Journal of Clinical Oncology (JCO) Podcast

Latest Episodes:

Intratumoral Immune Infiltration in Follicular Lymphoma: Novel Insights into Early Relapse and Survival Dec 01, 2019

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TRANSCRIPT

This JCO Podcast provides observations and commentary on the JCO article "Progression of Disease Within 24 Months (POD24) in Follicular Lymphoma Is Associated With Reduced Intratumoral Immune-Infiltration" by Dr. Tobin and colleagues. My name is Dr. Carla Casulo, and I am Associate Professor of Medicine, Hematology and Oncology at the Wilmot Cancer Institute of the University of Rochester in Rochester, NY, USA. My oncologic specialty is Lymphoma.

Follicular lymphoma is the most frequently occurring indolent non-Hodgkin lymphoma and has a long natural history, with median overall survival nearing two decades. Patients with follicular lymphoma may experience a variable clinical course, with periods of long remission punctuated by episodes of recurrent lymphoma requiring re-treatment. Among all patients, up to one third will have early disease recurrence, defined as occurring within 24 months of diagnosis. Please note that progression of disease within 24 months will be referred to as POD24 for the remainder of this podcast. These patients have inferior survival, ranging from 25-50% at 5 years. Consequently, POD24 has become a robust and well accepted indicator of identifying high-risk patients.

The implications of POD24 were first identified through our analysis of the National Lymphocare Study, which sought to test the hypothesis that time to disease progression had an impact on subsequent patient outcomes. 588 patients treated with RCHOP were included. Patients with POD24 were defined as early progressors, and those without relapse or death within 24 months were defined as the reference group. Patients with POD24 had OS of 50% at 5 years compared to 90% in the reference group. These findings have subsequently been independently validated by numerous investigators worldwide, corroborating the adverse prognostic impact of an early disease related event in follicular lymphoma. The largest of these validation studies pooled individual patient data from 5,453 patients on 13 Clinical Trials using the Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) Investigation.

In the FLASH analysis, we identified that male gender, poor performance status, high follicular lymphoma international Prognostic index (FLIPI) score, and elevated baseline beta 2 microglobulin B2M as predictors of early death and progression. Moreover, it confirmed POD24 as an early clinical endpoint of poor survival in follicular lymphoma that should be utilized to identify patients for prospective clinical trials.

The current status of biomarkers in follicular lymphoma has emerged from a wealth of clinical and laboratory-based factors to classify risk, towards a biologic based, molecular approach merging clinical factors with our current understanding of the follicular lymphoma genomic landscape.

There are numerous well-established and emerging clinical prognostic indices used at the time of diagnosis in follicular lymphoma that can help discriminate general outcome. These include the FLIPI and FLIPI -2. To an extent, these prognostic markers can identify subsets of patients with an expected POD24 with a sensitivity between 60-78%, and a specificity between 56-58%. However, in an attempt to use a precision approach, investigators from the German Low-Grade Lymphoma Study Group harmonized clinical and pathologic data to create a clinico-genetic risk model aimed at more accurate risk prognostication in patients receiving front line chemoimmunotherapy. They performed deep DNA sequencing from formalin fixed pre-treatment biopsies to analyze the mutational status of genes in 151 patients with follicular lymphoma tumor samples. The resulting prognostic tool, called the m7-FLIPI, distilled down 74 genes into 7 genes with non-silent mutations occurring at a variant allele frequency of 10% or greater, and combined these with high risk FLIPI status and ECOG performance status. These included genes that increased risk of progression, including EP300, FOX01, CREBBP, CARD11, and those that decreased risk of progression, including EZH2, ARID1A, and MEF2B. The cumulative risk score was calculated by combining relative weights of these genes in a multivariate analysis predicting failure-free survival. This m7-FLIPI score was tested to identify POD24 but only captured about 50% of patients as high risk. A later model included only 3 genes, including EP300, FOX01 and EZH2, performance status and FLIPI score. Defined as the POD24-PI, this was more sensitive at identifying POD24 patients but did not outperform other metrics due to lower specificity.

Biologic classification of POD24 patients remains an ongoing international research priority to seek actionable targets that might change the natural history of follicular lymphoma and improve survival of patients more likely to have morbidity and death from their disease. Several years ago, in the pre-rituximab era, the Leukemia and Lymphoma Molecular profiling project identified the importance of the follicular lymphoma tumor microenvironment in predicting favorable or poor outcome. The follicular lymphoma tumor microenvironment is composed of tumor infiltrating T cells, regulatory T cells, and lymphoma-associated macrophages. The immune survival score or ISS established that differential expression of gene expression signatures from intratumoral immune cells in the tumor microenvironment affected survival, and particular increased expression of macrophages was associated with poor prognosis.

The impact of the follicular lymphoma immune microenvironment on survival is changing in the current era of chemotherapy combined with antiCD20 immunotherapy, and particularly by available drugs that reverse tumoral immunosuppression by blocking programmed cell death. Studies from solid tumor literature demonstrate that low levels of tumor infiltration immune cells are associated with inferior survival. In follicular lymphoma, then, precise characterization of high or low immune infiltrating cells in the tumor microenvironment may have a critical effect on understanding the mechanisms of POD24. This particular relationship is what Tobin and colleagues investigated in the current study.

In this analysis, targeted gene sequencing using NanoString technology from paraffin-embedded tissue and multi-spectral immunofluorescence on a tissue microarray was applied to two groups: a discovery cohort of 132 patients from Princess Alexandria Hospital with early- and advanced-stage follicular lymphoma who received either chemotherapy or observation and two independent validation cohorts of 198 patients with advanced-stage disease treated with RCHOP and RCVP from the German Low grade lymphoma Study Group and the British Columbia Cancer Agency. They also performed T cell repertoire analysis, flow cytometry, immunofluorescence, and next-generation sequencing.

Here, they defined POD24 as primary refractory disease following treatment, transformation to a more aggressive histology, and relapse within 24 months of diagnosis, which is a more liberal definition from what was initially described in the national lymphocare study but does encompass patients at highest risk of lymphoma-related death.

Gene expression profiling revealed distinct clustering of follicular lymphoma samples based on high or low expression of immune infiltrating cells. Low expression of four immune markers, including PDL-2, TNFalpha, CD4, and CD68 were all associated with poor outcome, but the most specific marker with the highest specificity and sensitivity was PD-L2. They then dichotomized PD-L2 expression into "immune infiltration high" and "immune infiltration low" in subsequent analyses. PD-L2 is an immune checkpoint present broadly on both tumor cells and the tumor microenvironment. To localize its distribution, they performed flow cytometry in fresh FL samples and quantified PD-L2 expression by PCR. They identified that PD-L2 gene expression was distributed in both CD20+ tumor cells as well as non CD20+ cells in the tumor microenvironment. However, the proportion of PD-L2 was lower in the CD20+ cells. Overall, there was lower expression of all immune cells in the immune infiltration low phenotype compare to the immune infiltration high phenotype.

They tested the relevance of immune infiltration and POD24. Consistent with numerous other studies, POD24 events occurred in about 24% of patients. Patients with POD24 events in the Princess Alexandria discovery set were more enriched for the immune infiltration low phenotype. These findings were also validated in the British Columbia cancer agency and German lymphoma study group populations. Nearly 50% of patients with low PD-L2 had POD24 events, compared to 16% in those with high PD-L2, concluding that low PD-L2 identifies a subset of patients enriched for POD24. When evaluating the mutational profiles of those with immune infiltration high versus immune infiltration low based on the m7-FLIPI genes, mutations were detected equally among both populations, suggesting that this mutational profiling is not influenced by the immune infiltration phenotype.

The data presented by Tobin and colleagues makes an important contribution to our understanding of the biological and immune-based mechanism influencing early disease-related events in follicular lymphoma. They demonstrate that reduced immune infiltration is associated with greater chance of POD24. While the sensitivity of this was high, similar to other prognostic markers, it still did not capture the entire subset of future POD24 cases, underscoring the significant heterogeneity within this high-risk patient population. However, there remains opportunity to include PD-L2 as a surrogate for poor risk disease. If further applied to immunohistochemistry or other widespread diagnostic methods, it has the potential for more widespread application. Further validation is still required, particularly to patients treated with novel agents or other immunotherapies. However, the assessment of immune infiltration as described by these findings appears to be an encouraging step in determining risk of POD24.

This concludes this JCO Podcast. Thank you for listening.

MYC Rearrangements in Diffuse Large B-Cell Lymphoma: Impact and Implications for Diagnostic Testing Nov 20, 2019

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This podcast summarizes the findings of the Lunenburg Lymphoma Biomarker Consortium systematic evaluation of MYC rearrangements in DLBCL, and discusses the prognostic impact of MYC, BCL2 and BCL6 rearrangements, and implications for FISH testing in newly diagnosed DLBCL.

TRANSCRIPT

This JCO Podcast provides observations and commentary on the JCO article "Prognostic Significance of MYC Rearrangement and Translocation Partner in Diffuse Large B-Cell Lymphoma - A Study by the Lunenburg Lymphoma Biomarker Consortium" by Rosenwald et al. My name is Jeremy Abramson, and I am an attending physician at the Massachusetts General Hospital and an Associate Professor of Medicine at Harvard Medical School. My oncologic specialty is lymphoma.

MYC rearrangements occur in approximately 10% of diffuse large B-cell lymphomas and have been associated with a worse prognosis. When the MYC translocation occurs in concert with translocations of BCL2, BCL6, or both, initial series have suggested particularly poor outcomes with few patients achieving long term survival with conventional therapies. This entity has been classified in the current WHO classification as high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6 and is more conventionally known as double (or triple) hit lymphoma. Though initial series painted a grim prognosis for these patients, more recent larger series have suggested that approximately 40% of double hit lymphoma patients may be cured, and that outcomes may be improved with more intensive regimens such as dose-adjusted EPOCH-R. Most of these published series to date, however, continue to be limited by significant selection bias whereby cases with the most aggressive clinical or histopathologic features are likelier to be tested for MYC translocations, thus potentially excluding more prognostically favorable patients. The small size of series to date has also made it difficult to assess more granular questions in MYC translocated diffuse large B cell lymphoma, hereafter referred to as DLBCL, such as the prognostic impact of MYC translocations when occurring without other translocations, the impact of translocation partner with MYC (Ig or non-Ig gene locus) in double hit lymphoma, and the significance of MYC/BCL6 double hit lymphomas which are far less common than MYC and BCL2. Another practical question is who should we be testing for MYC translocations in the first place? Do we need to test every new case of DLBCL? Or should we routinely test only an enriched population, such as those with MYC protein expression by immunohistochemistry, or GCB-like DLBCLs, which include the majority of double hit lymphomas?

In the article that accompanies this podcast, the Lunenberg Lymphoma Biomarker Consortium presents the single largest and most systematic analysis to date of MYC translocations in DLBCL, and sheds significant light on many of the most outstanding questions in this population. The Consortium studied over 2000 cases of DLBCL with available tissue and clinical data, drawn from large prospective cooperative group studies as well as population-based registries in Canada, the United Kingdom and the United States. The median age of the cohort was 66 years, and the median follow up was mature at greater than 6 years. All patients were treated with R-CHOP or R-CHOP-like therapy. MYC rearrangements were found in 11% of patients. One third of these occurred as a sole rearrangement, 39% in concert with a BCL2 rearrangement, 15% with a BCL6 rearrangement, and 12% with both (i.e. triple hit lymphoma).

Patients with MYC rearrangements had higher risk features by the IPI score than the entire DLBCL population, and patients with double/triple hit lymphoma had higher clinical risk factors than patients with MYC rearrangements alone. Patients with double or triple hit lymphoma had a significantly inferior outcome in terms of both progression free and overall survival compared to the overall DLBCL cohort, while no negative prognostic impact was conferred by a MYC translocation alone. Notably, the prognostic impact was only observed in the first 2 years from diagnosis. They also compared the 31 MYC/BCL6 double hit patients with 82 MYC/BCL2 double hits, and found similar outcomes in the groups, validating that MYC/BCL6 double hit lymphomas should be considered high risk along with their BCL2 translocated counterparts. Prognosis for triple hit lymphoma was no worse than double hit lymphoma. Perhaps most striking, however, was how well double and triple hit lymphoma patients did when compared to previously published retrospective studies. In this comprehensive evaluation by the Consortium, approximately 60% of double and triple hit lymphoma patients remained progression free beyond 5 years, and two thirds remained alive. These remarkable data suggest that the majority of double and triple hit lymphomas identified by broad screening of the DLBCL population may be cured with chemoimmunotherapy and should offer encouragement to patients and providers alike. Importantly the Consortium's analysis includes only patients with DLBCL morphology, so excluded double/triple hit patients with Burkitt or Burkitt-like histology who may have an inferior outcome compared to the double hit lymphoma patients in this analysis.

MYC and BCL2 protein expression (so called dual expressor lymphomas) was also analyzed in 1414 cases with available tissue. MYC (≥40%) and BCL2 (≥50%) co-expression was associated with an inferior outcome compared to he general DLBCL population, though better than double/triple hit lymphomas, and notably the majority of dual expressor patients remained free from progression and alive at greater than 2 years of follow up after treatment with R-CHOP-like therapy. On evaluation by cell of origin, patients with GCB-like DLBCL had a slightly more favorable outcome compared to non-GCB, as defined by immunohistochemistry. GCB-like DLBLC more commonly had MYC rearrangements, and exclusively contained the MYC/BCL2 subset of double hit lymphoma, while MYC/BCL6 cases occurred within both cell of origin subgroups.

These robust data from this large systematic analysis address several pressing questions regarding MYC-rearranged DLBCL. First, they tell us that a MYC rearrangement in the absence of a rearrangement of BCL2 and/or BCL6 does not predict an adverse outcome in DLBCL and may be treated as a routine DLBCL with R-CHOP-like therapy. Second, we learn that MYC translocation partner in the setting of a double/triple hit lymphoma matters, with the negative prognosis driven by MYC/Ig translocations rather than MYC rearranged with a non-Ig partner which does not appear to confer negative prognostic influence. Third, while MYC/BCL6 double hit lymphomas are uncommon, they appear to predict similarly inferior outcomes as MYC/BCL2 double hit lymphomas and triple hit lymphomas. And fourth, very importantly, the outcome of double/triple hit DLBCL, though inferior to the entire DLBCL population, appears much better than previously estimated with approximately two thirds of patients achieving long term progression free and overall survival when treated with standard chemoimmunotherapy. It warrants emphasis that this applies to cases morphologically classified as DLBCL, not necessarily to cases with Burkitt-like or blastoid features which were not included in the LLBC study and likely have a less favorable outcome. For this reason, it is essential that pathologists signing out cases as aggressive B-cell lymphoma with translocations of MYC and BCL2 and/or BCL6 also indicate the morphologic subtype as DLBCL versus a higher grade appearance as this information will be essential for clinicians in applying the LLBC findings to prognostication in the clinic.

Finally, this study provides us critically needed guidance in determining which cases warrant evaluation with fluorescence in situ hybridization (FISH) to detect MYC, BCL2 and BCL6 rearrangements. Presently, practice patterns are mixed with some centers testing all cases for MYC, while others test only enriched populations such as GCB-like DLBCL or double expressor DLBCL, and still other centers not routinely evaluating MYC at all in DLBCL. The Consortium data validate that MYC translocations in DLBCL affect a sufficient proportion of the population and confer sufficient prognostic importance as to warrant testing. They also show us that conventional immunohistochemistry for either cell of origin or MYC/BCL2 double expression status are not sufficient to direct FISH testing. Testing only GCB-like DLBCL would indeed identify all cases of MYC/BCL2 double hit lymphomas but would fail to identify a significant proportion of MYC/BCL6 double hit cases. Performing FISH only on cases meeting current immunohistochemical thresholds for MYC and BCL2 double expressor lymphomas would fail to identify more than one quarter of cytogenetically defined double hit lymphomas, which would also be unacceptable. These data therefore support testing all newly diagnosed cases of DLBCL and high-grade B-cell lymphoma with FISH for MYC. A positive FISH assay for MYC should prompt reflexive testing for both BCL2 and BCL6, which would then differentiate cases of single hit cases with MYC translocations alone from the higher risk double and triple hit lymphoma patients.

The fact that the prognostic impact of double and triple hit lymphoma is seen only within the first 2 years from diagnosis underscores the need to optimize upfront therapy in these diseases. The data from the Lunenburg Lymphoma Biomarker Consortium suggest that R-CHOP-like therapy remains an acceptable standard of care in double expressor lymphomas, DLBCL cases with isolated MYC rearrangements, and perhaps even double/triple hit lymphomas with DLBCL morphology, though these cases have increasingly been treated with more intensive regimens such as dose-adjusted EPOCH-R or Burkitt-like regimens based on prior series. In the absence of data clearly supporting one approach versus the other, I would consider either intensive approaches or standard R-CHOP as reasonable considerations in cases of double hit lymphoma with DLBCL morphology and should be individualized to the patient. Ultimately, we would like to overcome biological liabilities with biologically directed therapies, and the US Intergroup is now conducting a randomized clinical trial evaluating chemoimmunotherapy with or without the BCL2 inhibitor venetoclax specifically in double hit and double expressor lymphomas, with the chemoimmunotherapy backbone being dose adjusted EPOCH-R for double hits, and R-CHOP for double expressors. Participation in this important study is encouraged.

This concludes this JCO Podcast. Thank you for listening.

Centralization of High-Risk Surgery: Real Benefits for Patients From Health Systems Nov 10, 2019

Show notes

This podcast discusses the work of Sheetz and colleagues describing the impact of centralization of high-risk cancer surgery within health care systems and networks in the United States.

TRANSCRIPT

This JCO Podcast provides observations and commentary on the JCO article "Centralization of High-Risk Cancer Surgery Within Existing Hospital Systems" by Sheetz et al. My name is Stephen Edge, and I am Vice President of Healthcare Outcomes and Policy and Professor of Surgery and Oncology at the Roswell Park Comprehensive Cancer Center and the University at Buffalo in Buffalo, NY. My oncologic specialty is surgical oncology.

Recent years have seen substantial consolidation of hospitals and practices into networked care systems. The benefits of health networks may include efficiencies of scale, better ability to thrive in the shifting health care economy, and enhanced quality.

In the article that accompanies this podcast, Dr. Sheetz and colleagues at the University of Michigan studied the impact of health care networks on the outcome of high-risk cancer surgeries for pancreas, esophagus, lung, colon and rectal cancer. They examined the distribution of these surgeries in health care networks, and the relationship between outcomes and the degree of centralization of surgeries to a high-volume network hospital.

There is a well-established relationship between hospital case volume and operative mortality for complex cancer surgery, most pronounced for pancreas and esophagus cancer. Some countries now mandate regionalization of these procedures to high volume centers. Most, but not all, studies show that regionalization improves outcomes for these procedures. Organized regionalization of cancer surgery in the United States has been limited though market forces have led to some consolidation of high-risk surgeries. This has been encouraged through recommendations of the Leapfrog Group that for the last 25 years has set minimum hospital volume standards for high risk surgeries.

Sheetz and colleagues used the Medicare Provider Analysis and Review (MedPAR) files that include all beneficiaries of Medicare Part A to identify persons age 65 and older undergoing pancreatectomy, esophagectomy, lung resection, colectomy and proctectomy for the years 2005 – 2014. They used American Hospital Association data to identify hospital characteristics such as size, teaching status and which hospitals are in the same health system if any. They combined these data with information from the National Inpatient Sample to derive estimates of the total number of cases of each type beyond Medicare beneficiaries.

They defined a "high volume hospital" and "high volume system" as one that met the Leapfrog Group volume criteria; and centralization of surgery as the proportion of surgeries of each type performed at the highest volume hospital in a given health network. Outcomes assessed were 30-day mortality after surgery, major complications, and hospital readmission.

The procedures most centralized in networks were pancreatectomy and esophagectomy with a mean of 71% and 51%, respectively. However, for pancreas surgery 74% and for esophagus surgery 84% of systems did not meet or have a hospital that met the Leapfrog Group volume recommendations for pancreatectomy.

Complications were about 20% lower for pancreas and esophagus surgery at health systems with the highest surgery centralization. The impact on complications of lung and colorectal surgery was less. More important was the reduction in risk-adjusted 30-day mortality. For pancreas and esophagus surgery the mortality at the most centralized systems mortality was 60% and 53% lower, respectively, then the least centralized systems. The absolute rates dropped from 8.9% to 3.7% for pancreas and 10.3% to 4.8% for esophagus surgery. The reduction for lung resection was less and there was no significant mortality difference for colorectal surgery. Importantly, the team observed the same level of reduction associated with system surgery centralization for low volume and high-volume systems, and those with and without a high-volume hospital.

Certainly, this study is not without its limitations. Because the MedPAR files include primarily fee-for-service Medicare, they had to estimate the total number of cases. They did not have specific information on the health systems or the distance of patients from a high-volume center. They did not know the systems' governance relationships or the degree of coordination between system hospitals, services and providers.

However, the study reinforces the well-established volume-outcome relationships in the context of hospitals with common governance. While individual surgeons may be excellent at low volume hospitals the finding of a greater relative impact on mortality than complications suggest that it not just the surgeon, but that high-volume hospitals with their larger teams and resources are less likely to "fail to rescue" a patient with a major complication. This was realized within these health systems.

Networks with a common governance and shared financial and reputation risk should be motivated to assure best outcomes and limit inefficiency. Networks have central program oversight and should pay more heed to factors that impact quality and have the ability to foster providing the right care at the right place. They also should be more attuned to the needs of their customers and their unique geographic and economic situations and can meet the needs of people in dense metropolitan areas and the vast expanses of rural America.

However, referral to the network flagship cannot be a one-way street. Health systems should establish programs that address these cancers across the continuum of the disease. Evidence shows that some of those who might benefit from these high-risk surgeries never see a team to help determine this. Conversely, many or people with pancreas, esophageal and lung cancer present with disease not amenable to surgery. It makes sense for a health system to assure that all patients with these cancers get a full, multidisciplinary evaluation and that those who cannot have resection receive appropriate referral or return to providers close to home who can provide the necessary care, clinical trials, and supportive services.

When the volume/outcome associations were first described, organized medicine was slow to address the issue and instead tried to fathom what factors led to better outcome with volume. In the absence of policy and professional leadership, market forces slowly changed practices so that now many or most of the very high-risk procedures are done at high volume centers. But this has taken 30 – 40 years and likely impacted many lives. Conversely, surgeons and policy makers have led the charge to regionalize other high-risk services such as trauma care, cardiac surgery, and pediatric surgery. The findings of Sheetz et al. support renewal of efforts in policy and practice to assure cancer patients receive the best options.

Sheetz and colleagues are to be congratulated for their insightful work. Despite its inherent limitations, they have shed light on a key area needing attention of health systems, professional societies and policy makers.

This concludes this JCO Podcast. Thank you for listening.

Microsatellite Instability as a Prognostic Marker for Resectable Gastric Cancer and a Potential Biomarker for Perioperative Chemotherapy Benefit Nov 01, 2019

Show notes

Dr. Osama Rahma, an Assistant Professor of Medicine at Harvard Medical School, Dana-Farber Cancer Institute, discusses the role of MSI in gastric cancer.

TRANSCRIPT

This JCO Podcast provides observations and commentary on the JCO article "Individual Patient Data Meta-Analysis of the Value of Microsatellite Instability as a Biomarker in Gastric Cancer" by Pietrantonio et al. My name is Osama Rahma, and I am an Assistant Professor of Medicine at Harvard Medical School, Dana-Farber Cancer Institute in Boston, Massachusetts. My oncologic specialty is Gastrointestinal Cancer and Cancer Immunotherapy.

Despite the advances in surgical approach and perioperative multimodalities in gastric cancer, the recurrence rate remains over 50%. While many patients benefit from perioperative chemotherapy many others don't derive such benefits and experience toxic side effects. Accordingly, there is an unmet need to identify prognostic markers to guide chemotherapy decisions in the neoadjuvant and adjuvant settings. Microsatellite instability has been well established as a prognostic marker in colon cancer that correlates with better overall survival and potential lack of benefit from adjuvant chemotherapy in stage II disease.

The question is whether microsatellite instable gastric tumors have similar behavior? To answer this question, subgroups analyses of patients with MSI high tumors were performed in both the MAGIC and the CLASSIC trials which established perioperative ECF chemotherapy in non-Asian population and adjuvant capecitabine and oxaliplatin in Asia, respectively as the standard of care in resectable gastric cancer. Although MSI tumors were found to be less likely to benefit from chemotherapy, the low incidence of MSI tumors in both trials of 8-10% made it very challenging to draw meaningful conclusions.

In the article that accompanies this podcast, Pietrantonio et al performed individual patient level data meta-analysis testing the prognostic significance of microsatellite instability in both the MAGIC and CLASSIC trials. In addition, the analysis included the ARTIST study, which tested adding radiation to adjuvant capecitabine and cisplatin in Asia and the ITACA-S study which tested adjuvant FOLFIRI, docetaxel and cisplatin vs 5-fluorouracil and folinic acid in Europe in radically resected gastric cancer. The meta-analysis included 1556 patients, 63% Asian and 37% Europeans. Patients were stratified using microsatellite instability status and based on whether they received multimodality therapy in all 4 trials or surgery only in the MAGIC and CLASSIC trials. 7.8% of patients had MSI high tumors and 70.8 % received multimodality treatment.

Consistent with prior reports of individual trials, patients with MSI high tumors had better outcomes compared to MSI low or MSS tumors. Specifically, the 5-year disease free survival rate was 71.8% vs 52.3% and 5-year overall survival was 77.5% vs 59.3%. MSI remained a significant independent prognostic factor for improved disease-free survival and overall survival in a multivariate analysis in addition to Asian ethnicity, low TNM staging, and receiving multimodality therapy. In addition, MSI was noted to be more prevalent in the Asian population and was a better prognostic factor in Asians compared to Europeans.

Importantly, MSI high tumors did not benefit from perioperative chemotherapy with 5-year disease free and overall survival of 70% and 75%, respectively for those who received chemotherapy compared to 77% and 83% for MSI high patients who did not receive chemotherapy. In contrast patients with MSI low or MSS experienced benefit from perioperative chemotherapy compared to surgery alone. Finally, MSI status did not affect post-recurrence survival. However, this was limited by the small number of MSI high patients who experience disease recurrence.

This study has several limitations including its retrospective nature, the relatively small number of patients with MSI high tumors of 121, and the heterogenicity of administered treatment in the 4 trials including different regimens of neoadjuvant and adjuvant chemotherapy with or without radiation. In addition, D1 surgery was performed in Europe while D2 surgery was performed in Asia.

In summary, I think this study supports the adoption of microsatellite testing as a routine biomarker in patients with operable gastric cancer. The result of microsatellite testing should be discussed in a multidisciplinary fashion since perioperative chemotherapy may result in more harm than benefit in MSI high tumors.

This study among others highlights the unique behavior of microsatellite instable tumors which is driven by their unique immune profile including increased T-cell infiltration and activation due to higher mutational load and neoantigens compared to microsatellite stable tumors. PD-1 inhibitors are effective in more than 50% of MSI tumors in the advanced setting and in 15-25% of gastric tumors with positive PD-L1 expression. Accordingly, future clinical trials should stratify gastric cancer patients based on their microsatellite status and PD-L1 expression while incorporating immunotherapy in the early disease setting.

This concludes this JCO Podcast. Thank you for listening.

Radiotherapy Dose Reduction Is Possible With Induction Chemotherapy for Pediatric Nasopharynx Cancer Oct 01, 2019

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This JCO Podcast provides observations and commentary on the JCO article, "Treatment of Childhood Nasopharyngeal Carcinoma with Induction Chemotherapy and Concomitant Chemoradiotherapy: Results of the Children's Oncology Group ARAR0331 Study" by Rodriguez-Galindo et al. My name is Suzanne Wolden, and I am the Director of Pediatric Radiation Oncology at Memorial Sloan Kettering in New York City, USA. My oncologic specialty is Pediatric Radiation Oncology.

This important manuscript summarizes the results of Children's Oncology Group protocol ARAR0331 for childhood nasopharyngeal carcinoma. The study enrolled 111 patients, of whom 75% were male and 47% were African American, with a median age of 15. Eligible patients had AJCC stage IIb-IVC disease and received three cycles of induction chemotherapy with 5-fluorouracil and cisplatin followed by concurrent cisplatin and radiotherapy. Three patients had progressive disease during induction chemotherapy, eight were removed from the study due to physician or parent preference, and another three were not evaluable. This left 97 patients evaluable for response and concurrent chemoradiotherapy. Responses and radiotherapy treatment plans were not centrally reviewed but were left to the judgement of the treating institution.

All patients received 45 Gy to comprehensive head and neck fields encompassing the nasopharynx and bilateral level I-V lymph nodes. A boost to the nasopharynx and residual gross nodal disease was prescribed based on response. The full dose of 70.2 Gy indicated for stable disease was given to 18.6% of patients while 77.3% received the protocol specified dose for complete or partial response of 61.2 Gy or lower. Another 4.1% of patients received intermediate non-protocol doses of 63.9-66.6 Gy. The trial was amended to reduce the cycles of concurrent cisplatin during radiotherapy to two from three after unacceptable rates of renal and gastrointestinal toxicities were reported.

This trial was limited to patients age 18 years and younger and consisted primarily of American patients. It is notable that the demographics of nasopharynx cancer in these young patients differ significantly from adults with this diagnosis. Most patients are teens since nasopharynx cancer is vanishingly rare in younger children. The majority were male, and nearly half were African-American. Nasopharynx cancer is quite rare in teens of Asian descent, in stark contrast to the adult population. In international series, it has been noted that teens in countries around the Mediterranean also have a relatively high incidence of this rare cancer. The study illustrates that pediatric patients are much more likely than adults to have advanced disease and WHO type III, Epstein Barr virus-associated histology.

Despite a lack of central review, the response rate appears to be quite high to induction therapy as one might expect with WHO type III carcinoma. It is surprising that any patients had progressive disease, and I suspect that the rate of partial and complete response may have been even higher than what is inferred from the radiation boost doses given. Nonetheless, the strategy of induction therapy was highly successful in allowing a large majority of patients to receive reduced doses of radiation. It is important to note that all patients received 45 Gy to initial comprehensive fields rather than the 50 Gy typically used for adults and that smaller, more forgiving fractions of 1.8 Gy were used in comparison to the standard 2 Gy for adult head and neck cancer. While some patients received a standard adult boost dose of 70.2 Gy, 81.4% received a lower boost dose. In most cases, this was the protocol specified 61.2 Gy, a 13% dose reduction. Even with these significantly lower doses, local control was exceptionally high, with only 5.5% of patients experiencing local failure with or without a distant relapse.

The successful reduction in radiotherapy doses in this study is incredibly important and by far the most newsworthy aspect of this paper. Even full or nearly grown teens experience dramatically more severe late effects of radiotherapy compared to older adults. The severity of soft tissue fibrosis 10 or more years after full doses of radiation to the head and neck is so great that many patients require feeding tubes and tracheostomies. The rate of second malignancy is also much higher in young patients.

The rate of distant relapse of 10.5% was low, considering that patients with metastatic disease at diagnosis were enrolled. It is possible that with more advanced staging scans such as FDG-PET, metastatic lesions can be more easily detected and defined. In that case, they can be targeted with radiotherapy to decrease the risk of relapse. This approach has been shown to be effective in achieving cure in adults. It is unlikely that an increase in chemotherapy beyond what was used in this protocol would be tolerated or worth the added toxicity. Indeed, it is unclear whether the 3rd cycle of concurrent cisplatin was beneficial since there was only a trend for improved EFS and the cumulative toxicity is significant. One must be mindful that increases in systemic therapy have been shown to decrease tolerance for head and neck radiotherapy. This can be counterproductive to outcome if there are delays, breaks or failure to complete the course of radiation.

This trial was so successful in its ability to decrease radiation exposure in young patients, that we should be inspired to go further. My thoughts regarding the next trial would be to use PET scans for staging and response assessment and to push the radiotherapy doses lower. This approach is currently being investigated for adult HPV associated head and neck cancer with doses as low as 30 Gy. Perhaps in pediatric (or even EBV positive adult) nasopharynx cancer, 30-36 Gy would be enough for the comprehensive initial fields with boost doses in the range of 50-60 Gy for those who respond favorably to induction chemotherapy. Dose reductions of this magnitude would make major differences in the acute and especially the late toxicities. In addition, modern radiation technologies such as proton therapy allow improved avoidance of normal tissue exposure for these young, curable patients.

In summary, this article provides evidence that response-based radiation dose reduction is possible for pediatric nasopharynx cancer. Even with numerous limitations, the outstanding results of this trial inspire us to continue moving forward in the direction of reducing radiation exposure for these young patients. Long-term follow up is also urged to quantify the expected benefits of these therapeutic changes.

This concludes this JCO Podcast. Thank you for listening.

Fine Tuning Therapy for Intermediate-Risk Neuroblastoma Using Clinical Response and Tumor Biology Sep 09, 2019

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This JCO Podcast provides observations and commentary on the JCO article "Maintaining Outstanding Outcomes Using Response and Biology-Based Therapy for Intermediate-Risk Neuroblastoma: A Report From the Children's Oncology Group Study ANBL0531" by Twist et al. My name is Javed Khan, and I am Deputy Chief and Senior Investigator at the Genetics Branch and an Attending for the Pediatric Oncology Branch of the National Cancer Institutes of the NIH in Bethesda, Maryland. My oncologic specialty is Pediatric Hematology Oncology.

Childhood cancer is a life-threatening disease where survival rates have increased exponentially to over 75% over the past three decades. However, this has come at a considerable cost with significant incidence of late effects including hearing loss, scoliosis, hypothyroidism, growth and development delay, infertility, psychological, emotional, cognitive and neurological sequelae, and secondary malignancies. Most of these late effects have been attributed therapy including chemotherapy, surgery and radiation.

In the manuscript that accompanies this podcast, Twist et al report on the results of the Children's Oncology Group study ANBL0531, whose primary aim was to reduce therapy for subsets of children aged <=12 years old, with intermediate-risk neuroblastoma using a biology- and response-based algorithm that assigns the length of treatment duration while maintaining a 3-year overall survival (OS) of >=95% for the entire cohort.

Neuroblastoma is an extracranial pediatric malignancy of neural crest origin that has often been described as an enigmatic cancer due to its significant clinical, molecular and biological heterogeneity. For example, some patients with widely metastatic disease are cured with minimal or no therapy whereas others have relentless progression to death despite intensive therapies. There has been considerable progress in dissecting out the causes of this heterogeneity and developing prognostic biomarkers to stratify the risk based on several clinical, histological and molecular markers. At the time this clinical study was performed, and the manuscript written, the authors stratified patients using several clinical and biologic parameters including age, the International Neuroblastoma Staging System, MYCN amplification status, the International Neuroblastoma Pathology Classification of histopathology, and tumor DNA index. An additional marker utilized in this study was loss of heterozygosity determination of the tumors at chromosome bands 1p36 and 11q23. This stratification strategy has led to the identification of low and high-risk groups where therapy is more clearly defined and patients with low risk have excellent outcome for most patients with surgery alone and watchful waiting. For high-risk disease, significant strides have been made using a combination of surgery, aggressive chemotherapy, radiation followed by Chimeric Antibody 14.18 anti GD2 therapy, GM-CSF, IL-2 and Isotretinoin, however the five-year survival remains guarded at 40-50%. In the intermediate-risk group, the subject of this study, although the 5-year survival rates of 90-95% have been achieved, this group is significantly heterozygous raising the possibility of reducing therapy for subsets of patients within this group. This was the motivation for this study.

Thus, the goal of this clinical protocol, ANBL0531, was to refine the minimal therapy needed to achieve excellent outcomes for patients with intermediate-risk neuroblastoma, with the aim to maintain an overall 3-year OS rate of > 95% for the entire cohort. Patients were stratified into Groups 2, 3, or 4, who were assigned to receive a minimum of 2, 4, or 8 cycles of chemotherapy, respectively. Chemotherapy was identical to that used on a previous study A3961.

Reduction of therapy was planned to be achieved for patients with biologically favorable tumors (Groups 2 and 3) by using the achievement of Partial Response (PR) to chemotherapy +/- surgery to be the endpoint of therapy, rather than the achievement of Very Good Partial Response (VGPR) as was previously used on A3961. If the treatment endpoint was not achieved after completion of the scheduled chemotherapy courses, additional cycles of therapy could be administered, and patients re-evaluated following every 2 cycles to determine if the treatment endpoint has been achieved. VGPR, a more stringent response criteria, was used for Group 4 patients which includes those with age1). These patients also received Isotretinoin (13-cis-retinoic acid, Accutane) for maintenance therapy, as they would have previously received this treatment on high-risk protocols. Thus, these patients would receive a significant reduction in therapy compared to prior studies. These patients were closely monitored by interim stopping rules. Rescue therapy for this study for patients with an inadequate response to initial therapy and for patients with progressive, non-metastatic disease utilized standard cyclophosphamide and topotecan.

Reduction of therapy was also planned and achieved on their study by reducing potential surgical morbidity for patients with stage 4S disease, who would no longer be required to undergo resection of their primary tumor.

In the manuscript, the authors report that 404 evaluable patients were enrolled between 2007 and 2011, They found that compared to legacy COG studies, subsets of patients with locoregional disease, infants with stage 4 or 4S tumors, and toddlers with stage 3 or 4 disease had a reduction in treatment. The 3-year event-free survival (EFS) and OS were 83.2±1.9% and 94.9±1.1%, respectively.

Infants with stage 4 favorable biology tumors (n=61) had superior 3-year EFS compared to patients with >= unfavorable biological feature (n=47; 86.9±4.4% versus 66.8±7.0%; p=0.02), with a trend towards OS advantage (95.0±2.8% and; 86.9±5.1% respectively p=0.08. For patients with localized disease OS was 100%.

They conclude that comparable/excellent survival was achieved with this biology- and response-based algorithm, with reduction of therapy for subsets of intermediate-risk neuroblastoma patients.

However, more effective treatment strategies are still needed for infants with unfavorable biology stage 4 disease. For the 32 infants with hyperdiploid, favorable histology (FH) stage 4 tumors with LOH at 1p36 or 11q23, or missing LOH data, intensification of treatment on ANBL0531 compared to A396110 did not reduce the risk of relapse previously reported for infants with tumors that harbor these genetic anomalies. Three-year EFS for this cohort was 68.6% (95% CI: 52.2-85.1%) versus 86.9% (95% CI: 78.3-95.4%) for stage 4 infants with favorable biology (p=0.04). Overall survival was not significantly different, indicating that many of the infants with 1p36/11q23 aberrations were successfully salvaged. Of the 20 patients who received CPM/TOPO due to an inadequate response to initial therapy, 9 achieved ≥VGPR. However, 6 of the 20 patients developed PD or relapsed, and 1 died, indicating that more effective treatment is needed for patients who do not meet the defined treatment endpoint after 8 cycles of chemotherapy.

Take home messages:

This is an important study with clinical implications for intermediate-risk neuroblastoma where the authors show that it is possible to reduce therapy based on a clinical Partial Response (PR) endpoint compared to Very Good Partial Response (VGPR). This most likely reflects the biology of the disease such that tumors that are responding to therapy will continue to involute. However, more effective therapy is needed for those patients who develop progressive disease (PD) or relapse or do not meet the defined treatment endpoint after 8 cycles of chemotherapy as these patients continue to have poor outcome.

This will await the result of current biological and genomic studies and the development of novel therapies targeting ALK or RAS, or epigenetic targeting of MYC or MYCN activated tumors, or immunotherapeutic approaches such as adoptive cell therapies consisting of chimeric antigen receptor (CAR T cell) or, NK cells, or the use of immunocytokines such as hu14.18-IL2 or antibody drug conjugates. All these holds promise for future sub-stratification and new therapies for children with intermediate and high-risk neuroblastoma.

This concludes this JCO Podcast. Thank you for listening.

Déjà Vu or Predicted: The Failure of Dose Adjusted EPOCH-R to Improve Outcomes in Diffuse Aggressive Lymphomas Jul 03, 2019

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This JCO Podcast provides observations and commentary on the JCO article "Dose-Adjusted EPOCH-R Compared to R-CHOP as Frontline Therapy for Diffuse Large B Cell Lymphoma: Clinical Outcomes of the Phase III Intergroup Trial CALGB 50303 (Alliance)" by Bartlett et al. My name is Patrick Stiff, and I am Division Director of Hematology-Oncology at Loyola University Stritch School of Medicine in Maywood, Illinois. My oncologic specialty is hematologic malignancies and stem cell transplantation.

CHOP has remained the chemotherapy backbone of choice for the treatment of diffuse aggressive non-Hodgkin lymphoma since the 4 arm randomized SWOG study was performed 25 years ago1. Since then, only the addition of rituximab has improved patients' outcome2. Investigators have tried to improve outcomes by employing other strategies like increasing drug intensity, shortening the interval between cycles, adding newer agents, changing the method of administration, and adding transplantation, but none clearly demonstrated a survival advantage.

Among these strategies is an infusional one designed to increase apoptosis and inhibit BCL6 and p-glycoprotein in resistant cells. While SWOG tested infusional CHOP in 2001 and found no difference in outcomes, compared to bolus CHOP3, the NCI group has explored a modified CHOP infusional regimen known as EPOCH consisting of etoposide, vincristine, and doxorubicin given simultaneously as a continuous 4 day infusion with a bolus dose of cyclophosphamide at the end of the 4 days along with daily oral prednisone Combined with aggressive dose escalations based on nadir myelosuppression, they tested this regimen with rituximab, EPOCH-R, reporting an impressive 5 year PFS of 79% in an unselected study of 72 patients from 3 centers4. Based on this, 18 CALGB institutions treated 69 patients with dose adjusted EPOCH-R, demonstrating a similar 62 month TTP of 81%, with an impressive 100% TTP for the germinal center B cell subgroup as defined by the Hans algorithm, all seemingly superior to R-CHOP5. Equally impressive was a Phase II study in mediastinal B cell NHL with a 5-yr EFS of 93% administered without consolidative radiotherapy, added frequently to R-CHOP6. Therefore, a head-to-head comparison was the natural next step.

The trial that accompanies this podcast was designed to compare the PFS and OS at 3 years between patients treated with 6 cycles of dose adjusted EPOCH-R to the standard R-CHOP. The trial opened in 2005 and enrolled 524 patients with either DLBCL, primary mediastinal BCL or intravascular large cell NHL over an 8+ year period to its close in 2013. Seventy-four % had stage III/IV disease and 12% high IPI disease. Eighty-eight percent of the R-CHOP and 82% of the dose adjusted EPOCH-R cycles were administered with 75% of the dose adjusted EPOCH-R patients receiving initial dose escalations per protocol. At a median follow-up of 5.2 years the 5 year PFS and OS were 66 and 85% for the R-CHOP treated patients no different from the 68 and 77.5% for the dose adjusted EPOCH-R patients. Prognostic factors for PFS were age > 60, IPI, and double expressers (15.6% of the 270 with complete data) for MYC, BCL-2 and BCl-6.

There were a number of post hoc subgroup analyses performed. Of these, the PFS for the combined High and High intermediate IPI group was higher for the dose adjusted EPOCH-R group (p = 0.041) but no difference in OS was noted. In none of the other subgroups was a benefit seen for dose adjusted EPOCH-R including CNS relapses, mediastinal B cell NHL, double expressors or those with MYC positivity although percentages of these subgroups were small. There were however significantly increased grade III-IV myelotoxic and non-myelotoxic complications for the infusional regimen.

Should we take these results as the final word on the lack of a benefit of dose adjusted EPOCH-R in the treatment of DLBCL? In other words is this a case of "déjà vu all over again"?. This trial recruited slowly, 524 patients over more than 8 years, with 2 (20% of the phase II study5) were excluded. Second there was the requirement for submission of fresh/frozen material including a second biopsy if needed thereby likely eliminating mostly patients with rapidly progressing disease. Together possibly with some investigator bias, given the promising Phase II data, there was a decrease in High IPI enrollment of only 12% versus the 20% in the Phase II study, which extended to other high risk patients including double expressors, C-Myc positive, and mediastinal B cell disease. Combined these led to the 3 year PFS for R-CHOP of 72%, 17% better than the planned outcome. However, considering the trial exclusions, and ultimately a PFS similar to that of other recent R-CHOP experiences7,8 one could argue that the 3-yr 55% PFS endpoint for this trial was far too conservative.

While the R-CHOP PFS was 17% better than planned, the dose adjusted EPOCH-R 5-yr PFS was 7% worse than the Phase II results, which is difficult to explain considering the earlier studies, in which the more favorable patients did better5. A lower administered dose intensity compared to prior studies4,5 was not apparent with the incidence of grade III/IV febrile neutropenia and neurotoxicity similar to the Phase II trial. However 82% vs 91% of those in the Phase II study completed all dose adjusted EPOCH-R cycles with the decrease mostly due to on treatment deaths and AEs, suggesting that when used in a more 'real world setting' this regimen is more toxic than initially seen. Might those who completed therapy also have had dose reductions or delays that could also have impacted PFS? Finally, this report does not include PFS based on cell of origin(COO), which for patients with germinal center B cell of origin in the Phase II study was 100%. Perhaps the germinal B cell percentage was lower than in the Phase II studies as well.

So what can be concluded about these negative results? The authors conclude that there was a "potential patient selection bias", at least partially explainable by trial design, and that this "may preclude generalizibility….to specific subgroups". I would conclude that given the outcome and toxicity data, for the low and low intermediate IPI patient, R-CHOP remains the treatment of choice. The post hoc PFS improvement for the high risk subgroup might argue for dose adjusted EPOCH-R, but the lack of an OS advantage in this subgroup needs to be acknowledged. However, other compelling phase II studies in high risk subsets, e.g double hit, underrepresented in this trial, still makes the efficacy of dose adjusted EPOCH-R in certain circumstances an open question.

This concludes this JCO Podcast. Thank you for listening.

Tackling Stage III EGFR Mutation-Positive Lung Cancer: Do We Really Know How? Jul 02, 2019

Show notes

This JCO Podcast provides observations and commentary on the JCO article "Erlotinib Versus Gemcitabine Plus Cisplatin as Neoadjuvant Treatment for Stage IIIA-N2 EGFR-Mutant NSCLC (EMERGING-CTONG 1103): A Randomized Phase II Study" by Zhong et al. My name is Tony Mok, and I am a Professor of Clinical Oncology at the Chinese University of Hong Kong in the Prince of Wales Hospital in Hong Kong. My oncologic specialty is Medical Oncology.

With the advent of molecular targeted therapy, patients harboring driver oncogenes may now survive longer and better than before, and EGFR mutation is the prime example of such achievement. However, evidence for "cure" of patients with metastatic EGFR mutation positive lung cancer remains scanty. In contrast, It may be more reasonable to first attempt cure of patients with earlier stage disease using molecular targeted therapy. CTONG 1103, published in this issue of Journal of Clinical Oncology, is the first randomized study comparing neoadjuvant erlotinib with chemotherapy for patients with stage IIIA EGFR mutation positive lung cancer.

CTONG 1103, the report that accompanies this podcast, is not an easy study to conduct. Between December 2011 and December 2017, investigators from 17 centers across China managed to screen 386 patients with stage IIIA non-small cell lung cancer (NSCLC) and identified only 72 (which is about 19%) eligible EGFR mutation positive patients. They were randomized to receive either erlotinib 150mg daily for 42 days or two cycles of chemotherapy using gemcitabine and cisplatin as neo-adjuvant therapy. After neoadjuvant therapy, 73% of the erlotinib arm, and 63% of the chemotherapy arm, received curative surgery, including two patients in erlotinib arm who received pneumonectomy. The primary endpoint of this study is tumor response rate, which is 54.1% for erlotinib and 34.3% for chemotherapy. However, the odds ratio of 2.26 for tumor response rate was not statistically significant. Two other important and impactful endpoints include major pathological response and progression free survival (PFS). Major pathological response is defined as less than 10% residual viable tumor cell and it occurred only in 10.7% of patients who received erlotinib and none with the chemotherapy. But on the other hand, PFS was significantly better with erlotinib arm, reporting median of 21.5 month comparing with 11.4 months with chemotherapy arm.

In reference to the primary endpoint of tumor response rate, we should conclude that CTONG 1103 is a negative study. Zhong et al has reasonably estimated the sample size based on a presumptive response rate of 70% in the erlotinib arm and 36% in the chemotherapy arm. The reported response rate at 54.1% with erlotinib in this study has significantly fallen short of the expected rate of 70%, which was actually the widely accepted response rate in patients with stage IV disease. The authors selected to offer 42 days of neo-adjuvant erlotinib in order to match the two cycles of neo-adjuvant chemotherapy. While there is no biologic reason to explain the low response rate in earlier stage disease, the shorter duration of treatment may contribute to the relatively lower response rate. The other important outcome is the major pathological response of 10.7% with neo-adjuvant erlotinib, which is supposed to be a surrogate for overall survival. Hellman et al were among the first groups to suggest the predictive power of major pathological response for neo-adjuvant chemotherapy for patients with early stage lung cancer. The lower than expected major pathological response may be considered a surrogate indicator for overall survival but it is more important to wait for the mature survival outcomes.

A negative study can still be impactful. This study has established the feasibility of neo-adjuvant EGFR TKI for patients with potentially resectable EGFR mutation positive lung cancer. The first single arm phase II study on pre-operative gefitinib published in 2009 in the Journal of Clinical Oncology enrolled 36 patients but only 6 harbored the activating EGFR mutations. Tumor response was observed in 4 patients and all were positive for the mutations. Another single arm study published in 2018 in the journal The Oncologist enrolled 19 patients with EGFR mutation positive stage IIIA NSCLC and treated with neoadjuvant erlotinib for 56 days. Tumor response rate was 42.1% and resection rate was 68.4%. Only 5 of the 14 patients (35.7%) with surgical resection had documented pathologic downstaging from N2 to N0/N1 disease. The median PFS and OS was 11.2 and 51.6 months respectively. CTONG 1103 is the first and only randomized comparative study that confirmed the feasibility and efficacy of neo-adjuvant EGFR TKI. Tumor response rate is higher than chemotherapy by 20% although not statistically significant, but toxicity profile is better, which is an established fact from multiple phase III studies on advanced stage disease. The resection rates were similar between the two arms but it was unclear how many of the enrolled patients had unresectable disease prior to neo-adjuvant therapy. Key objectives of neo-adjuvant therapy are to down-stage tumor/nodal disease and to improve resectability. This randomized study may potentially document if erlotinib is more capable of converting unresectable stage IIIA disease to being resectable, however, this data is not currently available.

The authors of the current study have also reported improvement in progression free survival, but we cannot conclude that the improvement is solely due to the neo-adjuvant therapy. As per study protocol, patients from neo-adjuvant EGFR TKI arm did receive 12 months of erlotinib as adjuvant therapy while the chemotherapy arm received only 2 more cycles of similar treatment. Considering the duration of therapy, the adjuvant erlotinib may in fact contribute more to prolongation of progression free survival than the neo-adjuvant therapy. In 2017 in the journal Lancet Oncology, the same group of investigators have reported a randomized phase III study comparing adjuvant gefitinib with chemotherapy and the median disease free survival was 28.7 months and 18.0 months, respectively. All patients enrolled in this study had resectable lung cancer with over 60% of patients having N2 disease, and the authors had concluded on the potential survival advantage of adjuvant EGFR TKI. Thus, the improvement in progression free survival should be explained by both neo-adjuvant and adjuvant erlotinib.

In summary, CTONG 1103 is a negative study but it has significant impact on management of stage IIIA EGFR mutation positive lung cancer. With high screening failure rate at 80%, it took the authors 6 years to enroll 72 patients. This study will remain the only randomized study on this patient group for a long time as similar large scale phase III trials of this strategy will be unlikely. Clinicians are obligated to share and explain CTONG 1103 to patient with stage IIIA EGFR mutation positive lung cancer. For patients with resectable disease at presentation, the benefit of neo-adjuvant EGFR TKI may be debatable. But for patients with un-resectable stage IIIA disease, neo-adjuvant EGFR TKI may potentially downstage the disease status and facilitate resection.

This concludes this JCO podcast. Thank you for listening.

The Need for Continued Vigilance in Patients with Diffuse Large B-Cell Lymphoma Jun 06, 2019

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This JCO Podcast provides observations and commentary on the JCO article 'Late Relapses in Patients With Diffuse Large B-Cell Lymphoma Treated With Immunochemotherapy' by Yang et

My name is Ann LaCasce, and I am an Associate Professor of Medicine at the Dana-Farber Cancer Institute in Boston, USA. My oncologic specialty is lymphoma.

This podcast discusses the recent paper evaluating the risk of late relapse in patients with diffuse large B-cell lymphoma who are event free 24 months after diagnosis.

The goal of upfront chemoimmunotherapy in patients with diffuse large B-cell lymphoma (DLBCL) is the permanent eradication of disease. In the era of rituximab, few studies with sufficient follow-up have examined the risk of late recurrence. An analysis of patients with DLBCL from the University of Iowa/Mayo and validated in a separate cohort from the French Study Group of Adult Lymphoma demonstrated that patients who were alive and disease free at 24 months from diagnosis had overall survival rates equivalent to the age and sex matched general population. Despite this finding suggesting cure, late relapses are not uncommon.

In this manuscript, patients enrolled in the Molecular Epidemiology Resource of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence with newly diagnosed diffuse large B-cell lymphoma or DLBCL with concurrent indolent lymphoma were identified. 847 of the 1324 patients treated with chemoimmunotherapy with or without radiotherapy between 2002 and 2015 were event free at 24 months. These patients were subsequently analyzed for late relapse. The majority of patients (87%) had DLBCL without evidence of co-existing indolent lymphoma.

With a median follow-up of 62.9 months, 78 patients developed recurrent disease, and the cumulative incidence of late relapse was approximately 7% at 3 years, 9% at 5 years and 10 % at 8 years after achieving EFS24. Of the patients who developed recurrent lymphoma, 55 had DLBCL alone at baseline and 23 had DLBCL with concurrent indolent lymphoma. Among the patients with DLBCL alone. 36 developed recurrent DLBCL and 13 ad indolent lymphoma (12 with follicular lymphoma and 1 with marginal zone lymphoma). 6 patients did not have pathologic confirmation of disease subtype at the time of recurrence. For the 59% of patients with cell of origin data determined using the Hans algorithm, rates of relapse in patients with DLBCL alone did not differ between those with germinal center derived (GCB) versus non-GCB subtypes. Individuals with GCB DLBCL were more likely to relapse with indolent lymphoma. Of the 23 patients with concurrent indolent lymphoma at baseline, 9 relapsed with DLBCL and the remaining 11 relapsed with indolent lymphoma 10 of whom had the same subtype at initial presentation (7 with follicular lymphoma, 1 marginal zone lymphoma, 1 chronic lymphocytic leukemia, one unspecified). One patient who had current DLBCL and FL relapsed with MCL and the subtype was unknown in 3. Patients with concurrent indolent lymphoma at initial diagnosis were more likely to experience late relapse which was driven by indolent recurrence. In multivariable analysis, concurrent indolent lymphoma and GCB subtype were independent predictors of relapse. In patients with DLBCL alone, GCB subtype was associated with indolent relapse but not DLBCL relapse. Advanced stage and higher IPI score were associated with higher risk of recurrent DLBCL but not indolent relapse. In terms of outcome, median survival after recurrence was approximately 39 months after EFS24, 30 months for those with DLBCL and the median was not reached in patients with indolent lymphoma.

This study emphasizes the importance of long- term follow-up of our patients with DLBCL. Hematologists/oncologists typically see patients frequently after the completion of initial therapy but over time, visits become less frequent or not at all for some patients who remain in remission beyond the 5 year mark. Multiple studies have examined surveillance strategies in this setting. The likelihood of identifying recurrent disease in an asymptomatic patient with a normal physical exam is extremely low. In addition, there is no clear evidence that surveillance imaging or early detection of an asymptomatic recurrence impacts on overall survival. This is particularly true for patients who relapse with indolent disease, some of whom may be followed expectantly. Others may be candidates for low-dose palliative radiation or reduced intensity therapies. The National Comprehensive Cancer Network Guidelines , which are widely used by physicians as well as payors to determine insurance coverage, recommends symptom guided imaging in patients with a history of early stage DLBCL and CT scans no more often than 6 months for up to 2 years after the completion of therapy in patients with advanced stage disease. Imaging is associated with false positives, radiation exposure and is expensive for our health care system. In addition, anxiety associated with scans is common and may have negative impact on patients.

None-the-less, given that recurrences do occur, educating survivors and their physicians, including primary care providers, to be vigilant for the development of persistent symptoms without clear explanation, as well as B symptoms and lymphadenopathy is important. Setting expectations with patients is also essential, as is caution in using the term cure. Although the vast majority of patients who remain in remission beyond 2 years after the completion of initial therapy are likely to remain disease free, a small minority will go on to develop recurrent aggressive or indolent lymphoma. In patients with GCB subtype of DLBCL, discussion of the risk of the subsequent development of an indolent lymphoma may be warranted. Future studies examining changes in cell free DNA during and after therapy, as well as the development of other novel biomarkers may eventually allow us to be more accurate in our prognostication for patients. In addition, understanding the biology of late recurrence to ascertain whether the recurrence represents the original clone or is distinct may ultimately be important for therapeutic approaches and outcome.

This concludes this JCO Podcast. Thank you for listening.

A Second Chance at Checkpoint Inhibition After Initial Immune-Mediated Diarrhea and Colitis Jun 06, 2019

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This JCO Podcast provides observations and commentary on the JCO article "Resumption of Immune Checkpoint Inhibitor Therapy After Immune-Mediated Colitis" by Abu-Sbeih et al. My name is David Oh, and I am an Assistant Professor at the University of California, San Francisco. My oncologic specialty is genitourinary medical oncology and cancer immunotherapy.

While immune checkpoint inhibitors, or ICIs, can lead to durable responses even when other standard therapies have failed, their therapeutic window is often limited by immune-related adverse events or IRAEs which are thought to be autoimmune in nature. Immune-mediated diarrhea and colitis are a frequent IRAE with ICIs, affecting up to a third of patients receiving anti-CTLA-4, approaching half of patients receiving anti-CTLA-4 in combination with anti-PD-1 or anti-PD-L1, and less frequently patients receiving anti-PD-1 or anti-PD-L1 alone. Since there is often overlap between IRAEs and response or survival with ICIs, and IRAEs such as colitis can require interruption of treatment and immunosuppression in patients who may have failed other treatment options, many providers are faced with an important question: is it safe to resume ICIs after patients have initial diarrhea and colitis, and what are the risk factors for another episode of diarrhea and colitis?

To address this question, which has not been well studied, Abu-Sbeih and colleagues in this issue of JCO performed a retrospective multicenter analysis of patients who had initial immune-mediated diarrhea and colitis requiring ICI interruption, and then subsequently resumed ICI from 2010 to 2018. From a starting population of 550 patients with initial diarrhea and colitis with ICI, they identified 167 patients who subsequently resumed ICI for a re-treatment rate of 30%. This represents a notable cohort with this degree of clinical annotation. For their initial therapy leading to diarrhea and colitis, about half of these patients had initially received anti-PD-1 or PD-L1 therapy, and a quarter each had initially received either anti-CTLA-4 therapy or combination. The majority of these patients had melanoma, with a smaller proportion of non-small cell lung and genitourinary cancer patients. At the time of re-treatment, 80% of these patients received an anti-PD-1 or anti-PD-L1 alone, while the others were re-treated with anti-CTLA-4 alone.

An important observation by the authors was that upon re-treatment of the 167 patients, 57 patients, or about a third, experienced recurrent diarrhea and colitis requiring permanent discontinuation of therapy. The grade of diarrhea and colitis most frequently seen was less severe, graded as less than or equal to Grade 2. As expected, 81% of these patients with recurrent diarrhea and colitis received steroids, while 12% of patients required further immunosuppression with either infliximab or vedolizumab which blocks the integrin alpha-4-beta-7.

Univariate and multivariate analyses were used to identify risk factors for recurrent diarrhea and colitis upon ICI resumption. Univariate analysis identified more severe initial diarrhea and colitis as a risk factor for having recurrent diarrhea and colitis on ICI re-challenge. Initial severity was determined either by longer duration of initial symptoms or requirement for initial immunosuppression. Multivariate analysis confirmed initial severity as a risk factor, and also found that a lower risk of recurrent diarrhea and colitis was associated with initial anti-CTLA-4 use, as well as with choice of anti-PD-1 or anti-PD-L1 therapy at the time of re-challenge regardless of their initial therapy. Importantly, even though resumption of anti-CTLA-4 was associated with a higher risk of recurrent diarrhea and colitis, the severity of recurrence, as determined by frequency of immunosuppression and grading of diarrhea and colitis, were actually similar to when anti-PD-1 or anti-PD-L1 were resumed.

Overall, then, despite the limitations of retrospective analysis, this work provides evidence from a substantial patient cohort across tumor and treatment types that recurrent diarrhea and colitis with ICI retreatment following initial interruption for diarrhea and colitis may occur in less than half of patients and is generally less severe. Furthermore, the risk of recurrent diarrhea and colitis is less likely in patients who had less severe episodes of initial diarrhea and colitis, who previously received initial anti-CTLA-4, or who are re-challenged with anti-PD-1 or anti-PD-L1 therapy. Although the choice of anti-PD-1 or anti-PD-L1 for re-treatment reduces the risk of recurrent diarrhea and colitis, the actual severity of recurrent episodes is similar to re-treatment with anti-CTLA-4 therapy. As a practical matter this can provide guidance to providers about whether to consider ICI resumption, and which agents to consider, based in part of characteristics of their initial treatment and IRAE. This will be particularly important for patients who experienced clinical benefit from their initial ICI therapy, or have limited other treatment options. At the same time, this work also prompts a number of questions for further investigation. Why does prior anti-CTLA-4 therapy leading to initial diarrhea and colitis yield a lower risk of recurrent episodes? Is there an association between recurrent diarrhea and colitis after ICI re-challenge and ongoing response to therapy? Finally, do different ICI-responsive cancer types exhibit higher or lower risk for recurrent diarrhea and colitis? These and other questions can be addressed by future studies involving larger and well-annotated patient cohorts at multiple centers.

This concludes this JCO Podcast. Thank you for listening.

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