interim chief of Hematology-Oncology. Dr. Shroff is also the chair-elect for the Gastrointestinal Cancer Symposium. Today we'll be discussing key abstracts in GI cancer that were featured at the 2022 ASCO Annual Meeting. Our full disclosures are available in the show notes and disclosures of all our guests on the podcast can be found on our transcripts at asco.org/podcasts. Dr. Shroff, thank you for being on the podcast today. Dr. Rachna Shroff: Thank you so much for having me. Dr. Shaalan Beg: Let's begin by reviewing what is new in the realm of precision medicine in GI cancers. One of the diseases where precision medicine has not made adequate inroads is pancreatic cancer. One of the most common mutations in pancreas cancer is KRAS, but there haven't been a lot of treatments that can target the most common forms of KRAS. What did we hear at ASCO22 regarding precision medicine and pancreatic cancer? Dr. Rachna Shroff: I agree, I think that the area of precision oncology is, unfortunately, lagging behind a little bit in pancreatic cancer. But I think as we have gotten better and better with our comprehensive genomic profiling, we are identifying subsets of patients within pancreas cancer who are potentially amenable to targeted therapies. You already mentioned KRAS mutations, and we obviously have a number of inhibitors in development in that space, though, we are still missing that key G12D mutation that we see in pancreas cancer. But what I think was really interesting that came out of ASCO22, was a lot of interest and emphasis on better understanding the KRAS wild-type patients in pancreatic cancer. Now, this is obviously a smaller subset of patients, given that the majority of patients have KRAS mutations. But there was a really interesting abstract, LBA4011, that looked at patients with locally advanced or metastatic pancreatic cancer, who were KRAS wild-type. They actually received gemcitabine in combination with a monoclonal antibody targeting EGFR and nimotuzumab. This was a study that was done entirely in Asia. It involved 92 Chinese patients that were randomly assigned to receive the combination of nimotuzumab with gemcitabine. What was interesting in this study is that the patients were found in the full analysis set to have a significantly longer median overall survival of 10.9 months versus 8.5 months with a hazard ratio of 0.5. So, that of course was intriguing and provocative for sure. Similarly, the other endpoints were also somewhat intriguing in terms of improvements in the median progression-free survival (PFS), etc. And specifically, patients without biliary obstruction had a longer PFS, which was an interesting finding as well. The nimotuzumab overall was pretty well tolerated and not any sort of surprising treatment-related adverse events (TRAEs) were noted. And so, this is definitely a drug that, I think, piques our interest in terms of being able to target patients with KRAS wild-type pancreatic cancer. I think that questions, however, that remain, and I think require further study is really understanding what this drug could do in combination with the chemotherapy combinations that we use more frequently in metastatic pancreatic cancers such as gemcitabine and paclitaxel or 5FU-based regimens like FOLFIRINOX. I think given that it is a relatively well-tolerated drug, it would be a very reasonable thing to investigate this drug further in the KRAS wild-type population with the kind of modern-day chemotherapy regimens that we use. And I think, of course, we all know that it is useful to be able to look at these types of drugs in a more global population. And so, a larger patient set I think would be very useful as well, but at least it tells us that there is a way to think about our KRAS wild-type patients with pancreas cancer and that perhaps we really need to understand and identify those patients' potential for precision oncology. Dr. Shaalan Beg: One of the GI cancers that has been a hotbed for precision medicine is cholangiocarcinoma, a disease that's very close to your heart. What updates did we hear at ASCO22 regarding cholangiocarcinoma and precision medicine? Dr. Rachna Shroff: This space of targeted therapy and cholangiocarcinoma has been incredibly exciting for the last few years and I think drug development has been rapid-fire in that space. The oldest, if you will, target that we've been thinking about for some time is the FGFR2 fusion patient population. And in Abstract 4009 by Dr. Goyal and colleagues, we saw the results of the FOENIX-CCA 2 trial which was looking at an oral FGFR inhibitor (futibatinib) in patients with intrahepatic cholangiocarcinoma, who harbor FGFR2 fusions and gene rearrangements. We had initially seen some of this data presented a few years back, but this was the updated data set. It was a single-arm phase 2 study that involved patients with advanced intrahepatic cholangiocarcinoma who had identified FGFR2 gene fusions, and they received futibatinib daily until progression. This was a traditional single-arm phase 2 study with a primary endpoint of overall response rate. At the final data cut, with a median follow-up of 25 months, there's actually a confirmed overall response rate of 41.7%. And I think that what was really exciting about this is this is a refractory patient population. So, in patients who have refractory cholangiocarcinoma, the other drugs, the non-targeted therapy drugs that we think through, really have response rates more in the single-digit to 10% range and so to have a confirmed overall response (OR) over 40% is truly exciting. The duration of the response was also exciting. This is not just a drug that works briefly, it has a duration of response of 9.5 months. And the mature median overall survival was 20 months. And in a disease which we talk about with the ABC-02 data of GemCis, a median OS in advanced disease of 11.7 months. This is really, really exciting for patients who harbor this fusion or gene rearrangement. We know that that's seen in about 10 to 15% of patients. So, again, we're dealing with a smaller subset, but it clearly demonstrates the need to identify FGFR2 gene fusions, so that we can offer these types of targeted therapies. This was not the first FGFR inhibitor that we have seen data on and in fact, we have 2 drugs already U.S. Food and Drug Administration (FDA) approved. And so, when we look at the common treatment-related adverse events that were identified with the futibatinib, there are really class effects related to FGFR inhibition like hyperphosphatemia, alopecia, dry mouth, nothing that really stood out or that was concerning. And so, I think this final analysis for the FOENIX study really just reaffirms the utility of futibatinib in patients with FGFR2 gene fusions, and the mature OS data, the duration of response, all of this really aligns with the need to identify patients with this alteration so that we can, post-gemcitabine based therapies, offer this targeted therapy or an FGFR inhibitor in general to these patients. I think the other really exciting abstract in the glandular carcinoma or biliary tract cancer space was Abstract 4006. This was the updated data from the HERB trial, which was an investigator-initiated multicenter phase 2 trial looking at trastuzumab deruxtecan (T-DXd) in patients who have HER2 expressing unresectable or recurrent biliary tract cancer. Trastuzumab deruxtecan, I'm sure everybody has been hearing about because it has been incredibly effective in HER2 alterations across a myriad of different disease sites. And so, not wanting to be left out, biliary tract cancers were investigated in this study with patients who had HER2 expression, so, that was HER2-positive IHC3+ or IHC2+/ISH+, and they also looked at HER2-low expressing patients, and [whose disease] were refractory or intolerant to gemcitabine-based therapy with the primary endpoint of overall response rate. So, in the HERB trial, a total of 32 patients were enrolled. 24 of them were HER2-positive and 8 were HER2-low and they all received trastuzumab deruxtecan. When you look at the efficacy data, the confirmed overall response rate in the patients with HER2-positive was 36.4%, which again, as I said, in a refractory patient population is certainly very exciting data. And the overall disease control median, PFS, and median OS were all pretty encouraging in terms of efficacy. What was also kind of intriguing was that there was some efficacy seen even in the patients who are HER2-low. Now, this is, in my opinion, a slightly less exciting amount of efficacy, but still important to note that the overall response rate in HER2-low was 12.5% with a median PFS that was also somewhat exciting at 4.2 months. And so, there is a potential clearly for targeting patients with HER2-high or HER2-positive with trastuzumab deruxtecan, and I think in the patients who are HER2-low, we need to better understand the potential utility. The common treatment-related adverse events that we see were the typical things that we've heard about with trastuzumab deruxtecan, but I think the one thing that was really worth noting was 8 patients or 25% of patients had interstitial lung disease (ILD), which we know is an important identified safety concern for patients who receive trastuzumab deruxtecan, and I think that's a pretty sizable number of 25%, so, I think that's going to really require a little bit more fleshing out for us to understand the safety for these patients. One question that a lot of us have had is whether these are patients who have received gemcitabine, which we know can also cause pneumonitis. And so, I don't know if we're seeing a higher percentage of ILD because of, 'priming' with prior gemcitabine. But regardless, I think this is just proof of principle that again, we need to identify patients with biliary tract cancers that have HER2-positivity because we now have a number of drugs including potentially trastuzamab deruxtecan to target [their disease] with after gemcitabine-based treatments Dr. Shaalan Beg: Absolutely. Any new biomarkers to keep on the radar for our listeners? Dr. Rachna Shroff: I think there are a lot of really exciting targets. One that was talked about and that we saw data on at ASCO [Annual Meeting] was from Abstract 4048, which looked at claudin [18]. Claudin is basically a transmembrane protein that kind of helps maintain the tight junctions between cells. In gastric cancer, in particular, we look at claudin 18 isoform 2, and there are 18.1 and 18.2 gene expressions that have been identified in gastric cancer. So, there was a very comprehensive abstract that was presented of over 1,900 samples that underwent comprehensive profiling by next-generation sequencing. And the patients were identified with claudin 18.1, and 18.2, high versus low. Claudin 18.2 expression was actually detected in 97% of the samples. It's slightly lower with claudin 18.1 at 63%. It's important to note that the primary tumors had higher expression levels than the metastatic tumors, so those were really the tumors in which they did a deeper dive. And in the process of doing this deeper dive, they did a really interesting kind of better understanding of the immune microenvironment and the immune profile in the samples that had claudin expression. And what was identified is that there was an inverse relationship basically between claudin 18.1 and 18.2 expression and correlation with PD-L1 positivity, tumor mutational burden (TMB)-high, M1 macrophages expression, NK cell presence, CD4 positive T-cells, myeloid dendritic cells. And so, there's clearly something between the presence of this claudin expression and the effect it has on the immune microenvironment. I think that's very relevant to keep in mind because as we all know, there's a whole space of drug development focused right now on anti-claudin 18.2 monoclonal antibodies, as well as a target for antibody-drug conjugates (ADC) and cellular therapies with CAR T-cell therapies being developed specifically against claudin 18. And so, understanding the immune microenvironment and the interaction between the claudin expression will be really important as we continue to charge forward in that space. Dr. Shaalan Beg: Absolutely. Very, very exciting. Sticking with the liver pancreas theme, what other studies piqued your interest with regards to hepatocellular carcinoma (HCC)? Dr. Rachna Shroff: It's a really exciting time in HCC. I mean, we actually have drugs that are working in the advanced space. And so, now there's a lot of interest in shifting to looking at preoperative neoadjuvant, and adjuvant approaches and what we can do to improve disease-free survival and overall survival in patients who are able to undergo prior resection. So, Abstract 4013 looked specifically at the efficacy and safety of adjuvant hepatic arterial infusion chemotherapy with FOLFOX. And this was a randomized open-label phase 3 trial. It actually included a total of 315 patients between 5 different centers and patients were randomly assigned to receive either 1 to 2 cycles of adjuvant HAIC FOLFOX (Hepatic Arterial Infusion Chemotherapy FOLFOX) versus just follow up, the control group had no adjuvant treatment, and the primary endpoint was disease-free survival here and in the intention to treat population, there was a significantly improved median disease-free survival at 27 months versus 11 months in the patients who were on the control arm. And there was a protocol analysis, there were a number of other efficacy endpoints including disease-free survival rates at 1, 2, and 3 years. And everything kind of leaned towards and or suggested an improvement with the utility of HAI FOLFOX in patients who undergo complete resection. It should be noted that this included patients specifically who had microvascular invasion on their resection. And so, these are patients who are at higher risk for recurrence as we know. This to me suggests that there could be a role for adjuvant treatment in patients who undergo complete resection with microvascular invasion (MVI). HAI is a very specific technique and it requires a highly skilled center in the placement of HAI pumps. And we're seeing more and more trials across the U.S. as well investigating the role of HAI in advanced disease and in perioperative approaches. And so, I think this is an area of much-needed continued research. There are, of course, a number of ongoing adjuvant studies looking at immunotherapy in the adjuvant setting. And so, it'll be really important to see how those read out and then to try to put all of these in context so that we can better understand local therapy like HAI FOLFOX versus more systemic adjuvant approaches like immunotherapy. Dr. Shaalan Beg: Thank you very much, Dr. Shroff for sharing your valuable insights with us. I really appreciate you taking the time to spend with us and our listeners. Dr. Rachna Shroff: Thanks so much. I enjoyed it. Dr. Shaalan Beg: And thank you to our listeners for your time today. You will find links to the abstracts discussed today in the transcript of this episode. Finally, we'd really like to hear your feedback. If you could please take a moment to rate, review, and subscribe wherever you get your podcasts. Thank you very much!   Disclosures: Dr. Shaalan Beg: Employment: Science 37 Consulting or Advisory Role: Ipsen, Array BioPharma, AstraZeneca/MedImmune, Cancer Commons, Legend Biotech, Foundation Medicine Research Funding (Inst.): Bristol-Myers Squibb, AstraZeneca/MedImmune, Merck Serono, Five Prime Therapeutics, MedImmune, Genentech, Immunesensor, Tolero Pharmaceuticals Dr. Rachna Shroff: Consulting or Advisory Role: Exelixis, Merck, QED Therapeutics, Incyte, Astra Zeneca, Taiho Pharmaceutical, Boehringer Ingelheim, SERVIER, Genentech, Basilea Research Funding: Pieris Pharmaceuticals, Taiho Pharmaceutical, Merck, Exelixis, QED Therapeutics, Rafael Pharmaceuticals, Bristol-Myers Squibb, Bayer, Immunovaccine, Seagen, Novocure, Nucana, Loxo/Lilly, Faeth Therapeutics Disclaimer: The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.  

An interview with Dr. Nancy Baxter from the University of Melbourne in Melbourne, Australia, and Dr. Jeffrey Meyerhardt from Dana-Farber Cancer Institute in Boston, MA, co-chairs on “Adjuvant Therapy for Stage II Colon Cancer: ASCO Guideline Update.” This guideline updates recommendations for adjuvant therapy for patients with resected stage II colon cancer. Read the full guideline at www.asco.org/gastrointestinal-cancer-guidelines.   TRANSCRIPT [MUSIC PLAYING] ANNOUNCER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today, I'm interviewing Dr. Nancy Baxter from the University of Melbourne in Melbourne, Australia, and Dr. Jeffrey Meyerhardt from the Dana-Farber Cancer Institute in Boston, Massachusetts, co-chairs on adjuvant therapy for stage II colon cancer ASCO guideline update. Thank you for being here, Dr. Baxter and Dr. Meyerhardt. NANCY BAXTER: Thank you for having us. JEFFREY MEYERHARDT: Thanks. BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines in ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Baxter, do you have any relevant disclosures that are directly related to this guideline topic? NANCY BAXTER: I don't, Brittany. BRITTANY HARVEY: Thank you. And Dr. Meyerhardt, do you have any relevant disclosures that are directly related to this guideline topic? JEFFREY MEYERHARDT: I don't, either. Thank you. BRITTANY HARVEY: Thank you, both. And getting into the content of this guideline, what prompted this guideline update, and what is the scope of this guideline? NANCY BAXTER: Well, it's been since 2004 that we've had a guideline that gives us advice about stage II colon cancer and the use of adjuvant therapy in this group of patients. And it's one where clinicians often have a lot of challenges in helping patients make decisions about what's best for them in terms of long-term survival from colon cancer. There have been changes in guidelines for stage III colon cancer. And so we thought it was timely to reevaluate our best practice recommendations for stage II colon cancer patients. JEFFREY MEYERHARDT: Yeah, I agree, Dr. Baxter. I think that this is one of the most challenging conversations that oncologists have with patients. Should they get chemotherapy? What type of chemotherapy? And as you know, there are a variety of higher risk features, of which we're able to sort of tease out a little better relatively, in terms of thinking about someone's stage II disease and trying to bring all that data together and provide some framework in the conversation for clinicians to have with patients. BRITTANY HARVEY: Great, thank you both for that background information. So then this guideline covers four clinical questions. And I'd like to review the recommendations for each question. So Dr. Baxter, starting with question 1, what does the guideline recommend for patients with resected stage II colon cancer regarding the benefit of fluoropyrimidine-based adjuvant chemotherapy versus surgery alone? NANCY BAXTER: So overall, what we did was we looked at the risk that individual patients with stage II colon cancer have. So for patients that are at low risk of recurrence-- and so those are patients with stage IIA or T3 tumors that have at least 12 sample lymph nodes in the surgical specimen and don't have any high-risk features, and I'll go over those with the later recommendations-- these patients do not need adjuvant chemotherapy. It should not be routinely offered to them because the harms may outweigh the benefits. And so the evidence of that, although the quality of the evidence was relatively low, there is quite a bit of evidence that, really, the benefits do not outweigh the risks in this particular group. That is different for patients that are at higher risk, though, within the stage II group. And so those are the patients with stage IIB or stage IIC colon cancer. So those are T4 lesions that either penetrate through the visceral peritoneum or invade surrounding organs. And in those patients, adjuvant chemotherapy may have more benefit. And so a discussion of the potential benefits and risks of harms associated with chemotherapy should be had with patients. And those are patients that should be offered adjuvant chemotherapy for their disease. Now, there's a group of patients with high-risk features-- so not the stage IIB or stage IIC-- but there's a group of patients within stage IIA. So these are patients that are T3 patients where there are high-risk features. And chemotherapy may be offered to these patients, based on their risk features. So I'll go over a little bit about what the high-risk features are that might make patients included in this group. So that is sampling of fewer than 12 lymph nodes in the surgical specimen, perineural or lymphatic invasion, poor or undifferentiated tumor grade, intestinal obstruction, tumor perforation, and grade BD3 tumor budding. That's more than, or equal to, 10 buds in the tumor. And so that's because these patients are at higher risk of recurrence, and the chemotherapy may be more beneficial in these patients because they have a higher baseline risk of recurrence. There were a few risk factors that it was really challenging to make any decision on. And that was specifically circulating DNA. We know that that's an area of great interest, but there really was not enough evidence of the predictive value of ctDNA when you're looking at adjuvant chemotherapy in this group to make a recommendation. We'd expect future versions of this guideline to have some recommendations about that. We do know that there is controversy around the timing of chemotherapy. So we didn't include reports on this for the guideline because we didn't have enough related to stage II colon cancer and the role of adjuvant therapy. But the trials have generally started patients on chemotherapy within six to seven weeks of surgery. And finally, all of this needs to be a part of shared decision-making. So particularly for patients at higher risk-- so stage 2A at higher risk-- it's important that this is discussed-- the risks and benefits of chemotherapy, and the possible benefits with respect to the risk of recurrence for these patients-- is discussed as part of the shared decision-making process to come to an ultimate decision about the use of chemotherapy. BRITTANY HARVEY: Understood. Thanks for detailing those recommendations stratified by risk and identifying what those high-risk features are. So then, additionally, Dr. Meyerhardt, is there a benefit of fluoropyrimidine-based adjuvant chemotherapy for patients with tumors that exhibit mismatch repair deficiency or microsatellite instability or patients with proficient mismatch repair, or microsatellite-stable, tumors? JEFFREY MEYERHARDT: Yeah, so this was a specific question that we also looked at. What we know is about 15% of stage II colon cancers have evidence of mismatch repair or microsatellite insufficiency. And data that was realized now several decades ago on several different papers-- one larger one published in The New England Journal by Dan Sargent-- showed that patients who have stage II disease who receive a fluoropyrimidine only seem to not benefit if they have microsat instability. And there was actually some evidence that they may actually have harm, or have a worse outcome. So it is not a routine recommendation to use a fluoropyrimidine-only treatment regimen in patients who have MSI-high or deficiency of mismatch repair in stage II disease. However, there are some qualifying statements that we reviewed and were important to think about in patients. So what we know is, again, some of those patients will have some high-risk features and particularly T4 tumors or some other high-risk features, except for poor differentiation, that the use of oxaliplatin may actually be a consideration in those patients. And that's basically from indirect evidence of a disease-free survival benefit with the addition of oxaliplatin in the population of patients with stage II disease that were included in the MOSAIC trial, one of the original trials that looked at the addition of oxaliplatin to a fluoropyrimidine as adjuvant therapy for colon cancer. We specifically carved out poor differentiate is not considered a high-risk prognostic feature in those patients. And so poorly differentiated tumors alone should not be a part of the decision in offering adjuvant therapy with a fluoropyrimidine or fluoropyrimidine-oxaliplatin for MSI-high or deficient mismatch repair protein tumors. And the other patients who have either proficient mismatch repair proteins or microsatellite instability are actually including the other parts of the guideline, so what Dr. Baxter just talked about and some of the other questions that we tackled that you'll be going to next. BRITTANY HARVEY: Great. Thank you for covering those recommendations for that particular patient population. So then, Dr. Baxter, if adjuvant therapy is recommended, is there a benefit to adding oxaliplatin to fluoropyrimidine-based chemotherapy? NANCY BAXTER: Well, this is obviously a question that oncologists will face when they're deciding to give adjuvant chemotherapy to high-risk stage II colon cancers or people with T4 stage IIB or C colon cancers. And you know, here's where it's challenging to make recommendations. Because we don't have a lot of evidence for this specific group. And this is why clinicians have such a challenge making recommendations for these patients. Because actually, there's insufficient evidence to routinely recommend the addition of oxaliplatin, meaning that we have to base our decisions on the best evidence that we have. And the best evidence we have, as we've talked about, is the MOSAIC trial. And so in the MOSAIC trial, a time to recurrence was longer with oxaliplatin-based adjuvant chemotherapy. And so it may be for some patients that the addition of oxaliplatin makes sense in terms of improving their overall outcome. And again, it needs to be a shared decision-making approach with the discussion of the potential benefits and risks of harms of the addition of oxaliplatin to fluoropyrimidine-based chemotherapy, so again, discussions between the oncologist and the patient. But that is with the exception of patients who are MSI-high. So those patients need oxaliplatin. If they're going to get chemotherapy, they shouldn't have 5FU-based chemotherapy alone, as we've just discussed. BRITTANY HARVEY: Great. And definitely, that shared decision-making is key. And I appreciate you reviewing the evidence behind these recommendations, as well. So then, the last clinical question addressed in this guideline, Dr. Meyerhardt, if adjuvant oxaliplatin-containing chemotherapy is considered, are outcomes affected by reducing the treatment duration from six months to three months? JEFFREY MEYERHARDT: Sure. So this was the last clinical question that the committee considered. And it is based on the IDEA collaboration. So the IDEA collaboration was the International Duration Evaluation of Adjuvant Chemotherapy. It was six trials that were done internationally-- one in the United States, one in Japan, and four in Europe-- that included patients both with stage II and stage III colon cancer. They receive three versus six months of therapy. Each of the trials had different chemotherapy choices in the sense that the United States trial, FOLFOX was the only choice that could be offered to patients, where in all the other trials, it was a physician and patient choice regarding the use of FOLFOX or capecitabine and oxaliplatin. And that, as people who know the data, is relevant to some of the discussion. And so the goal of the collaboration was to look at if we can give patients three months of therapy and not compromise outcome. And the main reason for that is we know that the peripheral neuropathy that's cumulative with oxaliplatin increases with more months of treatment. So patients who only receive three months of oxaliplatin have less likelihood of more significant cumulative neuropathy and will have less impact on function by receiving less oxaliplatin overall. Four of the trials included patients with stage II disease. And those trials, again, pooled their data and looked at the duration question in terms of for stage II patients. Those patients had high-risk disease, some high-risk feature, as discussed earlier. And what was shown is that for the patients, overall, there was not clear evidence of noninferiority with three versus six months. But when you looked at the patients who received capecitabine and oxaliplatin, the absolute five-year disease-free survival was 81.7% versus 82% for three versus six months of CAPOX, so essentially the same, with a hazard ratio of 1.02, and the confidence interval spanned across 1. And so those really didn't look like there was any compromise in outcome for patients to receive CAPOX for three months versus six months. For those patients who received FOLFOX, three months of chemotherapy led to a five-year disease-free survival of 79.2% versus 86.5% if you received six months of FOLFOX with a hazard ratio 1.41. So again, those data would suggest that if one was to choose FOLFOX, giving six months of therapy for high-risk stage II patients may be preferable to not potentially compromise some benefit in terms of disease-free survival. So again, the overall conclusion was it's a discussion with a patient regarding choice of therapy, whether receiving capecitabine, oxaliplatin or FOLFOX and then, based on that, consideration of the duration where we were most comfortable saying that three months of capecitabine, oxaliplatin is sufficient for high-risk patients when appropriate discussion between the clinician and the patient. BRITTANY HARVEY: Great. Thank you for explaining the nuance of that trial and your recommendation. So finally, to wrap us up, in your view, how does this guideline impact both clinicians and patients? JEFFREY MEYERHARDT: Yeah, so again, the last time ASCO had addressed guidelines for stage II patients was over 15 years ago. And there are more data. It was really early in the days of understanding the incorporation of oxaliplatin. There was no data versus the three versus six months. And there were less analyses trying to look at some of those particular high-risk features. So these are all important considerations in those discussions with stage II patients. And the importance of the guidelines are really to provide that framework on the various things you think about when you have a stage II patient and how to have those shared decision-making discussions with the patient. Again, it's not, probably, appropriate for all patients to receive adjuvant therapy, particularly lower risk. And even for higher risk patients, it is weighing the plus or minuses of the potential toxicities with what we know potentially are benefits. NANCY BAXTER: Yeah, I think that's very true. And I think, as anyone who treats colon cancer, or stage II colon cancer patients, is aware, this is not a homogeneous population. So in terms of the outcomes, there are people that do extremely well with surgery alone and people who, unfortunately, recur even after chemotherapy and surgery. And the future needs to focus on being able to differentiate those patients most likely to benefit from chemotherapy from those that are not likely to benefit. What we found in reviewing the evidence is we've moved forward from 2004, but we still have a long way to go. So I really hope when the next guideline is written that we're much closer to being able to identify those patients who would most benefit from chemotherapy in this group. Because we know there are patients who benefit from chemotherapy in this group. It's just we're still not perfect at identifying those people. So again, these conversations with patients are so important to talk about the limits of our knowledge, which I think is another important thing of this guideline is establishing what the limits of our knowledge are. But I think there are patients that you can confidently not give chemotherapy to. And that's very reassuring, both to clinician and to patients. And then this guideline kind of outlines the limits of our knowledge. And that's also important for clinicians and patients to understand. BRITTANY HARVEY: Definitely. I appreciate you both highlighting the importance of shared decision-making throughout this conversation that we've had. So I want to thank you so much for your work on this important guideline update and for taking the time to speak with me today, Dr. Baxter and Dr. Meyerhardt. NANCY BAXTER: Thank you very much. JEFFREY MEYERHARDT: Thank you. BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/gastrointestinal cancer guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in iTunes or the Google Play store. If you've enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode. [MUSIC PLAYING]

Ai Live: November 2021: Possible Side Effects of Fillers & How to Manage Them What are all the potential side effects that can happen with fillers? Are you prepared to manage them? Types of filler complications early onset- filler lump Late onset nodule < 1month Inflammatory vs non-inflammatory Chronic - biofilm infection/abscess Biostimulants issue/nodule - 5FU / kenalog / hylenex How to reduce injection risk How to recognize the symptoms Do you have the right tools to manage complications What are the right questions to ask your patients

Expert: Paolo Bossi, University of Brescia, ASST Spedali Civili, Brescia, Italy Questions: 1-Is there a role for induction chemotherapy for head and neck squamous cell carcinoma other than laryngeal preservation? 2-Could we use weekly cisplatin instead of high-dose three-weekly cisplatin concomitantly with radiotherapy? 3-Do you prefer cetuximab or carboplatin for chemoradiotherapy in patients ineligible for cisplatin? 4-What is the current role of positron emission tomography (PET) in patients with localized head and neck squamous cell carcinoma? 5-What's the best option for induction chemotherapy in nasopharyngeal cancer (docetaxel-cisplatin-5FU or gemcitabine-cisplatin)?

According to the American Association for Cancer Research, 80-90% of the administered dose of the cancer medication 5-fluorouracil of 5FU is degraded by the enzyme dihydropyridine dehydrogenase or DPD for short. (https://clincancerres.aacrjournals.org/content/5/8/2006). According to the Institute of Safe Medication Practices (www.ismp.org/resources/screening-dihydropyrimidine-dehydrogenase-dpd-deficiency-fluorouracil-patients-why-not) the incidence of DPD deficiency is low like 1-7% of the population but the consequences can be unfortunately fatal for those few.  Christina Delsoldato, wife and mom of 3 beautiful children has spent most of her life laughing and loving as much as she can. Christina has built a successful professional career in hospitality, customer service and sales. Christina has faced many obstacles and traumatic events during her life. Christina took her mother's quickly declining health into her own hands. Despite having no clinical and medical background, she spent countless nights reading, learning and researching to find answers. These efforts and findings are what allowed her beloved mother to come home to spend her last days on earth surrounded with the love and support of her closest family. Since her mother's diagnosis with Pancreatic Cancer and 5FU toxicity, Christina has become determined to help guide others to self-educate, research and ask questions about potential life-threatening side effects that could indeed be prevented and/or reversed. Tragically, only three months after her mom passed away, her father died suddenly. Christina is on a mission to empathize and advocate not just for her family, but for anyone in need. See omnystudio.com/listener for privacy information. Learn more about your ad choices. Visit megaphone.fm/adchoices

According to the American Association for Cancer Research, 80-90% of the administered dose of the cancer medication 5-fluorouracil of 5FU is degraded by the enzyme dihydropyridine dehydrogenase or DPD for short. (https://clincancerres.aacrjournals.org/content/5/8/2006). According to the Institute of Safe Medication Practices (www.ismp.org/resources/screening-dihydropyrimidine-dehydrogenase-dpd-deficiency-fluorouracil-patients-why-not) the incidence of DPD deficiency is low like 1-7% of the population but the consequences can be unfortunately fatal for those few.  Christina Delsoldato, wife and mom of 3 beautiful children has spent most of her life laughing and loving as much as she can. Christina has built a successful professional career in hospitality, customer service and sales. Christina has faced many obstacles and traumatic events during her life. Christina took her mother's quickly declining health into her own hands. Despite having no clinical and medical background, she spent countless nights reading, learning and researching to find answers. These efforts and findings are what allowed her beloved mother to come home to spend her last days on earth surrounded with the love and support of her closest family. Since her mother's diagnosis with Pancreatic Cancer and 5FU toxicity, Christina has become determined to help guide others to self-educate, research and ask questions about potential life-threatening side effects that could indeed be prevented and/or reversed. Tragically, only three months after her mom passed away, her father died suddenly. Christina is on a mission to empathize and advocate not just for her family, but for anyone in need. See omnystudio.com/listener for privacy information.

According to the American Association for Cancer Research, 80-90% of the administered dose of the cancer medication 5-fluorouracil of 5FU is degraded by the enzyme dihydropyridine dehydrogenase or DPD for short. (https://clincancerres.aacrjournals.org/content/5/8/2006). According to the Institute of Safe Medication Practices (www.ismp.org/resources/screening-dihydropyrimidine-dehydrogenase-dpd-deficiency-fluorouracil-patients-why-not) the incidence of DPD deficiency is low like 1-7% of the population but the consequences can be unfortunately fatal for those few.  Christina Delsoldato, wife and mom of 3 beautiful children has spent most of her life laughing and loving as much as she can. Christina has built a successful professional career in hospitality, customer service and sales. Christina has faced many obstacles and traumatic events during her life. Christina took her mother's quickly declining health into her own hands. Despite having no clinical and medical background, she spent countless nights reading, learning and researching to find answers. These efforts and findings are what allowed her beloved mother to come home to spend her last days on earth surrounded with the love and support of her closest family. Since her mother's diagnosis with Pancreatic Cancer and 5FU toxicity, Christina has become determined to help guide others to self-educate, research and ask questions about potential life-threatening side effects that could indeed be prevented and/or reversed. Tragically, only three months after her mom passed away, her father died suddenly. Christina is on a mission to empathize and advocate not just for her family, but for anyone in need. See omnystudio.com/listener for privacy information. Learn more about your ad choices. Visit megaphone.fm/adchoices

Today we interview Dr. Alan Venook of UCSF, a renowned expert in clinical trial design and gastrointestinal malignancies. We talk about the evolution of the treatment for colorectal cancer over the last few decades, starting with 5FU. We also discuss his time working as an editor for the Journal of Clinical Oncology and we talk about his advice for budding clinical trialists.  Back us on Patreon! www.patreon.com/plenarysession Check out our YouTube channel: www.youtube.com/channel/UCUibd0E2kdF9N9e-EmIbUew

Fluoropyrimidine Cardiotoxicity   |Not Medical Advice or Opinion|

Dr. Hope Rugo, professor of medicine and director of Breast Oncology and Clinical Trials Education at the University of California, San Francisco Helen Diller Comprehensive Cancer Center, highlights key studies in breast cancer featured at the 2021 ASCO Annual Meeting.   Transcript: ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. My guest today is Dr. Hope Rugo. She is a professor of medicine and the director of Breast Oncology and Clinical Trials Education at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco. Dr. Rugo joins me to discuss key advances in the breast cancer field featured at the 2021 ASCO Annual Meeting. Dr. Rugo has received research support for clinical trials through the University of California from Pfizer, Merck, Novartis, Lilly, Roche, and other organizations. Her full disclosures are available on the transcript of this episode at asco.org/podcasts. Dr. Rugo, it's great to have you on the podcast today. Dr. Hope Rugo: Oh, it's great to be here. ASCO Daily News: There were many interesting studies in breast cancer featured at the Annual Meeting. Thank you for being here to highlight some of them. Let's start with the OlympiA trial. This is LBA1. This remarkable study found that adjuvant olaparib extends disease-free survival in BRCA-mutated early stage HER2-negative breast cancer. What can you tell us about this trial? Dr. Hope Rugo: Well, this is really such an amazing study, in terms of the results and its practice-changing impact. The study actually kind of interestingly was published in the New England Journal [of Medicine] 2 days before it was presented. And even though we had all seen the data, it was really such a, I think, moving presentation in terms of really changing the face of treatment for women and men with BRCA1 and BRCA2 associated breast cancer. Of course, olaparib and talazoparib are both PARP inhibitors that are approved to treat metastatic breast cancer associated with BRCA1 and BRCA2 mutations. And in those randomized trials, they showed improvement in response and progression-free survival, but not clear differences in overall survival. So, of course, when we have an impact in the metastatic setting, the next step is to move into early-stage breast cancer. But that's quite a challenge given the fact that you have to test and find the mutation, which is challenging in some parts of the world. And then you have to decide which group of patients need more than standard therapy. So the OlympiA trial randomly assigned patients who had pathogenic BRCA1 or BRCA2 mutations and HER2-negative, either hormone receptor-positive or triple negative breast cancer, to receive a year of olaparib or a placebo. And the patient eligibility was further defined. If you had triple negative breast cancer, you could have had any residual disease after neoadjuvant therapy, or you had to have a tumor greater than two centimeters or a positive node. If you have hormone receptor-positive disease keeping in mind the benefit of adjuvant endocrine therapy. If you didn't have a pathologic complete response to neoadjuvant therapy, you had to have a few other high-risk features using the CPS plus EG score. And if you received adjuvant therapy, you had to have four or more positive nodes, so stage III disease. All patients had to have received at least six cycles of chemotherapy, radiation as indicated, and of course, hormone therapy was given for hormone receptor-positive disease. There were over 1,800 patients randomly assigned, which was pretty, I think, impressive given the fact that everybody had to be tested. And the whole idea behind the trial is that you would enroll a group of patients who still had a high residual risk of recurrence, even though you got standard and reasonable adjuvant or neoadjuvant therapy. It's important to keep in mind when you think about the results of this trial is that having a BRCA mutation, and in particular BRCA1, increases sensitivity to chemotherapy. So the pathologic complete response rates, for example, in the neoadjuvant setting for triple negative breast cancer with the BRCA1 gene mutation, are higher than in patients who don't have a germline mutation. And so you're really looking at a group of patients who have high-risk disease because they didn't have a pathologic complete response if it was the neoadjuvant setting. Now, of the patient population, a little over 70% had BRCA1 mutations. The rest had BRCA2 mutations. And for the triple negative group, that represented a large portion of the population, about 80%. Again, the rest, a little under 20%, had hormone receptor-positive disease. As you would expect, more than 50%, about 60%, were premenopausal. And about 50% received neoadjuvant therapy. There's always a question about whether or not treatment with prior platinum-based therapy, which is also effective when you have DNA repair deficiency, such as in the germline BRCA mutations, whether or not that would affect sensitivity. A little more than a quarter of the patients had received a platinum chemotherapy agents. And the invasive disease-free survival, the primary endpoint of this trial, was really remarkable. There was an 8.8% improvement in a 3-year invasive disease-free survival rate in patients taking olaparib versus placebo, a very big p-value, and a hazard ratio 0.58. This is really dramatic. The curves separated early, and they remained separated. So that it was the IDFS was 77% for patients on placebo and about 86% in patients who were receiving olaparib, just really very impressive. And one of the things you want to find out about is are you changing the rate of distant recurrence. And indeed, not only were there less distant recurrences, but if you look at distant excluding the brain, that's where you really saw the biggest difference. There was a small difference--hard to know if it really is significant--1.5% less brain recurrence is a big issue for patients, particularly with triple negative disease. It was a little less contralateral invasive disease, but it wasn't anything significant. So really, what you were preventing was the kind of recurrence we don't want to see, which is distant recurrence. And then if you looked at the distant disease-free survival, the absolute improvement for metastatic disease was 7.1%. Again, the curve separated early and stayed separated over time. Now, overall survival, of course, is the golden endpoint that you want to look at. There were numerically less deaths in the olaparib arm, 59 versus 86 in the placebo arm. Most of these deaths were due to breast cancer. And the hazard ratio is 0.68. Although the p-value was 0.024, that didn't meet the statistical plan, which was a p less than 0.01 in terms of how the statistics can be balanced in this trial. But the overall difference was 3.7%. And of course, there were subgroup analyses done, which showed that everybody benefited. It was impossible to see a difference. And again, only a small number of patients relatively receive platinum, so it's hard to know whether or not that changed the response. In terms of the side effects--you always want to think about side effects--it was exactly what you would have expected from what we [expect] in the metastatic setting. Not a lot of grade III or greater toxicities. Mainly anemia was the most common at 9%, and 5% neutropenia, a little bit increase of grade III fatigue, but only 2%. The rest of the toxicities were all grade I and II. And of note, olaparib does cause nausea, 57% of patients versus 23% reported nausea with olaparib versus placebo. But normally, you can manage this nausea and the anemia by actually dose reducing and first holding and then dose reducing. One of the big questions, of course, with PARP inhibitors is if you're inhibiting repair of DNA, are you causing leukemia--new primary cancers? And it was very encouraging. Again, it's 3 years, so we need to be followed a little bit longer, maybe 5, but it was 0.2% or 0.3%. There was no increase in myelodysplasia or myeloleukemias with the use of the PARP inhibitor, which is really important. And the global quality of life scores were identical. So even with these side effects, they could be managed and didn't impact global quality of life. And then in terms of the paper, the additional information the paper gave is that most of the people who required a transfusion received only one transfusion of red blood cells. So I think with the caveat that there are some additional side effects, they are generally able to be managed well. Quality of life is maintained. And there's a huge early difference in the most important endpoints that we look for in these trials--invasive disease-free survival and most importantly, distant disease-free survival. So definitely history in the making. ASCO Daily News: Excellent. Thank you for sharing these fantastic results from the OlympiA trial. The ECOG-ACRIN Research Group presented EA1131, a study of platinum-based chemotherapy or capecitabine in patients with residual triple negative basal-like breast cancer following neoadjuvant chemotherapy (Abstract 605). This interim analysis really highlighted the need for better therapies for this patient population. What are your thoughts on this trial? Dr. Hope Rugo: Well, this, I think, is an important trial. Ingrid Mayer from Vanderbilt designed the trial with ECOG and actually presented the data. There will be a lot more data coming from this study because they collected tumor tissue and are doing a lot of different analyses, which might help us understand the benefits of different treatments in different subgroups of patients with triple negative breast cancer. Now, this trial really focused on patients who have the highest risk disease after neoadjuvant therapy, clinical stage II or III triple negative breast cancer diagnosis. They received the standard neoadjuvant chemotherapy. And they had to have tumors that were greater than one centimeter in the breast at the time of surgery or any positive lymph nodes. So this is actually a group of patients who we already know have a high-risk of distant recurrence. They did do an analysis of the tissue using a PAM50 assay to understand which tumors were basal or non-basal like. And patients were randomly assigned to receive capecitabine by the CREATE-X trial, which showed an improvement in overall survival when capecitabine was given to patients with residual triple negative breast cancer after neoadjuvant chemotherapy in Japan and Korea, versus carboplatin or cisplatin by treating physician discretion (DOI: 10.1056/NEJMoa1612645). The patients received four cycles every 3 weeks of carbo or cisplatin. Now, one thing that's important to keep in mind is in Japan where the CREATE-X trial was designed in Korea where it also participated, the capecitabine dose was the original U.S. Food and Drug Administration (FDA)-approved dose, where it was a little bit higher, 1,200 milligrams per meter squared twice a day, 2 weeks on, 1 week off. In the U.S., patients don't tolerate this very well. And there is a different metabolism in Asian patients, where they can tolerate a higher dose of 5FU and capecitabine with not as much toxicity due to pharmacogenomics. The patients in the ECOG-ACRIN trial received capecitabine at 1,000 milligrams per meter squared twice daily with the same schedule, which is really all that's tolerated. So the objective of this trial was to see whether or not you could do better or the same if you received a platinum versus capecitabine with the idea that DNA damaging agents work very well in basal-like triple negative breast cancer. So the patients were enrolled in this trial. 415 patients were randomly assigned. And then the data safety monitoring group who were following the results at the interim analysis ended up closing the trial because they found that based on the statistics so far that it was unlikely that the platinum arm would either be better or worse than the capecitabine arm. And they saw more toxicity in the platinum arm. So the trial was closed. And that's the data that was presented. So there was a total of 160 patients who received capecitabine, [and] 148 [patients] who received platinum. Most of the patients had basal-like disease. The age, it was about 52. It's all what you would have expected to see in this patient population. So I don't think we have any concerns about the patient population. The 3-year invasive disease-free survival in patients with basal-like triple negative breast cancer, the primary endpoint of the trial, was identical between the two arms. But actually, discouragingly, it wasn't great. So IDFS for capecitabine was 49% and platinum 42%. So this was actually very disappointing data. And I think it just highlights how we really need to provide better treatment for our patients who don't achieve pathologic complete responses to the best neoadjuvant therapy. It is true that the ECOG-ACRIN trial didn't require that patients receive anthracyclines, but 85% did. So I think that we feel really comfortable that they got good chemotherapy. They looked in the non-basal-like sub-type. And in the non-basal-like sub-type, which are cancers that are more likely to be responsive to capecitabine in the metastatic setting, actually, the outcome, although small numbers, looked better with capecitabine than with getting the platinum-type therapy. And if you looked at non-basal versus basal, regardless of therapy, the patients who had non-basal-like disease did much better than the patients who had basal-like disease, something that we would have guessed, but hasn't been shown before. So I think it was really important, [and] really helps us to identify the patients who need the most intervention. But even the basal group, the IDFS, the non-basal group, it was 55.5%. So better than basal at 46%, but still you got 45% of patients with invasive disease-free survival event over a 3-year medium follow-up. Overall survival at 3 years, also, was disappointing at about 66% for capecitabine and 58% for platinum. So I think that, really, this trial just identified, I think, in a very confirming way how we need to make progress in the treatment of these patients who have residual disease after neoadjuvant chemotherapy. In terms of toxicity, the platinum-based therapy clearly was more toxic. Most of the toxicity that was seen was grade I and II, as you would expect, but there was more grade III toxicity even with the platinum-type therapy. Again, as you would expect. You get hand-foot syndrome with capecitabine and not with platinum. But there was more of the standard toxicities that you would expect with the platinum or bone marrow suppression, primarily some thrombocytopenia, et cetera. So when they looked overall at the trial population, I mentioned that most had basal sub-type by PAM50. It was 80%. So it is a group of patients where I think even going into neoadjuvant therapy about 80% have basal-like disease. So I think it makes us very interested in the results that we expect to see in the very near future from the KEYNOTE 522 trial, where we've seen an improvement in pathologic complete response, particularly in patients with node positive disease with the addition of pembrolizumab, to standard taxane platinum and anthracycline-based neoadjuvant chemotherapy (DOI: 10.1056/NEJMoa1910549).  But a very recent press release noted that they have reached their event-free survival endpoint. And that pembrolizumab improves event-free survival. And the importance of this data, which, of course, has not yet been shared, so we have to see what it looks like and what the differences are, is that they had shown earlier at the FDA's ODAC meeting in February of this year that possibly patients who don't achieve a PCR, who received pembrolizumab before and after surgery, had a better outcome than patients who did not receive pembrolizumab and received placebo. So how we incorporate capecitabine into the post-neoadjuvant treatment or other novel agents will very much be a subject of the next few years as we sort this out. But if the pembrolizumab data is indeed exciting--and we'll talk more about the durvalumab data in just a moment--then I think the question would be, what chemotherapy do you give? And based on this trial, there is absolutely no indication for platinum postoperatively in patients with residual disease after neoadjuvant therapy. Capecitabine should be given. But clearly, we need better options for therapy. And this is also being studied with some of the new antibody drug conjugates, like sacituzumab govitecan to see whether or not we can improve outcome in these patients. ASCO Daily News: Right. Well, let's look at Abstract 506. This is the phase II GeparNuevo study. The data presented by the German Breast Group showed that neoadjuvant durvalumab improves long-term outcomes for patients with triple negative breast cancer. What is your takeaway from this study? Dr. Hope Rugo: You know, this was really interesting, and I think unexpected results based on their original presentation. This was a phase II neoadjuvant trial in patients with triple negative breast cancer. And the data by the GBG and Sibylle Loibl, who runs the GBG, had already presented the data from the primary endpoint of this smaller neoadjuvant trial, which was pathologic complete response. And what they did in this trial was they treated patients with a nab-paclitaxel followed by epirubicin and cyclophosphamide. And the patients were randomly assigned to receive the checkpoint inhibitor durvalumab versus placebo. There were 174 patients stratified by a low, medium, or high TILs. And their main endpoint, as I mentioned, was PCR. So this is a secondary endpoint of invasive disease-free survival. A group of patients received 2 weeks of durvalumab as sort of a lead-in first. And they've looked at that group separately. But it's hard to know because it's such a small trial what that means. And nobody is using a lead-in right at the moment. So their primary endpoint, as I mentioned, has been published already in Annals of Oncology in 2019 (DOI: 10.1093/annonc/mdz158). Although numerically there was a higher PCR rate in the durvalumab treated arm, this was not statistically significant. The p-value is in no way significant. And they looked at, in a forest plot, they showed that the patients who had the window seemed to have a higher PCR, but it was hard to justify exactly why that was the case in this group of patients. Now, it's important to keep in mind that the data that we have from KEYNOTE 522, the neoadjuvant trial with pembrolizumab, and IMpassion 31, the trial with the atezolizumab, showed the benefit, particularly in patients with node-positive disease. In this trial, about a third of the patients had stage zero or I breast cancer. So 61 out of the total of 174 patients did not have positive nodes. So we thought the PCR difference really wasn't seen because they had a low-risk population. But now, they're presenting their secondary endpoint of invasive disease-free survival in this group of patients. And what they saw, actually, at a median follow-up of about 44 months, they saw a 12 IDFS events in the durvalumab arm and 22 in the placebo arm. And actually, there were twice as many distant recurrences in the patients treated with placebo versus durvalumab. So 13 versus six events for distant recurrence. So I think that's actually a really important endpoint. And if you looked at the invasive disease-free survival at 3 years, it was 77% for placebo and almost 86%. So almost a 9% difference in favoring the patients who received durvalumab. Pretty dramatic, you know? A hazard ratio of 0.48. And they did have a p-value of 0.0398. So that was quite interesting. And they looked at distant disease-free survival. Numbers are small here, but I think it's a really important endpoint, and overall survival. Overall survival is early to see, but they could see--this is a long follow-up, but it's a small study rather than early--and they showed that overall survival difference was 83.5% in the placebo arm and 95.2% in the durvalumab arm. Again, secondary endpoints with a hazard ratio is 0.24 and, again, a p-value of 0.1. Distant disease-free survival, such an important endpoint, was a huge difference 78.4% versus 91.7%. Again, hazard ratio of 0.31. So pretty dramatic. And when you looked at subgroups of patients, and they looked at PD-L1 positive versus negative. Almost all of the patients had PD-L1 positive disease, so 138 versus 20 that were PD-L1 negative. So it's kind of hard to interpret any of that. And that trial was stratified by stromal TILs anyway. They did show that patients who had a PCR had a better outcome than patients who did not have a PCR. But among the patients who had a PCR, the patients who had durvalumab did better, again, with almost a 10% difference, favoring durvalumab versus placebo. Now, this is a phase II randomized trial, so it's small. And so this is really hypothesis generating. But given the fact that KEYNOTE 522 and IMpassion 31 (NCT03197935) gave the checkpoint inhibitor for a year, and in this situation patients received durvalumab only in the neoadjuvant setting, it suggests that they saw this impact in patients who had a PCR that was greater in patients receiving durvalumab placebo. So it suggests that even though the PCR improvement was not significant, that just the treatment with a checkpoint inhibitor changes long-term outcome. And we know that there's more toxicity by giving longer course checkpoint inhibitor therapy, so we expect that we might see approval of pembrolizumab based on the KEYNOTE 522 trial. And it will bring up the question of whether or not you need a whole year of treatment to improve outcome. And whether or not simply treatment preoperatively might be sufficient, particularly in the patient group who achieves a PCR. It will be, I think, very, very important to be able to evaluate this in order to reduce the toxicity, both the physical toxicity, as well as financial toxicity from use of checkpoint inhibitors in patients with triple negative breast cancer. Also, we know that a third of these patients had stage I disease. And I think we really need to look at the larger trials quite carefully to understand whether or not all patients need checkpoint inhibitors who have triple negative disease. Or whether or not we could more correctly focus on the patients who have higher risk disease, node-positive disease who've been shown to have less tumor infiltrating lymphocytes than patients who have less burdensome disease at diagnosis. ASCO Daily News: Right. So what about the subset analysis in Abstract 1011 that looked at outcomes in patients who are age 65 and older in the phase III ASCENT study of sacituzumab in metastatic triple negative breast cancer? Can you tell us about ASCENT and the toxicities associated with this antibody drug conjugate in this older patient population? Dr. Hope Rugo: Well, ASCENT, of course, is a practice-changing trial as well. It led to the final formal approval of sacituzumab govitecan for patients with metastatic triple negative breast cancer in the second line or greater earlier this year after accelerated approval was granted earlier in 2020. This antibody drug conjugate is given 2 weeks on, 1 week off. And the primary toxicity is neutropenia, and then to a lesser degree diarrhea. But overall, the drug is quite well-tolerated. In the overall parent ASCENT trial, as the listeners know, showed an improvement in progression-free and overall survival at the first analysis. Very impressive data with sacituzumab in these heavily pretreated triple negative breast cancer population, compared to treatment of physician choice with standard chemotherapy options, where about 50% of the patients received eribulin, which had already been shown to be better in terms of overall survival compared to other chemotherapy in the subset of patients treated in the past with eribulin who had triple negative disease. So at ASCO this year, Kevin Kalinsky presented on behalf of our authorship group a subset analysis looking at patients who were age 65 and older to better understand whether there was more toxicity and as much benefit in this group of patients. So important when we're looking at novel therapies. So overall, there were 44 patients treated with sacituzumab and 46 with treatment of physician choice who were age 65 or older. Most of the patients had received two to three lines of therapy. And about 40% had received greater than three lines of therapy. The median prior anticancer regimen was pretty similar to the overall group. Most of the patients had initially been diagnosed with triple negative disease, but really, interestingly, about a third of the patients had ER-positive or something else disease initially and were triple negative on biopsy in the metastatic setting. So an interesting subgroup of patients that were also looked at separately and appeared to benefit to the same degree as the triple negative patients. So we looked at progression-free survival in this group of patients looking at patients under age 65 and age 65 and older. A hazard ratio was even greater in the age 65 or older for--it's hard. These are subset comparisons, but the hazard ratio is 0.22 going from 2.4 months with standard therapy to 7.1 months with sacituzumab. The hazard ratio in the younger group was 0.46. But still a big difference in progression-free survival. And then in terms of overall survival in the age 65 and older group, it went from 8.2 to 15.3 months with a hazard ratio of 0.37. And so also really quite dramatic. And overall response was also significantly increased with, in fact, the only responses seen in the age 65 or older group seen in the sacituzumab group. There were no complete or partial responses in the treatment of physician choice group. Of course, really important to look at safety in our older patients because we know that generally there is more toxicity in that group of patients. But actually looking at grade III or greater toxicity, keeping in mind it was 49 [patients] in the older group versus 209 patients in the younger group, there was no difference in grade III or greater toxicities. There were more dose reductions. So 35% reduced their dose versus 19% older versus younger. But there was no difference in adverse events that led to discontinuation between the younger and older group. So that was really encouraging. We see this in almost all trials that older patients have more dose reductions and that was seen here as well. And we also looked at this very small subset of patients who are age 75 or older versus age 65 or older. And the rates of adverse events were similar, albeit smaller number of patients. There was, if you looked at specific treatment-related adverse events that led to dose reduction, it was a neutropenia, fatigue, diarrhea, febrile neutropenia in a small number, 6% versus zero in the treatment of physician choice and nausea. So it's helpful to know what those toxicities are when you're thinking about treating these patients in clinical practice. And in a patient who might be a little less strong, a little older, more comorbidities, so slightly more frail, I would consider starting potentially at a 3/4 of the dose and then going up if they tolerate it well, versus starting at the full dose and getting a lot of toxicity. But this was really encouraging data that showed that you can give the drug to patients who are older and even elderly at age 75 or greater. So that was good to see. And then Lisa Carey presented additional data looking at patients who were treated in the second line or greater because the formal approval by the FDA is in second or greater line. But most of the data looked at patients who were treated in the third or greater line. So you were supposed to have at least two chemotherapies for advanced disease, but you could have had one in the early stage setting if your progression occurred within 12 months. So there were 33 and 32 patients in the sacituzumab and treatment of physician arm, respectively, who had a recurrence within 12 months of neo or adjuvant chemotherapy. They got one line of chemotherapy in the metastatic setting. And then they were randomly assigned on the ASCENT trial. And as you would expect, tiny numbers, right? 33 and 32 patients. But you get a lot of events in this patient population. The PFS was much greater in patients getting sacituzumab than treatment of physician choice. Hazard ratio of 0.41. And also, if you looked at overall survival, it was double. The hazard ratio is 0.51, even in the second line setting. I think it's really interesting to look to see what the toxicity is relative to the lines of therapy. But because the numbers are so small, it's really hard to look at this now. We'll see more data on toxicity when we see data in the first line, as well as the post-neoadjuvant setting in ongoing trials. And I think that will help us a lot to understand what I think we see in the current clinical trials and in practice, which is that patients who are treated in this second line setting have less hematologic toxicity as well as GI toxicity and need less growth factor intervention, et cetera. And I expect that we'll see that in the post-neoadjuvant setting as well. These numbers are too small to really look at any differences in toxicity. But all of this data I think was incredibly encouraging for us in terms of the use of sacituzumab in patients with metastatic triple negative disease, as well as the expansion to the first line and to post-neoadjuvant setting. ASCO Daily News: Excellent. Investigators of the phase III MINDACT trial, that's Abstract 500, evaluated the survival of patients with an ultra low risk 70 gene signature. How will MINDACT inform clinical practice? And do you think this study might guide more appropriate choices of chemotherapy in women with node-negative or one to three node-positive disease? Dr. Hope Rugo: Well, how MINDACT will inform clinical practice is a very big question. And it already has informed clinical practice identifying patients who are better candidates for chemotherapy and endocrine therapy versus endocrine therapy alone who have stage I and II hormone receptor-positive early stage breast cancer based on their primary outcome results. This particular analysis was something different. So we think about using this 70 gene score and the recurrence score from the TAILORx trial (DOI: 10.1056/NEJMoa1804710) and RxPONDER to try and identify which patients need more therapy versus less therapy. Now, we also know that these scores have some prognostic impact. Clinically, we mainly have used them to decide who should get chemotherapy in addition to endocrine therapy. This trial looked at a different way to use a gene expression scoring system. It's really to identify which patients need less. Given the fact that your middle of the line therapy is endocrine therapy, which patients do we know who will do very, very well with any endocrine therapy and don't need extended duration endocrine therapy? That's really the question here. So they looked at the patients who were in the MINDACT trial and used data published by my colleague, Laura Esserman who looked at a cohort of patients retrospectively and found that patients who had an ultra low score in MINDACT. And that's a score greater than 0.355 where plus 1 is the lowest end of low risk, and minus 1 is the highest end of high-risk, so greater than 0.355. She identified a group of patients who did well, regardless of whether they received tamoxifen or not apparently in this retrospective long-term outcome where there was 15-year follow-up. So they use that data to go into the MINDACT population and to try and understand which patients benefit. And the MINDACT is a much higher risk group of patients. So if you looked at that original trial that Laura Esserman published, these patients had screen detected cancers. And in fact, the 70 gene signature low and ultra low-risk tumors are, as you would expect, over-represented in screen detected cancers. So you've got this excellent survival regardless of treatment. So how did they apply to MINDACT? So in MINDACT, patients were randomly assigned, of course, who had clinical low, genomic high, or clinical high genomic low to receive chemotherapy or not. In this situation, you're really looking at the patients who have genomic ultra low disease. So most of those patients would not be getting chemotherapy because they would already have ultra low disease. So what they found actually when they looked at the overall population of MINDACT, 6,700 or so patients, they found 15% of patients or 1,000 patients fell into this ultra low category. And if then you looked at the patients who were high-risk, it was 36%. And patients who fell into the big low-risk group, it was about 49%, so about half of the population of patients. So they looked at the different metastasis-free interval rates in patients who had genomic low and ultra low-risk disease, regardless of the treatment the patients receive. They all receive endocrine therapy, remember? So they actually found that in patients who were ultra low versus low-risk, that the hazard ratio is 0.65, showing that patients who had ultra low-risk--remember, this was 1,000 patients at 8 years--there was only 36 events. So they had a 97% 8-year distant metastasis-free interval, compared to 94.5% for low-risk and 89.2 in high-risk disease. They looked at breast cancer-specific survival rates as well. And for ultra low-risk in 1,000 patients, there were exactly eight events. 99.6% 8-year breast cancer-specific survival. So really, quite remarkable. So clinical high-risk tumors tend to have larger size, higher grade, be node-positive. We already know that. For the 1,000 genomic ultra low-risk patients, about almost 70% were greater than 50 years. 80% were node negative. 81% had tumors that were T1, so up to two centimeters. And most of them, except for 4%, were grade I and II. 97% were hormone receptor-positive HER2-negative. Only 14% of patients who had ultra low-risk disease received chemotherapy in MINDACT. And most of the rest received endocrine therapy. Some actually didn't receive endocrine therapy. 16% had no adjuvant systemic treatment at all. So if you looked at the genomic ultra low-risk patients and divided them into clinical low-risk and clinical high-risk, there was really no difference in the events overall, a little bit less 8-year distant metastases-free survival, but not much of a difference. So really, a quite remarkable outcome. Now, what you want to know, of course, then is, does it make a difference if you get endocrine therapy at all? And they looked at the patients who had chemotherapy versus no chemotherapy. And as you would expect, it made no difference. Again, it was a tiny number of patients. But if you looked at endocrine therapy versus no endocrine therapy, it was hard to tell. Because, again, no adjuvant systemic therapy was only 157 patients. There were four events. And for the patients, 685 patients who got endocrine therapy, there were 23 events. So the 8-year metastasis-free interval was identical, but there just aren't enough patients in that no adjuvant systemic therapy group to really understand. So what we know is ultra low-risk defines a group of patients who have excellent outcomes. Does it tell us that they don't need adjuvant systemic therapy? No. Eight years really isn't enough time, unfortunately, in is group because 50% of recurrences occur after five years and out to 20 plus years. We have to keep in mind the Early Breast Cancer Trials Group data showing how many recurrences occurred after five years of endocrine therapy. But in this group of patients who have ultra low-risk disease, they clearly do not benefit from chemotherapy. And I think that's regardless of their clinical risk. And it's likely that 5 years of adjuvant endocrine therapy is absolutely all those patients would ever need. If you have a small cancer that's ultra low-risk, could you get by with less than 5 years of endocrine therapy in a patient with a lot of toxicity? Potentially. And I think that's a really important bit of information to take back into clinical practice when you're talking to patients about the duration of endocrine therapy. But a stage I tumor or stage II with ultra low-risk disease, in general, I would treat for 5 years. I think it's important to keep in mind that premenopausal women, even with ultra low-risk stage II disease, have an ongoing risk of recurrence. And I still think that those patients should be treated with a varying function suppression and aromatase inhibitor if tolerated and tamoxifen otherwise because our very young patients tend to have higher risk of recurrence over time. And it's very hard to separate them out in these studies. Interestingly, there are a few young women who have ultra low-risk disease. So I think this really helps us understand yet another impact of genomic tests, which is who needs less therapy, not just who needs more. ASCO Daily News: Great. That's good to hear. Well, finally, the theme of the Annual Meeting was equity. And in Abstract 1092, you and your colleagues at University of California, San Francisco (UCSF) looked at decreased enrollment of patients with advanced lobular breast cancer compared to ductal breast cancer in interventional clinical trials. Can you tell us about this study? Dr. Hope Rugo: Yes, this was a really interesting evaluation. My colleague surgeon Rita Mukhtar at UCSF actually led this evaluation with a very good student who's working with us on some of our research trials. And the idea was that we had observed anecdotally, as have others, that patients with invasive lobular cancer tend to be less likely to meet criteria for clinical trials. So they don't have measurable disease as much. We tend to see sclerotic bone lesions, diffuse infiltration without measurable disease. And it can be much, much more difficult to meet the criteria for clinical trials. So actually, what my colleagues did in this trial is look at whether or not patients with lobular breast cancer are underrepresented in clinical trials. And so they looked at the proportion of interventional stage IV clinical trials that used RECIST in clinicaltrials.gov. And then actually looked at the patients who have RECIST measurable disease who have lobular cancer. And it's really interesting. I mean, we just have a lot less RECIST measurable disease. And in the UCSF cancer registry, patients who were enrolled in clinical trials, if you looked at invasive lobular cancer were markedly decreased if you compare it to patients with other sub-types of breast cancer. So we think that that's probably due to the requirement for measurable disease. And that what we should do in patients who have metastatic lobular cancer is develop trials that are specifically for lobular cancer that focus on the unique biology. And there's a lot of work going on now looking at that biology. And allow patients to enroll based on their disease control rates rather than response. So that we don't require RECIST measurable disease since that's hard to come by in invasive lobular cancer. So I think it's a really important area. It's about 15% of invasive breast cancers. We see a lot of lobular cancer in the metastatic setting. And I think it's unfortunate not to be able to enroll these patients in clinical trials. There is a lot of interest in the cooperative groups in the United States in Europe and in Asia, of course, in trying to do trials that are focused on addressing the needs of patients with lobular cancer, both in the early and late-stage setting. ASCO Daily News: Excellent. Thank you, Dr. Rugo. It's been great to have you on the podcast today. Thanks so much for sharing your valuable insight with us on the ASCO Daily News podcast. Dr. Hope Rugo: It was really a pleasure to participate and thank you for putting together these podcasts. ASCO Daily News: And thank you to our listeners for your time today. If you enjoyed this episode, please take a moment to rate and review us, wherever you get your podcasts.     Disclosures: Dr. Hope Rugo Honoraria: Puma Biotechnology, Mylan and Samsung Research Funding (Institution): Pfizer, Merck, Novartis, Lilly, Roche, Odonate, Daiichi, Seattle Genetics, Macrogenics, Sermonix, Boehringer Ingelheim, Polyphor, Astra Zeneca and Immunomedics. Travel, Accommodations, Expenses: Pfizer, Novartis, Mylan, AstraZeneca, Merck Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

La Dra. Marytere Herrera, oncólogo médico adscrita al Instituto Nacional de Cancerología (Ciudad de México, México), junto con el Dr. Marcelo Garrido, oncólogo clínico en la Pontificia Universidad Católica de Chile (Santiago, Chile), nos comentan sobre los resultados más relevantes de los últimos estudios presentados durante el Congreso de ASCO 2021 en tumores gastrointestinales: Cáncer colorrectal: KEYNOTE-177: Estudio fase III, que evaluó el uso en primera línea de pembrolizumab vs. quimioterapia en pacientes (aleatorizados 1:1) con cáncer colorrectal metastásico e inestabilidad microsatelital alta/reparación deficiente. FIRE-4.5: Estudio fase III, aleatorizado 2:1 para investigar FOLFOXIRI más bevacizumab o cetuximab como tratamiento de primera línea en pacientes con cáncer colorrectal metastásico y mutación BRAF V600E. BREAKWATER: Breve revisión al diseño del estudio fase III, que aleatorizó a pacientes con cáncer colorrectal metastásico, BRAF V600E mutado, a recibir encorafenib más cetuximab ± quimioterapia para el tratamiento de primera línea. PANAMA: Estudio diseñado para evaluar al 5FU más panitumumab vs. 5FU solo como terapia de mantenimiento en pacientes con cáncer colorrectal metastásico, RAS wt. FOCUS4-N: Estudio aleatorizado con capecitabina de mantenimiento vs. vigilancia activa para pacientes con cáncer colorrectal metastásico estables o que respondieron después de 16 semanas de tratamiento a la primera línea. DESTINY: Resultados del estudio que evaluó a pacientes con cáncer colorrectal que sobreexpresaban HER2 (IHC 3+ o IHC 2 + / ISH +) a recibir trastuzumab deruxtecan. CHRONOS: Estudio fase II, que reportó los resultados del rechallenge de panitumumab, con la detección de DNA circulante, en pacientes con cáncer colorrectal metastásico. Cáncer gástrico, de esófago y unión gastroesofágica: CheckMate 577: Resultados del análisis de eficacia y seguridad ampliados de nivolumab adyuvante vs. placebo para el tratamiento de pacientes (aleatorizados 2:1) con cáncer de esófago o de la unión gastroesofágica, resecado, después de quimioterapia + radioterapia neoadyuvante. ESCORT-1st: Resultados del estudio fase 3, aleatorizado 1:1, doble ciego, controlado con placebo, que evaluó camrelizumab más quimioterapia vs. quimioterapia en pacientes con cáncer escamoso de esófago metastásico o avanzado, no tratado. CheckMate 648: Primeros resultados del estudio fase III que evalúo la combinación de nivolumab más ipilimumab o nivolumab más quimioterapia vs. quimioterapia como tratamiento de primera línea para el cáncer escamoso de esófago avanzado. Neo-AEGIS: Resultados preliminares del ensayo neoadyuvante, de pacientes con adenocarcinoma localmente avanzado de esófago y de la unión gastroesofágica, aleatorizados al azar a recibir CROSS (una terapia multimodal neoadyuvante de carboplatino, paclitaxel y radioterapia) o regímenes quimioterapéuticos perioperatorios (MAGIC o FLOT). CheckMate 649: Datos actualizados de calidad de vida en pacientes con cáncer gástrico avanzado y de la unión gastroesofágica o adenocarcinoma de esófago, que recibieron nivolumab más quimioterapia vs. quimioterapia.

Dr. Hayes interviews Dr. Anne Moore on pioneering the field of survivorship.   TRANSCRIPT SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. [MUSIC PLAYING] DANIEL F. HAYES: Welcome to JCO's Cancer Stories-- The Art of Oncology, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all of the shows, including this one, at podcast.asco.org. [MUSIC PLAYING]   Today, my guest in this podcast is Dr. Anne Moore. Dr. Moore has been instrumental in the field of breast cancer, especially related to her clinical and educational contributions to our field. Dr. Moore was raised and spent much of her formative years in Peru. She received her undergraduate degree at Smith and her medical degree at Columbia University College of Physicians and Surgeons. She completed a residency in internal medicine, as well as her hematology and medical oncology fellowship at Cornell, where I believe she's basically spent the rest of her professional life now as a professor of clinical medicine, and a director of the Iris Cantor Weill Cornell Breast Cancer Survivorship Program at the Weill Cornell Medical College of Cornell University. Dr. Moore, welcome to our program. ANNE MOORE: Thank you, Dan. DANIEL F. HAYES: I hope I got all that right. I think I did. Very happy to have you. And I consider you a real pioneer in that regard, being a woman physician in the decade and decades when that wasn't very common, and a woman oncologist, when it was almost unheard of, frankly. So I know you've probably got some great stories about your med school class, where I think you were 1 of 10 women in your class or something like that, and in your training. Can you fill us in on what it took for you to become a physician? ANNE MOORE: Well, I must say, I went to all women's college. I went to Smith College. So coming into a class where 10% of the class the women was a big change for me, but a very exciting one. The women, we respected each other. We were respected by our male colleagues. We were well-treated. We were included at Columbia. The faculty were always gracious. We didn't have a sense of being excluded. So it was very-- it was a fabulous place to be and very exciting. DANIEL F. HAYES: Did you feel encouraged to pursue your ambitions? Or were there efforts to pigeonhole you into places that were better for women that you might not have wanted to? For example, I interviewed-- I did interview Clara Bloomfield before she passed away. And she made it clear that the things she wanted to do weren't considered ladylike where she trained, but she did it anyway. Did you run into that? ANNE MOORE: No, we didn't. I remember the head of orthopedics speaking to me about an orthopedic fellowship. Some of my classmates did become pediatricians, which of course, was a typical field for women. But I was interested in hematology/oncology even in medical school. And there was never a sense that that was not an appropriate place for me. DANIEL F. HAYES: Well, that's good to hear. I also know in a chat you and I have before this that you were telling me, by the way, I Googled you. And I found your original New York Times wedding announcement. I won't betray the date, but you had a very nice picture. You looked very young. You told me an interesting story about how much time you got off for your honeymoon. ANNE MOORE: That's right. We got married over a Labor Day weekend so we could get an extra day. And I had to go to my chief resident, whom I called Dr. Steinberg, and request not just a two day weekend, but a three day weekend. There was a lot of thought, but my fellow interns jumped in and covered for me for that great event. DANIEL F. HAYES: Those are different times, that's for sure. So I want to talk a little bit about your career. I know in the early 1990s, you began a multidisciplinary breast clinic at Cornell, which at the time, even in the country, was pretty unusual. I'm going to throw out my mentor, Craig Henderson, had started one in the early 1980s in Boston. But now it seems like everybody has a multidisciplinary clinic for every disease in oncology. What made you think that was a good idea then? ANNE MOORE: Well, it was a very practical idea, but we saw a patient for a new diagnosis of cancer. And at that time, I was already becoming very interested in breast cancer. And the patient would come with her slides, with her mammograms. And I would run to surgical pathology, look at the slides, run over to the radiologist, interrupt them to look at the mammograms, run back downstairs to see the patient. And each specialist that I saw was teaching me so much while I was there, just looking over the microscope or looking at the screens. There's too much running around, number one. We all need to learn from each other. And it would certainly benefit the patients. And the decisions were becoming, at that time, a little more complex. We were beginning to think about adjuvant chemotherapy, adjuvant radiation therapy for the new class of patients that had breast conservation. So it was clear that we had to get together. We realized that we had to speak to each other and it would be much easier if we were all in one room. So we started, in 1991, picking up illustrative cases. And we didn't discuss every case by any means. And we would talk to the radiation therapists, the pathologists, the radiologists ahead of time. They would prepare their sections, and we would all meet. The joy that we had of doing this and the excitement in those first few meetings, it's the first time we had ever had a meeting like that. And everybody was very excited to be there. And we met solidly up until today with those multidisciplinary meetings. They have become much more common. And now the group tries to present every case in some form of a multidisciplinary format. But those early tumor boards were enormously important and exciting for us. DANIEL F. HAYES: And who were we back in-- ANNE MOORE: It was basically the surgeons, of course, played a big role, the medical oncologists, the radiation oncologists, the pathologists, the radiologists. And they were sort of the center of the group. We brought the nurses. We brought-- we didn't have genetic counselors involved at that time. We certainly do now. If we had special issues, we would bring in a specialist to help us, a gynecologist, for instance, or a gynecologic oncologist if we had a case that involved removal of the ovaries or risk of uterine cancer, to talk to us. We had the obstetricians come with our first case of giving chemotherapy during pregnancy back in 1991, 27-year-old woman with an inflammatory breast cancer. We needed to give chemotherapy in the six month pregnancy. We had never done it before. And we had a conference including the obstetricians, again, all together in one room. And then, I had the practice of scheduling a telephone call with the patient who was presented. Because very often, they were my patients. I was the person doing the most with breast cancer. We would have a scheduled telephone call the night of the conference after the conference. And I would review who was at the conference and tell them what the recommendations were. And sometimes, we had two recommendations, one from one group, and one from the other. And I explained that to the patient. And of course, they were thrilled at the idea of all those people sitting there thinking about them. DANIEL F. HAYES: Was the surgeon Mike Osborn? ANNE MOORE: Michael Osborn was later the chief of breast surgery. The original surgeons were really, our private practitioners. Because at that time, most of the surgery was done by private practitioners. And most of the medical oncology, primitive though it was, was also done by private practitioners. I was one of the first to be a full time employee of the hospital doing medical oncology. DANIEL F. HAYES: Wow. In Boston, it was interesting. There was a, I won't call political split, but there was reluctance among some of the surgeons to engage in such an activity because they felt it would take away their autonomy and they didn't need it. And others who wouldn't miss a week, who loved it. Ultimately, everybody joined. But did you run into that as well, people who just didn't want to do this? ANNE MOORE: No. I must say, our surgeons were eager. Because this was the time when the question about breast conservation was coming up from the patients. And these are surgeons who all had trained in the radical mastectomy. And New York City women weren't keeping their work quiet. They were really in there, saying, what do you think about breast conservation? And I must say, the surgeons at our hospital-- wasn't true probably at every hospital-- were willing to listen, but they hadn't had the experience of breast conservation. And that's one reason why they were happy to have the multidisciplinary group discuss that. DANIEL F. HAYES: So you must have been at the same time or just before that, this was started at Memorial as well. And I know that then it became that. Was there a citywide breast cancer group that met routinely? ANNE MOORE: Memorial was later with the multidisciplinary tumor board at their hospital, as were the other hospitals in New York. However, we did meet together starting around 1971 with the New York Metropolitan Breast Cancer Group, which was a multidisciplinary group of the surgeons, oncologists, pathologists, the same group that we were meeting with on a smaller scale. And this was an enormous benefit to the doctors treating breast cancer in New York, that we were able to not only hear our own group, but we could hear the doctors from Memorial, from Mount Sinai, from Columbia, from Albert Einstein, from Montefiore come. And we would meet together. We'd always have a social hour. They like their scotch, these surgeons. They like scotch. So we would buy the scotch. DANIEL F. HAYES: That must have been a real cast of characters. Was that, like, Jerry Urban in those days? ANNE MOORE: It was just after Jerry Urban. It was just after Jerry Urban. DANIEL F. HAYES: After him? Wow. And how about Ezra Greenspan? Would he come to that? ANNE MOORE: Ezra had his own ideas. He was not so interested in this group, but he was just a little bit too early. DANIEL F. HAYES: And could you get Jim Holland to come to that? ANNE MOORE: The answer is Jim Holland was also not someone who felt he needed to hear a lot of opinions about management of cases. But on an individual basis, Jim Holland was very helpful with patients. DANIEL F. HAYES: I would have loved to have been at those meetings. That sounds like a lot of fun. ANNE MOORE: It was great. And we still have them to this day. We meet four times a year with an annual meeting on one Saturday every year. DANIEL F. HAYES: And I know now that the last decade or so, you've really focused on survivorship as well as your breast cancer work. I talked to Patty Ganz as part of this series. And in my opinion, she really began the field of survivorship. She started thinking about it 25 years ago. But you've really been a mover and shaker now, especially, I think, in the New York City area. Can you tell us about the clinic you've started and how that works? ANNE MOORE: Well, the survivorship has always been interesting to me, partly because I started so early giving chemotherapy, for instance. And the patients, many of them, had early stage II or stage I breast cancer. And 10 years has gone by, 20 years, 30 years, some cases, 35 years. And they still come to see us once a year. And I became more and more interested in what was going on with them, as well as obviously, with the new patients and the new treatments. So it's always been an interest on an informal basis. I have followed Patty Ganz wherever she goes. I'm always asking her advice. I go to any lecture that's anywhere near me. DANIEL F. HAYES: And I'm pretty sure she stays as late as she needs to and gives it to you well. I've never seen anybody as gracious as she is. ANNE MOORE: Absolutely. Absolutely. DANIEL F. HAYES: Let me ask you. This is an opinion question on my part. There are three models. One is that we just keep our patients as long as we're alive and they're alive. The second is that we start separate survivorship clinics, probably run by not by us. And the third is we say you've had enough of oncology. Go back to your primary care. And we trained our primary care doctors to be the survivorship. Which of those do you prefer? ANNE MOORE: Oh, I think about it a lot. Our primary care providers or gynecologists, to whom we could refer patients, especially our very early stage patients after, let's say, five years for their follow-up, I think they're very happy to have an oncologist on board. They have questions themselves. They don't have the confidence that they're giving the best follow-up, whereas of course, they are. But they're anxious that they don't know how to do it. So I think if we're going to hand them over-- that is, the patients-- we really have to prepare the gynecologists and primary care providers with what we think is the most helpful way to follow these patients. And I don't, at least in New York, we have not been good about that part. I know other programs are trying hard to educate their primary care providers to take these patients back in. I think it depends a lot on who's available. In New York, we have a lot of oncologists. Some of the oncologists will continue to follow their patients for the rest of their lives. Many of our oncologists are finding that they just don't have enough chairs in their waiting rooms to continue to follow the patients. And they want to hand them over. The patients themselves would like to stay with a breast cancer specialist or a special clinic for breast cancer survivors. And that's the model we've used. And some institutions have made it a nurse practitioner program, which I think, again, in the right situation, is certainly suitable. DANIEL F. HAYES: Yeah, that's what we've done, sort of a hybrid. It depends on the patient, depends on other factors. By the way, I found this is a wonderful problem to have. I was talking to a patient a few years ago. And I was saying, you can just go back with your primary care doctor. You don't need to see me anymore. And she said, no, I want to stay with you. And I said, well, the problem is there are too many of you for me to take care of. As soon as I said, that I thought, no, no, no. That's not a problem because there's too many of you for me to take care of. So we've all come up with it. All right, to move on a little bit, you've already kind of alluded to this. But why oncology, and why and when breast cancer? I will tell you that I read your CV and I saw your first paper was titled "The Development of Neural Control of Elementary Motor Function in Vertebrates." And this, in surgical journal, a far cry from breast cancer. And I know some of your earlier work as a fellow was in hematology and platelet function. So when did you change gears? ANNE MOORE: Well, I did my fellowship in 1973, 1974, finishing in '75. And really, the work in solid tumor for oncology wouldn't have filled up a half day in the clinic. We had 5FU for colon cancer. We didn't treat lung cancer with chemotherapy. Those were two of our top cancers. And breast cancer pretty much was treated by the surgeons. The surgeons had a surgical oncology clinic where they give their 5FU to the breast cancer patients. So they're really, or they did, of course, the oophorectomy followed by adrenalectomy followed by hypothesectomy for the estrogen receptor positive from their patients whom they didn't know whether they were estrogen positive or not. So there wasn't much to do. And so hematology, I really took a hematology fellowship later on called hematology medical oncology. But it was such an early time. What happened there was that all of a sudden, around 1976, I think it was, right after I finished my fellowship, came the reports of adjuvant chemotherapy improving disease-free survival for node positive patients. All of a sudden, these were now healthy women who'd had a mastectomy, most of them. And somebody had to give them the chemotherapy. And my first case was a doctor called me, a surgeon. And he said-- I hadn't really known him. He said, is this Dr. Moore? I said, yes. He said, I got a lady here. She just did her surgery. She wants a lady doctor for therapy. I said, great. I'll do it. So it was my first oncology patient. And she was exactly my age in her 30's. And I gave her the adjuvant chemotherapy, trembling. My hands were trembling when I started doing it. We gave, of course, our own chemotherapy. And she did well and went on to live about 30 years, and did die of metastatic breast cancer. DANIEL F. HAYES: So you mixed up your own chemotherapy and gave it yourself? ANNE MOORE: Oh, sure. Yeah, absolutely. There was nobody else to do it. There were no nurses who specialized in oncology. So we mixed it up. While we sat and talked to the patient, we shook the bottle of chemotherapy on the desk, took a syringe, drew it up, and put on a little butterfly needle and pushed the chemotherapy. DANIEL F. HAYES: I hope there are young people listening to this. ANNE MOORE: No worries, no nothing. DANIEL F. HAYES: I mean, the flip side is I think they're overwhelmed with the vast amount that there is to learn now. As you pointed out, when you started, it was 5FU. On the other hand, I don't think they realized how difficult it was to be an oncologist in those days. You must have been in one of the first rounds of the boards that BJ Kennedy pushed through. ANNE MOORE: The first round of the medical oncology boards, I was. I wasn't in the first class, but I was pretty close to it. DANIEL F. HAYES: Yes. And then you sat on the ABIM for a while, correct? ANNE MOORE: I did. It was 10 years for the ABIM on the hematology board. DANIEL F. HAYES: Oh, really? ANNE MOORE: And then I chaired the hematology board. And by the end of the time I was chairing the hematology board, I really was pretty much just doing breast cancer. Well, I was still doing sickle cell disease, thalassemia, breast cancer, lung cancer. And during those 10 years, slowly drifted just into breast cancer. I just scraped through as chair of the hematology board. DANIEL F. HAYES: That's fascinating. So I'm going to take you way back now. Tell me about why you were in Peru. Were you born in Peru? ANNE MOORE: When I was two years old, my father worked for WR Grace and Company, which was Grace Lines at that time. And they were very active in South America. And he was sent to Lima, Peru. And he went there with four children, came back with five, had a sixth later on. And we just went along, started school there, and then came back to the states. And then I went back right after high school and worked in a medical clinic outside of Lima, and what they call a barriada, which is a poor area where very, very poor people lived. I said, I would love to work in a clinic. I had been a candy striper, that was my experience. So they let me work there. And literally, they would give me syringes. I don't know what was in the syringe and they taught me to give injections to these patients. I had no idea what I was doing. DANIEL F. HAYES: I suspect you did not have malpractice insurance. ANNE MOORE: There was no malpractice insurance involved in these situations. But I sure learned a lot, loved it. DANIEL F. HAYES: And have you been back on medical trips or anything to Peru? ANNE MOORE: Not to Peru, no. I haven't been back to Peru since that time. DANIEL F. HAYES: Wow. That's fascinating. All right, another question that I've been dying to ask you, I'm going to call it an obscure role you've had, which has been the president of the American Clinical and Climatological Association. A very interesting group, to which I frankly belong. But it is the oldest honorific society in America, I believe. Is that true? ANNE MOORE: It was founded in 1884. DANIEL F. HAYES: Can you just give-- I suspect very few people on this call have ever heard of it. Can you give people what's the climatologic about? What's the story on this organization? ANNE MOORE: The American Clinical and Climatologic Society was actually founded in 1884 as a group to study climate. And the reason they were studying climate was they were trying to figure out how to treat tuberculosis. So they figured it had to do with climate. So they studied being near hot springs, being near cold springs, being in a warm climate, being in a dry climate, and gave papers on that subject. It was an all-male group for many, many years. The first women were elected around the 1980s. The wives were invited early on to come to the meetings and to sit in on the lectures, but they had to sit in the back rows of the auditoriums. There was one woman member, and then pretty soon, there were two women members. Then I came along as the next wave of women in the American Clinical and Climatologic. And the group has no longer concentrates on tuberculosis. It's a very diverse group with very different medical interests. The vast majority are internists. We meet and listen to papers. and the papers are from all different fields, which again, for an oncologist who loves going to ASCO and listening just to the breast cancer talks, it's really exciting to hear the latest in kidney disease, the latest heart disease. Perhaps one of the medical doctors who's interested in history of medicine will give us a talk. So it's a very varied group, different from our usual meetings. And everything is published in the transactions, which is on PubMed. And the papers are absolutely first rate. DANIEL F. HAYES: Yeah, I have to say, I've loved going and listening to things I know nothing about. One talk was on the importance of the oak tree in history. Because we built ships out of oak trees, they made all kinds of things, and how that then related to medicine. I'll never forget that. ANNE MOORE: That's right. DANIEL F. HAYES: OK, I want to end up with one other. It's timely, and I understand that when you were a resident, you worked with the now legendary Tony Fauci. How did that happen? ANNE MOORE: Tony was at the National Cancer Institute, the NIH. He had been at Cornell. They invited him back to be chief resident. He came on July 1 and I was his assistant chief resident. So we shared a very small office, as chief resident and my entire house staff just loved Tony. We would do anything for him. He was smart. He was fair. He was hard, hard working. Working next to him was absolutely a joy. It turns out, I didn't know at the time, and I wish I had, his father and mother graduated from the New Utrecht High School in Brooklyn in 1928. They had lived in Bensonhurst. Well, my father graduated in that same class and was class president. So I know he knew the Fauci's, mother and father. And I just wish I had known, because of course, that generation has gone now. But they all were alive at that time. DANIEL F. HAYES: He's been kind of busy lately. I don't know if you've heard, but maybe when this all boils over, you can have dinner with him and ask him that question. ANNE MOORE: A Brooklyn reunion, absolutely. But we loved him as a resident, as you can imagine. DANIEL F. HAYES: So I want to finish with the work you've actually done for ASCO. You are a fellow of ASCO. And I'm sure you're proud of that. You should be. And you've had a lot to do with the self-evaluation program. And I know you've been a mentor for the IDEA program. You were one of the lead of the leadership development program. And now you're on the board for the Conquer Cancer Foundation. And would you just give a few-- this is a little self-serving because I'm one of the foundation's greatest supporters. The stuff they do is amazing. But tell us a little bit about the Woman Who Conquer Cancer that Sandy Swain has started. ANNE MOORE: Women Who Conquer Cancer is a very focused initiative from the Conquer Cancer Foundation, started by Sandy Swain, to try to support with young investigator awards, with career awards, specifically, women. And I think it's so important. The ones I think are the most important are the young investigator awards for women who are coming out of their fellowship. Maybe they're married. Maybe they have a baby at home. They've got their hands full. And to have somebody recognize their work and say, we're going to support you, I think, is fabulous. I think that's a very hard time for women. They can begin to flounder right at that moment. And there's the Women Who Conquer Cancer awards to be able to focus on them. DANIEL F. HAYES: It is their most vulnerable time. And it's actually not a lot of money, but it keeps them alive. And all they got to do is get one paper with their name on it, and we got-- and they're hooked. And I've had two or three now who've had them. And they're wonderful awards. So for those of you who are listening, sit down and write a check to the foundation. ANNE MOORE: That's right. Absolutely. DANIEL F. HAYES: I'm shameless. Well, that's about all. We've run out of time now, unless there's any other great anecdotes or anything you'd like to share with us with your career. ANNE MOORE: No, just how important ASCO is, and very central to my career. And I hope anybody who's listening appreciates ASCO and the opportunities to serve on many, many, many of the committees and facets of ASCO. DANIEL F. HAYES: It's a lot of fun. Thank you for the shout-out. Well, thanks for taking your time to speak with me today. You've been very important to our field in general and to especially women in New York City with breast cancer. I don't know anybody who doesn't know of and respect Anne Moore if they live somewhere in the New York City area, let alone the rest of the world. So thanks for your time. I very much appreciate it and look forward to seeing you in person when this COVID thing goes away. ANNE MOORE: Thank you, Dan. And thank you for doing this series. [MUSIC PLAYING]   DANIEL F. HAYES: Until next time, thank you for listening to this JCO's Cancer Stories-- The Art of Oncology podcast. If you enjoy what you heard today, don't forget to give us a rating or review on Apple Podcasts or wherever you listen. While you're there, be sure to subscribe so you never miss an episode. JCO's Cancer Stories-- The Art of Oncology podcast is just one of ASCO's many podcasts. You can find all the shows and podcast.asco.org. [MUSIC PLAYING]

Full show notes @ https://thesternmethod.com/mark-simon/ Mark Simon, CN, CHCC, CPBN Mark Simon established the Nutritional Oncology Research Institute (NORI) in 2011 as an organization focused on advancing cancer care through optimization of diet and application of targeted nutraceuticals. Mark Simon's background and interests are in diverse fields including clinical nutrition, biomedical engineering, plant-based nutrition, naturopathic medicine and neuroscience. ***Resources Mentioned*** Nutritional Oncology Research Institute  Cancer Schmancer Can Dietary Methionine Restriction Increase the Effectiveness of Chemotherapy in Treatment of Advanced Cancer? NORI PROTOCOL - methionine video by Dr. Mark Gregor Fruit, The Lymphatic System & Cancer: Dr. Robert Morse Book: Fit for Life by Harvey Diamond Scientific papers on Methionine, Sodium Selenite, Vit E, Melatonin AntibioticWatchdog Nutritional Oncology Research Institute - Cbd, Hemp CBD, Hemp NORI CBD - Cbd, Cbd, Alternative Health Products, Cbd Oil Nutritional Oncology Research Institute - Home Pure Organic Super-Greens Powder Algae Omega-3 Oil, 400 mg DHA per ml  https://norinutraceuticals.com/shop/ols/products/selenium Zinc Chelate, 15 mg, 90 tablets  Vitamin D3, 2,000 IU, 360 tablets Iodine, 1.8 mg/drop Sublingual Vitamin B12, 500 micrograms Methylcobalamin, 120 Tablets 1 oz. Organic Broccoli and Radish Sprout Powder (High Sulforaphane Content) Vitamin E Delta, Gamma Tocotrienols, Annatto Derived (DeltaGold), 60 ml, 21,000 mg  Melatonin, 50 mg, 360 Tablets  Glucosamine HCl Powder, 8 oz., 227 grams Sodium Selenite, 2 mg, 180 Slow Release Tablets   *Use code STERN at checkout to receive a discount     The Stern Method Website - What We Use: Top Anti-Cancer Supplements Essential Oils We Use Including Our Targeted Blends Cancer Fighting Tools for Detox and Cancer Fighting My Kid Cures Cancer Anti-Cancer, Non-Toxic, Healthy Lifestyle Products We Use           *** In This Episode: Our guest today, Mark Simon, talks about how eating a low methionine diet can lead to better health and cancer cell death (apoptosis).  In this episode, Mark and Ryan discuss the benefits of a plant-based diet which is high in fruits and berries, moderate in vegetables and void of animal products. Through his work at the Nutritional Oncology Research Institute, Mark has developed the NORI protocol, based on the two core concepts of restricting methionine intake and using high doses of sodium selenite (selenium salts) and other targeted nutraceuticals to reduce tumor cell growth. In-vivo studies and clinical experience affirm the effectiveness of this type of diet. The concept of using pro-oxidants versus anti-oxidants is discussed as is the mechanism of sodium selenite and the relationship between methionine and cancer. This conversation may challenge the way you currently view your nutritional protocol. We encourage you to keep an open mind. Be prepared to stretch your current point of view and perhaps gain some new insight and ideas. Please enjoy this next installment of the Anti-cancer Revolution! Be sure to let us know what you think below.   0:41 Fruit or no fruit – That is the million dollar question Mark promotes a methionine restricted diet - high fruit, moderate vegetables, no animal products Utilizes Vitamin E, tocotrienol, selenium, iodine 2:30 Overview of the NORI protocol Based on two core ideas -  methionine restricted diet &  high dose selenium (sodium selenite) Mark started the diet based on personal experience after his wife was diagnosed with stage 3 breast cancer Diet plays a huge role as a tool in cancer prevention Sodium selenite is a form of selenium studied for over 40 years Is a selective chemo-therapeutic agent Can kill cancer cells without causing harm to other cells High bio-availability Can be administered intravenously or orally 6:00 Relationship between methionine and cancer cells Mark discover the work of Dr. Daniel E. Epner, MD - clinical studies using methionine restricted diet Video by Dr. Mark Gregor on Mark’s website describing methionine and what it does Methionine is an amino acid If methionine is restricted, cancer cells die Could potentially work as stand-alone therapy 8:30 How do you reduce methionine in the body and what is the end goal? Through the diet methionine levels can be brought quite low All whole foods contain some level of methionine Fruits contain the least amount of methionine Grains, nuts, beans, seeds, animal products contain the most Best to cycle methionine levels on and off In the future hope is to be able to bring methionine levels to zero 10:05 What do cancer cells do with methionine? Cancer cells use methionine as a building block  Methionine is not needed for normal cell growth- not an essential amino acid MTOR pathway is stimulated less with methionine restriction Methionine restriction makes cancer cells more sensitive to treatment NORI diet is a platform to slow down tumor growth and make cancer more sensitive to treatment 13:50 What are your thoughts on eating fruit? Fruit is not the same thing as table sugar Most fruits are low glycemic Fruitarian diet does not cause high blood sugar 80-10-10 diet (80% fruit, 10% protein, 10% fat) Sugar does not encourage tumor growth, insulin does Ketogenic diet doesn’t work long term because glutamine is not cut out of diet 18:00 NORI diet restricts other cancer-dependent amino acids besides methionine Glutamine Phenylalanine Isoleucine Tryptophan Asparagine 18:30 NORI diet is an alkaline diet Alkaline diet helps neutralize acidity around tumors Anti-inflammatory Anti-angiogenesis Dr. Robert Morse recommends a similar program 20:05 Where do you stand on juicing fruit? Is there a difference between eating fruit and vegetables with or without fiber? A little bit of freshly squeezed citrus juice is fine Bottled juices - no Believes juicing is counter-productive More antioxidants flooding the system makes it harder to fight cancer Hasn’t seen data showing success with juicing and stage 4 cancer Plant based diet is a good idea Cancers are crazier today than years ago Gerson’s original diet involved orange juice and lower protein (lower methionine) Juicing probably doesn’t get phytochemicals up to appropriate levels 23:45 Can you elaborate on antioxidants and cancer? Study with animals on low-antioxidant diet slowed tumor progression Normal cells operate on a low level of oxidative stress Cancer cells operate at a high level of oxidative stress because of altered metabolism Adding oxidative stress will push cancer cells over the edge Cancer cells are dependent on anti-oxidant systems like: Glutathione Thioredoxin Catalyse Superoxide dismutase If you block glutathione synthesis, cancer cells die off Putting anti-oxidants into the system aids cancer survival such as: Vitamin E (alpha-tocopherol form) Vitamin C NAC (N-Acetyl Cysteine) Vitamin A NORI program is careful not to incorporate juicing or other antioxidant supplements NORI program utilizes pro-oxidants which increase oxidative stress Sodium selenite Generates hydrogen peroxide Generates ROS (reactive oxygen species) Triggers cell apoptosis 28:30 What are your thoughts on using antioxidants to increase chemotherapy and drug success? Oncologists tell patients no antioxidant supplements because they know they will interfere with treatment Antioxidants protect cancer cells Mark hasn’t seen any research showing antioxidants make chemo work better Research shows pro-oxidant therapy helps chemo work better  Sodium selenite Ozone therapy Sulforaphane (need 10-20 grams or more) - not too efficient 32:30 Can you give us a breakdown of the different levels of methionine within food groups? Foods highest in methionine: Chicken and fish Next: other animal products- beef, dairy, eggs Mark has been vegan for 30 years (supplements with B12 occasionally) Caution: B-12 can be used by cancer cells for protein synthesis Soy, sesame seeds, and brazil nuts are high in methionine Lowest: apple, most fruits  Dark green veggies are fairly high Hard part is getting enough calories on a low methionine diet Potatoes and rice work to bring up weight 38:40 Cycling on and off low-methionine foods Encourage fruit-only breakfast (easily digested, full of enzymes, fiber, water, cleansing, detoxifying, extends a fast) Book: Harvey Diamond, Fit for Life  Food combining Methionine restriction is anti-aging Ketosis is not necessarily a healthy state -  not natural/normal  Not a proponent of fasting for cancer patients - too stressful Recommends a fruit-only diet instead of fasting Super-charge your system by eating raw, high-energy, plant-based foods 44:30 What is the distinction between nutraceuticals and supplements? Use supplements to fill in gaps Recommends supplementing with iodine, selenium, vitamin D, zinc, B12 Nutraceuticals can be used to lower inflammation Sodium selenite is used as an anticancer nutraceutical  Vitamin E delta tocotrienol- high dose kills cancer cells Glucosamine alters cancer cells High-dose zinc is effective in killing cancer cells Melatonin effective in fighting cancer (300 mg)  Curcumin - plant derived medicine - not very bioavailable Medicines work because of toxic effects on system/system modulation 50:20 How did selenium and tocotrienols stand out to you?   High index of therapeutic value High bioavailability Water solubility ADME Absorption, Distribution, Metabolism and Excretion - nutraceuticals are analyzed according to this standard Sodium selenite has reached animal and human clinical studies (in-vivo) Methionine restriction is being used in ongoing human clinical studies   55:20 What is the mechanism of action of sodium selenite?   Selective pro-oxidant Study which shows it inhibits glutamine metabolism Natural high uptake into tumor tissue Radioactive sodium selenite (SE-75) was used in the 1960s to highlight cancer cells on imaging tests Relatively small amount of sodium selenite (10-20 mg) is typically needed at therapeutic threshold levels 9 hour half-life Cells need to be exposed 24 to 72 hours or more - the longer the better Lower doses can be sustained for longer periods of time .3 mg/kg of body weight is dosage for IV sodium selenite IVs are used for pulsing in addition to oral dosage IVs can become cost-prohibitive   1:01:30  Hazards of buying sodium selenite online   Can be risky - might be over a toxic dose or too weak Mark sells some on his website Might not be pharmaceutical dose Signs of overdose Hair loss Brittle nails Use under supervision   1:03:00  Is this an extract of selenium versus a whole compound?    Sodium selenite is a mineral salt - inorganic form of selenium- trace mineral Chemical formula Na 2 Se0 3 Body needs it all the time Organic forms vary in the level of anti-cancer activity 100% water soluble- easily crosses blood-brain barrier Vitamin E used is extracted from annatto seed - delta tocotrienol Pro-oxidant  Looks and behaves like unsaturated fatty acid Initiates lipid peroxidase chain reaction Ends up in mitochondrial membrane Interacts with and generates more ROS Triggers cancer cells to die - apoptosis Mitochondria are dysfunctional in cancer cells Breaks the positive feedback loop of the mitochondria so cells can die   1:09:39  You mentioned DHA. Where do you get yours?   Mark uses an algae oil Studies show DHA can be used therapeutically in cancer (6g/day) DHA will become incorporated into the cancer cell membranes and will undergo lipid peroxidase reactions Algae oil is unstable and oxidizes easily  Antioxidants are added to maintain stability and this can be enough to interfere with NORI protocol   1:11:20  Budwig diet - similarities and differences   Fruit, berries, no animal products Cottage cheese and flax oil mixture Flax contains ALA, a polyunsaturated fat Studies show ALA can trigger cancer cells to die Flaxseed oil must be freshly pressed (15-30g) Cottage cheese/quark works as an emulsifying agent to break up the oil for bioavailability Theoretically based on the science, it should work Not in favor of it right now because there are better methods Tocotrienol does the same thing only with more efficiency   1:15:30 Lithium Chloride   Still under study Has a favorable effect on cancer pathways Used as treatment booster Studies with lithium chloride used in conjunction with 5FU in animals   1:17:07 NORI protocol is currently using 6 agents   3 core agents make up the cytotoxic cocktail Vit E tocotrienol (1200mg), sodium selenite, Vit K3 3 other agents working around the cocktail Glucosamine (8g), zinc citrate (150mg), melatonin (300mg) Used in conjunction with methionine-restricted diet Protocol is continually evolving based on clinical experience Simple, low-cost   1:19:10 Where can we find you?   https://antibioticwatchdog.com/ Website covering relationship between antibiotics and cancer Free ebook https://norinutraceuticals.com/ (store)  https://noricbd.com/ https://nutritionaloncology.net/ Info on program and protocol Mailing list CBD products and nutraceuticals - Use code STERN Free consultations (30-60 min)   1:22:00 Closing remarks   Please check out the podcast links and the links on our website (“What We Use” section). Your patronage is greatly appreciated and helps keep the lights on.  For more info about fruit in the diet and to view our most popular video, see Ryan’s podcast with Dr. Robert Morse. Link Below. Use your intuition and try different options if a current protocol is not working. There are many paths to wellness. Future podcast idea: feature two experts on opposite sides of a topic and let them discuss the pros and cons of each Please send your ideas for future speakers to info@anticancerrevolution.com As always, if you are going through cancer….just keep going!     Related Podcasts Fruit, The Lymphatic System & Cancer: Dr. Robert Morse     If you have a question or comment about this episode let us know below!!

Dr. Hayes interviews Dr. Muss on geriatric oncology.   TRANSCRIPT PRESENTER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   DAN: Welcome to JCO's Cancer Stories, The Art of Oncology brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insights into the world of cancer care. You can find all of the shows, including this one, at podcast.asco.org. Today, my guest on this podcast is Dr. Hyman Muss. Dr. Muss has been instrumental in several facets of the history of oncology, the generation and conduct of cooperative groups, the establishment of medical oncology as our board of the subspecialty, and perhaps he's most well known as one of the founders of the field of geriatric oncology.   Throughout his career, he's devoted much of his efforts to research in breast cancer mentoring many young investigators, and, frankly, I'm very proud to consider myself one of those. Dr. Muss's personal journey is fascinating. He was raised in Brooklyn, which even though he spent the last 50 years in other locations, including Boston, North Carolina, and Vermont, our listeners will appreciate from his dialect within the first 10 words from his mouth that he is, indeed, from Brooklyn.   He received his undergraduate degree at Lafayette College in Eastern Pennsylvania, where he was elected to Phi Beta Kappa. He got his medical degree at the State University of New York downstate in Brooklyn, where he was elected to the AOA. He did his internship and his residency at the then Peter Bent Brigham Hospital, now the Brigham and Women's Hospital in Boston. That shows how old you are, Dr. Muss.   HYMAN MUSS: [LAUGHS]   DAN: Then he took a tour to Vietnam for a military tour of duty. He won a bronze star during that experience. He returned stateside, and he obtained his medical oncology fellowship at the then Sidney Farber Cancer Institute, which is now, of course, designated the Dana-Farber Cancer Institute. Following his fellowship in 1974, Hy joined the faculty at Bowman Gray School of Medicine at Wake Forrest, and there he served many roles over the next 22 years before he then moved to the University of Vermont to head the division of hematology oncology.   After 10 cold years in Vermont, he got tired of the snow, and he returned to North Carolina and this time at the University of North Carolina, where he is now the Mary Jones-Hudson distinguished professor of geriatric oncology and the director of the geriatric oncology program in the University of North Carolina Lineberger Cancer Center. Dr. Muss has authored over 500 peer reviewed papers, and like most of the guests on this program, he's just simply won too many awards for me to list them all. However, in addition to his bronze star from the US military, I know he is particularly proud of being an eagle scout. And if you ever meet Hy and he's got his tie on, you have to ask him about his tie tack because it is an eagle scout tie tack, one of the few people I know who has one of those.   Dr. Muss has served ASCO faithfully in many roles. He served on the board of directors from 2004 to 2007, and perhaps importantly, he was the recipient of the Allen S. Lichter Visionary Leader Award in 2020, which was well deserved. I knew of very few people with the vision that Hy Muss has shown for our field. Dr. Muss, welcome to our program.   HYMAN MUSS: Thank you so much. My mother would have loved that introduction.   DAN: [LAUGHS] Let's start with your origin story. I know you weren't bit by a radioactive spider in Brooklyn and became Spider-man, but seriously, I've heard you speak about your father, who was a dentist, and your uncle, a family practitioner, who, I think, shared an office or something. And this sounds a little bit different than the typical medical establishment that we work in these days. How did that influence you?   HYMAN MUSS: Oh my god. How different it is. I grew up in Brooklyn. And I went to PS-167, and we lived in a little brownstone. And my father was the neighborhood dentist, and my uncle was the neighborhood GP, a term not used anymore.   And I grew up with them, and I didn't always know I wanted to be a doctor. But I used to do house calls, especially with my uncle. And patients loved him. An interesting digression is he went to Howard University. He got a minority scholarship. He was picked out of Brooklyn.   He had a lot of African-American patients too, and he would take me in his Buick. And I'd go, and I'd get candy and ice cream and love what he did. And I loved the patient interaction that he had. And I think that was instrumental eventually in college of me after working in a chemistry lab for a semester doing research on cyclic ketones to say I don't think I can do this for a living and consider medical school, which I think was probably one of my best choices. So I had a great upbringing and saw medicine. If my parents saw a credit card or an Epic EMR, they wouldn't know what it was. They'd think it was science fiction.   DAN: And I'm sure you were HIPAA compliant when you were making the rounds with your uncle, right?   HYMAN MUSS: Oh, yeah. So when he got very sick and he couldn't really do his practice anymore, my father said go to your uncle's office and take his records down to the basement. And I went in, and my uncle's records were 3 by 5 index cards with the name of the patient, Mary Jones, diabetes, and her phone number. That was it. That was it. And I could move them down in a cardboard box. And today when we see one patient and start one Epic note, we got 85,000 documents in there, so it was great.   DAN: How did you get to Lafayette College?   HYMAN MUSS: My father had a patient, and I inherited from both my parents loquaciousness. And my dad would talk with all his patients, and bring them up occasionally, have a scotch with them. And he had a patient-- I was probably a junior or a senior in high school. I was really-- didn't know what I wanted to do. I wasn't the greatest student academically in high school.   Although, I went to Brooklyn Tech, a terrific high school. Rich Schilsky went to Stuyvesant, and the patient told my dad that he knew of a small college in Pennsylvania, a boys college, that was really good academically about 100 miles from home. Told me about it. I went and saw it, and liked it, and went there, and it really changed my life going to Lafayette. I got one on-- I went from 6,000 boys in my high school, no women, to a small college with maybe 1,200 boys, but I got to know my professors. It was a lot of one to one. It was terrific, and it still is.   DAN: It's amazing how many people I've interviewed where what they do is serendipity. This sort of thing. Didn't know what I wanted to do, and I was-- you may have heard Dr. Freireich when I interviewed him. Told me that when he grew up in Chicago, his mother was a single parent, and so he started stealing hubcaps to pay for his tuition. [LAUGHS] The founder of our field was a juvenile delinquent.   HYMAN MUSS: Oh, god. Yeah, no, I wasn't that bad. But Lafayette really changed my life, and I had people who actually knew me, knew my name, knew what I was interested in. I had some-- I was a chemistry major, not a really premed. And I had some wonderful professors, and I think they were disappointed when I didn't go for PhD graduate school in chemistry.   DAN: Again, it's just amazing, and I remember this every time I run into a med student, where I think I don't have time to do this. And just one little comment or pat on the back and suddenly they're off in a different way, so I think all of us keep that mind. I've interviewed several of the pioneers, who many of them were so-called yellow berets at the NIH in the 1960s to avoid going to Vietnam and, frankly, changed the picture of medicine in America I think, especially oncology. But so far, only you and one other interviewee, Larry Baker, who I know you know and good friends, actually joined the military and was sent overseas.   He did it sort of unwillingly. It looks, to me, like you did it more willingly. It's not that he was unwilling, but it wasn't in his career plans. That must have really been a very frightening but enlightening experience. Are you willing to give us any back stories on this and talk about it?   HYMAN MUSS: Of course. So I was in medical school. Vietnam was going, and the draft was hot. And we were all worried that if we got drafted out of medical school or out of residency, we'd have to repeat a whole year. So there was something called the Barry plan. And what it was is you joined the military, you could join any service, and they would let you finish medical school and actually credit me for time in the military during medical school.   And then they promised in residency not to draft me in the middle of the year. So I joined the Barry plan, and so I knew I had to go into the military. And so when my time came because I had good training, I was at the Brigham then, the military said, well, if you want to do three years instead of two years, we'll send you to this place or that to do research. And I didn't want to spend another year, so I know the minute I told them that I was heading to Vietnam. I did go to the NIH to look at a cardiology training.   And I got there, and I was the only guy sitting in that interview area who hadn't written 10 papers. So I knew I was going to Vietnam after that day too. And I didn't about the NCI. I didn't know about cancer. Some of my close friends and your friends went to the NCI.   Had I known, it would have been a terrific thing, and I would have applied. I would have worked with the greats there at the time. But I didn't know, so I went to Vietnam. And I was with an artillery battalion. I wasn't anything elegant. I never saw any units with MASH with women or anything.   I was married three months. It was extremely hard on my wife, Loretta, who you know well, but I learned a lot about myself then. I was 27 years old. I didn't have 25 smart people behind me to ask questions to, residents, and terrific faculty, and colleagues, and I got to know myself. I was terrified when I went, terrified, but I got to know the system.   And you learn how well-run the military is. Unlike some of our clinics, they really know how to do it. I got a very valuable experience there, and I set up a drug amnesty program, which is why I won the bronze star. It wasn't anything like I was in front of a machine gun. We had a major drug problem in Vietnam.   Young people, nothing to do, time on their hands, frequently poor kids who got drafted and went in. It was the poor kids. World history, so I set up a program to try to help a lot of them not really get deep into bad drugs. And I think we had some success. Hard to measure.   DAN: So when you say you were an artillery unit, were you like the doctor for the artillery unit?   HYMAN MUSS: I was it.   DAN: Were you patching up injuries and stuff, or taking care of sore throats, or what?   HYMAN MUSS: I did. I did a lot of sore throats. I did a lot of venereal disease. I did back pain. I set one or two fractures. The first fracture I set, I had a big book in another part of our little aid station called the Palma.   It was like a-- we didn't have YouTube. I needed YouTube videos. I put this cast on this guy. It probably weighed 300 pounds, and he said, doc, have you done this before? And I said, oh, yeah, I've done this a lot.   So I did that, and I took care of a heart attack or two on the base in the base hospital. Although, I was in a unit that had little field units out with artillery, and I used to go a few times a week in a helicopter and check on the medics and troops. So it was an extremely valuable experience.   DAN: That's incredible. Well, let's go on. You already sort of alluded to this, but I've asked almost everybody. What made you go into oncology, especially in the 1960s when there wasn't oncology? You came back to the Brigham. What got you interested in doing cancer?   HYMAN MUSS: When I was an intern and resident at the Brigham, our chief of hematology was a guy named William Moloney, and I know you know him.   DAN: I sure do.   HYMAN MUSS: And he was an incredible guy. He was a professor at Harvard, but if you think my Brooklyn accent is heavy, you should have heard his Boston-Irish accent. It was off the wall. And he was the most terrific guy. He kind of served as my dad for part of the time because my dad had passed.   He would round every day, and we'd see all the hem patients. And we had all the AMLs, so I'm talking about, oh, 68 to 70. I never saw a remission. Never.   And they all passed away, but he loved the patient care. And I got interested, and so when I was in Vietnam and when I got out of the Vietnam and was back, I thought, what do I want to do? And I said, I really like that hematology.   DAN: I'll just say that Dr. Moloney was almost exclusively hematology.   HYMAN MUSS: He was almost all exclusive. He used to grow little AML cells in little chambers in mice and treat them with drugs, and so I decided to do hematology. And I came back, and I think in my first weeks there he said, Hy, you're not going to believe this, but you can actually put these people into complete remission and take their leukemic bone marrow and make it look normal. And I'm saying, oh, yeah, right, because I had used all these regimens like VAMP, methotrexate, all the things that never worked.   And we had two new drugs, ara-C and daunomycin. And so I used to go up and treat these patients' IV pushes, ara-C and daunomycin, big doses, and I started seeing remissions. And I said, this is amazing. And then during that year, we had our first child, and I started to run out of money.   DAN: So this is when you're still a resident?   HYMAN MUSS: This is when I'm now a fellow. That year, we were very short of cash. I had a new baby, and I went to Dr. Moloney and talked with him. And he said, I'll try to help you, and he talked with a guy named Dr. Francis Moore, who was chief of surgery, one of the icons of surgery. And Dr. Moore talked with some of his donors in the Brooklyn area, and I became the first Sidney Farber Cancer Research fellow.   I knew nothing about cancer, solid tumors. So as the requirement was, I had to go over to the Jimmy fund, the Sydney Farber Cancer Center and see cancer patients. And all my hardcore hem friends said, oh, you're not going to like it, but it's worth doing for the stipend I got. The first day I was there I knew medical oncology was for me. I loved-- it was open.   We were treating everyone with CAF-- CMFVP, the old regimen, every single cancer. There was so much to be learned. There was so much opportunity for clinical trials. And then in the middle of that year, Tom Frei came, and he was so inspiring. And I knew that I was going to do an onc career.   There were no hem-oncs then. There were hardly any oncology fellowships, so I got to love that. I did two years, not three.   DAN: So let me interrupt you for just a moment just for our speakers-- our listeners. So Tom Frei was one of the three who were the first to put combination therapy together.   HYMAN MUSS: Right.   DAN: Jay Freireich, Jim Holland-- actually, it was Jim Holland's idea frankly. I figured that one out, and Tom Frei. So, again, in terms of pioneers, you were right there with the first pioneer.   HYMAN MUSS: And I did little combinations of things I'm not going to tell you about. They're embarrassing. They didn't work, but I learned so much. And actually, Ezra Greenspan was in that early group in breast cancer treating patients with hormonal agents and chemotherapy. But I learned from them, and I just love the clinical environment.   And those days, there was nothing. I've witnessed other miracles like Larry Einhorn developing platinum and curing testis patients. I'm old enough, every male I saw with testis cancer and mets died. Everyone. Drugs like that were virtually miraculous, and we're doing so many great things today. So I was at a really great crossroads.   DAN: Who else was at your level at the time, especially before Dr. Frei? You must have been pretty much alone.   HYMAN MUSS: There was a fellow named Jacob [INAUDIBLE] you may remember, who was there and was really interested in chemotherapy timed by your biologic clock, and a few other people, people like Craig Henderson and others who came in after. I preceded them, so I was virtually one of the few oncology trainees at that time.   DAN: And who mixed up your chemotherapy?   HYMAN MUSS: I did.   DAN: And who started the IVs?   HYMAN MUSS: I did.   DAN: And who--   HYMAN MUSS: You don't want to know. I was very careful with daunomycin, and so Dr. Moloney had a little office in the Brigham. And it had a little bathroom, and a very popular regimen-- and we had a lot of lymphoma patients-- was COP, cyclophosphamide, vincristine, and prednisone, COP. So I would go into that little bathroom. It's very hard to dissolve this stuff.   I put it all in a little sink. I'd have to tell the patients I'm going to be in here a minute. Don't come in. And I would put it all in syringes. I'd put them in a little chair, like kids sit in in school.   Put your arm on the side. I'd start the IV and give it to them. When I got to the Farber in the second year, now they were training because they had so many kids. They had nurses that could do some of that, but I think I recall giving it there. But in the Brigham, I gave the chemo.   DAN: Did you do any pediatric work with Dr. Nathan?   HYMAN MUSS: I did a few months in peds with Dave Nathan, another amazing, amazing guy, and that's where I met people like Larry boxer.   DAN: Larry was a colleague of mine here at Michigan.   HYMAN MUSS: I know.   DAN: Passed away about two years ago. Just a wonderful guy. He also, by the way, was my attending physician when I was a med student at Indiana on pediatrics--   HYMAN MUSS: Oh my gosh.   DAN: --just by coincidence.   HYMAN MUSS: His wife, Grace, was one of my colleagues.   DAN: Let's move on a little bit. From there, I know you went to Wake Forrest. And I have to say, how does a kid from Brooklyn, who has been at Harvard in the middle of, really, no oncology probably outside of the coast, end up in North Carolina?   HYMAN MUSS: At the Brigham, I knew I wanted to do a career in-- I wanted to try academics, but I didn't want to go in the lab. And I was actually offered a job by Gene Brown Wald and others at that time to work to stay in the Harvard system and do work on methotrexate in the lab. High dose methotrexate was hot then, and I couldn't see myself in a lab. I worked with Frank Bunn, one of the world's great hematologist at the Brigham, who is-- really became a great friend and knew me. And he said, Hy, I know you don't-- laboratory work isn't for you, so he knew someone at Wake Forrest doing work on sickle cell anemia.   They were infusing urea to try to prevent sickling. And he called this fellow, and they said they were looking for oncologists, clinicians. And I went down there and another open place. I met my future boss at that time, a guy named Charlie Spurr, who is also one of the pioneers in oncology. Gave nitrogen mustard after the war.   Just a terrific guy and probably my most-- among my most impressive mentors, and they offered me the job. And I told Loretta about it. I was thinking of Rochester and some other places, but I decided on this job. And one of the reasons was the other places I went it had snowed, and I was delayed and couldn't get out. True story.   You talk about serendipity. And I came out here. There was some azaleas blooming, and I said, I'm going. And it was a difficult adjustment for a kid from Brooklyn to go down here. My mother, who was alive at that time, never heard of North Carolina.   She was one of these women born in a candy store in Greenwich Village over a candy store by a midwife, and she said, they're going to kill you down there. And I said, I think it'll be fine, and Loretta got out of the car when we drove down here and cried. But it turned out that Wake Forrest and my mentorship and ability to work in their cancer center was incredible in my career, so I was able at Wake Forrest to really set up lots of research studies in breast cancer, prostate cancer, brain tumors. It was an open field there. They didn't have, really, many people like me, and it just was absolutely terrific.   DAN: Let me segue that. There's a lot more I want to talk to you about, but I got to know you because of our experience in CLGB and the cooperative groups. And it was clear to me right away you were a major player, but I also-- and you still are as far as I can see at CLGB Alliance. But you're one of the few people I know who then went off and started his own group, the Piedmont Group. What was the background? What made you think you could compete with the big boys, and how did you get those folks to play? And how did you also straddle two different groups at once?   HYMAN MUSS: Well, we had a very-- Dr. Spurr was an amazing man, and he realized that most oncology was going to be practiced in the community. Even at that time when I started my career, I would drive out to these small towns occasionally once a week, once a month, and actually give some of the chemo still or train nurses in practices. There were no medical oncologists around there. I took the second set of boards, so I think I'm talking about 1975 or something.   And so he knew that, and we cultivated some very strong community relationships. And we didn't have CCOPs and NCORP there. Although, Dr. Spurr and his colleagues were instrumental in getting CCOPs and things going in this country, so community people didn't have a lot they could do. It wasn't a formal mechanism. And so we formed a little small group called the Piedmont Oncology Association.   It was kind of fluffy. We didn't have 5,000 bylaws or anything. It was just a conglomerate group, and ironically, I published a New England Journal study out of that group reviewing all the things, and how long to give chemo, things that people like yourself have really expanded on and made much better. But we work with them, and then there was an announcement to form regional cooperative groups from the NCI. And I was involved in CLGB but not heavily at that time.   We didn't have all the traveling and things that we had, and now we've replaced it with Zoom meetings and things. And so I knew a lot of these people. I'd seen a lot of their patients. So we applied, and we got funding for the POA. And we did OK for a few years, and it actually is still in existence as an educational group.   But we couldn't compete with the large cooperative groups. We did well with accrual, but the brainpower to develop and keep up all the diseases-- disease sites were emerging. I was writing prostate cancer stuff. I couldn't keep up with the expertise nor could my colleagues. So it was a good experiment, and a lot of them ended-- my colleagues ended up in CCOP and now NCORP and have made major contributions. And I suspect we got people used to trials and protocols, but it was a short lived experiment.   DAN: Well, short lived but changed practice. And by the way, some of your colleagues still talk about it and what a great experience it was, so you're the-- all right the next thing I want to talk to you about is your real love, which is geriatric oncology. And you got involved in geriatric oncology before the word existed as far as I can see.   Two things, one is you weren't geriatric at the time. Although you are now, as am I. And, two, is-- just talk about the people you got involved. I know Dr. Hazzard had a big influence on you, but also Ludovico Balducci and Harvey Cohen. And tell us about how that all got started.   HYMAN MUSS: Yeah, so when I was in my career at Wake Forrest, Bill Hazzard, who's one of the grand old men of geriatrics, wrote one of the first textbooks, and is still hanging around as professor emeritus, came to all the faculty and said, I'd like you to work with one of our residents in a project related to your specialty and geriatrics. So he came to me specifically and said you would like to do this. He's my chair.   He's got to promote me someday, so I said, oh, of course. So what we did is Dr. Spurr was ahead of his time, and actually, we had codified all people in local protocols, our POA, into a database system with the punch cards from IBM, those little cards. I can remember that great movie about those African-American women where there's one woman who's the only one who knows how to use those cards.   DAN: In NASA, yeah.   HYMAN MUSS: I could go and actually ask our statisticians to run things, so what we did was we compared. We had metastatic breast cancer. We had no upper limits of age on protocols, which was very common then. We were patronizing to older people, and we compared women above 70 with 50 to 70 and less for metastatic breast cancer. And when I looked at the data, I had about 60, 70 patients, and I work with a wonderful woman who's now a medical oncologist named Kathy Christman.   She was the resident, and we put this together in a paper. And we submitted it to JAMA, and I thought, oh, they're going to-- this will be gone. And they accepted it actually without any revision. Then I had to get my friends to read it because if you read the-- if you hear the way I talk and see the way I write, we need a lot of editing here. So in any event, it got there, and I really enjoyed the project.   And I started learning about other people. Then what happens-- and you know this, Dan, your biomarker and all your expertise-- your friends start calling you. Hey, Dan, should we be doing this or that? And so they'd start to call me about older women with breast cancer and say, you think she could tolerate chemo? And so I got more and more interested. And then in the CALGB at that time, there were some other people interested, Peggy Kemeny, et cetera.   DAN: Harvey Cohen, I think.   HYMAN MUSS: Harvey Cohen. And we formed the-- and Rich Schilsky.   DAN: And Stuart Lichtman was also a big player, as I recall.   HYMAN MUSS: Stu Lichtman, yeah. I'm going to mention-- so we thought we'd form something on cancer in the elderly, and Rich Schilsky backed this up. And we made a working group, and one thing led to another. And then we became a committee. We were very successful.   We wrote clinical trial protocols not just in breast cancer. We had terrific people like Stu Lichtman. Harvey and I chaired that committee for 22 years. We didn't even know it was that long, and we saw such evolution in our field. At that time, there was expertise evolving nationally with people like Ludovico Balducci.   And I should add that early in my career at ASCO, BJ Kennedy, who's really considered one of the fathers of oncology, used to get up at meetings and when he heard a presentation and there were no older people, he said, where are all the older people there? And if you know BJ, he was not a man who was afraid to get up and speak his mind. And so he was really-- pushed this too, and Ludovico, and our cooperative group. And we slowly built up a wonderful committee. It really evolved, and then we pulled in people like the late Arti Hurria, one of the world's most incredible people, who really taught us how to get geriatric assessment into clinical trials and do it in the community. And it just evolved, and it's never--   DAN: You just stole my question, which is that you just told us about the first generation, and the second generation has taken this and run with it. This is why you're being interviewed. You were a pioneer. Arti was a settler.   HYMAN MUSS: Oh, yeah.   DAN: In terms off-- and we miss her so much. For our listeners, I think many of you know, she was tragically-- lost her life. She tragically lost her life in a car accident a few years ago, and she was on the board of directors. I remember standing with her during cocktail hour before one of the board of directors meetings, and I said, you know, Arti, you're going to be president of ASCO someday.   And, well-- and she kind of looked at me like, are you kidding? And I said, no, I'm not kidding at all. You're on your way. It's such a tragedy.   Actually, the final thing I want to do is I was going to ask about BJ Kennedy and his role in geriatrics, which you covered, but that allows me to segue into BJ's role in our field becoming a field. And you sort of stepped into his shoes, in my opinion, with the American Board of Internal Medicine, but BJ, I think, was responsible for our becoming a boarded subspecialty. Can you talk more about that?   HYMAN MUSS: Oncology, we were relatively new, and to become an ABIM subspecialty, you have to show a need, that there's a need and enough patients and that you're doing something uniquely different and beneficial. And for a long time, the hematologists were a little-- think what do those oncologists do? They have one drug. They have 5FU.   DAN: 5FU for colon cancer.   HYMAN MUSS: Yeah. And maybe nitrogen mustard or something. But so they felt there's certainly a need. There's no question cancer was a need, but they really can't do much for their patients. And it was people like BJ, Jim Holland, and other visionary guys that really worked with ABIM and pushed to make it a specialty.   And I think we began in 1973. I think hematology was 30, 50 years before because there was so much more knowledge in that field. And so it took people like BJ and Jim Holland, strong, outspoken people, to convince the board and not back off. Well, come back when you guys really have something to do for patients. No, we're doing things for patients now.   This was well before pall care and all the other things we do non-treatment related that are so wonderful for patients. And they pushed it, so this was crucial in BJ building this, and being on the front line, and doing this, and building the whole field. And then what can I say? I think we're all in the greatest field in medicine, most exciting, best biology, can do tremendous things for many sick patients. But they were the people that really got us going or it would have taken 10, 20 years more.   DAN: Yeah, it's a remarkable story. And actually to cap it off, I think you probably saw two days ago, the ACS, Siegel et al, put out their annual cancer statistics. And the last year, which was to 2018 to '19, was the greatest reduction in age specific mortality in the history of the statistical thing. And overall, since the '80s, there's been about a one third reduction in the odds of dying of cancer in this country. And it all started back with you and the generation ahead of you. I mean, there are very few specialties that can look at that kind of success, and look backwards, and talk to the people who were there. The cardiologists can't talk to Harvey and--   HYMAN MUSS: Yeah, I owe so much to my friends supporting us through the years, like you, like Larry Norton, one of my also great mentors and friends, Rick Schilsky, for just supporting the field, and the studies, and things or it never would have happened as well, and so many wonderful people involved. And so many nice things that ASCO has done, like education, and developing YIAs, and things. As you say, it's got to be the new generation. It's going to be the [INAUDIBLE], and William Dales, and all these absolutely terrific people that are going to have to push this field, Heidi Klepin. And I just was in the right place at the right time in all of this and had tremendous friendships and mentoring.   DAN: Well, and I can't remember who said it, but those who don't remember history are destined to make the mistakes of others. So one reason I'm doing this is so all those people know what it took to get us there and the history behind it. So I want to finish this by thanking you for all you've done for me as a mentor, and all you've done for our field in terms of pioneering geriatrics, and the Board of Internal Medicine, which you've been on now for, what, 15 years I think.   HYMAN MUSS: Yeah. Well, I'm off now, but I--   DAN: Oh, you're off now. OK. And mostly for our patients. So many of our patients are alive and doing well because of what you've done, so thank you very much. Appreciate your time today, and looking forward to being on the river with you someday soon.   HYMAN MUSS: Oh, yeah.   DAN: For our listeners, we both like to fly fish, so--   HYMAN MUSS: Thank you so much, Dan. I appreciate you allowing me to do this. I'm very grateful to ASCO. Thank you.   DAN: Until next time, thank you for listening to this JCO's Cancer Story, The Art of Oncology podcast. If you enjoyed what you heard today, don't forget to give us a rating or review on Apple podcasts or wherever you listen. While you're there, be sure to subscribe so you never miss an episode. JCO's Cancer Stories, The Art of Oncology podcast is just one of ASCO's many podcasts. You can find all the shows at podcast.asco.org.

An interview with Dr. Jun Ma from Sun Yat-sen University Cancer Center in Guangzhou and the Chinese Society of Clinical Oncology on “Chemotherapy in Combination with Radiotherapy for Definitive-intent Treatment of Stage II to IVA Nasopharyngeal Carcinoma: Chinese Society of Clinical Oncology and American Society of Clinical Oncology Guideline.” Read the full guideline at www.asco.org/head-neck-cancer-guidelines. Transcript ASCO: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Hello, and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org. My name is Brittany Harvey, and today I'm interviewing Dr. Jun Ma from Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy in Guangzhou, and the Chinese Society of Clinical Oncology, author on Chemotherapy in Combination with Radiotherapy for Definitive-intent Treatment of Stage II to IVA Nasopharyngeal Carcinoma, Chinese Society of Clinical Oncology and American Society of Clinical Oncology Guideline. Thank you for being here today, Dr. Ma. JUN MA: Yes. BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines in ensuring that the ASCO conflict-of-interest policy is followed for each guideline. The full conflict-of-interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Ma, do you have any relevant disclosures that are directly related to this guideline topic? JUN MA: Thank you, Brittany. Hi, everyone. I'm Dr. Jun Ma from the Sun Yat-sen University Cancer Center in China. And I don't have any potential conflicts of interest related to this guideline topic. BRITTANY HARVEY: Great. Thank you. Then can you give us a general overview of what this guideline covers? JUN MA: Yes. This guideline aims to highlight significant clinical questions about the chemotherapy in combination with the radiotherapy for the definitive treatment of stage II to stage IVA NPC, nasopharyngeal carcinoma, It will clarify the fundamental principles of the radiotherapy planning and how to combine chemo with radiotherapy for a patient's success. BRITTANY HARVEY: Great. Then this guideline covers five clinical questions. I'd like to review those key recommendations for our listeners. First, what does the guideline state regarding radiotherapy for patients with stage II to IVA nasopharyngeal carcinoma? JUN MA: Yes. For all nasopharyngeal carcinoma patients, we support the use of IMRT summarized in the current evidence. We don't recommend the use of other techniques, such as 2D or even 3D radiotherapy. If IMRT is not available at that spot, patients should be transferred to the institution that could that could implement IMRT whenever possible. For all NPC patients, a prescribed dose of 70 Gy in 33 or 35 fractions delivered over seven weeks should be offered. It should be noted that the radiation dose may be adjusted according to the tumor volume and its response to the chemoradiotherapy. In terms of the target delineation, we recommend you to follow several existing consensus guidelines. Thank you. BRITTANY HARVEY: OK. Then what is recommended regarding chemotherapy sequence in addition to radiotherapy? JUN MA: OK, generally speaking, patients with low disease burden, such as the lower end category of clinical stage, could receive lower intensity of chemotherapy. For T2, and if not negative of patients, chemotherapy is not routinely recommended, while for T1 or 2, N1 patients concurrent chemotherapy may be offered, particularly for T2 N1 patients. For locoregional advanced disease, except the T3 lymph node negative patients, we recommend the use after concurrent chemotherapy with induction or adjuvant chemotherapy. It should be noted that there is a lack of head-to-head trials comparing induction chemo plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy plus adjuvant chemo. Thus, which sequence performs better in the contemporary era remains uncertain. Finally, for T3 lymph node-negative patients, concurrent chemoradiotherapy should be offered. Adjuvant or induction chemotherapy may also be offered if there are adverse features, such as the bulky tumor volumes or high EBV DNA copy numbers. BRITTANY HARVEY: Great. Then you just mentioned some chemoradiotherapy regimens. So for patients with nasopharyngeal carcinoma receiving concurrent chemoradiotherapy, what are the recommended chemotherapy options? JUN MA: OK, for all NPC patient without contraindications, concurrent cisplatin should be offered along with radiotherapy. Weekly use after suspending with 48 milligrams per square meter or three weekly with eight or 200 milligram per square meter is acceptable. We recommended the cisplatin dose should be attempted to achieve a cumulative dose of at least 200 milligrams per square meter. For patients with contraindications to cisplatin, nedaplatin, carboplatin, or oxaliplatin may be alternative choice. For patients with contraindications to cisplatin-based chemotherapy, Fluoropyrimidines such as 5FU with concurrent chemotherapy also may be offered. Thank you. BRITTANY HARVEY: Great. And then for patients with nasopharyngeal carcinoma receiving induction chemotherapy, what are those recommended options? JUN MA: Yes. For all patients receiving induction or adjuvant chemotherapy, platinum-based induction regimens should be offered in terms of induction chemo, such as GP, TPF, TP, PF, and the PX regimens are recommended. So induction regimens should be administered every three weeks for a total of three cycles, or at least the minimum two cycles. If the patients receive induction chemotherapy, chemoradiotherapy should be commenced within 21 to 28 days from the first day of the last cycle of induction chemotherapy. BRITTANY HARVEY: Great. And then for the final set of recommendations for patients with nasopharyngeal carcinoma receiving adjuvant chemotherapy, what are those recommended chemotherapy options? JUN MA: Considering that adjuvant chemotherapy is a choice of adjuvant regimens were much fewer than those of induction chemotherapy, according to current evidence. PF regimen administered every four weeks for a total of three cycles is recommended. If with contraindication to cisplatin, carboplatin may be combined with 5-FU. It should be noted that for all patients receiving adjuvant chemotherapy and with contraindications to platinum-containing chemotherapy, the use of non-platinum based regimens remain experimental at this time and should not be offered routinely outside of the context of a clinical trial. The main difference between the recommendation for the induction and adjuvant chemotherapy are primarily due to the number of the randomized trials in which there are few studies regarding the adjuvant chemotherapy in nasopharyngeal carcinoma. Thank you. BRITTANY HARVEY: Thank you for reviewing each of those recommendations. So then, what is the importance of this guideline? And how will it impact clinical practice in patients with nasopharyngeal carcinoma? JUN MA: For nasopharyngeal carcinoma, it has extremely uneven geographically global distribution. More than 70 percent of this new diagnosis worldwide in the 2018 year, occurred in the East and Southeast Asia. Therefore, nasopharyngeal carcinoma remains a significant public health problem in these regions, which emphasize the significance of this guideline for providers and patients from the endemic area. From my point of view, one of the novel features of this joint deadline is that it was developed through the international collaboration with the regional groups. Experts from the CSCO and ASCO shared interpretation of the evidence while accounting for the organizing national or cultural diversity of different regions. In brief, the guideline provides the guidelines on how to plan radiotherapy and when and how to add chemotherapy. Through the interpretation protecting the guideline, care providers can avoid over or under-treatment. And providing the most suitable chemoradiotherapy for NPC patients. Besides, for the patients, they could receive the most suitable treatment, which is the balance of the efficiency as a quantity of the life. Thank you. BRITTANY HARVEY: Great. Definitely, we appreciate the collaboration between the American Society of Clinical Oncology and the Chinese Society of Clinical Oncology. So thank you so much for your work on these guidelines. And thank you for your time today, Dr. Ma. JUN MA: Thank you. BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/head-neck-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

Dr. Hayes interviews Dr. Lawrence Baker on his early involvement with SWOG ANNOUNCER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. DANIEL HAYES: Welcome to JCO's Cancer Stories-- The Art of Oncology, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all of the shows, including this one, at podcast.asco.org. Today, my guest on the podcast is Dr. Laurence H. "Barry" Baker. Dr. Baker has a long and distinguished career in oncology. It dates back to the early 1970s, when he was intimately involved in new drug development, including doxirubicin or adriamycin, as we know it. He's also led early studies in preoperative chemotherapy in anal cancers. He was instrumental in advances in sarcoma research, and he led the Southwest Oncology Group-- now designated SWOG-- for eight years in the last decade. Dr. Baker was raised in Brooklyn, and since this interview is taking place just a week after the sad loss of Supreme Court Justice Ruth Bader Ginsburg, Dr. Baker informed me that he and his wife Maxine were married in 1964 in the Midwood Jewish Center, Justice Ginsburg's home synagogue. He received his undergraduate degree from the Brooklyn College at the University of New York, and then he graduated from Des Moines University of Osteopathic Medicine in Iowa. He completed a residency in internal medicine at Flint Osteopathic Hospital in Flint, Michigan, and then he has a curious two-year break in his curriculum vitae during which he was on active duty in Vietnam. Upon discharge from the Army, he returned to Michigan, and he served a three year fellowship at Wayne State University, where he stayed on faculty from 1972 to 1994, serving at various times as the chief of the Division of Hematology and Oncology, the chair of the Department of Medicine, and director of the Cancer Center. In 1994, he moved west about 30 miles to Ann Arbor, where he served as the director for the Clinical Research and Translational and Clinical Research Program for the UM Comprehensive Cancer Center, now called the Rogel Cancer Center. And he was also the associate chief of the Division of Hematology and Oncology and currently is the Laurence H. Baker Collegiate Professor in developmental therapeutics. Dr. Baker has authored hundreds of peer-reviewed papers, and like so many of our guests on this program, he has a list of honors that are just, frankly, too long to recite, except two that I want to highlight. He received the ASCO Distinguished Service Award for Scientific Leadership in 2007, and he was named an ASCO Statesman, now designated as a fellow of ASCO in 2010, for his many services to our society. Dr. Baker, welcome to our program. LAURENCE H. BAKER: Thank you. Nice to be here. DANIEL HAYES: Well, it's really great to have you. A lot of questions, but I want to start out, I just can't help but ask you, to be trite, how does a nice boy from Brooklyn end up in the Midwest for the rest of his life? Can you give us some stories about how you got there? LAURENCE H. BAKER: I graduated high school at 15 and went into what some know-- but not everyone knows-- was a very competitive college. Brooklyn College accepted-- was a free school. The grades used in the New York City school system were numerical. They weren't letters. And you had to have a 90 average on high school and certain scores on the state, New York State examinations to get in. And that was it. It didn't matter where your parents went to school. It didn't matter if you had money. And so it was a school largely of relatively low-income families. But that's the one who took me, and I guess they accepted me at 15. To not make this into a long story, but to drag it out a little bit, I was fascinated that I was 15 and I could date 18-year-old girls, and they didn't know it. So that's how I spent the first two years of college. And my grades showed that that was my focus of attention. I did pretty well on the MCAT examination. I would not have gotten into a medical school in this country, and I didn't speak a language that would be sufficient for me to go to Europe, for example, to school. So osteopathy he was where I went. I went to Iowa, but their admitting question to me is, do you have $2,000 a year tuition? To which, of course, I lied. And that's how I ended up being a DO, and that's how I came to the Midwest. And I actually got to like the-- I didn't know anybody from Iowa, as you make reference to my Brooklyn background, but I actually came to really appreciate the Iowa people, and particularly the community people that I came to know. At the time there were-- the really good programs in residency in medicine were in Michigan. That's the direct answer to your question. That's how I came to Michigan. Just about then, just about could have gone to California and gotten an M.D. degree just by taking the licensure examination. And then, that closed. That opportunity closed. So a long story to your question. So I came to Detroit, into Flint, and then returned back to Detroit, and I've been in Michigan ever since. DANIEL HAYES: Now, that raises the second issue I talked about a minute ago. And that is, many of our guests were so-called Yellow Berets at the NIH in the late 1960s and really changed our practice. But you actually ended up in the Evacuation Hospital at Cu Chi in Vietnam. And I've heard horror stories about this. How did that happen? What did you do there? Enlighten me. LAURENCE H. BAKER: Well, there were good and bad things about being an osteopath. The American Osteopathic Association was always in conflict, was always trying to defend itself. And at the time that the Vietnam War was going on, the DOs were not eligible for military service as an officer. You could go in as an enlisted man, but not as an officer. But there was a great need for primary care physicians in Vietnam, and the understanding of the military physicians was that all DOs were primary care physicians. So a deal was struck between the AMA and the Department of Defense that led to the drafting of everyone in my medical school class. Every one of the men-- not women. Every one of the men was drafted. There was a universal draft. I then-- I was given a choice. I could volunteer for the Army or go to jail. Those were the choices. And I had, at the time, two little children with Maxine, and I was not-- you might guess-- not a big fan of the Vietnam War. The alternative was to go to Canada, and I wasn't secure enough to consider that I could actually practice medicine. It was uncertain. So I went in. When I got there, they asked me, did I have any interest in anesthesiology or radiology, because they were really short of those two. And of course, being who I am, I said, if you need a radiologist or an anesthesiologist, why don't you go draft one and let me go home? That didn't work, and so I became-- I was assigned to radiology. DANIEL HAYES: [LAUGHS] LAURENCE H. BAKER: They sent me to Fort Jackson, where-- no, that was actually a good experience then, because I learned a lot about imaging, and I still have interest in imaging, but I don't qualify anymore. This is before CAT scans and MRIs. This is IDPs and upper GIs, right? So anyhow, barium lower bowel examinations. So I was trained for six months, and I stayed on for another few months on staff there and then, lo and behold, was sent to Vietnam. I was sent for a year, but I volunteered to stay an extra month so that I could return without any further obligation to the military and begin my fellowship on July 1, which I had actually secured before I went to Vietnam. So that's the gory details of that. I was elevated to Major about, oh, a few months before I was discharged. And then, because they weren't nasty enough to me when I got home, into my fellowship, I then got a letter congratulating me on being in the active reserve. So I had to go two weeks every summer. That was my summer vacation during fellowship and beginning of faculty. And I had to go once a month for a weekend to play soldier with a bunch of guys who were lucky enough that they didn't have to go to Vietnam. And now we're even, I think. So it was an interesting experience, as I've shared some of it with you. It still is a painful experience in some ways. I was out the busy [INAUDIBLE]. DANIEL HAYES: If you don't mind, a quick story you've told me before about the child with leukemia. LAURENCE H. BAKER: Yes. So they made me a radiologist. I'm not a great-- it doesn't matter where you call me. I am who I am, and I'm really interested in patient care. And there were already five internists, and there was only so much gonorrhea that the troops could acquire. So I volunteered to open a pediatric clinic. And the Army thought that was a good thing for publicity. They did stories about it. Anyway, I opened the clinic for pediatrics. I knew nothing about pediatrics. I mean, the truth is, I had a month of rotation. My wife sent me my textbook. It was Nelson's Textbook of Pediatrics. Nothing I ever saw in Vietnam was ever in Nelson's Textbook. But I did what I could of trying to treat the children as best I could. And along came a young girl, eight years old, who had acute lymphacytic leukemia. I had a wonderful pathologist who was my hoochmate. "Hooch" is translated, there were eight guys who lived in a place. That was called a hooch. And he was a pathologist, and he made the diagnosis of ALL. I had my books from my mentor teaching me about chemotherapy. So even though I hadn't started the fellowship, I had some resources about chemotherapy. And now I had to find chemotherapy. Treated her with-- I started with steroids and penicillin, and then I went to find drugs. I was able to-- I won't tell all the details, but I was able to get drugs at an old French hospital in Saigon. And so I would visit that hospital pretending great interest in the pharmacy, but of course, I stole whatever drug I could steal when the pharmacy wasn't looking. And that included some alkylating agents, methotrexate, 6MP. And so I tell Jay [INAUDIBLE]-- to get to where you want to be, perhaps-- that I invented the bicycle therapy, which was every month, you changed the drug to try to avoid resistance. So that's what I did by necessity. [LAUGHS] And I actually-- there was a second child that I also treated. When I left, they were both in complete remission. And I think that that's what you're asking me. I was lucky that I didn't get shot or thrown in jail for many of these escapades. But I look back and think that at least I did somebody some good. So-- DANIEL HAYES: Kind of makes the current generation who complains about work hours look in a different light, I think. LAURENCE H. BAKER: Yeah, we worked every day. We worked seven days a week with-- there was no such thing as time off. This was the busiest American hospital, certainly in Vietnam, and some think the busiest hospital since the Atlanta train station in the Civil War. It was in Cu Chi, which was on the way to Cambodia, which is, of course, where the North Vietnamese troops would enter into South Vietnam. So it was a major, major place. It was about an hour, an hour and a half west of Saigon. DANIEL HAYES: Let's move on to the rest of your career. You come back, then, and trained at Wayne State, and at the time, [INAUDIBLE]-- and I can never pronounce his name. I'll have you do it. Dr. Venutius Vicevicius-- I always heard him Dr. V.-- who was, I think, a real character and really was one of the first chemotherapy pioneers. Can you tell us more about him? Because we've heard a lot about the folks on the East Coast and the folks in Texas, but not so much what was going on in the middle of the country at the time. LAURENCE H. BAKER: Yeah, Dr. V, or Dr. Vicevicius, who was Lithuanian, he has a story of his life that certainly makes me look like a slump. He was a guest of the Nazis, and then he was a guest of the Russians when Auschwitz was freed. So this was as a child. He grew up in a very educated and somewhat affluent family in Vilnius. And when he got out of these camps, he actually got to medical school in Frankfurt, Goethe Medical School in Frankfurt. He had major interest in biochemistry and, without speaking more than three words of English, chose to come to the United States. And he landed-- I don't really know why; I've heard so many different versions-- but he landed in Detroit and showed up at the Detroit Receiving Hospital-- this would be like LA County or Bellevue in New York, that sort of thing, knife and gun club-- not speaking any English but wanting to do training. And somebody was smart enough to accept him. And so he did his training. He also trained-- after medicine, he trained with Mike Brennan-- that's another name from the past who is a past president of ASCO, by the way, the second or third person, perhaps. Mike was present of the Michigan Cancer Foundation and was the card-carrying medical oncologist in the Detroit area. He trained Dr. V., and he trained another man named Bob Tally, who had a great deal of history to contribute to oncology. And then, V was recruited by Wayne to come there and started a program. He was an extraordinary person. English was the eighth language he learned, and he actually taught me how to write. I flunked college English. I had to take it twice. But he taught me how to write and, I think, made me a better writer. He certainly was an inspiration. His devotion to patients was extraordinary. His knowledge was extraordinary. And so he was a great, great teacher. And one of his major early contributions was the recognition that you could make the drug float-- they had four drugs or five drugs at this time-- but one of them was 5-fluorouracil, that was developed by Fred Ansfield in Minnesota. The drug was given for five days and then every other day until their mouth fell out or their white count got to zero. And maybe that's a little of an exaggeration, but not much. At any rate, he figured out if you gave the drug by continuous infusion-- because it had a rather short half-life-- you could avoid a great deal of the toxicity. And that's how infusion of fluorouracil got its start. He then went on to combine it with other drugs and with radiation, and that was the backbone of this anal canal achievement that you mentioned in the introduction. I had very little to do with it, but I was a cheerleader. It was a rectal surgeon who came to us at the time, and those familiar with that disease-- which we now know is a virus disease that could be prevented, but at that time, nobody had any of that-- the treatment was abdominal perineal resection, and it had to be among the most horrible things we did to people. And the surgeon came to us and said, listen, you guys always squirt those drugs in after they relapse, and I'm really tired of this. Maybe you could give those drugs first, OK? And that's how neoadjuvant chemotherapy got started. It wasn't our idea. It was a surgeon's idea. That story gets repeated again in orthopedics, but that's how it began in anal canal tumors. And so we gave 5FU infusion, and mitomycin, and radiation preoperatively. That almost always shrunk the tumor, by the way-- almost always significantly shrunk the tumor. The patient then once they went through that operation but was cured. And so you took a horrible disease and changed its natural history with that development. If it works once, you know, in oncology, then you try it a second and third time. And I had very shortly thereafter the opportunity to work with a wonderful Japanese pediatric oncologist in Houston, Watsu Tao. He was looking for a partner because he was tired of seeing osteosarcoma patients die. Cure rate at the time was around 20%, 30%, and the surgery that was done for osteosarcoma was amputation, usually of the lower extremities. So 2/3 of osteosarcomas occur around the knee, and the orthopedics really dislike the idea of taking a child's leg off. Every teenager and child wants to be exactly like every other teenager and child, so you can imagine how disruptive it is to have a high amputation of your leg. It took about three months to make a prosthesis, and everyone knew that you didn't really have to do an amputation. You could just cut out the bad bone and replace it with a prosthetic device. But it took three months to make it, because they were handmade at the time. And so the idea came to several people-- Jim Holland was involved in this; Tom Frei was involved in this as well. Different cities were approaching it in this way. And we all ended up giving chemotherapy to these young people-- children, teenagers-- and then having the operation. And osteosarcoma went a cure rate of 20% to 30% to 70% or 80%. And they didn't lose their legs. DANIEL HAYES: I have two personal comments on this. One is you mentioned Dr. Brennan and the Michigan Cancer Foundation. Just for our listeners, Michigan Cancer Foundation is MCF. And if you've done any breast cancer work at all, you've worked with MCF-7 cells or MCF-10 cells [INAUDIBLE], which came from that organization. I think people have forgotten what MCF stands for, except for you and me. LAURENCE H. BAKER: That cell line that you talked about, MCF-7, that was developed by a man with, I think, a high school degree who just had a green thumb at that growing cells-- a wonderful man. And that came from a patient of ours. When I say "ours," I mean Dr. V. I was just the flunky, but it was his patient. And she had ascites from breast cancer. And we would tap ascites, in those days, with some frequency. And the cells for MCF-7 came out of that patient. That's its actual origins, and more papers have been written about MCF-7 than even you and I could count. DANIEL HAYES: Including by me. LAURENCE H. BAKER: I understand. No, it was incredibly useful. I mean, we learned about hormone receptors from this [INAUDIBLE]. DANIEL HAYES: Yep, that's [INAUDIBLE]. LAURENCE H. BAKER: It's was incredible. DANIEL HAYES: My other personal story related to your stories is, as a fellow at the then Sidney Farber Cancer Institute, Dr. Frei was my boss. And he, as you mentioned, was starting to work with Holland and others that had already worked with neoadjuvants. And he would cite your data all the time. Now, I didn't know Larry Baker for us from all the tea in China, but we heard a lot about the Wayne State experience when we were fellows. I don't know if that would have [INAUDIBLE] or not, but people definitely-- LAURENCE H. BAKER: No, I came to SWOG-- which is really why you wanted, I think, to talk to me-- in '70 or '71, I can't remember exactly. And Dr. V, it was an incredible experience. He took me with him. You ran into Tom Frei. They knew each other. And he said, Tom, I want you to meet my colleague, Larry Baker. I just had never been introduced like that. DANIEL HAYES: [LAUGHS] LAURENCE H. BAKER: And Tom was the friendliest person I think I've ever met in oncology. He had a wonderful smile. He clearly-- I was always paranoid that I'm a osteopath. Maybe I went on too long about that story. But when they tell you in school you're just as good as the MDs, you can quickly figure out if you were just as good, they wouldn't keep saying it, right? So that's socially accepted paranoia, and that's how I was brought up. So here is the wonderful, famous Tom Frei being nice to me! I was just amazed. DANIEL HAYES: He used to come to the lunch room in the Dana Farber two or three times a week and would just sit with us, and was constantly thinking of new stuff. This is not an interview with me, but someday, I'd like to tell the stories he told us. He was really just a fabulous man. I want to segway into your work with adriamycin, which is now, of course, also one of the workhorses of oncology. We've all used it. And I believe you were an author on either the first or one of the first phase II trials of adriamycin in Cancer in 1973. Is that an outgrowth of that introduction you just told us? LAURENCE H. BAKER: Yes. That study-- it's in Cancer, I think, not-- I don't think JCO existed. But that study didn't distinguish what the primary was. So it was a phase II study of cancer. And so there was, I don't know, 800 patients. I worked with Bob or Brian on that study. Bob was at Henry Ford, and there was a student of Bob Tally that I had mentioned, and I was the student of V. And the two of us were basically the schleppers for them. And so it had hundreds of patients in it. And in that study, we recognized that it worked in breast cancer, that it worked in lymphoma, and it worked in sarcoma-- and nothing worked in sarcoma. So that was the study. It's often quoted by Jim Dorshow because he said, we do everything that's disease-specific, but look what came out of one study that, by the way, accrued, as I say, 600 or 700 patients in 18 months. And this is before computers, so you can imagine how much work was done to evaluate the flow sheets. It was an incredible opportunity here to work. But it was an amazing paper, and it changed my life, of course. That's how [INAUDIBLE] and other things. DANIEL HAYES: So at the time, you recognized that this was not just another drug off the shelf, that it really was going to be a game-changer? LAURENCE H. BAKER: Absolutely, absolutely. You saw people getting better. And my experiences were mostly in breast cancer patients getting better, and some lymphoma patients that were refractory. First time I saw solid tumor patients dramatically improve. DANIEL HAYES: So I saw that your name is before another giant in the field who was a young Italian investigator who spent time in the United States named Johnny [INAUDIBLE]. LAURENCE H. BAKER: Yeah, that's how I first met him. I don't know that this story's been told. We were trying to make some level of peace with the Russians, and the Russians, of course, claimed that they discovered adriamycin. I don't know, but if you don't know this, I'll continue. DANIEL HAYES: Please go. LAURENCE H. BAKER: OK, but we all-- everyone knew, and certainly [INAUDIBLE] knew, this was an Italian drug, OK? "Adriamycin" is for the Adriatic Sea. As far as I know, you can't see the Adriatic Sea from Russia. But this was a time when our government wanted to be nice. They cared more about building a relationship with the Soviet Union than they did continuing a friendship with the Italians. Jim Holland was then sent to Moscow to negotiate this. That's where the name doxirubicin came from. In other words, we didn't know generic names, trade names. This didn't exist in the early '70s. So we called it adriamycin, which was not only the generic name, it was the trade name, right? Made by adria-- I think far Pharmitalia is the name of the company, right? And as a result of Jim Holland's diplomacy, it became doxirubicin as the generic name. It's a true story. DANIEL HAYES: Yeah. I know that "adria--" came from the Adriatic Sea, but I've not heard that's where "doxi-" came from. That's a good story. That segways into the next segment of your life that fascinates me, and this is your work in SWOG. When I moved here to the University of Michigan, you were on your way to becoming the chair of SWOG, which you did. And it occurred to me that University of Michigan wasn't even in Southwest Michigan, let alone the Southwest of the United States. Just reminisce a little bit about Dr. Coltman, who ran SWOG, the beginnings of SWOG, even before that, and where you see the [INAUDIBLE] groups now. LAURENCE H. BAKER: So Dr. V brought me to a SWOG meeting in San Antonio, Texas, as you said, in 1970 or '71. At the time, Tom Frei was running the group. J. Freireich was chairman of the Leukemia Committee. Chuck Coltman was chairman of the Lymphoma Committee. V specifically chose to work with this group because of those people. You're right, Michigan is not in the Southwest, obviously, and, there were other groups that wanted-- we had a large population of patients we treated, so there was actually some competition, if you will, for us to join other groups. V was adamant that we would be SWOG and that was it, for reasons that I told you. Tom Frei then was invited to go back to Boston. That's how you came to know him. And there was an election for a replacement. And J. Freireich was somebody that we clearly supported. There was no doubt that J. an absolutely brilliant man-- he still is-- and taught a lot of people, trained a lot of people, and taught us a great deal. But he had one flaw. He could not control his ability to saw inappropriate things. If you knew him, you loved him. If you didn't know him, you were like your reaction to the debate, OK? That's how he ground on people. I grew up with the respect for J., as I told you, as I was introduced to him, and he was always incredibly kind to me. Anyway, so we were actively supporting J. To be the replacement. There were some other people that did not want Freireich. So you had some people who didn't have the same feeling. And that's how Boris Hoogstraten became chairman. Boris Hoogstraten was a hematologist from the University of Kansas. And I remember-- and you'll be very proud of me, Dan-- one of my colleagues from Wayne wanted to do a study of this new drug called tamoxifen-- DANIEL HAYES: [LAUGHS] LAURENCE H. BAKER: --for breast cancer, OK? [LAUGHS] And Hoogstraten said, don't you get it, Baker? We're a chemotherapy group. What's with this hormone stuff? I don't have to tell another story, but that one is true. So SWOG didn't study tamoxifen for a long time. Any rate, Boris was an interesting man. I don't want to cut him short. But there came a time when it was clear that SWOG needed to go in a different direction. And we all thought that the right person for that was Chuck Colton. At the time, I have to tell you, there was two things relevant to this. There were lots of regional cooperative groups that don't exist anymore. I led a revolt-- that's what Colton said-- that included the University of Indiana-- Larry Einhorn was in Detroit plotting against Hoogstraten-- along with the University of Michigan. Al Labulio was in Detroit doing that. So you got the idea. So it was a group of institutions, if you want, that were geographically somehow related to the Great Lakes in some way. There were seven or eight of us. And we represented probably 40% of the [INAUDIBLE] of SWOG. And Coltman came to me and said, listen, stay with the group. Don't do this. Stay with the group. And I said, I can't stand this nonsense. I mean, we're not working anymore. We're just-- Anyway, he said, please stay. And he ended up becoming the chairman. And then he turned to me and he said, listen, Larry, I want you to be the deputy. I don't need a title. I don't want a title. He said, no, no, no, I don't care what you need or what you want. I need you right next to me, because if you led a revolt once, I don't want to see it happen again. DANIEL HAYES: [LAUGHS] LAURENCE H. BAKER: Absolutely true story. And so we abandoned the idea of a regional group. I still think that may have been a dynamite group, by the way. But we all stayed-- Indiana was not [INAUDIBLE] SWOG, so let me be clear. That was ECOG, I think. I think that's right. Anyway, so that's how I came to know Chuck, and I was his deputy for 25 years. I had the best job as deputy, because I had nothing to do. He just wanted me sitting there, and that's what we wanted. Then there was some push from the NCI that maybe to 25 years of being chair is a long time, and maybe there's a reason to move on. From that team the suggestion from Bob Livingston and John Crowley, that I was the natural person to do that. I really didn't want it, to be honest. I still maintain that. But there was a good deal of pressure exerted, both from within the group and from the NCI, for me to do that. So I became the chairman, I think, for a couple of terms. I made some changes in the group. I think as groups go on, institutions either get better or they get worse. I think that's true. And we made a number of different ways of appointing disease chairs and things like that, that the group did get better and started on a better path. But I really didn't want to continue it, and there was a time when I was not only running SWOG, but I was also running this sarcoma group called SARC. And it became overwhelming to me. I was working literally 80 hours a week there. So I gave up SARC first. That really-- University of Michigan was thrilled that I did that-- and stayed with SWOG another year or two. But I knew that I wasn't going to stay at that. And so after two terms, I thought I would set the precedent that, maybe, group chairs should have two terms and move on. Witshoski had two two terms. [LAUGHS] But anyway, being serious, I really think there should be a limited amount of time. There's so many talented people in our field that it's silly to think that one person has to stay in these jobs. And so that's-- I think I answered your question. I'm not sure my [INAUDIBLE]. DANIEL HAYES: I have to tell just a brief-- Nobel laureate Bruce Beutler was my intern when I was a resident at UT-Southwestern. After he won the prize, he came up here as a visiting professor, and we went to dinner. And I said, Bruce, I kind of lost track. I know you did an internship with us, but I never heard if you finished your clinical training. And he said, no, I went-- I loved the lab and went back into it. I never did go back and finish my training [INAUDIBLE]. And then he looked at me and said, but I think I worked down all right, don't you? LAURENCE H. BAKER: [LAUGHS] DANIEL HAYES: And in a similar manner, I would say, for all your humility that you've laid out, I think it worked out all right. SWOG is a powerhouse and has changed practice in so many ways. And part of that, a lot of that, was your doing. So we've actually run out of time. I had hoped, actually, to-- you've done too much in your lifetime, Larry. I was hoping to get into the sarcoma work, but we've run out of time. I think everybody who's listening to this who knows about the work you've done in sarcoma-- and lord knows there's plenty of work to do in sarcoma, so-- LAURENCE H. BAKER: Can I give you just one more anecdote, and you can cut it, and I'll try to be very [INAUDIBLE]? DANIEL HAYES: No, no. Please do, please do. LAURENCE H. BAKER: Remember I told you I became chair of the Sarcoma Committee of SWOG? The man I replaced was a man named Jeff Gottlieb. Jeff was a pediatric oncologist-- little did people know-- who was a student of J and Tom at the NCI. Jeff died in his mid-30s of cancer, by the way, but he was the most brilliant medical oncologist I ever met. He was the originator of combination chemotherapy that became popular in breast cancer, and he was involved in sarcomas in combinations as well. I was handpicked by Jeff to be his replacement, which was probably the nicest thing that ever happened to me. And during that period when Jeff died, I went to Houston to his funeral. And I can give you one-sentence description of J. Freireich going to speak at Jeff's funeral. He stood up, and he said, Jeff-- and he broke down and cried for minutes. And that was his talk. When anyone says something to me critical of J. Freireich, I remember that love he showed to his colleague. So that's worth [INAUDIBLE]. DANIEL HAYES: No, that's-- LAURENCE H. BAKER: Not many people were at that funeral. DANIEL HAYES: --very touching. He also gave Dr. Frei's eulogy in Boston, and he got through it, but just barely. It was very similar. These are the kinds of stories I'm hoping to capture in this series. Larry, I'd really like to thank you for taking time to be on. I'd also like to thank you for all you've done for the field, for me personally, frankly, with my time here in Michigan the last 20 years, and most importantly, for our patients who have benefited from all your contributions, your training of-- we could go on about all the people you've trained. So anyway, thanks a lot. We appreciate it. LAURENCE H. BAKER: Thank you. DANIEL HAYES: And have a nice day. LAURENCE H. BAKER: Thank you very much. I appreciate your kind words. DANIEL HAYES: Until next time, thank you for listening to this JCO's Cancer Stories-- The Art of Oncology podcast. If you enjoyed what you heard today, don't forget to give us a rating or review on Apple Podcasts, or wherever you listen. While you're there, be sure to subscribe so you never miss an episode. JCO's Cancer Stories-- The Art of Oncology podcast is just one ASCO's many podcasts. You can find all the shows at podcast.asco.org

Dr. S. Lindsay Davis, medical oncologist and assistant professor at the University of Colorado Cancer Center, highlights key abstracts on GI cancers that were featured at the #ASCO20 Virtual Scientific Program.   Transcript ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carol, a reporter for the ASCO Daily News. I'm delighted to welcome Dr. Lindsay Davis to the podcast today. She's a medical oncologist and assistant professor at the University of Colorado Cancer Center, where her clinical focus is gastrointestinal tract cancers.   She joins me today to discuss key abstracts in the GI field that were featured at the ASCO20 Virtual Scientific Program. Dr. Davis reports no financial conflicts of interest relating to the issues discussed in this podcast. Full disclosures relating to all daily news podcasts can be found on our episode pages. Dr. Davis, it's great to have you on the podcast today.   Dr. Lindsay Davis: Thank you, Geraldine. I am excited for the opportunity to discuss some of the key abstracts related to GI malignancies with you today. I must say the virtual scientific program was a bit of a different ASCO experience than we're accustomed to. However, the high quality of the data and presentations we expect at the annual ASCO meeting was really beautifully maintained in the virtual sessions.   ASCO Daily News: Well, what are the abstracts, Dr. Davis, that really caught your attention in the GI field this year?   Dr. Lindsay Davis: To me, the results from the KEYNOTE-177 study, abstract LBA4, which was presented at the plenary session, is really the standout in terms of GI malignancies from this ASCO meeting. KEYNOTE-177 is a randomized, open label, phase III study, comparing pembrolizumab to standard of care chemotherapy as first-line treatment for microsatellite instability-high and mismatch repair deficient metastatic colorectal cancer.   With a median follow-up of 32 months, the primary progression-free survival endpoint was met, with a median PFS in the pembrolizumab group of 16.5 months, as compared to 8.2 months in the chemotherapy group. So that's a doubling of PFS and a hazard ratio of 0.6.   In addition, and as expected, the toxicity rates were significantly lower in the pembrolizumab versus chemotherapy arms, with grade 3 or higher events occurring in only 22% of patients treated with pembrolizumab. And that's compared to 66% of patients treated with chemotherapy. This, of course, provides us the best case scenario of a treatment that is more effective, but also less toxic.   And though the MSI high population represents a relatively small proportion of our patients with metastatic colorectal cancer, this study is still clearly practice changing, making pembrolizumab the first-line treatment of choice for patients with metastatic MSI high disease.   In addition, I think this object is also important, as it provides further direction toward the biomarker-driven treatment of metastatic colorectal cancer. So I would encourage our listeners to look at abstract 4000, the DESTINY-CRC01 study.   There are a couple of additional biomarker-based trials in colorectal cancer that I wanted to touch on as well. The first is the PANDA study. This is abstract 4002. This is a randomized phase II trial, evaluating 185 patients aged 70 and above. The median age in this study was actually 77.   These patients had untreated RAS and BRAS wild-type metastatic colorectal cancer and were treated with FOLFOX plus the EGFR inhibitor panitumumab, or with 5-fluorouracil plus leucovorin and panitumumab for up to 12 cycles, followed by panitumumab maintenance. So really, the key difference between the arms here is that oxaliplatin was not included in the second arm.   Interestingly, approximately 20% of patients treated in each arm on the PANDA trial had right-sided primary tumors, which we now have data to suggest in a general population, not specific to age, would be less likely to benefit from EGFR inhibitor therapy in the first-line setting.   The primary endpoint for this study was progression-free survival in each arm, with no direct comparison made between the arms in this trial. The median PFS was 9.6 months in the FOLFOX panitumumab arm and very similar at 9.1 months in the 5-fluorouracil leucovorin panitumumab arm.   This was accompanied by a significant decrease in grade 3 and greater toxicity, including, of course, neurotoxicity-related to oxaliplatin as well as neutropenia and diarrhea. In general, these results are promising for our elderly patients with RAS and BRAF wild-type metastatic colorectal cancer and warrant further assessment in a phase III study for formal comparison of the arms.   And importantly, I'll say in clinical practice, we do encounter elderly patients who are not candidates for oxaliplatin or who are unlikely to tolerate intensive chemotherapy due to competing medical risks. So this data provides us some evidence for proceeding with 5FU and EGFR inhibitor therapy in this population.   That said, given the data regarding the decreased benefit of EGFR inhibitor therapy as part of first-line treatment for RAS wild-type right-sided colorectal cancer, I would limit the use of this strategy to elderly patients with left-sided tumors that are RAS and BRAF wild-type.   I would also like to just briefly mention a third biomarker-based abstract for metastatic colon cancer, abstract 4001, which detailed the updated survival results from the phase III BEACON CRC trial. And I wanted to mention this study because these results are the basis for the recent FDA approval of the encorafenib cetuximab doublet for the treatment of BRAF V600E mutant metastatic colorectal cancer beyond first-line.   This subset of metastatic colorectal cancer has historically been associated with a very poor prognosis with minimal response to cytotoxic chemotherapy. The BEACON CRC trial evaluated the doublet of encorafenib plus cetuximab, as well as a triplet of encorafenib plus cetuximab and MEK inhibitor binimetinib, as compared to standard chemotherapy for the treatment of BRAF V600E metastatic colorectal cancer. This was in the second or third-line setting.   The results presented at this ASCO are a post-hoc analysis of the previously published BEACON data, including an additional six months of follow-up. This data demonstrated a median overall survival of 9.3 months for both the encorafenib, cetuximab doublet, as well as the encorafenib, cetuximab, binimetinib triplet. And this was compared to only 5.9 months in the control arm with chemotherapy.   As expected, there was added toxicity in the triplet arm as compared to the doublet arm, consistent with the known toxicity of MEK inhibitor therapy. So as the FDA approval supports, this targeted regimen of encorafenib, cetuximab should be considered the standard of care for this population in the second-line setting and beyond, given improved survival outcomes as compared to standard chemotherapy and improved side effect profile as compared to the triplet combination.   ASCO Daily News:  Dr. Davis, are there any new agents that will potentially change standard of care moving forward?   Dr. Lindsay Davis: Some very promising data was presented on the compound trastuzumab deruxtecan, or T-DXd, an antibody drug conjugate composed of anti-HER2 antibody with a topoisomerase I inhibitor payload. Studies evaluating this compound were presented both for patients with HER2 expressing metastatic colorectal cancer, as well as HER2 expressing gastric cancer. We'll talk about each of these.   In the DESTINY-CRC01 study, T-DXd was evaluated in patients with HER2 expressing RAS wild-type metastatic colorectal cancer in the third line and beyond. 78 patients received T-DXd, of whom about 90% had left colon rectal cancer, which was heavily pre-treated with a median prior lines of therapy of 4, and it ranged from 2 to 11 prior lines.   The primary endpoint in this open label phase II study was objective response rate in patients with HER2 IHC 3+ or HER2 IHC 2+ with a positive ISH test. Confirmed overall response rate in this population was 45% with one complete response, which was quite impressive, given these patients are heavily pretreated with the median of four prior regiments.   Also of note is the overall response rate in patients with prior HER2 treatment, which actually represented 30% of the population. The overall response rate in this group was 44%. In terms of toxicity, grade 3 and greater treatment emergent adverse events were documented in 62% of patients, with the most common being cytopenias, neutropenia, and anemia mostly.   However, in addition, five patients developed interstitial lung disease related to treatment. This is a toxicity that has been seen in other trials of this compound. But in this study, it included two fatal grade 5 events of interstitial lung disease. So in terms of HER2 positive RAS wild-type metastatic colorectal cancer, I think T-DXd represents an encouraging option for treatment of this molecular subgroup, with notable effects in patients pretreated with HER2 targeted agents.   However, given the notable risk of treatment-related interstitial lung disease, this will need to be further vetted in a phase III trial. I think the study further highlights the importance of broad molecular testing in colorectal cancer, as though HER2 positivity is only identified in 2% to 3% of patients with this disease. Effective targets for this and other uncommon molecular alterations are being developed.   Similarly, promising results were presented in the DESTINY-Gastric01 study. This is abstract 4513, an open label, randomized, phase II trial evaluating T-DXd and HER2 expressing advanced gastric or GE junction adenocarcinoma. Patients had centrally confirmed HER2 positive disease, according to the same definition as the CRC01 study with progression on at least two prior lines of therapy.   Patients were randomized 2 to 1 to T-DXd or physician's choice of chemotherapy, which included irinotecan or paclitaxel. All patients in the trial had received prior HER2 therapy, of course, as this is standard of care for HER2 positive gastric and esophageal cancers. The primary endpoint on the study was overall response rate. And in the 187 patients treated, the overall response was 51% in patients treated with T-DXd, as compared to only 14% in those treated with chemotherapy.   With central confirmation of response, this overall response rate was a bit lower at 43% in the T-DXd arm, versus 13% in the control group. In addition, overall survival was prolonged in the T-DXd arm at 12.5 months versus 8.4 months in the chemotherapy group with a hazard ratio of 0.59.   Grade 3 and greater adverse events occurred in 86% of patients treated with T-DXd, as compared to 57% treated with standard chemotherapy, and were similar to those documented in the CRC01 study, including treatment-related interstitial lung disease documented in 12 patients.   Though there were no grade 5 events of ILD documented in this Gastric01 study, one grade 5 occurrence of pneumonia was noted in the treatment arm. These results are important, as they suggest a potential effect of a HER2 targeting therapy beyond trastuzumab, the only HER2 targeted therapy shown to be effective for the treatment of HER2-positive gastroesophageal cancers to date.   However, similar to the CRC01 study, the pulmonary toxicity documented in this trial remains a concern. We will look forward to a phase III study to further expand upon these findings.   ASCO Daily News: Are there any additional biomarker-focused studies of interest presented for GI malignancies outside of metastatic colon cancer?   Dr. Lindsay Davis: Yes, there are two additional studies focused on HER2-positive gastroesophageal cancers that were presented at this meeting. Here, they're evaluating the addition of HER2 targeted agents in the curative setting. The PETRARCA study, which is abstract 4502, evaluated perioperative FLOT, or FLOT with trastuzumab and pertuzumab, followed by nine cycles of trastuzumab plus pertuzumab in patients with resectable HER2-positive gastric or GE junction adenocarcinoma.   The primary endpoint for this study was pathologic complete response rate, which was significantly improved in the trastuzumab pertuzumab arm at 35% versus only 12% in the FLOT alone arm. There's also suggestion of benefit on PFS and OS in this study, though it was not powered for formal analysis.   Important to note is the added toxicity of trastuzumab pertuzumab to the FLOT regimen, which is already associated with a significant burden of adverse effects. Grade 3 or greater adverse events were documented in 85% of patients in the trastuzumab pertuzumab arm versus 75% of patients in the FLOT alone arm. And diarrhea and leukopenia were the most notable in the arm that added trastuzumab and pertuzumab therapy.   It should be noted that this trial was originally designed as a phase II/III study, but it was halted at phase II due to the emerging results from the JACOB trial. The JACOB trial was a phase III study which failed to meet its primary endpoint of improved overall survival for the addition of pertuzumab to trastuzumab and chemotherapy in the metastatic setting.   Despite this, I believe these phase II results from the PETRARCA study suggest there is rationale for proceeding with further assessment of this combination in the phase III setting. In contrast to these promising results for the addition of HER2 targeted therapy to standard chemotherapy and HER2-positive gastric and GE junction adenocarcinoma, the RTOG 1010 study, abstract 4500, did not meet its primary endpoint.   This study evaluated the addition of trastuzumab to tri-modality therapy with carboplatin, paclitaxel chemoradiation, followed by surgery in 571 patients with HER2 overexpressing esophageal or GE junction adenocarcinoma. Patients receiving carboplatin paclitaxel chemoradiation followed by surgery had a median disease free survival of 14.2 months as compared to 19.6 months in the trastuzumab arm.   However, this did not meet the prespecified primary endpoint of increasing disease free survival from 15 to 25 months. These results further confirm that defining the role of anti-HER2 therapies for the treatment of HER2-positive gastroesophageal cancers in the curative setting is complex, though deserving of continued attention and investigation.   ASCO Daily News: Dr. Davis, are there any updates on immuno-oncology therapies for the treatment of GI malignancies beyond colorectal cancer?   Dr. Lindsay Davis: Yes, updated results from the randomized phase III KEYNOTE-061 study were presented at this virtual meeting in abstract 4503. The KEYNOTE-061 study is a randomized phase III trial evaluating pembrolizumab versus paclitaxel as a second-line therapy for advanced gastric or GE junction adenocarcinoma in patients with PDL1 combined positive scores greater than or equal to 1.   In the previously presented primary analysis of this study, the primary overall survival endpoint was not met. However, duration of response was significantly longer at 18 months in the pembrolizumab arm versus 5 months in the paclitaxel arm. Presented in this abstract is data from an additional two years of follow-up, as well as further assessment according to additional combined positive scores of greater than or equal to 5 and greater than or equal to 10.   The survival benefit of pembrolizumab over paclitaxel seemed to increase with increasing combined positive score. In the general cohort of CPS greater than or equal to 1, patients treated with pembrolizumab had an overall survival of 9.1 months versus 8.3 months with paclitaxel. This is a hazard ratio of 0.81.   This is compared to an overall survival of 10.4 months with pembrolizumab versus 8.3 months with paclitaxel, a hazard ratio of 0.72 in the CPS 5 or greater population. And finally, in patients with CPS 10 or greater, the overall survival in the pembrolizumab versus paclitaxel arms was 10.4 versus 8.0 months, with the hazard ratio of 0.69.   In addition, the duration of response numerically increased with increasing CPS score, from 19 months in the CPS 1 group to 33 months in the CPS 5 group. And the duration of response has actually not been reached in the CPS 10 group.   I think the conclusion from these updated results is that a proportion of patients have long-term survival benefit from second-line pembrolizumab, which might be somewhat improved with higher CPS. This calls into question a need to adjust our selection criteria for pembrolizumab in patients with gastroesophageal cancers.   In summary, I think the underlying theme of this group of abstracts focused on GI malignancies is that we are continuing to move toward personalized cancer care for the treatment of gastrointestinal tract cancers. These studies also highlight the importance of broad molecular testing for GI cancers, as well as the importance of involvement of our patients with targetable alterations in clinical trials in order to help us continue to improve the individualized care we provide our patients.   ASCO Daily News: Well, thank you, Dr. Davis, for sharing your valuable insights with us today on these promising developments in the GI field.   Dr. Lindsay Davis: Thank you, Geraldine. It was my pleasure.   ASCO Daily News: And thank you to our listeners for joining us today. If you're enjoying the content on the podcast, please rate and review us on Apple Podcasts.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Actinic keratoses are premalignant lesions that occur in sun exposed skin. 25% of Americans will develop these. Treatment can be medical, with 5FU or Picato, or surgical with cryotherapy or surgery. We discuss these "lesions" as well as a new treatment for chest actinic keratoses. My guest was Dr. Robert Grant, chief of plastic surgery at Columbia and Cornell - we spoke about "distracted surgery" and also about finding truthful medical information on the internet. Finally, we discussed rejuvenation after chemotherapy. Whew!

In this episode, I continue with our book review of Wheelbarrow Profits and then move to a very interesting study that used 5% Fluorouracil instead Modified Carnoy’s solution to decrease the recurrence rate of keratocystic odontogenic tumors with a decrease in paresthesias.  If you treat these lesions you will not want to miss this discussion.  The Interesting Case shows the surgical approach to removal of a mandibular bicuspid that is an extra tooth.  The pictures are worth checking out!  Resources Mentioned: dentistbraincandy.com/dentistinventory/

Oncology Times Broadcast News: Metastatic Colorectal Cancer: Capecitabine Equivalent to 5-FU in Irinotecan/Bevacizumab Combos Adding the oral drug capecitabine to a regimen of bevacizumab plus irinotecan was as effective as adding infusions of 5FU/folinic acid for patients who had metastatic colorectal cancer in a phase II study presented to the World Congress on Gastrointestinal Cancer in Barcelona (24-27 June, 2009; Abstract: 0-0013). Michel Ducreux, Head of the Gastrointestinal Service at the Institut Gustave Roussy in Villejuif, Paris, discussed the new evidence and its clinical implications with Peter Goodwin.

The hallmark of embryonic stem (ES) cells is their ability for self-renewal (capability of unlimited cell division without the loss of pluripotency) as well as for differentiation into all cell types of the adult organism. One factor supposed to be involved in self-renewal is the rapid proliferation rate of ES cells, which is coupled to an unusual cell cycle distribution with the majority of cells in S-phase and a very short G1-phase. This is linked to the lack of a functional G1/S-phase checkpoint, which allows the cells to enter the S-phase almost directly after mitosis. Generally, cells have to closely coordinate growth and cell cycle progression during proliferation to prevent premature division. One important factor for cell growth is ribosome biogenesis. In mature cells, disruptions in ribosome biogenesis are directly linked to the cell cycle machinery by a p53-dependent activation of the G1/S-phase checkpoint, leading to an arrest of cells in G1-phase. During this work, the function of the proteins Pes1, Bop1 and WDR12, which were shown previously to be involved in ribosome biogenesis of mature cell lines, was investigated in mouse ES cells. Moreover, a putative crosstalk between ribosome biogenesis and proliferation of ES cells was assessed. A high expression of Pes1, Bop1 and WDR12 was observed in ES cells, which strongly decreased during in vitro differentiation. Localization of the proteins was predominantly nucleolar and the formation of a stable complex (PeBoW-complex), including all three proteins, was experimentally validated in mature mouse cells as well as in mouse ES cells. The function and stability of the proteins seems to be dependent on incorporation into the PeBOW-complex, as protein levels were interdependent on each other and no free, non-incorporated proteins were observed, except for WDR12. According to their nucleolar localization, depletion of Pes1 and Bop1 were shown to inhibit maturation of the 28S rRNA and thereby the large 60S ribosomal subunit. Further, impaired proliferation of ES cells was observed. Thus, the PeBoW-complex seems to be an essential factor for the rapid proliferation of ES cells and might therefore also be involved in self-renewal. However, first results suggest that the complex is not directly involved in the maintenance of pluripotency. No changes in the expression levels of pluripotency-genes like Nanog, KLF4 and Sox2 were observed. Moreover, alkaline phosphatase activity was equally detectable after depletion of Pes1 or Bop1 and no morphological changes within the ES cell colonies were observed. Impaired ribosome biogenesis is known to activate a p53-dependent checkpoint in mature cell lines, which leads to an arrest of cells in G1-phase. Treatment of mouse NIH3T3 cells with 5FU, a potent inhibitor of rRNA maturation, confirmed an activation of this checkpoint, leading to weak induction of the tumor suppressor p53, induction of the Cdk-inhibitor p21, an increase in active, hypo-phosphorylated Rb, and to accumulation of cells in the G1- and S-phase with an increase of cells in G1-phase. In contrast, ES cells showed strong induction of p53, but no induction of its target gene p21. The overall levels of Rb were strongly induced, but the ratio between inactive, hyper-phosphorylated Rb and active, hypo-phosphorylated Rb was not changed towards the active form. These results were observed upon 5FU treatment and upon depletion of Pes1 or Bop1. Hence, ribosomal stress does not lead to checkpoint activation via the p53-p21-Rb pathway in ES cells. Moreover, no robust accumulation of cells in G1-phase was observed. 5FU treated ES cells showed an accumulation of cells in S-phase instead. Whether this effect is regulated by the induced p53 needs further investigation. Overall, the results suggest that ES cells use different mechanisms as mature cells to coordinate their proliferation rate with ribosome biogenesis.

Der programmierte Zelltod (Apoptose), ist ein evolutiv konserviertes Selbstmordprogramm der Zelle, um auf äußere oder endogene Signale zu reagieren. Es dient dazu, überflüssige und/oder geschädigte Zellen zu entfernen. Dieser Prozess ist bei Krankheiten wie z.B. Krebs teilweise außer Kraft gesetzt, und bei Parkinson- oder Alzheimer-Erkrankung zu stark ausgeprägt. Im Rahmen dieser Arbeit wurden zwei Gene biochemisch und molekularbiologisch näher charakterisiert. Bei diesen zwei Genen, die mit Hilfe eines speziell zur Identifikation dominanter, Apoptose–induzierender Gene entwickelten Screnningsverfahrens identifiziert wurden, handelt es sich um CybL, eine Komponente von Komplex II der Atmungskette, und um Saip (Small apoptosis inducing protein) einem Protein, das am endoplasmatischen Retikulum (ER) lokalisiert ist. Bisher war bekannt, daß die Atmungskettenkomplexe I und III bei der Fas-Ligand und der Ceramid-vermittelten Apoptose beteiligt sind. Über einen Zusammenhang von Komplex II und Apoptose-Induktion war zu Beginn dieser Arbeit nichts beschrieben. Im Rahmen dieser Arbeit wurde entdeckt, daß neben CybL kann auch noch die kleine Untereinheit von Komplex II (CybS) Apoptose auslösen kann, wohingegen die übrigen Komponenten von Komplex II, das Flavinprotein (FAD) und das Eisen–Schwefelprotein (FeS), nicht in der Lage sind, Apoptose zu induzieren. Die laut Datenbank vorhergesagten vier Transmembrandomänen von CybL sind für die apoptoseinduzierende Eigenschaft notwendig. Darüber hinaus führt nur eine 3,8–fache Induktion von CybL über dem endogenen CybL zu Apoptose in Säugetierzellen. In der vorliegenden Arbeit konnte auch gezeigt werden, daß CybL einerseits bei Überexpression Apoptose induzieren kann, und andererseits Apoptose durch seine Inaktivierung reduziert wird. Daß CybL damit ein spezifischer Sensor für Apoptose ist, konnte dadurch ermittelt werden, daß eine Reihe verschiedener Apoptosestimuli (Doxorubicin, Etoposid, Menadion, Cisplatin, Taxol) und der Fas-Rezeptor einen intakten Komplex II zur Signalvermittlung benötigen. Dazu wurde mit sogenannten B9/B30 Zellen gearbeitet. B9/B30-Zellen sind Lungenfibroblasten aus Hamsterzellen, in denen CybL inaktiv ist (B9), wohingegen die B30-Zellen ein Fusionsprotein zwischen CybL und GFP enthalten, welches die physiologische Aktivität von Komplex II wiederherstellt. In den B9-Zellen ist die Apoptoseinduktion durch Cytostatika (Ausnahme Arsentrioxid) bzw. durch den Fas-Rezeptor reduziert, verglichen mit den B30-Zellen. Auch Untersuchungen an HeLa WT- bzw. HeLa 0-Zellen (die keine intakte Atmungskette besitzen) zeigten, daß für die Apoptoseinduktion mit den oben genannten Reagenzien eine intakte Atmungskette benötigt wird. Im Jahre 2000 wurde CybL als Tumosupressor beschrieben. Es ist daher zu vermuten, daß die Tumorsuppressor-Eigenschaften von CybL auf der Fähigkeit von Komplex II beruhen, proapoptotische Signale aufzunehmen und weiterleiten zu können. Bisher war bekannt, daß eine transiente Inhibition einiger Atmungskettenkomplexe (Komplex I, II, III) zur Bildung von reaktiven Sauerstoffintermediaten (ROI) führt. Es konnte gezeigt werden, daß auch CybL bei Überexpression reaktive Sauerstoffintermediate produziert, und daß viele proapoptotische Signale zur spezifischen Inhibition von Komplex II führt. Da bereits eine geringe Expression von CybL ausreichend ist, um Komplex II zu inhibieren, und dadurch Apoptose ausgelöst wird, kann Komplex II als spezifischer Sensor für Apoptose angesehen werden. Das bisher unbekannte Gen mit dem Namen Saip löst dominant Apoptose in Säugetierzellen aus. Die proapoptotische Eigenschaft von Saip ist vermutlich auf einen evolutiv konservierten Mechanismus zurückzuführen, da auch ein Homolog aus C.elegans nach transienter Transfektion in Säugerzellen Apoptose auslöst. Dabei induziert Saip Caspase-abhängige Apoptosewege, die zur Apoptose-typischen DNA–Fragmentierung und Bildung von apoptotischen Körperchen (Membran blebbing) führt. Es konnte auch eine physikalische Protein-Proteininteraktion (mittels Co-Immunpräzipitation) mit Bap31 gefunden werden. Dieses Protein ist ebenfalls am ER lokalisiert und Bestandteil eines lokalen Apoptose-Sensors, der einen Proteinkomplex mit Procaspase-8L sowie antiapoptotischen Mitgliedern der Bcl-2-Familie (Bcl-2 bzw. Bcl-XL) bildet. Des weiteren interagiert Saip auch mit einer Deletionsmutante von Spike (Small protein with inherent killing effect-SpikeN19), einem neuen proapoptotischen BH3-only Protein, das ebenfalls am ER lokalisiert ist, und an Bap31 bindet. Saip ist ein ubiquitäres Protein und wird in sehr vielen der getesteten Gewebe und Zelltypen exprimiert. Im Northern-Blot-Verfahren konnte vergleichsweise eine hohe Expression an humaner Saip-mRNA in Niere, Placenta, Herz, Leber, Dünndarm und Skelettmuskulatur detektiert werden. Mit Hilfe von weiteren Northern-Blots wurde herausgefunden, daß Saip durch diverse Reagenzien, die bekanntermaßen Apoptose induzieren können, transkriptionell hochreguliert wird. So ist zum Beispiel das Signal von Saip nach 5-Fluorouracil-Behandlung (5FU), um das 80-fache gegenüber der Kontrolle erhöht. 5FU ist ein sehr effektives und bekanntes Zytostatikum, das in der Klinik zur Behandlung von Colon- und Mammakarzinomen erfolgreich eingesetzt wird. Wird Saip mittels der RNAi–Methode deaktiviert, wird die 5FU-induzierte Apoptose um 1/3 reduziert. Saip könnte somit eine wichtige Rolle in der Behandlung von Tumoren spielen, die mit 5FU therapiert werden.