ASCO Education

Wendy Vogel is a Nurse Practitioner and President of APSHO, the Advanced Practitioner Society for Hematology and Oncology. In this week's episode, she presents a self-evaluation question about the correct chemotherapy treatment of obese patients and provides an explanation of the correct choice.

Dr. Sparano is Professor of Medicine & Obstetrics, Gynecology, and Women's Health at the Albert Einstein College of Medicine, Associate Chairman for Clinical Research in the Department of Oncology at Montefiore Medical Center, and Associate Director for Clinical Research at the Albert Einstein Cancer Center. He also serves as Vice Chair of the ECOG-ACRIN Research Group and Vice Chair of the AIDS Malignancy Consortium. He is former director of the Hematology-Oncology Fellowship Program at Einstein/Montefiore, co-directs the ECOG-ACRIN Young Investigator Program, and is a faculty member of the Calabresi K12 Oncology Training Program. He is co-principal investigator of the Montefiore-Einstein Minority/Underserved National Community Oncology Research Program (NCORP) grant (in conjunction with Dr. Bruce Rapkin), which funds multicenter, NCI-sponsored clinical trials in cancer therapeutics, cancer prevention/control, and cancer care delivery research. He is also the recipient of funding from the Breast Cancer Research Foundation that is supporting creation of a biospecimen bank designed to identify determinants of late relapse. Dr. Sparano is a practicing clinician who specializes in medical oncology and clinical and translational cancer research. His research has focused on developmental therapeutic approaches for breast cancer, lymphoma, and HIV-associated cancers, and therapeutic application of molecular profiling in cancer. TRANSCRIPT Welcome to the ASCO University Weekly Podcast. My name is Joseph Sparano, and I am Associate Director for Clinical Research at the Albert Einstein Cancer Center, and chief of the section of breast medical oncology at Montefiore Medical Center in New York. Today, we contrast two cases on adjuvant treatment of breast cancer. The standard treatment for hormone receptor positive, HER2 negative, early stage breast cancer is surgery, followed by endocrine therapy. Since the early 2000s, adjuvant chemotherapy has also been recommended to the majority of these women, but the added benefit from chemotherapy is modest for most. Many different gene expression assays have been developed to determine prognosis and identify which woman may be more likely to benefit from chemotherapy. One commercial test that is recommended in clinical practice guidelines is a 21 gene recurrence score assay. Based on the recently completed TAILORx study, it was known that woman with low recurrence scores on the 21 gene expression assay do well with adjuvant endocrine therapy alone. Whereas woman with high recurrence scores benefit from adjuvant endocrine therapy and chemotherapy. The TAILORx study clarified the best treatment option for women with an intermediate recurrence score, which was defined as a recurrence score of 11 to 25 in the trial. This is particularly important because the majority of patients fall in this intermediate risk category, up to 70%, in fact. Before we discuss the new evidence reported from this study, let's take a look at two intermediate risk cases. These two cases are very similar, yet the recommended treatments may be very different. Can you identify the key differences between these two cases? We begin with the first case. Case 1 is a 55-year-old postmenopausal woman with a node negative, ER positive, PR positive, HER2 negative breast cancer. The size of the tumor is 1.6 sonometers. The 21-gene recurrence score is 24, which is in the upper range of the intermediate risk category. Which option would you recommend as the best systemic treatment. The choices in this case include endocrine therapy alone or chemotherapy followed by endocrine therapy. The correct answer to this question is, A, endocrine therapy alone. We will discuss the rationale for this recommendation shortly, but first let's move on to the second case. The second case is a 44-year-old premenopausal woman with node negative, ER positive, PR positive, HER2 negative breast cancer. Like case 1, the size of the tumor is 1.6 centimeters and the 21-gene recurrence score is 24. Which option would be the best adjuvant treatment in this case? The choices here include endocrine therapy alone or chemotherapy, followed by endocrine therapy. The correct answer in this case is chemotherapy, followed by endocrine therapy. Both of these cases had nearly identical clinical presentations. That is, they presented with ER, PR positive, HER2 negative breast cancer, associated with negative axillary nodes, a primary tumor size of 1.6 sonometers, and a 21-gene recurrence score of 24. However, the key difference was the age at presentation, with one patient being in her mid 50's and postmenopausal, and the other patient being in her mid 40's and premenopausal. The TAILORx trial found that endocrine therapy was not inferior to chemotherapy plus endocrine therapy in the overall population with a mid-range 21-gene recurrence score of 11 to 25. However, there was an interaction between age, chemotherapy treatment, and recurrence score. About 1/3 of women who participated in the trial were 50 or younger. These women seem to have some chemotherapy benefit if the recurrence score was between 16 and 25. For those who had a recurrence score of 21 to 25, the absolute reduction in the risk of distant recurrence was approximately 7% at 9 years. For a woman who had a recurrence score of 16 to 20, the absolute reduction in distant recurrence by the addition of chemotherapy was about 2%. It remains unclear as to whether the benefit from chemotherapy in younger woman was due to a true cytotoxic effect associated with chemotherapy in eradicating micrometastatic disease, or a castration effect in inducing early menopause. Nevertheless, the findings from the TAILORx trial provide the highest level of evidence supporting the greatest level of precision in using the 21-gene assay to guide the use of adjuvant chemotherapy in early stage breast cancer. Thank you for listening to this week's episode of the ASCO University Weekly Podcast. For more information on the adjuvant treatment of breast cancer, including additional patient cases and opportunities for self-evaluation, visit the comprehensive e-learning center at university.asco.org. Thank you for your attention. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Arun Singh, Co-Clinical Director of UCLA Sarcoma Clinic and Assistant Professor of Hematology and Oncology at UCLA, presents a self-assessment question from an ASCO University course focusing on the treatment of non-small cell lung cancers.

TRANSCRIPT The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Hello, and welcome to the ASCO Guidelines podcast series. My name is Shannon McKernin and today I'm interviewing Dr. Jennifer Griggs from the University of Michigan, senior author on "Adjuvant Endocrine Therapy for Women with Hormone Receptor Positive Breast Cancer: ASCO Clinical Practice Guideline Focused Update." Thank you for being here, Dr. Griggs. And thank you for the opportunity to talk about this focused update to the guidelines on extended adjuvant therapy. I would, of course, like to thank all my co-authors in the ASCO guidelines team for their contribution to this effort. So first, can you give us a general overview of what this guideline covers and their research which informed this focus update? Yes. First of all, the goal of the guideline was to give an update to the previous guidelines on this topic. And we specifically focused on extended adjuvant therapy. In particular, the aromatase inhibitors in women who had completed five years of adjuvant endocrine therapy. And it goes without saying, but it's worth reminding our listeners that the guideline is restricted only to post-menopausal women with hormone receptor-positive breast cancer. And, of course, our guidelines are only as good as the data upon which we rely. So for this guideline, six phase III randomized controlled trials met the pre-specified eligibility criteria for the updated systematic review and provide the evidence base for the guideline recommendations on the duration of aromatase inhibitor therapy. Each of the trials used the standard doses of the drugs that we use in practice today. So I'm not going to say the doses of each of the medications. So I'm going to go briefly over those six trials and just describe them so everybody's up to date with how the studies were designed. So briefly, the first trial I'll describe is MA17R, which compares letrozole to placebo for five years in over 1,900 women who had already received 4.5 to six years of adjuvant therapy with an AI, proceeded in most women by treatment with tamoxifen. The second study is NSABP B-42. And this also compares letrozole to placebo in nearly 4,000 women who'd completed five years of endocrine therapy with either five years of an aromatase inhibitor or up to three years of tamoxifen followed by an aromatase inhibitor, for a total of five years. The third study that we looked at is the DATA trial, which stands for the Different Durations of Adjuvant Anastrozole Therapy. This trial compared six years of adjuvant anastrozole with three years of adjuvant anastrozole in over 1,600 women after two to three years of adjuvant tamoxifen. The fourth trial out of the six is the IDEAL trial, the Investigation on the Duration of Extended Adjuvant Letrozole. This study randomized over 1,800 women to either 2 and 1/2 or five years of letrazole after five years of tamoxifen, an AI, or a combination in sequence of tamoxifen and an AI. So very similar study designs. The fifth study is the ABCSG-16 trial, the Austrian Breast Cancer Study Group Trial 16, which randomized nearly 3,500 women following four to six years of adjuvant therapy with tamoxifen and AI or a sequence of tamoxifen and then an AI, to either two or five years of anastrozole as extended therapy. And finally, the study of letrozole extension, or the SOLE trial, randomized over 4,800 women with node-positive breast cancer who had completed five years of adjuvant endocrine therapy to receive either continuous letrozole for five years or five years of an intermittent schedule of letrozole given nine months on and three months off in years one to four and on continuously for a year or five. So I know that's a lot to take in, but I do think it was important for our audience to understand the six trials that were included. These were all large studies, randomized, and patients had completed five years of adjuvant endocrine therapy. And then, were randomized either to placebo or different durations of an aromatase inhibitor or a placebo. For all of these studies, it's important to know that the primary outcome was disease-free survival. Overall survival and adverse events where secondary outcome. Great. So given that research and those trials, what are the key recommendations for this guideline update? Five key recommendations are included in this focused update to the previous guidelines. And they are for women with node-negative breast cancer, extended adjuvant aromatase inhibitor therapy can be offered for up to a total of five years of adjuvant therapy. Recommendations are based on considerations of recurrence risk using our usual established prognostic factors. However, since the recurrence risk is lower, the benefits are likely narrower in node-negative patients. The guidelines panel recommends that women with low-risk, node-negative tumors should not routinely be offered extended adjuvant therapy. Now, that might sound vague. We did not make recommendations using genomic profiling results because we don't have sound data to support such views that we felt were strong enough to integrate genomic testing results. Our second recommendation is that women with node-positive breast cancer should be offered extended AI therapy for up to a total of 10 years of adjuvant endocrine therapy. And that means combined tamoxifen and aromatase endocrine therapy. That's the total that we meant to recommend. Third recommendation is that women receiving extended adjuvant endocrine therapy should receive no more than 10 years of total treatment. The fourth recommendation is when given as prevention of secondary or contralateral breast cancer, the risk of second breast cancers based on prior therapy should inform the decision to pursue extended therapy. So what this means is specifically, a woman who has had a bilateral mastectomy will not reap the benefit of preventative therapy with endocrine therapy. The fifth recommendation is that extended therapy carries ongoing risks and side effects, and these should be weighed against the potential absolute benefits of longer treatment in a shared decision-making process between the clinical team and the patient. Specifically, to date, none of the studies have shown improvement in overall survival with longer duration aromatase inhibitor therapy. As such, the recommendations, therefore, an extended adjuvant AI therapy are based on benefits that include prevention of distant recurrence and prevention of second breast cancers. So why is this guideline so important and how will it change practice? The importance of this guideline rests in the fact that it supports what many clinicians and patients are already doing in practice. The second is it recommends against durations of endocrine therapy longer than 10 years in the absence of data supporting such a practice. So it's our thought that doctors and patients and other care providers, nurse practitioners, physician assistants, primary care doctors, are already practicing what we're recommending, and it supports doing so. And the second is that for those providers and patients who aren't sure that 10 years is enough, this guideline suggests that 10 years is sufficient. We don't have any data supporting giving more than 10 years. And the third recommendation is that this guideline really supports the need for shared decision-making, given the absence of data supporting an improvement in overall survival. So finally, since you did mention shared decision-making, how does this guideline recommendation affect patients? Well, the panel strongly believes that the tailored decision-making process is key in the decision to recommend extended adjuvant therapy. So tailoring on disease factors plays a role in the recommended duration of therapy. Obviously, since we stratified by high-risk and low-risk and what treatment's been received specifically. And if a woman's had bilateral mastectomy, she's not going to benefit from the risk reduction that's achieved with giving somebody extended therapy. But in addition to disease factors, patient preferences and tolerance of therapy should inform clinician and patient decision-making. Again, since none of the studies have shown improvement in overall survival with longer duration of AI therapy, patients and their medical providers need to make decisions based on an awareness that the benefits include, specifically prevention of distant recurrence and prevention of second breast cancers. And the importance of those benefits is going to vary according to a patient and how she views her life going forward and how bad her side effects have been, how well she tolerates the therapy. From my own personal point of view, as a breast oncologist, I believe two things. Number one, we should provide aggressive support for managing symptoms in patients who are most likely to benefit from extended therapy. That is, we should not stop therapy early if she is very likely to benefit if we haven't maximized control of her symptoms. There are many things we can do to improve symptoms and we shouldn't just stop therapy because she's not tolerating treatment if we haven't done the most that we can to improve her quality of life and her symptoms. Conversely, my hope is that we are not doggedly persisting in recommending prolonged therapy in a patient who has a fear of recurrence but who has little to gain from extended therapy. In the latter case, high quality information support is more therapeutic than extended therapy with a medication that's proven, in randomized controlled trials and in her own personal experience, to decrease her quality of life with marginal, if any, medical benefit. Thank you so much for the overview of this guideline today and thank you for your time. Thank you. And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. If you've enjoyed what you've heard today, please rate and review the podcast and refer this show to a colleague.

Dr. Daniel George is Professor of Medicine and Surgery, Director of GU Oncology for the Duke Cancer Institute, and Co-Chair of the DCI Center for Prostate and Urologic Cancers. Dr George's primary areas of interest are in drug development and optimizing care for patients with GU cancers, particularly prostate and kidney cancers. In this week's episode, Dr. George presents two contrasting cases with nephrectomy as a possible treatment path. Can you determine the best course of treatment for each patient? If you enjoyed this podcast, make sure to subscribe for more weekly education content from ASCO University. We truly value your feedback and suggestions, so please take a minute to leave a review. If you are an oncology professional and interested in contributing to the ASCO University Weekly Podcast, email ascou@asco.org for more information. TRANSCRIPT Welcome to the ASCO University Weekly Podcast. My name is Dr. Daniel George. And I'm a professor of medicine and surgery at Duke University. I'm also the director of GU oncology at the Duke Cancer Institute and co-chair of the DCI Center for Prostate and Neurologic Cancers. Today we'll discuss two similar cases of patients presenting with metastatic renal cell carcinoma in our multidisciplinary management options. Without any standard screening procedures, 20% to 30% of kidney cancer patients today present with metastatic disease. Historically, debulking nephrectomy has been our standard of care. And this has been based on old trials from the interferon era of treatments. Since then, many drugs have been approved for the management of patients with metastatic renal cell carcinoma, many of which have improved the progression free survival and overall survival of patients with metastatic disease, which may have had an impact on the landscape and role for debulking nephrectomy. Furthermore, metastatic kidney cancer patients can be risk stratified. There's a number of criteria used. But historically the most commonly used criteria has been the Memorial Sloan Kettering Cancer Center criteria. Which included five factors, including KPS score less than 70, a calcium score greater than 10, A serum hemoglobin of less than the lower limit of normal, and LDH greater than 1.5 times the upper limit of normal, or having their primary tumor in place, meaning no prior nephrectomy. If patients had zero of these factors they were considered good risk with the best survival. Patients with one or two of these factors are considered intermediate risk. And patients with three or more of these factors historically have been very poor risk, with median survivals of six months or less. The Carmena Study was a prospective, multi-center, randomized, non inferiority trial comparing upfront nephrectomy followed by sunitinib therapy, compared to upfront sunitinib therapy alone in patients with metastatic renal cell carcinoma amenable to cytoreductive nephrectomy. We'll get to these results in a moment. But the study population included, importantly, patients with e cog performance status zero or one. And 40% plus of these patients were considered poor risk, with the average sum of metastatic tumor burden being greater than five centimeters. So now, let's get to some modern cases. The first case we'll discuss is George. He's an 83-year-old man who presented with gross hematuria and a hemoglobin of 13.8 in the normal range. A CT scan revealed an eight centimeter right renal mass and multiple pulmonary mets, up to two centimeters in size. His e cog performance status is zero. And his calcium was 8.4, and LDH was normal as well. Our second case, for comparison, is Philip, a 76-year-old man who was found to have a 16 centimeter left renal mass incidentally on a spine MRI. This was confirmed by CT scan, along with some pulmonary nodules measuring up to 1.8 centimeters, as well as enlarged mediastinal lymph nodes up to two centimeters, and an eight millimeter liver lesion. His calcium score was 10.4. And his hemoglobin was 12.5, which was below the limit of normal. He had a normal LDH and an absolutely zero performance status. So for these two cases, we have four choices. The first choice is for both cases a nephrectomy followed by systemic treatment, our historical approach. The second is systemic therapy first, with plus or minus a subsequent nephrectomy for both cases. Our third choice would be to treat case number one with a nephrectomy, followed by systemic therapy, and case number two with systemic therapy first. And our fourth option would be systemic therapy first for case one and a nephrectomy first for case two. Now, to me, when I look at these cases, the correct answer is three. Nephrectomy first for case one, and systemic therapy first for case two. Let me explain. Even though these cases are fairly similar in age, gender, performance status, and had the presence of a large primary tumor, for case one this is an intermediate risk patient. This patient has lung only disease that's relatively low volume, a good performance status, and normal labs. In addition, he's symptomatic with gross hematuria. For these reasons, a debulking nephrectomy is really indicated. And because of his good performance status, he's very likely to recover well from the surgery, despite the fact that he's 83 years old. Case two is subtly different. This is actually a poor risk patient. Even though his e cog performance status is zero, he has an elevated calcium, a decreased hemoglobin, and he's got his primary tumor still in place. That puts him into a poor risk category. And some of these patients never recover from surgery well enough to get systemic therapy. He also has multi organ involvement, involving his lungs and nodes, and possibly even his liver. This is a patient that really mirrors the patient population of Carmena. Based upon this, I think systemic therapy first is a reasonable treatment option for this patient. If we actually look at the results of Carmena, the study confirmed that sunitinib therapy alone, systemic therapy, was non inferior, and actually trended towards improved survival compared to cytoreductive nephrectomy followed by sunitinib. The results suggest that for poor risk or for high volume metastatic patients, that systemic therapy first should be the standard of care. But, importantly, not included in a Carmena study were patients that had low volume metastatic disease and intermediate risk features, or good prognosis. These patients not included in the Carmena study might still benefit first from a debulking or cytoreductive nephrectomy. So thank you for listening to this week's episode of the ASCO University Weekly Podcast. For more information on the role of cytoreductive nephrectomy, including additional patient cases and opportunities for self-evaluation, visit the Comprehensive eLearning Center at university.asco.org. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Yosef Landman is a graduate of the Sackler School of Medicine, Tel Aviv University. He is currently a medical oncology resident at Davidoff Cancer Center, Rabin Medical Center in Petach Tiqva, Israel. In today's episode, he discusses the recent approval of larotrectinib for tumor-agnostic treatment of advanced solid tumors containing NTRK gene fusion. Dr. Landman, a co-author on the journal paper Rapid Response to Larotrectinib (LOXO-101) in an Adult Chemotherapy-Naive Patients With Advanced Triple-Negative Secretory Breast Cancer Expressing ETV6-NTRK3 Fusion (Clinical Breast Cancer, June 2018), provides background on the recent approval as well as a case-based example of larotrectinib treatment. If you enjoyed this podcast, make sure to subscribe for more weekly education content from ASCO University. We truly value your feedback and suggestions, so please take a minute to leave a review. If you are an oncology professional and interested in contributing to the ASCO University Weekly Podcast, email ascou@asco.org for more information.

Dr. Ian Flinn, Medical Oncologist specializing in hematologic malignancies at Tennessee Oncology, discusses the recent FDA approval of duvelisib for adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). If you enjoyed this podcast, make sure to subscribe for more weekly education content from ASCO University. We truly value your feedback and suggestions, so please take a minute to leave a review. If you are an oncology professional and interested in contributing to the ASCO University Weekly Podcast, email ascou@asco.org for more information. TRANSCRIPT (Intro Music Playing) As a background to today's discussion, the PI3K are a family of lipid kinases that sit at the crossroads of numerous signaling events that drive many malignancies, including certain lymphomas, and chronic lymphocytic leukemia. There are four isoforms of the PI3K-- alpha, beta, delta, and gamma. Isoform specific inhibitors are attractive because they may lead to efficacy without the toxicity of pan inhibitors. Idelalisib, which is a delta isoform inhibitor, was the first PI3K inhibitor be approved for lymphoma in CLL. The delta isoform is a particular interest in B cell malignancies because its expression is normally restricted to cells of a hematopoietic origin. In data from gene knockout models, show that it has a key role in B cell signaling, development, and survival. Selective targeting of the delta isoform should not alter insulin signaling, which is mediated by the ubiquitously expressed alpha isoform. However, narrow targeting could lead to mechanisms of resistance to upregulation of other isoforms. This has been demonstrated in mantle cell lymphoma where the alpha isoform is expressed in relapse patients. Duvelisib is a dual inhibitor of both the delta and gamma isoforms of the PI3K. Inhibiting the gamma isoform may be important because of its inhibitory effect, not only in the malignant cell, but also in the micro-environment, which provides important survival signals to malignant cells. Both idelalisib and copanlisib, an inhibitor of the delta and alpha isoforms, are currently FDA approved for third line follicular cell lymphoma. And idelalisib is approved in combination with rituximab in relapse CLL. On September 24, 2018, the Food and Drug Administration granted approval for duvelisib for patients with relapsed refractory chronic lyphocytic leukemia, small lymphocytic lymphoma, and follicular lymphoma after at least two prior therapies. The approval of duvelisib in CLL was based on the DUO trial, a large international randomized phase III trial comparing duvelisib, at 25 milligrams orally, twice daily, to ofatumumab, given according to the package label. The results of the duo trial have been published in Blood. In a subset analysis of 196 patients receiving at least two prior therapies, the median progression pre-survival was 16.4 months in the duvelisib arm, and 9.1 months in the ofatumumab arm, with a hazard ratio of 0.40. The overall response rate of 78% with duvelisib was twice the 39% seen with ofatumumab. The follicular lymphoma indication is based on the Dynamo trial, a single arm multi-center trial of duvelisib, which enrolled 83 patients with follicular lymphoma who are refractory to rituximab and to either chemotherapy or radioimmunotherapy. The overall response rate, determined by an independent response committee, was 42%. Of the 35 responding patients, 15, or 43%, maintained responses for at least six months. And 6, or 17%, maintained responses for at least 12 months. The most common adverse reactions with an instance of greater than or equal to 20% were diarrhea, or colitis, neutropenium, rash, fatigue, pyrexia, cough, nausea, upper respiratory tract infection, pneumonia, muscle skeletal pain, and anemia. Over the last decade, we've seen substantial advances in the treatment of low grade lymphoma and CLL, especially in the front-line setting. Unfortunately for patients with relapse and refractory disease, new agents are needed. The approval of duvelisib is an important addition to our armamentarium for these patients. And we'll have an immediate impact. However, to have its greatest effect, strategies will need to be devised to move this drug earlier in the natural history of these diseases. Such approaches might include alternative dosing and scheduling, as well as combination regiments. Duvelisib is a novel PI3K inhibitor and is differentiated from other PI3K inhibitors, because it targets both the delta and gamma isoforms. Consequently, it is being studied in a broader array of diseases, including T cell malignancies, where promising activity has been seen. (Outro Music Playing) Thank you for listening to this week's episode of the ASCO University Weekly Podcast. For more information on drug approvals visit the comprehensive e-learning center at university.asco.org.

If you enjoyed this podcast, make sure to subscribe for more weekly education content from ASCO University. We truly value your feedback and suggestions, so please take a minute to leave a review. If you are an oncology professional and interested in contributing to the ASCO University Weekly Podcast, email ascou@asco.org for more information. TRANSCRIPT The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Hello, and welcome to the ASCO Guidelines Podcast Series. Is my name Shannon McKernin and today, I'm interviewing Dr. Elena Stoffel from the University of Michigan, lead author of "Evaluating Susceptibility to Pancreatic Cancer: ASCO Provisional Clinical Opinion." Thank you for being here today, Dr. Stoffel. I'm delighted to join you. So first, can you tell us what a professional clinical opinion is and why this topic is so important to ASCO? Well, a provisional clinical opinion is a statement that ASCO puts out when we are seeing trends that are relevant to the care of our patients but that may not necessarily have the level of evidence needed to include in a true clinical guideline. This particular provisional clinical opinion that deals with the management of patients with pancreatic cancer and their families is based on some new data that has been published regarding the prevalence of inherited factors influencing pancreatic cancer risk. So what are the key statements of this Provisional Clinical Opinion or also known as a PCO? This particular provisional clinical opinion, which is about just the inherited susceptibility to pancreatic cancer, was prompted by several recent publications, which found that the prevalence of genetic predisposition among patients with pancreatic cancer was much higher than we had originally anticipated. And this is relevant because in talking about pancreatic cancer as one of the deadliest cancers in both in the United States and worldwide, we are very interested in finding ways to reduce the morbidity from this cancer to patients and their families. And this particular provisional clinical opinion addresses the role that genetic risk assessment should have in the care of pancreatic cancer patients and also the role for clinical genetic testing, as well as the risks and benefits of pancreatic cancer screening for at risk family members. What considerations are there for having these conversations with patients and their families? Well, many times when we see families affected with cancer, one of the questions they have is what is the likelihood that this will happen to other individuals in our family and what can we do to prevent cancers in other family members. And I think what's important here is that review of the data from multi-gene panel genetic testing in unselected individuals diagnosed with pancreatic cancer identified pathogenic germline variants in 1 out of every 10 individuals. And this is really important because when you think about it, if 1 out of every 10 patients with pancreatic cancer develop their cancer in the setting of a genetic predisposition syndrome, this has tremendous implications for management both for them as well as for their family members. One of the most common inherited cancer syndromes identified in families affected with pancreatic cancer is hereditary breast ovarian cancer associated with mutations of BRCA1 and BRCA2. As you know, there are definite screening recommendations we make for individuals who carry these genetic alterations. And certainly if a family member is diagnosed with a genetic alteration, then that has an impact for cancer screening and management. Furthermore, there are emerging data about the utility of pancreatic cancer screening in high risk individuals. And while there's still some controversy about how to screen individuals at risk for pancreatic cancer, certainly there are some emerging data suggesting that this may have a role for early detection. And finally, the panel included a discussion section on the limitations of the research and future directions. So what are the key points of this section? I think that what we're learning is with genetic testing, and particularly with multi-gene panel testing, we are we often find unexpected results. Certainly variants of uncertain significance are not uncommon when multi-gene panel tests are used. And being able to interpret the clinical significance of some of these genetic test results can pose some challenges, especially for clinicians who don't have specific expertise in genetics. Certainly being able to deal with the volumes of patients who need genetic testing who are also battling pancreatic cancer, we want to make sure that we have the resources to be able to offer genetic testing to everyone who needs it. And finally, in talking about screening for pancreas cancer, while there are some studies that have demonstrated that screening with MRIs and/or endoscopic ultrasounds has led to early detection and down staging of cancers in some cases, larger studies are needed to be able to refine more specifically who and how to screen individuals at risk for pancreas cancer. Great. Thank you so much for taking your time today to discuss this PCO with us, Dr. Stoffel. Thank you very much for having me. And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast series. If you've enjoyed what you heard today, please rate and review the podcast and refer the show to a colleague.

If you enjoyed this podcast, make sure to subscribe for more weekly education content from ASCO University. We truly value your feedback and suggestions, so please take a minute to leave a review. If you are an oncology professional and interested in contributing to the ASCO University Weekly Podcast, email ascou@asco.org for more information. TRANSCRIPT The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Hello and welcome to the ASCO Guidelines Podcast series. My name is Shannon McKernin and today I'm interviewing Dr. Scott Morgan from the Ottawa Hospital and University of Ottawa, lead author on "Hypofractionated Radiation Therapy for Localized Prostate Cancer: an ASTRO, ASCO, and AUA Evidence-Based Guideline." Thank you so much for being here today, Dr. Morgan. It's my pleasure, Shannon. I'm happy to take part in the podcast and hopefully share the highlights of the guideline with your listeners. So first, can you give us a general overview of what this guideline covers? Yeah. So the guideline covers really hypofractionated external beam radiation therapy, which is a treatment for localized prostate cancer, and for the non-radiation oncology folks in your audience, I think it's important to begin by placing the guideline sort of in its context and going over some of the terminology that we use as radiation oncologists. So external beam radiotherapy, it's a standard treatment-- standard local treatment option for men with localized prostate cancer. It gives outcomes which are really equivalent to those of radical prostatectomy or brachytherapy, which are the other two standard local treatment options. And traditionally, it's given in small daily fractions over several weeks and the usual daily fraction size is 1.8 to 2 Gray per day. And this is called conventional fractionation. And that really translates into a course of about seven and a half to nine weeks of treatment. And so that total dose which is delivered in those daily treatments, five days a week, is about 76 to 80 Gray. And that's what we call conventional or standard fractionation. And there's a theoretical framework in radiation medicine and there's some evidence to accompany that that suggests that prostate cancer is quite sensitive to radiation fraction size. And just to give a brief primer, for any tissue, cancerous or non-cancerous, there's a sensitivity to fraction size and it's characterized by something called the alpha-beta ratio. And for prostate cancer, that's felt to be low compared to most other cancers, the alpha-beta ratio, and indeed, it's thought to be lower than the adjacent dose-limiting normal structure, which is the rectum. And so an implication of that is that hypofractionation, and by that we mean daily fraction size of more than 2 Gray, might improve the therapeutic ratio of radiation therapy in localized prostate cancer. Now the guideline-- and I think it's important to emphasize this-- it draws a distinction between what we call moderate hypofractionation and ultra-hypofractionation. Clearly, fraction size is a continuous variable, so any subdivision that we might make is necessarily a bit arbitrary, but it turns out that at least in clinical practice, there's been really two distinct approaches to hypofractionation that have arisen. And one of these is moderate hypofractionation and that's an approach where the fraction size is modestly higher than 2 Gray per fraction, and in the guideline, it's been defined as a fraction size between 2.4 and 3.4 Gray, whereas ultra-hypofractionation, this is defined in the guideline as a fraction size greater than 5 Gray. And it's also been referred to in the literature as extreme hypofractionation or Stereotactic Body Radiation Therapy, SBRT, or SABR, Stereotactic Ablative Radiation Therapy. But in any case, we are talking here about, with ultra-hypofractionation, with radical courses of treatment that are often delivered over as few as five fractions, often on an alternate day approach over two or two and a half weeks. And so the guideline really was largely motivated by the publication of a number of randomized trials, including four large-scale trials in the past two years that have compared conventionally fractioned radiation therapy and moderately hypofractionated radiation therapy. So that is really what stimulated the guideline, which was the evidence concerning moderately hypofractionated radiation therapy. But at the same time, there has been an increasing use in routine clinical practice that's been observed of ultra-hypofractionated radiotherapy, so the decision was made to make recommendations on it as well. So ASTRO, American Society for Radiation Oncology, in collaboration with ASCO and the AUA, convened a panel of radiation oncologists, medical physicists, urologists, radiation oncology resident, patient representative, and a systematic review of the literature was conducted and their recommendations have been made on the basis of this systematic review. So the aim was to provide recommendations on use of both moderate hypofractionation and ultra-hypofractionation, in particular with reference to oncologic outcomes, toxicity, and quality of life. So we didn't directly consider health economic endpoints, though clearly the very nature of hypofractionation is such that there are potential advantages in terms of cost and convenience for patients. And what are the key recommendations of this guideline? We separated the key recommendations into three main groups and the first set of recommendations pertains to moderate hypofractionation, and these are generally based on the highest-quality evidence. So they could be viewed as the strongest recommendations in the guideline. And the second set of recommendations concern ultra-hypofractionation. They're somewhat less strong given they're based on somewhat weaker evidence. And then the third set of recommendations relate to some of the technical aspects of the planning and delivery of hypofractionated radiation therapy. So, dealing with the moderate hypofractionation recommendations first, arguably the most important recommendation of the guideline is that the panel has recommended that in patients with localized prostate cancer who are candidates for external beam radiation therapy, moderate hypofractionation should be offered. And this is graded as a strong recommendation. It's based on high-quality evidence and it applies to patients across all risk groups. So it applies to patients with low-risk prostate cancer who require active treatment or who have declined active surveillance and it also applies to patients with intermediate-risk or high-risk localized prostate cancer. And why really does it apply to all these groups? It's essentially because these groups are well-represented in the trials of moderate hypofractionation. And the trials have shown that moderate hypofractionation really gives similar outcomes in terms of efficacy to conventional fractionation. Now one caveat I guess that I should say is that the trials generally only looked at radiation therapy to the prostate rather than radiation therapy to the prostate as well as the pelvic lymph nodes. So the panel's recommendations regarding moderate hypofractionation don't apply to the scenario where the clinician has decided to include the pelvic lymph nodes in the radiation therapy volume. The panel also made recommendations with respect to toxicity and quality of life, and specifically, they did recommend that men should be counseled about a small increased risk of acute gastrointestinal toxicity, typically rectal toxicity, with moderately hypofractionated radiation therapy. And they should also be counseled that moderately hypofractionated radiation therapy has a similar risk of late GI toxicity and also has a similar risk of both acute and late GU toxicity compared to conventional fractionation. The only difference was seen in acute GI toxicity. And I think it's probably worth dwelling on this a little bit more. Probably the most granular data on acute GI toxicity comes from the CHHiP trial. This was a trial from the UK. It was far and away the largest randomized trial of moderate hypofractionation versus conventional fractionation. And they followed the amplitude of GI toxicity very carefully over the short and long term and what they did found was that in the early weeks, there was greater peak acute GI toxicity with moderate hypofractionation, but this difference had really disappeared by about 18 weeks after the start of radiotherapy. So within a few months, there was no difference, and afterwards, there was no consistent difference in long-term GU or GI toxicity across these trials. Now I guess I should mention that, at the current time, that the median follow-up of most of these trials is between five and six years, so arguably, the last word hasn't been written. The panel also offered conditional recommendations on particular moderate hypofractionation regimens. There were multiple different regimens that were evaluated but most were not compared head-to-head. And the panel preferred two particular regimens-- 60 Gray and 20 fractions over four weeks or 70 Gray and 28 fractions over five and a half weeks, as these were the two regimens that were evaluated in the largest populations. And of these two, likely the strongest evidence supports 60 Gray and 20 fractions, given it was used in two different trials and it was used across all risk groups and with or without concomitant hormonal therapy. So those were the recommendations regarding moderate hypofractionation. So moving to ultra-hypofractionation, again, this is talking about fraction size of at least 5 Gray, typically a course of as few as five fractions over perhaps two or two and a half weeks. I think it's important to say that, at the time we were preparing this guideline, there were no published efficacy or toxicity data from randomized trials comparing ultra-hypofractionation and conventional fractionation. So the strengths of the recommendations made by the panel is correspondingly lower than was the case for moderate hypofractionation. But having said that, there are several prospective non-randomized studies that have been published and have documented safe delivery of ultra-hypofractionation for appropriately-selected patients and pretty good biochemical control and low toxicities have been observed in these studies. But again, relatively few have follow-up beyond five years. So what the panel recommended was that in men with low-risk prostate cancer-- and the bulk of the data to date for ultra-hypofractionation has been in this group-- panel conditionally recommended that in those who decline active surveillance and choose active treatment with radiation therapy, that ultra-hypofractionation may be offered as an alternative to conventional fractionation. Again, this is a conditional recommendation. In men with intermediate-risk prostate cancer, the panel has conditionally recommended that ultra-hypofractionation may be offered as an alternative to conventional fractionation but it's strongly recommended in this group that these patients be treated as a part of a clinical trial-- and there are several clinical trials ongoing-- or as part of the multi-institutional registry. And then finally, in patients with high-risk localized prostate cancer, there was really insufficient comparative evidence for the panel to suggest offering this outside of a clinical trial or outside of a registry. Regarding particular regimens, that the panel again made a conditional recommendation that a schedule of 35 Gray to 36.25 Gray and five fractions delivered to the planning target volume could be offered and that it recommended against consecutive daily treatments for this schedule. So I think it's again important to note that compared to moderate hypofractionation, the ultra-hypofractionation literature is really substantially less mature and it is evolving rapidly. And therefore, a short-term update of this guideline to address new data pertaining specifically to ultra-hypofractionation is likely going to be necessary. And then I mentioned there was a third set of recommendations and these pertain to the technical aspects of planning and delivering radiation therapy. And these probably are not of core interest to your audience, but briefly, the guideline recommends that in the planning of hypofractionated radiotherapy, that normal tissue constraints and target volumes derive from published reference standards the use and that image guidance and intensity modulation at one form or another are recommended in delivering hypofractionated radiotherapy. Great. Thank you for the overview of those guideline recommendations. So why is this guideline so important and how will it change practice? Yeah. I guess the first point to make is that the guideline potentially can inform the care of a very large number of patients. Across North America, about 200,000 patients a year are diagnosed with prostate cancer and its far and away that the most prevalent non-dermatologic cancer in men and it's the third-leading cause of cancer death in men, at least in North America. So the vast majority of those 200,000 men are diagnosed with localized disease at the time of presentation and therefore they're potentially treatable with radiation therapy and therefore the guideline is relevant to these patients. Prior to the publication of the trials that motivated this guideline, the overwhelming majority of these men who chose external beam radiotherapy as their primary treatment have been treated with conventionally fractionated therapy. In other words, seven and a half to nine weeks of treatment. And already, since the publication of these trials-- the trials of moderate hypofractionation-- we're talking really about moderate hypofractionation because I think that is where the guideline will have its impact, at least in the short term. In the jurisdiction where I practice in Canada, practice has already substantially changed in light of these trials, and I think a large majority of patients with localized prostate cancer choosing external beam radiation therapy are now typically being treated with a moderately hypofractionated approach, typically a four-week schedule. So it will be interesting to see if a similar change is occurring or will occur over time in the United States, particularly informed or potentially informed in part by this guideline. And then finally, with respect to ultra-hypofractionation, I think again I have to note that this is a very dynamic space in terms of evidence and there are a number of large-scale trials looking at ultra-hypofractionation and comparing it to either conventional fractionation or moderate hypofractionation that are in progress or near to reporting. And so again, an update of the guideline in the short-term as data emerges from these studies will likely be important and it may ultimately influence practice as well on a large scale. And finally, how will these guideline recommendations affect patients? So I think in the short term, that the recommendation that has the potential to impact patients in the greatest way is the recommendation regarding moderate hypofractionation. And the guideline really recommends that this is a management approach that substantially reduces the treatment burden without compromising treatment efficacy and without increasing the risk of long-term side effects. So in my view, the move to moderately hypofractionated radiation therapy is a win for patients with localized prostate cancer who choose radiation therapy as their primary treatment modality. And so moderate hypofractionation really represents about a halving of the overall treatment time in some patients. And those who live, for example, in rural or remote areas and who need to travel considerable distance to have their treatment, a halving of treatment time is significant. But I think even more generally, halving of treatment time is significant for patients regardless of where they live. And clearly there are also benefits potentially in terms of cost and also benefits in terms of for the health care system but those really weren't specifically studied in the guideline. Great. Thank you so much for your time today, Dr. Morgan, and thank you for your work on this important guideline. My pleasure, Shannon, and thank you for having me. And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast series. If you've enjoyed what you've heard today, please rate and review the podcast and refer the show to a colleague.

Dr. Axel Hauschild, professor of dermatology and head of the dermato-oncology department at the University Hospital of Kiel in Germany, discusses the recent FDA approval of cemiplimab, a PD-1 antibody treatment for patients with metastatic or locally advanced cutaneous squamous cell carcinomas. If you enjoyed this podcast, make sure to subscribe for more weekly education content from ASCO University. We truly value your feedback and suggestions, so please take a minute to leave a review. If you are an oncology professional and interested in contributing to the ASCO University Weekly Podcast, email ascou@asco.org for more information. TRANSCRIPT [MUSIC PLAYING] Welcome to the Recent Approvals episode of the ASCO University Weekly Podcast. My name is Axel Hauschild. I'm a professor of dermatology and head of dermato-oncology at the University Hospital of Kiel in Germany. Today, we will discuss the approval of cemiplimab, a new PD-1 antibody for the treatment of patients with metastatic or locally advanced cutaneous squamous cell carcinomas. As a background to today's discussion, immune checkpoint inhibitors are active therapies in patients with other cutaneous malignancies, like melanomas and mucosal carcinomas already. So far, chemotherapy was given as a routine for patients with advanced or metastatic cutaneous malignancies, and occasionally, cetuximab, an EGFR inhibitor. However, in almost all of these patients, the responses were short-lasting. The analysis of the tumor mutational burden indicated a high sensitivity of more or less all UV-induced cutaneous malignancy for immune checkpoint inhibitors. Therefore, theoretically, cutaneous squamous cell carcinomas are ideal tumors for the treatment with PD-1 or PD-ligand 1 antibodies. On September 28 of 2018, cemiplimab was approved by the FDA for the treatment of patients with metastatic or locally advanced cutaneous squamous cell carcinomas who are not candidate for curative surgery or curative radiation. These data led to the approval of a flat dose of 350 milligrams cemiplimab infused over 30 minutes every three weeks. The approval of cemiplimab was based on a high number of clinically meaningful and durable objective responses observed in patients with two different clinical trials. The results have already been published in 2018, in June, in the New England Journal of Medicine. Both clinical trials were non-randomized, multicenter studies in patients for whom surgery or irradiation was not recommended. Among 108 patients with advanced cutaneous squamous cell carcinomas, including 75 metastatic patients, the overall response rate was 47%, with 4% complete and 44% partial responses. There were no significant differences in the response rate between patients with metastatic and those with locally advanced disease. The median response duration was not reached. And 61% of the responses were durable for six months or longer. Response rates and durability results were consistent across the advanced squamous cell carcinoma subtypes. For patients with locally advanced cutaneous squamous cell carcinomas, the radiographic response rate correlated with clinically relevant shrinkage of visible and often disfiguring tumors demonstrated in the photographic data obtained in these clinical trials. Safety data were evaluable from 434 patients who received cemiplimab in both clinical trials. Serious adverse events were typically immune-mediated, such as colitis or pulmonitis. And in some patients, infusion reactions were observed. The most common adverse events were fatigue, rash, and diarrhea. The treatment discontinuation rate was 12%. The approval of cemiplimab marks a significant advancement in the treatment of patients with metastatic or locally advanced cutaneous squamous cell carcinomas. Cemiplimab is considered as a new standard of care in these patients, since not only an impressive response rate of almost 50%, but also durable responses were observed. As mentioned before, previously, chemotherapies and cetuximab have been used for these patients with limited efficacy, particularly because most responses were only short-lasting. Important to mention is that the approval is not going along with a biomarker test, such as the measurement of PD-ligand 1 expression. Therefore, cemiplimab can be used for all comers with metastatic or locally advanced cutaneous squamous cell carcinomas. So far, there are no data available when cemiplimab has been combined with other agents or irradiation. Also, data from the adjuvant of PD-1 antibodies in high-risk cutaneous squamous cell carcinoma patients are outstanding. However, clinical trials on cemiplimab and other PD-1 antibodies are already planned. In conclusion, cemiplimab adds significantly to the success story of PD-1 and PD-ligand 1 antibodies in cutaneous malignancies. The approval of cemiplimab for cutaneous squamous cell carcinomas leads to changes in the current guidelines for this tumor. Thank you very much for listening to this week's episode of the ASCO University Weekly Podcast. For more information on immune therapy and the treatment of cutaneous squamous cell carcinomas, visit the comprehensive eLearning Center at university.asco.org. [MUSIC PLAYING] The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.