Podcasts about children's oncology group

This Week in Pediatric Oncology (TWIPO) - our host, Timothy Cripe, MD, meets with the new Chair of the Children's Oncology Group (COG), Douglas Hawkins, MD, to discuss the future of the pediatric cancer research landscape.   Have any thoughts? Questions? Ideas for future topics? Email us at TWIPO@solvingkidscancer.org. Subscribe to TWIPO to get notifications of new uploads.   You can now watch TWIPO podcasts on our YouTube Channel! Watch this episode here & subscribe: https://youtu.be/p7rMXwAu3qA

This JCO Podcast provides observations and commentary on the JCO article “Impact of Surveillance Imaging Modality on Survival After Recurrence in Patients with Favorable Histology Wilms Tumor: A Report from the Children's Oncology Group” by Mullen et al. My name is Dr. Meredith Irwin, and I am an oncologist and Professor at the Hospital for Sick Children and University of Toronto in Toronto, Canada.  My oncologic specialty is pediatric solid tumors. Wilms tumor is the most common pediatric kidney tumor. With current therapies, the 5-year overall survival for newly diagnosed patients is 90%. For the 15% who relapse, most commonly in the lung or abdomen, the cure rates still often exceed 50%. The likelihood for cure is based on a number of risk factors, including histology, stage and previous therapies. Thus, similar to many pediatric cancer patients, those with Wilms undergo surveillance imaging during and following completion of upfront therapy in order to potentially discover recurrences sooner with the hope that early identification of lower disease burden will translate to higher salvage rates. However, to date, several small studies have failed to demonstrate that early detection of recurrence by surveillance imaging is associated with better prognosis for pediatric cancers including medulloblastoma, lymphoma and neuroblastoma. Moreover, with increasing awareness of the potential risks from imaging-associated ionizing radiation exposures and associated financial costs, there is significant interest in generating evidence to determine optimal surveillance strategies and limit cumulative exposures. To address these issues for Wilms tumor, the study by Mullen et al was designed to determine whether, compared to relapses detected by surveillance with chest x-ray and ultrasound, those detected with cross-sectional CT imaging were associated with improved survival rates. To do this, four authors retrospectively reviewed flowsheets and imaging reports for patients who recurred on the 5th National Wilms Tumor Study (NWTS-5) between 1995 and 2002 to determine whether their relapses were identified by signs/symptoms or scheduled surveillance imaging.  If by imaging, they recorded the modality- CT, ultrasound and/or chest x-ray. The study cohort included the 281 patients who recurred following initial diagnosis of favorable histology unilateral Wilms. All patients underwent imaging at specified time intervals, but the modalities varied. The 5-year overall survival for this cohort post-relapse was 67%, which is similar to other studies. 48% of recurrences were detected with routine surveillance by chest x-ray or ultrasound, 25% by surveillance with CT, and 25% presented with symptoms between scheduled imaging, most commonly pain or abdominal mass. Certain characteristics differed among these groups. The CT-detected patients were more likely to be stage 4, and in the symptoms group, more relapses were extrapulmonary and occurred post-treatment.  The authors asked whether the specific method of detection of relapse impacted prognosis. Although recurrences detected by symptoms were associated with an inferior 5-year survival of 55%, versus 76% for the imaging-detected group, there were no differences in survival for patients based on the imaging modality used for detection at any point during or following therapy. There was also no significant advantage to CT over u/s or x-ray for abdominal and chest relapses, respectively. Although a higher number of foci detected at recurrence and larger relapse size correlated with inferior outcomes, analyses failed to find a significant advantage for CT use in the subgroups of lung-only relapses or advanced-stage patients. The authors also examined financial burden and radiation exposures. To determine the economic impact, the authors predicted costs based on US Medicaid/Medicare reimbursement rates.  For patients with stage III disease, more than 200 imaging studies (with estimated costs between $20,000 and $45,000) were required to identify one relapse. For stage IV, between 158 and 190 studies costing more than $15,000 were needed. Estimated radiation exposures from these surveillance protocols varied between 9.4 and 83 mSv, depending on the total number of CTs. Although it is difficult to quantify how cumulative radiation doses may impact future cancer risks, expert groups have estimated that there is a 1 in 1,000 increased risk of future cancer deaths for every 10mSv exposure at age 10, and these risks are higher for patients exposed at younger ages. Other potential negative consequences of surveillance imaging not examined by these authors include the associated psychological stress for families, which is termed “scanxiety,” and possible adverse neurological effects of anesthetic agents for young children.   The significance of this report is that it is the first study to compare the utility and cost of different imaging methods for the identification of Wilms tumor recurrences. In comparison to x-rays or ultrasounds, there was no advantage to using CT, which is costlier and resulted in higher radiation exposures. It is possible that an advantage to CT was not identified in part because only the best prognosis patients, those with favourable histology, were included. The authors excluded those with bilateral disease, who often have germline predisposition syndromes, and patients with anaplastic histology, which has a higher relapse rate Ideally, a prospective RCT design would be performed to determine whether cross-sectional imaging would be superior to ultrasounds/x-ray combinations. However, given the overall excellent survival for Wilms tumor, the number of patients required to detect a significant survival advantage would likely be very large. In addition, given the cost and potential late effects of radiation exposures, engagement from oncologists, radiologists and families might be challenging.  In conclusion, the findings in this manuscript support the recommendations by Mullen and colleagues that surveillance post completion of therapy for favorable histology unilateral Wilms does not need to include CT scans and can instead be based on symptoms and ultrasound and/or x-rays. These authors did not specify whether duration of surveillance could be limited; however, a recent publication in Lancet Oncology by Brok and colleagues supported consideration of a cut-off of two years. Their SIOP study reported that the detection of one relapse 2-5 years post-therapy required 500 scans. Importantly, it remains possible that for rare patient subsets with anaplastic histologies or other biomarkers of unfavorable disease, which may include 1q LOH, surveillance protocols might need to be adjusted. This may be similar to strategies for other tumors, such as neuroblastoma, where, in comparison to patients with high-risk disease, those with low or intermediate-risk disease with survival rates of more than 80-90% are increasingly undergoing surveillance regimens without frequent CT scans, which, in part, is determined based on clinical and biological risk factors. These approaches to risk stratification of imaging are increasingly being used. Thus, clinicians may begin to modify surveillance based on the risk of recurrence for a particular subgroup of patients, similar to precision medicine approaches for treatment. However, it will be important to perform studies similar to the accompanying manuscript to generate evidence to inform and support precision surveillance imaging recommendations that are specific to different tumor types. This concludes this JCO podcast. Thank you for listening.

September is National Childhood Cancer and Sickle Cell Awareness Month. Dr. Kim Whelan talks about the Alabama Center for Childhood Cancer and Blood Disorders, and its impact on patient care in the state of Alabama and across the country. Together, the University of Alabama at Birmingham (UAB) and Children's of Alabama are one of only 19 sites nationwide to participate in the Children's Oncology Group phase one and two consortium which allows our families to have access to the newest drugs and promising clinical trials without having to travel out of state. Each year, more than 1,500 children come to our center for care, and more than 300 dedicated pediatric healthcare professionals provide exceptional patient care, education and research. We are committed to finding a cure for all children – down the street and around the world.

Read the related article "Addition of Vincristine and Irinotecan to Vincristine, Dactinomycin, and Cyclophosphamide Does Not Improve Outcome for Intermediate-Risk Rhabdomyosarcoma: A Report From the Children's Oncology Group" on JCO.org This JCO podcast provides observations and commentary on the JCO article “addition of vincristine, irinotecan to vincristine, dactinomycin and cyclophosphamide does not improve outcome for intermediate risk rhabdomyosarcoma a report from the Children’s Oncology Group by Hawkins, et al.” My name is Alberto Pappo and I am a pediatric oncologist and Head of the Division of Solid Tumors at St Jude Children’s Research Hospital in Memphis, Tennessee. Investigators of the Children’s Oncology Group (COG) developed a prospective randomized study to improve the outcome of patients with intermediate risk rhabdomyosarcoma by comparing the addition of the doublet vincristine and irinotecan (which will be called the irinotecan arm) to standard vincristine actinomycin D and cyclophosphamide (which will be called the VAC arm) to VAC chemotherapy only. Intermediate risk disease comprises the largest subgroup of patients with rhabdomyosarcoma and comprises patients with embryonal histology who present with tumors that are non-metastatic and unresected and arise in unfavorable sites as well as patients who present with non-metastatic alveolar histology tumors. The authors nicely review prior failed strategies that were aimed at increasing the outcome of this group of patients including dose intensification of active agents as well as the  addition of novel agents such as ifosfamide, etoposide and topotecan. 1-3 Irinotecan is a prodrug that is converted to its active metabolite SN38 and inhibits topoisomerase I. In a front-line trial for patients with metastatic rhabdomyosarcoma demonstrated a high level of activity with a 70% early response rate and an 8% disease progression rate.4 Based strong preclinical and clinical data, this agent was incorporated into an upfront randomized trial for rhabdomyosarcoma testing the benefit of adding vincristine and irinotecan to standard VAC in intermediate risk rhabdomyosarcoma. Eligibility criteria included patients with embryonal rhabdomyosarcoma who had stage II and III clinical Group 3 disease and any alveolar rhabdomyosarcoma without evidence of distant metastases.  During the first 12 weeks the two treatments were identical in duration of schedule with the exception of the substitution of irinotecan for dactinomycin and cyclophosphamide at week 4 and for cyclophosphamide at week 7 and 10 in the irinotecan arm.  During the next 30 weeks irinotecan replaced actinomycin D and cyclophosphamide at weeks 16, 19, 25, 31 and 37 in irinotecan arm.  Patients were evaluated for response at week 15, 30 and at the end of therapy.  Radiation therapy unlike the prior COG D9803 trial  started early at week 4 instead of 12 and the dose was determined by the clinical group and histology with doses ranging to 36 Gy for those with clinical group I and II to 50.4Gy for those with Group III disease. The study was designed with an 80% power to detect an overall increase in the long term event-free survival from 65% with VAC chemotherapy to 76% with the doublet VAC VI with a sample size of 486 patients.   Between December 2006 and December 2012 there were 481 patients enrolled on the study of whom 33 were ineligible.  Of the remaining 448 eligible patients 222 were randomized to VAC and 226 were randomized to the irinotecan arm.  The patient’s characteristics were similar between both arms and to other COG trials. There was a slight predominance of males, 61% of patients were between 1 and 10 years of age and 71% were Caucasian.  Embryonal rhabdomyosarcoma was the predominant histology seen in 53% of the patients and 86% had clinical Group III disease. The most common primary site was parameningeal followed by bladder prostate, extremity and retroperitoneum.    With a median followup for surviving patients of 4.8 years the estimated 4 year event-free survival was 63% for the VAC arm and 59% for the irinotecan arm.  The estimated 4 year overall survival rates was 73% for the VAC arm and 72% for the irinotecan arm. There were no differences in radiographic response among clinical Group III patients as assessed by institutional report by week 15 and no evidence of differences in outcome by treatment arm in the histologic subgroup analysis.  When compared to the previous trial D9083 which had slightly different eligibility criteria, there were no differences in event and overall survival for patients with alveolar rhabdomyosarcoma. However, patients with embryonal tumors had an inferior 4 year event-free survival in this trial when compared to patients in D9803 although the 4 year overall survival rates were similar.  The vast majority of treatment failures were due to tumor progression or recurrence. The 4 year local failure rate was 22.4%, the 4 year regional lymph node failure rate was 5.7% and the 4 year distant failure rate was 18%.  Hematologic toxicity and febrile neutropenia were more commonly observed in the VAC arm whereas diarrhea and mucositis were more prevalent in the irinotecan arm. Hepatopathy was more common in the VAC arm and patients in the irinotecan arms who developed grade 3 4 diarrhea were more likely to carry the UGT1A1  7/7 genotype.  The authors conclude that the addition of vincristine and irinotecan to a VAC backbone failed to improve the outcome of patients with intermediate risk rhabdomyosarcoma. However, the lower cumulative doses of cyclophosphamide in the irinotecan arm which could potentially reduce the risk of infertility in selected patients and the lower rates of hematologic toxicity in this regimen have provided a rationale for the COG to use a VAC irinotecan backbone in their current up front randomized trial for intermediate risk rhabdomyosarcoma.   This trial highlights the lack of significant advances in the therapy of pediatric rhabdomyosarcoma despite the fact that irinotecan showed significant preclinical and clinical activity in metastatic patients with this disease.5,6 Similarly, in a previous study, the addition of another camptothecin, topotecan failed to improve the outcome of intermediate risk patients despite promising clinical activity in newly diagnosed metastatic patients 7suggesting that identification of novel agents based on their activity in  phase II window studies for high risk rhabdomyosarcoma is not an optimal method for selecting active compounds that could be incorporated into front-line studies for intermediate risk disease. As suggested by the authors of the paper just discussed, other novel mechanisms of drug testing such as randomized phase II studies in recurrent disease might offer alternative more effective strategies for identifying agents to be tested in intermediate risk patients. In contrast to this results, the European Pediatric Soft Tissue Sarcoma Study Group has recently reported at the ASCO 2018 meeting improved outcomes for a similar population of patients when maintenance therapy with low dose cyclophosphamide and vinorelbine is added to a backbone of vincristine, ifosfamide and actinomycin D (VAI). 8  In this trial, patients with non metastatic incompletely resected embryonal rhabdomyosarcoma arising in unfavorable sites and localized alveolar rhabdomyosarcoma without nodal metastases who achieved a complete remission after 9 cycles (27 weeks) of VAI with or without doxorubicin were randomized to stop treatment or receive maintenance chemotherapy with six 28 days cycle of vinorelbine and cyclophosphamide.  The study was initially designed with an 80% power to detect an increase in the 3 year EFS from 55% to 65% with a hazard ratio of 0.67 but was then amended to allow detection of a relativity reduction rate in the relapse rate of 50%.  This trial accrued 670 patients of whom 371 were eligible and 186 were assigned to the standard arm and 185 to the maintenance arm.  The clinical features were well balanced between the two groups. With median follow up of 5 years in surviving pts, the 3 year event-free survival and overall survival in the maintenance arm and the standard arm were  78.4% vs 72.3% (p value 0.061) and 87.3% vs. 77.4 (p value = 0.011).  The investigators concluded that the addition of maintenance therapy is a novel strategy that improves the outcome of this group of patients with rhabdomyosarcoma and establishes the new standard of care for patients in Europe.  The results of this trial however, need to be interpreted with caution and cannot be generalized. The follow-up of patients is relatively short and only those who achieved a complete radiographic response after chemotherapy were eligible to be randomized, no information was provided regarding outcomes of patients who were randomized to receive doxorubicin, there are only 9 cycles of chemotherapy given prior to randomization to maintenance therapy whereas the COG studies give 14 cycles of therapy and finally, there are slight differences in the eligibility criteria when compared to the previous COG  trials.    In conclusion, the addition of an irinotecan backbone to standard VAC chemotherapy does not improve the outcome of patients with intermediate risk rhabdomyosarcoma. However, the irinotecan containing regimen offers potential advantages such as outpatient administration of chemotherapy, reduced hematologic toxicity and cumulative cyclophosphamide exposure and has therefore become the standard backbone for patients with intermediate risk rhabdomyosarcoma in the United States.  This concludes this JCO podcast.  Thank you for listening.    

Dr Slayton talks to ecancertv at ASCO 2015, about the outcomes of Children's Oncology Group trial AALL0622 in patients 1-30 years old. Treating with dasatinib plus intensive chemotherapy versus stem cell transplant (SCT) for Philadelphia chromosome-positive acute lymphoblastic leukaemia. Results showed dasatinib with intensive chemotherapy was well tolerated; subjects with rapid response had excellent outcomes without SCT. Further follow-up and additional trials are necessary to define the relative role of dasatinib and imatinib in promoting long-term survival in paediatric Ph positive ALL.

Dr Raetz talks to ecancertv about results from a Children's Oncology Group study that looked at using a real-time disease classification protocol based on clinical, biologic and early disease response measures for childhood B-lymphoblastic leukaemia (ALL). The study involved over 10,000 children of whom around 5,000 met National Cancer Institute criteria for standard risk ALL and 2,700 were deemed high risk at the end of induction therapy. A large subset of children was identified who had favourable cytogenetic profiles and rapid responses to treatment resulting in high overall survival at 5 years. This suggests that there could be some children who would not benefit from further chemotherapy intensification.

Dr Landier talks to ecancertv at ASH 2015 about a study conducted by the Children's Oncology Group that looked at two different methods of monitoring adherence to maintenance chemotherapy in children and adolescents with acute lymphoblastic leukaemia (ALL). Young patients with ALL require approximately 2 years of maintenance chemotherapy that relies on a backbone of oral 6-mercaptopurine (6MP). Continued exposure to treatment is critical to ensure durable remissions and prevent relapse and the study looked at the accuracy of self-reported and electronically reported 6-MP intake. Results showed that self-report was less reliable than electronic monitoring with over-reporting of 6-MP being common, particularly in children aged 12 years or older, who were non-adherent, of non-White ethnicity and who came from household with lower parental education levels. In the interview Dr Landier offers some practical advice on how to monitor adherence in routine practice.

Dr Stock talks to ecancertv at ASH 2015 about results from a Children's Oncology Group study that looked at using a real-time disease classification protocol based on clinical, biologic and early disease response measures for childhood B-lymphoblastic leukaemia (ALL). The findings, presented by Dr Elizabeth Raetz of the University of Utah in Salt Lake City, USA, showed that the protocol could be used to identify children who may or may who may need intensified treatment after induction therapy. The study involved over 10,000 children of whom around 5,000 met National Cancer Institute criteria for standard risk ALL and 2,700 were deemed high risk at the end of induction therapy. A large subset of children was identified who had favourable cytogenetic profiles and rapid responses to treatment resulting in high overall survival at 5 years. This suggests that there could be some children who would not benefit from further chemotherapy intensification.

Dr Raetz presents, at a press conference at ASH 2015, results from the Children's Oncology Group report into genetic and response-based risk classification. It has identified a subgroup of NCI high risk childhood B-lymphoblastic leukaemia.

Dr Landier presents, at a press conference at ASH 2015, results from a study looking at 6-Mercaptopurine (6MP) intake during maintenance for childhood acute lymphoblastic leukaemia. The study was conducted by the Children's Oncology Group, comparing self-report and electronic monitoring.

The Children's Oncology Group study led by Larsen et al. showed that children and young adult patients with high-risk B cell acute lymphoblastic leukemia benefit from receiving high-dose methotrexate during interim maintenance 1 and that those aged 1 to 9 years benefit from receiving dexamethasone for 14 days during induction.

October 30, 2011Several just-published papers in the literature relate to recent podcast episodes, and host Dr. Tim Cripe and co-host Dr.  Lionel Chow review these interesting developments. 0:55 Hedgehog Signaling: Recent papers discussing this pathway in neuroblastoma and rhabdomyosarcoma are discussed, with implications for treatment in these tumor types with itraconozole. 6:40 Cell phone and brain tumor risk: The controversy concerning criticism by the Environmental Health Trust of a study showing that cell phone use does not increase risk of brain tumors in children is explored. Accelerated approval of cancer drugs by the FDA and implications for pediatric cancers. 15:30 Brentuximab for two types of lymphoma 21:20 Vemurafenib for melanoma 28:30 Crizotinib for non-small cell lung cancer (and potential use in neuroblastoma) 42:30 Response to email regarding personalized medicine TWiPO episode #17 and lab blog for Dr Charles Keller at OHSU References: Pediatr Blood Cancer. 2011 Dec 1;57(6):930-8. doi: 10.1002/pbc.23174. Hedgehog pathway activity in pediatric embryonal rhabdomyosarcoma and undifferentiated sarcoma: a report from the Children's Oncology Group. Int J Oncol. 2011 Oct;39(4):899-906. doi: 10.3892/ijo.2011.1076. Pharmacological inhibition of the Hedgehog pathway preventshuman rhabdomyosarcoma cell growth. Cancer Lett. 2011 Nov 28;310(2):222-31. Inhibition of the sonic hedgehog pathway by cyplopaminereduces the CD133+/CD15+ cell compartment and the in vitrotumorigenic capability of neuroblastoma cells. Cell Phone Study Was Flawed, Say Some Experts by Roxanne Nelson Medscape Oncology News. The JNCI Study by Aydin et al on Risk of Childhood Brain Cancer from Cellphone Use Reveals Serious Health Problems, Environmental Health Trust. N Engl J Med. 2010 Nov 4;363(19):1812-21. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. FDA Approves Brentuximab for Two Lymphomas By: ELIZABETH MECHCATIE, Oncology Report Digital Network. Clin Cancer Res. 2011 Oct 15;17(20):6428-36. Brentuximab Vedotin (SGN-35). FDA Approves Vemurafenib for Advanced Melanoma. By: JANE SALODOF MACNEIL, Oncology Report Digital Network. N Engl J Med. 2011 Jun 30;364(26):2507-16. Improved survival with vemurafenib in melanoma with BRAFV600E mutation. N Engl J Med. 2011 Jun 30;364(26):2547-8. Been there, not done that--melanoma in the age of molecular therapy. http://www.ncbi.nlm.nih.gov/pubmed/21639809 Biochem J. 2011 Aug 15. Activating ALK mutations found in neuroblastoma are inhibited by Crizotinib and NVP-TAE684. N Engl J Med. 2010 Oct 28;363(18):1693-703. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. Nature. 2007 Aug 2;448(7153):561-6. Epub 2007 Jul 11. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Science. 1994 Mar 4;263(5151):1281-4. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma.

October 07, 2011 Dr. Tim Cripe and co-hosts Dr. Lionel Chow and Dr. Lars Wagner welcome special guest Dr. Stephen Lessnick for an in-depth discussion on the progress to date in understanding the genetics of Ewing's sarcoma. The challenges of interpreting the gene expression data as well as the ethics of collecting tumor specimens for research purposes are also explored. Dr.Stephen Lessnick is a Professor of Pediatrics and Oncological Sciences at the University of Utah, where he also serves as an Attending Physician in Pediatric Hematology/Oncology at Primary Children's Medical Center in Salt Lake City, UT. He received his PhD in Molecular Biology from UCLA in 1994, and his MD from UCLA in 1996, followed by a residency at Children's Hospital in Boston, and a fellowship at the Dana-Farber Cancer Institute and Children's Hospital. Currently, Dr. Lessnick is the Director of the Center for Children's Cancer Research at Huntsman Cancer Institute, a Jon and Karen Huntsman Presidential Professor in Cancer Research at the University of Utah, and is the Vice Chair for Biology of the Bone Tumor Committee in the Children's Oncology Group. Please send questions or comments to twipo@solvingkidscancer.org

Please join me, Unstoppable Frankie Picasso on Tuesday, October 5th at 8:00 pm est when I am joined by Shirley Enebrad, an award-winning television/video producer/writer and Certified Grief Recovery Specialist, whose book, "Over the Rainbow Bridge" chronicles the journey of her only son Cory through the years of his cancer and beyond. Cory's short life affected thousands of people in a really positive way and his spirit to LIVE the best life he could, is a lesson to all of us. Cory was diagnosed with Cancer at the age of 3 and succumbed to his disease in his 9th year. His life like his passing continues to be a gift to the world. Cory had a deep connection with Dr Elizabeth Kubler Ross, the expert on death and dying. He was a source of inspiration for her and she used his artwork to affect emotion in her patients and help them to heal. Cory taught us not to fear death. If you have a child with Cancer or would like to speak to Shirley doing the show, please feel free to call in. We will be discussing reincarnation , heaven and death in a way that may not reflect all beliefs. Cory was a brave and wise old soul and you will find yourself laughing and crying throughout this wonderful life's tale. Shirley certainly has honoured her son's wishes and is giving back to the world in so many ways. She is an award winning volunteer, and the President of Candlelighters Childhood Cancer Foundation of Western Washington. Formerly she was the Washington State Team Leader for CureSearch National Childhood Cancer Foundation, which focuses on securing research funding for the Children's Oncology Group. This heartwarming and heartbreaking tale that is so life affirming, I highly recommend it for everyone.