Journal of Clinical Oncology (JCO) Podcast

Latest Episodes:

The Addition of Another Camptothecin Fails to Improve Outcomes in Patients With Intermediate-Risk Rhabdomyosarcoma Aug 09, 2018

Show notes

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.

The Addition of IKZF1 Deletion in Risk Stratification for Children with Newly Diagnosed B-Acute Lymphoblastic Leukemia Leads to Improved Survival: Results of the Malaysia-Singapore ALL 2010 Study Jul 26, 2018

Show notes

Intensifying therapy in children with pediatric B-ALL and IKZF1 deletions leads to improved survival.

Psychosocial Outcomes Following Contralateral Prophylactic Mastectomy: Insights and Opportunities Jul 25, 2018

Show notes

Discussion of a recent study that evaluated prospectively psychosocial well being measures in breast cancer patients before and after receipt of CPM.

Risky Business: PD-1 Immune Checkpoint Blockade in Thymic Epithelial Neoplasms Jun 18, 2018

Show notes

This podcast discusses the important risks and potential benefits of PD-1 immune checkpoint blockade in patients with thymic epithelial neoplasms.

Don't Treat Me Like a Child: The Intensification of Conventional Chemotherapy in Adults With Acute Lymphoblastic Leukemia Jun 04, 2018

Show notes

GRAALL-2005 study shows no overall benefit for cyclophosphamide intensification in older adults with ALL, despite a general improvement in outcomes for the younger adults.

Read the associated article by Huguet et al on JCO.org.

Multiple Myeloma Joins the Car T Race May 29, 2018

Show notes

Highlighting the importance of BCMA-CAR T therapy for patients with relapsed refractory multiple myeloma and discusses future avenues of clinical investigation.

Cardiotoxicity After Breast Cancer Radiotherapy: Which Part of the Heart Matters Most? May 23, 2018

Show notes

This podcast includes commentary upon a large case control series that examined the incidence of cardiac injury in association with radiation dose to distinct segments of the left ventricle and coronary arteries.

Read the associated article by Taylor et al on JCO.org.

Should Prophylactic Cranial Irradiation Be Used in Patients with Stage III Non-Small Cell Lung Cancer? May 22, 2018

Show notes

This is an evaluation of PCI in stage III Non-Small-Cell Lung Cancer. While the incidence of symptomatic brain metastases is reduced, neurological toxicity is increased and no effect on survival is demonstrated. This trial reconfirms that routine administration of PCI is not a current standard of care.

Read the associated article by De Ruysscher et al on JCO.org.

This JCO Podcast provides observations and commentary on the JCO article 'Prophylactic Cranial Irradiation (PCI) Versus Observation in Radically Treated Stage III Non-Small-Cell Lung Cancer (NSCLC): A Randomized Phase III NVALT-11/ DLCRG-02 Study' by De Ruysscher et al. My name is Everett Vokes, and I am the Chairman and Professor of Medicine at the University of Chicago in Chicago, United States of America. My oncologic specialty is head and neck and lung cancer.

De Ruysscher et al present a randomized trial evaluating the role of prophylactic cranial irradiation, referred to as PCI in this podcast, in patients with stage III non-small-cell lung cancer treated with curative intent. In doing so they have addressed an important issue. Brain metastases are a frequent site of treatment failure and can occur in isolation from additional system disease. It has been postulated that PCI could prolong survival and disease-free survival. In localized small-cell lung cancer, PCI has already been shown to decrease the incidence of brain metastases by about 50% with an impact on long-term survival. However, it is well established that PCI can lead to neurocognitive decline associated with reduced quality of life. Specifically, the authors initially staged patients with a contrast enhanced brain CT or MRI and randomized patients to observation or PCI after concurrent or sequential chemoradiotherapy with or without surgery.

Patients were randomized 1:1; PCI was designated to start at a maximum of 6 weeks after the last chemoradiotherapy and could be given as 36 Gy in 18 fractions, 30 Gy in 12 fractions or 30 Gy in 10 fractions. Patients were then monitored for disease progression including symptomatic brain metastases within 24 months from the time of randomization as primary endpoint. Quality of life measurements were performed as well. Key symptoms were defined as signs of increased intracranial pressure, headache, nausea and vomiting, cognitive or affective disturbances, seizures and focal neurological symptoms. MRI or CT was triggered by such symptoms.

The initial goal was to randomize 300 patients. However, accrual was slow and was decreased to 175 randomized patients overall. Between 2009 and 2012, 195 patients were registered, 175 were randomized, 87 to PCI and 88 to observation. The proportion of patients developing symptomatic brain metastases two years after therapy was 7% in the PCI group and 27% in the control group. This compares to a historical average of approximately 30%. PCI thus did decrease the cumulative incidences of symptomatic brain metastases. However; neurological adverse events were also increased. In particular, grade I-II memory impairment and cognitive disturbance were significantly increased in the PCI arm. Non-neurologically events such as alopecia, fatigue and headache were also significantly more frequent in the PCI group.

When evaluating patient reported adverse events, headache was reported to occur significantly more frequently in the PCI arm. Of interest, neurological side effects tended to increase over time after PCI whereas non-neurological adverse events were highest during PCI and decreased over time.

Overall survival at median follow-up of 51 months was not improved, with a hazard ratio of 0.9. PCI did significantly increase time to develop brain metastases, and the median progression-free survival was slightly longer at 12.3 versus 11.5 months in the PCI group, but again this was not statistically significant..

Overall, this study does demonstrate that PCI can significantly reduce the incidence of symptomatic brain metastases in patients with stage III non-small cell lung cancer. However, this comes at the cost of increased neurological adverse events even though most of these were mild in nature. Furthermore, an impact on overall survival was not demonstrated. It could be argued that this study was somewhat small and that a larger study could have shown a more pronounced effect, especially on progression-free survival, which did show a trend favoring PCI. On the other hand, symptomatic brain metastases nowadays can be treated at the time of recurrence with SBRT and other modern radiotherapy techniques. In addition, the recent durvalumab trial (PACIFIC) demonstrating that consolidation durvalumab can increase progression-free survival also demonstrated a reduction in brain metastases in durvalumab treated patients, suggesting that improved systemic therapy may emerge as a better approach to tackling the clinical problem of brain metastases in stage III NSCLC.

So is PCI a recommended standard of care for patients with stage III NSCLC? While I congratulate the authors on conducting this ambitious and randomized trial addressing an important key question, my answer is no. Treatment with durvalumab is an evolving new standard and neurological side effects of PCI are not to be ignored. Treating patients with cranial radiation at the time of actual progression seems like the better approach in the meantime.

This concludes this JCO Podcast. Thank you for listening.

The Medical Marijuana Conundrum: When Public Interest Outpaces Medical Knowledge May 11, 2018

Show notes

The public perception of medical marijuana has outpaced medical knowledge. Oncologists encounter an increasing number of patient questions and interest regarding its use. This study highlights the beliefs, attitudes and knowledge of medical oncologists regarding the therapeutic use of marijuana.

This JCO Podcast provides observations and commentary on the JCO article ''Medical Oncologists' Beliefs, Practices and Knowledge Regarding Marijuana Used Therapeutically: A Nationally-Representative Survey Study' by Braun and colleagues. My name is Kimberson Tanco, and I am an Assistant Professor at the University of Texas MD Anderson Cancer Center in Houston, Texas. I am a Palliative Medicine physician.

Medical marijuana is one of the fastest growing medical issues nationwide, so much so it is now legal under certain conditions in more than half of the country, with additional limited indications in certain "non-legal" states for pediatric refractory epileptic conditions.1 Most of the current trials are directed towards non-cancer conditions. In contrast, in the article that accompanies this podcast, Braun and colleagues highlight a variety of key issues that face oncology practitioners regarding cannabis and its potential uses and toxicities.

As healthcare professionals, it is inevitable that we will be asked by our patients and/or their caregivers about the use of medical marijuana, either in a legalized or a non-legalized state. This study does a good job of recording clinician beliefs and practices from different regions of the nation. It also points out a very important fact that the interest and curiosities about the use of medical marijuana far outpaces our knowledge base as demonstrated in their results. It was very interesting to know that up to 80% of oncologists conducted discussions and 46% recommended medical marijuana for clinical use as compared to only 30% feeling sufficiently knowledgeable enough to make informed recommendations. This is quite a change from 2010, when they cited that only 20% of family practitioner respondents in Colorado would recommend medical marijuana and

The authors highlighted key points from the study including the need for expedited clinical trials exploring potential medicinal effect of marijuana in oncology, the need for educational programs about medical marijuana and policies to incentivize the training of clinicians on this issue. In the next few minutes, I would like to discuss these points.

Their first point about the need for clinical trials is certainly a key step into understanding the pharmacology and effects of cannabis, which would help improve educational programs and open up federal, state and institutional policies. However, there are a variety of challenges faced in conducting medical marijuana research.2 In spite of changes in state policy and increasing prevalence of cannabis use, cannabis is still not legalized by the federal government and remains a Schedule I substance. Furthermore, an investigator must navigate through the National Institute on Drug Abuse or NIDA, Food and Drug Administration, Drug Enforcement Administration, state departments, state boards, institutional review boards, and funding sources among others. Additionally, supply of cannabis for research purposes is only available through NIDA and is sourced from the University of Mississippi, which has been the sole cultivator since 1968. An important point is that federal supplies of cannabis may also have been harvested earlier and stored in freezer, and may have lower potencies than those sold in state-regulated markets. Hence, investigator results may have to be taken with caution as they relate to appropriate dosing of cannabis products, particularly when they will be taken from state dispensaries. Additionally, there are drug delivery challenges in inhalation, vaporization or ingestion as well as what the author perfectly described as "entourage effects" in where the effect may be different after administering the whole plant vs. isolated cannabinoids.

On the other hand, as a benefit of conducting more standardized trials, we can also compare through head-to-head trials the benefits and toxicities against currently available oral cannabinoids such as dronabinol and nabilone. The study also demonstrated that oncologists believed that medical marijuana can be beneficial for certain symptoms like anorexia, nausea, and anxiety. Standardized trials would allow us to discover and outline indications, dosages, mode of delivery and more for these symptoms that plague cancer patients.

The second key point is about improving educational programs and is reflected by the results of the study showing only 30% of oncologists feel that they have sufficient knowledge regarding cannabis. In my personal experience, I have been noticing increasing sessions about medical marijuana in various national conferences. Although this is good to see, educational access needs to spread faster and broader. Key concepts including pharmacology, potential uses, adverse effects, and drug interactions should be continued into local, institutional and even into medical school level.

While there was no consensus by respondents regarding the comparative effectiveness of marijuana as a treatment for pain, majority supported using it as an adjunct to standard pain management strategies, which is an especially relevant issue in the setting of an opioid crisis. Cannabinoids may have inhibitory activity in certain cytochrome enzymes and glycopeptides. For example, it has potential inhibitory activity on CYP2D6 and CYP3A enzymes while inducing CYP2E1. These activities may affect levels of certain opioids such as fentanyl, methadone and other drugs like anesthetic agents.3 It may also have potential inhibitory activity to P-glycoprotein which may increase drug levels of certain agents like paclitaxel and etoposide. Further research is needed to be able to better understand these interactions.

A key finding this study demonstrated is the perception of oncologists that medical marijuana has a lower risk than opioids for addiction, overdose and death. With the ongoing opioid epidemic, similar to any national movements or epidemics, there is a natural trend to react and use other substances over opioids, which is still the gold standard for cancer pain treatment. Recent studies have shown decreases in opioid prescribing rates in states that legalized marijuana use.4,5 One wonders if the national and media scrutiny of the dangers of opioid use coupled with the increased excitement over the potential uses of marijuana downplay any of its potential adverse effects. It is also reasonable to consider whether we are opening a can of worms by substituting one addictive substance with another, or whether we are addressing the addiction issue by simply replacing the substance involved. These are important arguments that we do not have time for in this podcast and would be better discussed in another forum.

The third key point is development of policies. Statewide, we have seen increasing legislation to legalize cannabis not only for medical use but also for recreational purposes. Unfortunately, even in legalized states, several institutions do not have policies and guidelines that deal with this issue.6 Clinicians are left to make medical decisions regarding patients using cannabis by themselves or try to deflect the topic altogether.

The debate of medical marijuana is only starting. Clinical trials are needed to better understand its pharmacology to arm oncologists and other clinicians to better care for their patients. As the public perception of cannabis has blossomed over recent years and state-regulated dispensaries have provided medical marijuana to patients, the medical field has an opportunity to learn from what can already be observed and advance this into more standardized and scientific testing.

This concludes this JCO Podcast. Thank you for listening.

Racial Disparities in Medical Financial Hardship Among Cancer Survivors Apr 18, 2018

Show notes

This commentary summarizes findings from a study of racial disparities in medical financial hardship, identifies gaps in the current evidence base, and discusses health policy considerations for to reducing the risk of financial hardship.

Read the related article "Financial Impact of Breast Cancer in Black Versus White Women" on JCO.org

Our TOPPODCAST Picks

Follow Us

Stay Connected

Journal of Clinical Oncology (JCO) Podcast

Related Podcasts

Links

Stay Connected