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Dr. Greg Kalemkerian reviews the latest evidence-based rapid update from the Expert Panel on systemic therapy for small cell lung cancer. He discusses the updated recommendations for patients with limited-stage SCLC based on the ADRIATIC trial, and for patients with relapsed SCLC based on the DeLLphi-301 trial. Dr. Kalemkerian shares insights on what these changes mean for clinicians and patients, and highlights new trials in progress to provide more options for patients diagnosed with SCLC.

Read the full rapid update, "Systemic Therapy for Small Cell Lung Cancer: ASCO Guideline Rapid Recommendation Update" at www.asco.org/thoracic-cancer-guidelines.

TRANSCRIPT

This guideline, clinical tools, and resources are available at http://www.asco.org/thoracic-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02245

Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one at asco.org/podcasts.

My name is Brittany Harvey and today I'm interviewing Dr. Greg Kalemkerian from the University of Michigan, lead author on, "Systemic Therapy for Small Cell Lung Cancer: ASCO Guideline Rapid Recommendation Update".

Thank you for being here today, Dr. Kalemkerian.

Dr. Greg Kalemkerian: Thank you. Thank you for the invitation.

Brittany Harvey: Great. Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Kalemkerian, who has joined us here today, are available online with the publication of the update in the Journal of Clinical Oncology, which is linked in the show notes.

So then, to dive into the content of this rapid update, Dr. Kalemkerian, what prompted this update to the Systemic Therapy for Small Cell Lung Cancer Guideline, which was previously published in 2023?

Dr. Greg Kalemkerian: So even though the original guideline only came out a year ago, the past year we've seen two significant advances in small cell lung cancer with two reports, one in limited stage with the addition of immunotherapy, the other in the addition of a new immunotherapeutic agent in relapsed small cell lung cancer.

Brittany Harvey: It's great to have this new data in the small cell lung cancer space. So based on these new changes, what are the updated recommendations from the expert panel?

Dr. Greg Kalemkerian: So the first recommendations have to do with patients with limited-stage small cell lung cancer based on the ADRIATIC trial which added consolidation durvalumab for patients who had not had progression after standard chemotherapy and radiotherapy. And this study demonstrated a significant improvement in overall survival with about a 10% improvement in both 2- and 3-year overall survival, up to a 57% overall survival at 3 years for the patients receiving consolidation durvalumab. And based on those findings, we updated the recommendation for the standard treatment for limited-stage small cell lung cancer such that it included the use of consolidation immunotherapy with durvalumab for up to two years in patients who had had no disease progression, and completion of concurrent chemoradiotherapy for limited-stage small cell lung cancer. Of course, those patients would be those who do not have contraindications to the use of immunotherapy.

As a corollary to that recommendation, for patients who have poorer performance status, so performance status of 3 or 4, who had had initial treatment perhaps with sequential chemotherapy and radiotherapy, if their performance status improves with their initial treatment, then it would also be reasonable to add consolidation immunotherapy for those patients as long as their performance status maintains improvement and they have no evidence of progression.

The other update of the guidelines had to do with patients with relapsed small cell lung cancer and that was based on the DeLLphi-301 trial which was a phase II study looking at the use of tarlatamab, a bispecific T cell engager, binds to both DLL3 and CD3 in order to increase the immune killing of small cell lung cancer cells. So what this study did was it treated patients who had had at least two prior regimens. So this is third-line or beyond was what the population that this study looked at. And the majority of these patients had already had some immune checkpoint therapy. They all had good performance status and it did allow patients with brain metastases to be included in the study. When we look at the patients who received the approved 10 milligram dose of the drug, the response rate was about 40%. Responses were seen in both patients with sensitive and refractory based on the time since their prior treatment and the median duration of response was 10 months, which is much better than anything we've seen before with relapsed small cell lung cancer patients, remembering that all these patients were also third-line or beyond.

So based on the results of the DeLLphi-301 trial, we updated two of the recommendations regarding relapsed small cell lung cancer. In the first one, we stated that in patients with relapsed small cell lung cancer with a chemotherapy free interval of less than 90 days, single agent systemic therapy would be considered standard of care, and that the preferred agents would include topotecan, lurbinectedin, or, now, tarlatamab. We did mention as a qualifying statement that single-agent chemotherapy is preferred over multi-agent chemotherapy. And the second recommendation was that, in patients with relapsed small cell lung cancer with a chemotherapy interval longer than 90 days, the rechallenge with a platinum-based regimen or single-agent chemotherapy was considered standard and the preferred agents for single agent therapy would be topotecan, lurbinectedin, or tarlatamab being added in the recent study. Tarlatamab was approved by the FDA for use in patients with relapsed small cell lung cancer with no stipulations with regard to the treatment.

Brittany Harvey: Understood. I appreciate you describing those updated recommendations along with the supporting data for both limited stage small cell lung cancer and relapsed small cell lung cancer.

So then, what should clinicians know as they implement these new and updated recommendations into practice?

Dr. Greg Kalemkerian: So with regard to the ADRIATIC trial or the consolidation durvalumab being added for limite- stage small cell lung cancer patients, I think the important considerations are that this was done after patients had demonstrated no progression of disease after chemotherapy and radiotherapy, so the initial treatment does not change with platinum-etoposide plus definitive radiotherapy being recommended. The addition of durvalumab is going to be potentially useful in patients generally with good performance status, so performance statuses 0 to 1, and we still have to pay attention to the patients who may have contraindications to immunotherapy, things like interstitial lung disease, autoimmune problems that do occur in patients with small cell lung cancer where they develop paraneoplastic autoimmune syndromes such as Lambert-Eaton myasthenic syndrome. Those patients with those types of preexisting conditions would not be good candidates for immunotherapy use. So still having the tailored treatment to the individual patient is what's most important. The duration of the durvalumab was up to two years and not beyond that, so following those specific guidelines for the use of durvalumab in patients with limited-stage small cell lung cancer.

With regard to tarlatamab, tarlatamab is an immunotherapy treatment. So we still do have the exclusions of people who have had prior severe immune-related adverse events, people who have pneumonitis, people who have interstitial lung disease, people with autoimmune neurologic problems we can see with small cell lung cancer, these patients should not be considered good candidates for the use of tarlatamab. The study did include patients who had had treated and asymptomatic brain metastases and there is some evidence that tarlatamab can have some control of brain metastases. So that's not necessarily an exclusion.

Tarlatamab does have some other specific considerations to it in that 51% of patients had some evidence of cytokine release syndrome (CRS). Only 1% of those patients had grade 3 CRS. So even though they had frequent fevers and hypotension and hypoxia, it was generally not severe. But this concern for CRS and also for neurologic complications after treatment does require that patients be admitted to the hospital for a 24-hour observation period during the first and second doses. Subsequent to that, patients can be observed for some time after the infusion in the outpatient setting. But they also need to have very clear and strict guidance for when they go home about what things to look for. Looking for fevers, looking for shortness of breath, looking for any neurologic changes. It's a good idea for them to have a caregiver with them in order to observe them during that time. Most of these complications occur during the first or second cycles, but it is a drug that is going to require significant education not only of our staff, but also of the patients in order to ensure that the drug's used safely.

Brittany Harvey: Absolutely. For these new options, it's important to tailor cancer treatment to the individual patient and the factors that you mentioned and be mindful of these potential toxicities.

So, it's always great to learn of new options for patients. But in your view, how will this update impact patients with small cell lung cancer?

Dr. Greg Kalemkerian: Well, clearly we need longer term follow up. So, with regard to the limited-stage small cell lung cancer situation, that's a curative situation. We have been curing patients with limited-stage disease with chemotherapy and radiotherapy for several decades now, but the cure rates were relatively low with about 25%, 30% of people becoming long term survivors. Now the hope is with the durvalumab being added on, that we can increase that number. Thus far, we have three-year survival data with a three-year survival of 57% overall survival and we're hoping that that is maintained over time and that we're not just delaying recurrences, but that we're actually preventing recurrences and helping people live longer, as has been seen with non-small cell lung cancer in stage III disease with the addition of durvalumab to chemoradiotherapy. So hopefully, we will be improving the cure rate of people with limited-stage small cell lung cancer.

There are several other trials with immunotherapy in this space coming down the line and we're anxiously awaiting not only long term follow up from ADRIATIC, but also initial data from studies such as KEYLYNK and ACHILLES and NRG-LU005. So all of these studies in the next few years are hopefully going to guide treatment for limited-stage small cell lung cancer and hopefully improve the long term survival outcomes. With regard to tarlatamab, unclear at this point what the long term outcomes are going to be. Is a 40% response rate substantially better than what we've seen before? Well, lurbinectedin also had about a 40% response rate in patients who had sensitive disease, but the duration of response does look longer. And there are some patients now who have been on this study that are doing very well for quite long periods of time with the drug. So, the hope here also is that we will have some small subset of patients who continue to do better for long periods of time. Whether that'll translate into a cure or not, way too early to know, clearly hoping to add another brick in the wall so that we can keep the disease at bay, at least for a longer period of time for these patients.

How we will integrate tarlatamab into the regimens is a bit unclear. Whether most of us will start using it as second-line therapy or whether we will use perhaps lurbinectedin or topotecan as second-line and tarlatamab as third-line, we're all going to have to work that out based on the potential toxicities, the logistical complications of using the drug at this point in time. But I do think that it's nice to have more options to add to our armamentarium to treat this very, very challenging and difficult disease.

Brittany Harvey: Definitely. So, you've just discussed the need for both longer term follow up here along with some important ongoing trials in this space. So we'll look forward to future readouts of those trials to learn more about caring for patients in small cell lung cancer.

So, I want to thank you so much for your work to rapidly update this guideline and thank you for your time today, Dr. Kalemkerian.

Dr. Greg Kalemkerian: Okay. Again, thank you for the invitation, Brittany, and thanks to ASCO for developing the whole guideline structure to help all of us take better care of our patients.

Brittany Harvey: Absolutely. And also thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full update, go to www.asco.org/thoracic-cancer-guidelines.  You can also find many of our guidelines and interactive resources in the free ASCO Guidelines App available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

Dr. Lyudmila Bazheova share the latest updates to the ASCO living guideline on therapy for stage IV non-small cell lung cancer with driver alterations. She discusses changes for patients with EGFR driver alterations in both the first- and second-line setting, and reviews the evidence supporting these updated recommendations, from trials such as MARIPOSA, MARIPOSA-2, CheckMate 722, and KEYNOTE-789. Stay tuned for future updates to this continuously updated guideline.

Read the full update, "Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.2." at www.asco.org/living-guidelines.

TRANSCRIPT

This guideline, clinical tools, and resources are available at http://www.asco.org/living-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02133

Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one at asco.org/podcasts.  

My name is Brittany Harvey and today I'm interviewing Dr. Lyudmila Bazhenova from University of California San Diego Moores Cancer Center, lead author on "Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.2."

Thank you for being here, Dr. Bazhenova.

Dr. Lyudmila Bazhenova: It is my pleasure.

Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Bazhenova, who has joined us on this episode today, are available online with the publication of the guideline update in the Journal of Clinical Oncology, which is linked in the show notes.

So then, to kick us off on the content here, Dr. Bazhenova, this living clinical practice guideline for systemic therapy for patients with stage IV non-small cell lung cancer with driver alterations is being updated routinely as a living guideline. So what prompted the update to the recommendations in this latest version?

Dr. Lyudmila Bazhenova: Living ASCO Guidelines are developed to keep up with rapidly changing evidence which affect treatment of our patients with lung cancer. In this recently published guideline, we reviewed new evidence for patients with metastatic lung cancer harboring driver alterations. We reviewed evidence from four published studies, MARIPOSA, MARIPOSA-2, CheckMate 722 and KEYNOTE-789 that resulted in updated guidelines.

Brittany Harvey: Great. And then based off those four trials that you just mentioned, what are the updated recommendations for patients with stage IV non-small cell lung cancer and an EGFR exon 19 deletion or exon 21 L858R substitution?

Dr. Lyudmila Bazhenova: In the previous guideline, we detailed FLAURA 2 study which was presented and published in the past. In this guideline, we specifically highlighted a phase 3 MARIPOSA trial which took patients with untreated advanced non-small cell lung cancer which harbored classical EGFR mutations such as EGFR deletion 19 and L858R. In this study, patients were randomly assigned to receive amivantamab plus lazertinib or osimertinib or lazertinib alone. And the study showed that the primary endpoint which was progression-free survival was longer with amivantamab plus lazertinib compared to osimertinib, and numerically the progression free survival was 23.7 months with ami-lazertinib versus 16.6 months with osimertinib which was statistically significant. The challenge that we have to face when discussing that option with our patients is increased toxicity with amivantamab and lazertinib combination. For example grade 3 treatment adverse events were 75% with amivantamab and lazertinib and 43% with osimertinib. So this will require shared decision making between our patients and ourselves. We also noticed in the guidelines that there was a subgroup analysis of that study showing that the patients with a higher disease burden, central nervous metastasis or brain metastasis as well as disease which considered to be a higher risk such as commutation, for example, p53 and liver metastasis, they might benefit from intensified therapy. However, another thing that we are highlighting in the guideline is that at this point we do not know how the intensification of therapy will change overall survival of our patients. So one needs to take into account increased toxicity with that combination.

Brittany Harvey: So then Dr. Bazhenova, in addition to those updates for first line therapy, what are the updated recommendations for second line therapy?

Dr. Lyudmila Bazhenova: For patients who have progressive disease on osimertinib or other EGFR tyrosine kinase inhibitors, we also updated our guidelines highlighting MARIPOSA 2 study. In the MARIPOSA 2 study, patients were assigned to chemotherapy versus amivantamab plus lazertinib plus chemotherapy versus amivantamab plus chemotherapy. And both of the amivantamab arms showed superiority in progression-free survival compared to chemotherapy alone arm and therefore this becomes an additional treatment option for our patients who develop resistance to osimertinib. In addition, we also updated the results which highlight the lack of efficacy of immunotherapy in the patients who progressed on osimertinib.

There were two studies that we highlighted. One of them was a CheckMate 722 which randomly assigned patients with metastatic non-small cell lung cancer whose cancer has progressed on EGFR tyrosine kinase inhibitor to receive either chemotherapy or chemotherapy plus nivolumab which is an immune checkpoint inhibitor.

And the second study was KEYNOTE-789 which had a very similar study design. Again, patients who progressed on EGFR TKI also were assigned to receive chemotherapy plus pembrolizumab or chemotherapy alone and in both of those studies there was no improvement in progression-free survival when adding immunotherapy to chemotherapy. So for all your patients who are progressing on EGFR tyrosine kinase inhibitors and you're thinking if additional immunotherapy is necessary, we now have two randomized phase 3 studies telling us that immunotherapy should not be used in addition to chemotherapy for patients who develop progression on osimertinib.

Brittany Harvey: Understood. I appreciate you talking about the evidence that supports these latest recommendations from the expert panel.

So then you've already touched on this a little bit in mentioning shared decision making and discussing toxicity with these new therapies, but what should clinicians know as they implement these new recommendations and how do these new recommendations fit into the previous recommendations made by the panel?

Dr. Lyudmila Bazhenova: Our previous recommendations did not include a MARIPOSA trial, so did not include amivantamab and lazertinib. So in our current guidelines for patients with newly diagnosed treatment-naive EGFR classical mutations, we have three options. Number one is osimertinib, number two is osimertinib plus chemotherapy based on the FLAURA study that we highlighted in the prior version of the guidelines. And the third is amivantamab plus lazertinib. At this point, we do not have any randomized head-to-head studies of those combinations with an exception of FLAURA 2 which is osimertinib plus chemo versus osimertinib. And so the decisions will have to be made on a cross-trial comparison, taking into account patient wishes if they would like to receive chemotherapy or amivantamab plus lazertinib, understanding that this combination will result in increased toxicity.

Brittany Harvey: Absolutely. I appreciate you detailing those considerations.

So then finally, what do these new options mean for patients with non-small cell lung cancer and an EGFR alteration?

Dr. Lyudmila Bazhenova: As a patient, it is important to also be aware of what options we have and have a direct dialogue with the physician, with the treating physician, trying to understand what option will fit with each individual patient's goals, life goals, as well as toxicity concerns.

Brittany Harvey: Definitely. It's always great to have more options for patients and it's also important to discuss all of those options with their clinician as well.

So I want to thank you so much for your work on this update and thank you for your time today, Dr. Bazhenova.

Dr. Lyudmila Bazhenova: My pleasure.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/living-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Douglas Peterson presents the latest evidence-based guideline from ISOO, MASCC, and ASCO on the prevention and management of osteoradionecrosis (ORN) in patients with head and neck cancer treated with radiation therapy. He covers topics such as recommended initial workup, best practices for prevention of ORN of the head and neck before and after radiation therapy, nonsurgical and surgical management of ORN, and management of adverse events associated with ORN. Dr. Peterson also comments on the importance of this guideline and what researchers should address moving forward.
Read the full guideline, "Prevention and Management of Osteoradionecrosis in Patients with Head and Neck Cancer Treated with Radiation Therapy: ISOO-MASCC-ASCO Guideline" at www.asco.org/head-neck-cancer-guidelines.

TRANSCRIPT

This guideline, clinical tools, and resources are available at http://www.asco.org/head-neck-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.02750.  

Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts, bringing you timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all our shows, including this one, at asco.org/podcasts.  

My name is Brittany Harvey and today, I'm interviewing Dr. Douglas Peterson from UConn Health, lead author on "Prevention and Management of Osteoradionecrosis in Patients with Head and Neck Cancer Treated with Radiation Therapy: International Society of Oral Oncology, Multinational Association for Supportive Care in Cancer, American Society of Clinical Oncology Guideline." Thank you for being here, Dr. Peterson.

Dr. Douglas Peterson: Thank you, Brittany. My pleasure to be here.

Brittany Harvey: Before we discuss the guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensures that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Peterson, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. 

So then, to dive into the topic we're here to discuss, Dr. Peterson, could you first provide an overview of the scope and purpose of this joint ISOO-MASCC-ASCO guideline?

Dr. Douglas Peterson: I'll be pleased to do so, Brittany. Again, thank you for the opportunity to represent the panel in this guideline. The panel has strived to present a guideline that brings consistency in clinical practice regarding prevention and management of osteoradionecrosis of the jaw (ORN) based on the highest quality contemporary science. Given the mechanistic and clinical complexity of ORN, we also stress the importance of interprofessional oncology care of these patients. The team includes, but is not limited to, clinicians representing radiation oncology, head and neck surgery, medical oncology, otolaryngology, dental medicine, oral medicine, oral oncology, oral and maxillofacial surgery, and patient advocacy organizations. So it really is a collective enterprise that we bring to bear in the guideline. 

In some cases, the panel has been fortunate to be able to utilize a high quality evidence base in the literature upon which we could build strong recommendations. In selected other cases, however, we utilized informal consensus given the low evidence quality in the field. The recommendations presented have been carefully framed in this context, with the goal of providing state-of-the-science guidelines in clinical decision making and management of ORN. I'd also like to point out that the guideline brings linkage to other guidelines published by ASCO and other major oncology organizations, regarding management of symptoms and other supportive care needs associated with ORN. These companion guidelines include addressing pain, dysphagia, oral care, trismus, and psychosocial impact and survivorship, to name a few. I'd also like to say that combining the expertise of ISOO, MASCC, and ASCO has provided an important opportunity to produce this guideline. This has been a comprehensive effort by many experts. In addition to the outstanding input from the panel, I am also personally so very grateful for the expert input from ASCO's Evidence-Based Medicine Committee, as well as endorsements from other key organizations, including the American Head and Neck Society, the American Society for Radiation Oncology, and the American Academy of Oral Medicine as endorsees of the guideline. Finally in addition, Dr. Nofisat Ismaila's leadership as ASCO staff has been absolutely invaluable as well. 

Brittany Harvey: Excellent. I appreciate you providing that background on the development of this evidence-based guideline, which was developed by a multi-organizational and multidisciplinary panel.  

So to dive into the key recommendations of this guideline, this guideline addresses six clinical questions. So, starting with question one, what key points would you like to highlight regarding how ORN is characterized, graded, and reported, and what is the recommended initial workup for patients? 

Dr. Douglas Peterson: Osteoradionecrosis of the jaw of the mandible and maxilla should be characterized in the view of the panel as a radiographic, lytic, or mixed sclerotic lesion of bone, and/or visibly exposed bone, and/or, importantly, bone probed through a periodontal pocket or fistula. In the latter case, the clinical appearance of exposed bone may be extremely subtle. ORN is occurring within an anatomical site previously exposed to a therapeutic dose of head and neck radiation therapy. So we have a combined radiographic/clinical approach characterizing the lesion in the context of the patient having received previously a therapeutic dose of head/neck radiation therapy. We do recommend that clinicians evaluate ORN based on the most contemporary staging system, the ClinRad system, which is cited in the publication itself. We also advocate for the use of the ClinRad staging system not only in clinical assessment of patients, but also in clinical trials moving forward. We'll touch a little bit later on future research opportunities as well. 

Finally, the initial evaluation of ORN should include a clinical intraoral examination, and again, the appearance of exposed bone may be extremely subtle, and/or a formal radiographic examination. The guideline delineates the various types of radiographic examinations that we recommend. 

Brittany Harvey: Understood. Thank you for reviewing those recommendations regarding reporting and characterization of ORN, as well as the workup.  

The next section of the guideline, it focuses on best practices to prevent ORN of the head and neck prior to radiation therapy. What are the key recommendations of that section? 

Dr. Douglas Peterson: As with other adverse events in oncology patients, prevention is key. Prevention of ORN does require interprofessional management. The guideline lists several key recommendations along these lines. Now, an important caveat in what the guideline presents is that the target coverage of the tumor should not be compromised in order to avoid radiation dose to bone. So that's a very important caveat. Now having said that, focused effort should be made to reduce the mean dose to the jaw and the volume of bone receiving above 50 Gy whenever possible. So it's really a balance between maximizing target coverage of the tumor while limiting exposure to normal bone. In addition, a dental assessment by a dentist and dental specialist, if possible, is strongly advised prior to therapeutic-intent radiation therapy. The purpose of this assessment by the dental team is to identify and remove teeth which will place the patient at risk of developing ORN during the patient's lifetime, and to comprehensively educate the patient about the lifelong risk of ORN. Dental extraction in advance of radiation is often a consideration to these patients, and if clinically indicated, should occur at least two weeks prior to the commencement of radiation therapy. Now having said that, in the setting of a rapidly progressive tumor, extraction should be deferred and not cause delay in the initiation of radiation therapy.

Brittany Harvey: So you just touched on key points of prevention prior to radiation therapy. Following those recommendations, what does the expert panel recommend regarding best practices to prevent ORN after radiation therapy?

Dr. Douglas Peterson: This can be a challenging clinical issue. So the panel recommends that before finalizing dental treatment plans that may include extractions in patients with a history of head and neck radiation therapy, a review of the radiation therapy plan should be performed with particular attention focused on dose to the mandible and maxilla. For teeth in areas of high-risk for ORN, alternatives to dental extraction may be possible, for example, root canal or endodontic procedures, crowns, or dental restorations, or dental filling should be offered unless the patient has recurrent infections, intractable pain, or other symptoms that cannot be alleviated without extraction. So it really becomes a combined clinical decision making effort between the dental team and oncology team. 

One controversial area has been hyperbaric oxygen being administered prior to dental extractions in patients who have received head and neck radiation therapy previously. The panel does not recommend routine use of prophylactic HBO prior to dental extractions in these patients who have received prior head and neck radiation therapy. However, the evidence base here is limited with low quality and we offer a weak strength of recommendation. It is a controversial area, so we did also include a qualifying statement that prophylactic HBO may be offered to patients undergoing invasive dental procedures at oral sites where a substantial volume of the mandible and/or maxilla receive at least 50 Gy. This is an area of controversy. We can talk about this in the future research directions, but clearly, new high quality research related to the role of HBO in the management of these patients is needed. 

Brittany Harvey: Definitely. Thank you for touching on those points and that area of controversy. We can definitely touch on that a bit later as we talk about future research in this field. 

As you mentioned, Dr. Peterson, this guideline addresses both prevention and management. So, in moving into the management of ORN, how should ORN be managed nonsurgically? 

Dr. Douglas Peterson: The guideline relative to nonsurgical management of ORN is focused on the use of pentoxifylline. Now this maybe used in, and this is important, in cancer-free patients with mild, moderate, and severe cases of ORN. But pentoxifylline, the guideline also notes, is most likely to have a beneficial effect if the treatment is combined with tocopherol, antibiotics, and prednisolone as well. So there's clinical judgment involved in the nonsurgical management of ORN, centered with pentoxifylline in combination with tocopherol, antibiotics, and prednisolone.

Brittany Harvey: Understood. And then expanding on the management of ORN, what are the key points for surgical management of ORN?

Dr. Douglas Peterson: The panel offered several recommendations for which the strength of the recommendations was strong. Just to cite a few, in partial thickness ORN as defined by the ClinRad stage one and two that we talked about earlier, surgical management can start with transoral minor interventions which can lead to resolution over time. It may take time. It may take weeks or even a few months. Now this minimally invasive surgery may include debridement, sequestrectomy, alveolectomy, and/or soft tissue flap closure. Furthermore, small defects, clinically, for example, less than 2.5 cm in length, may heal spontaneously with local topical measures such as we described. It is recommended that larger defects, larger than 2.5 cm, in general be covered with vascularized tissue. 

Brittany Harvey: Appreciate you reviewing those recommendations regarding surgical management of ORN. So to wrap up our discussion of the recommendations with the final clinical question, what is recommended for assessment and management of adverse events associated with ORN? 

Dr. Douglas Peterson: This is a really important area as well in addition to prevention and management of ORN per se. The panel recommends that patients should be assessed by their healthcare providers for the presence of adverse events at the time of ORN diagnosis and periodically thereafter until the adverse event resolves based on patient status including any interventions or the adverse events that are clinically indicated. The panel and its literature evaluation learned that there is a relative lack of data specifically directed to the management of adverse events associated with ORN. However, this is such an important area that we wanted to address it head on. And so the management we recommend should be informed by pertinent available other guidelines that had been developed for analogous symptoms and/or disease states. The guideline provides links to these companion guidelines developed by ASCO as well as by MASCC and ISOO, the European Society of Medical Oncology, and NCCN. And so in the guideline we provide links on management of adverse events as produced by these other organizations. Table 3 presents a summary of the guidelines that address symptoms and supportive care needs associated with ORN. 

Brittany Harvey: Thank you for reviewing all of these recommendations. It's clear that the panel put a lot of work and thought into these recommendations and provided needed guidance in areas with limited evidence. We'll have links available in the show notes for listeners to be able to go and read these recommendations for themselves and refer to the tables that you mentioned. 

So in your view, Dr. Peterson, what is the importance of this guideline and how will it impact clinicians and patients with head and neck cancer?

Dr. Douglas Peterson: As we talked about throughout this podcast, the guideline is designed to synthesize the contemporary science regarding ORN and translate that into recommendations for clinical practice in both prevention and management. As noted in the guideline, oncologists plus other interprofessional healthcare providers have been directly involved in the creation of the guideline, that interprofessional theme, which we believe is so essential given the mechanistic and clinical complexity of ORN. 

Now, in addition to the expertise of the panel, the pending widespread distribution of the guideline represents an additional important opportunity for extending the impact across clinical oncology. So in addition to the publication in the Journal of Clinical Oncology, dissemination by MASCC and ISOO as well as our endorsees, the American Head and Neck Society, the American Society for Radiation Oncology, and the American Academy of Oral Medicine will also be key in broadening the impact and hopefully the utilization of the guideline. And members of these organizations may very well be involved in the management of these patients as well. 

And then finally, the guideline is also designed to stimulate future research based on current gaps of the knowledge and we touched on some of those gaps, for example, with HBO for which new high quality research is needed.  

Brittany Harvey: Absolutely. It's great to have so many partners in this guideline and we hope that this guideline will have a large impact for patients with head and neck cancer to improve their quality of life.  

So then your final comment leads nicely into my last question and that we've already talked a little bit about some of the future research opportunities that this guideline highlights. So, to wrap us up, Dr. Peterson, what are the outstanding questions regarding osteoradionecrosis of the jaw secondary to head and neck radiation therapy in patients with cancer? 

Dr. Douglas Peterson: There are several key areas that the panel identified as we went through a rigorous review of the highest quality literature. Some of the key areas to address moving forward include: prospective studies are needed to evaluate the clinical presentation, trajectory, and response to treatment of ORN-related symptoms and function impairment, in other words, the adverse event side of the story. In addition, social determinants of health, quality of life, and psychosocial impact of ORN warrant further investigation in head and neck cancer survivors as well. In addition, new research including randomized controlled trials and prospective multicenter trials regarding the systemic and surgical treatment of ORN is also warranted, and we touched on, for example, hyperbaric oxygen. Hyperbaric oxygen has been a long standing management strategy of ORN. However, the trials to date are of limited quality in relation to supporting its use. So high quality new research related to the role of HBO in these patients is needed.  

And the expert panel also encourages creation of predictive tools, a priori tools, directed to development, grading, and staging of ORN. These could include, for example, bone turnover markers and genetic markers to name two. And finally, the research opportunities that are presented in the guidelines such as what I briefly summarized today should ideally be addressed in large prospective multicenter observational studies of risk, outcomes, and financial cost of ORN or the various treatment strategies that are highlighted in the guideline.   

Brittany Harvey: Excellent. Well, we'll look forward to research that addresses those outstanding questions and I want to thank you so much for your all your work on this guideline and for taking the time to share the highlights of this guideline with me today, Dr. Peterson. 

Dr. Douglas Peterson: Thank you. My privilege to do so, Brittany.

Brittany Harvey: And thank you to all our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/head-neck-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app in the Apple App Store or the Google Play Store. If you have enjoyed what you heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

A preview of the interview by ASCO in Action podcast host ASCO CEO Dr. Clifford A. Hudis with retiring ASCO Chief Medical Officer Dr. Richard L. Schilsky examining Dr. Schilsky's trailblazing medical career, his leadership in ASCO and indelible mark on its research enterprise, and what he sees for the future of oncology. Dr. Hudis also shares what Dr. Schilsky's friendship and mentorship has meant to him and suggests that he will still be supporting ASCO on critical priorities. Find all nine of ASCO's podcasts and subscribe at podcast.asco.org.

TRANSCRIPT

Dr. Clifford Hudis: Hello, I'm Dr. Clifford Hudis, CEO of ASCO, dropping into your feed to let you know about a special episode of the ASCO in Action podcast featuring the extraordinary career of Dr. Richard Schilsky, ASCO's Chief Medical Officer. Rich and I discuss the advances that have revolutionized cancer care over the last 50 years and much, much more. Here's a preview of the episode.

Dr. Richard Schilsky: The 1980s in many respects were the doldrums of progress in clinical oncology. There really was not a lot of innovation in the clinic. But what was happening and what was invisible to many of us, of course, was that was the decade of discovery of the fundamental biology of cancer. That's when oncogenes were discovered, when tumor suppressor genes were discovered, when it became clear that cancer was really a genetic disease. And that is what transformed the field and put us on the path to targeted therapy and precision medicine as we think of it today.

Dr. Clifford Hudis: You can find the ASCO in Action Podcast on Apple Podcasts or wherever you are listening to this show. And you can find all nine of ASCO's podcasts which cover a wide range of educational and scientific content and offer enriching insight of the world of cancer care at podcast.asco.org.

An interview with Dr. Jun Ma from Sun Yat-sen University Cancer Center in Guangzhou and the Chinese Society of Clinical Oncology on "Chemotherapy in Combination with Radiotherapy for Definitive-intent Treatment of Stage II to IVA Nasopharyngeal Carcinoma: Chinese Society of Clinical Oncology and American Society of Clinical Oncology Guideline." Read the full guideline at www.asco.org/head-neck-cancer-guidelines.

Transcript

ASCO: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Hello, and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org.

My name is Brittany Harvey, and today I'm interviewing Dr. Jun Ma from Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy in Guangzhou, and the Chinese Society of Clinical Oncology, author on Chemotherapy in Combination with Radiotherapy for Definitive-intent Treatment of Stage II to IVA Nasopharyngeal Carcinoma, Chinese Society of Clinical Oncology and American Society of Clinical Oncology Guideline. Thank you for being here today, Dr. Ma.

JUN MA: Yes.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines in ensuring that the ASCO conflict-of-interest policy is followed for each guideline. The full conflict-of-interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Ma, do you have any relevant disclosures that are directly related to this guideline topic?

JUN MA: Thank you, Brittany. Hi, everyone. I'm Dr. Jun Ma from the Sun Yat-sen University Cancer Center in China. And I don't have any potential conflicts of interest related to this guideline topic.

BRITTANY HARVEY: Great. Thank you. Then can you give us a general overview of what this guideline covers?

JUN MA: Yes. This guideline aims to highlight significant clinical questions about the chemotherapy in combination with the radiotherapy for the definitive treatment of stage II to stage IVA NPC, nasopharyngeal carcinoma, It will clarify the fundamental principles of the radiotherapy planning and how to combine chemo with radiotherapy for a patient's success.

BRITTANY HARVEY: Great. Then this guideline covers five clinical questions. I'd like to review those key recommendations for our listeners. First, what does the guideline state regarding radiotherapy for patients with stage II to IVA nasopharyngeal carcinoma?

JUN MA: Yes. For all nasopharyngeal carcinoma patients, we support the use of IMRT summarized in the current evidence. We don't recommend the use of other techniques, such as 2D or even 3D radiotherapy. If IMRT is not available at that spot, patients should be transferred to the institution that could that could implement IMRT whenever possible.

For all NPC patients, a prescribed dose of 70 Gy in 33 or 35 fractions delivered over seven weeks should be offered. It should be noted that the radiation dose may be adjusted according to the tumor volume and its response to the chemoradiotherapy. In terms of the target delineation, we recommend you to follow several existing consensus guidelines. Thank you.

BRITTANY HARVEY: OK. Then what is recommended regarding chemotherapy sequence in addition to radiotherapy?

JUN MA: OK, generally speaking, patients with low disease burden, such as the lower end category of clinical stage, could receive lower intensity of chemotherapy. For T2, and if not negative of patients, chemotherapy is not routinely recommended, while for T1 or 2, N1 patients concurrent chemotherapy may be offered, particularly for T2 N1 patients.

For locoregional advanced disease, except the T3 lymph node negative patients, we recommend the use after concurrent chemotherapy with induction or adjuvant chemotherapy. It should be noted that there is a lack of head-to-head trials comparing induction chemo plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy plus adjuvant chemo. Thus, which sequence performs better in the contemporary era remains uncertain.

Finally, for T3 lymph node-negative patients, concurrent chemoradiotherapy should be offered. Adjuvant or induction chemotherapy may also be offered if there are adverse features, such as the bulky tumor volumes or high EBV DNA copy numbers.

BRITTANY HARVEY: Great. Then you just mentioned some chemoradiotherapy regimens. So for patients with nasopharyngeal carcinoma receiving concurrent chemoradiotherapy, what are the recommended chemotherapy options?

JUN MA: OK, for all NPC patient without contraindications, concurrent cisplatin should be offered along with radiotherapy. Weekly use after suspending with 48 milligrams per square meter or three weekly with eight or 200 milligram per square meter is acceptable. We recommended the cisplatin dose should be attempted to achieve a cumulative dose of at least 200 milligrams per square meter.

For patients with contraindications to cisplatin, nedaplatin, carboplatin, or oxaliplatin may be alternative choice. For patients with contraindications to cisplatin-based chemotherapy, Fluoropyrimidines such as 5FU with concurrent chemotherapy also may be offered. Thank you.

BRITTANY HARVEY: Great. And then for patients with nasopharyngeal carcinoma receiving induction chemotherapy, what are those recommended options?

JUN MA: Yes. For all patients receiving induction or adjuvant chemotherapy, platinum-based induction regimens should be offered in terms of induction chemo, such as GP, TPF, TP, PF, and the PX regimens are recommended. So induction regimens should be administered every three weeks for a total of three cycles, or at least the minimum two cycles. If the patients receive induction chemotherapy, chemoradiotherapy should be commenced within 21 to 28 days from the first day of the last cycle of induction chemotherapy.

BRITTANY HARVEY: Great. And then for the final set of recommendations for patients with nasopharyngeal carcinoma receiving adjuvant chemotherapy, what are those recommended chemotherapy options?

JUN MA: Considering that adjuvant chemotherapy is a choice of adjuvant regimens were much fewer than those of induction chemotherapy, according to current evidence. PF regimen administered every four weeks for a total of three cycles is recommended. If with contraindication to cisplatin, carboplatin may be combined with 5-FU.

It should be noted that for all patients receiving adjuvant chemotherapy and with contraindications to platinum-containing chemotherapy, the use of non-platinum based regimens remain experimental at this time and should not be offered routinely outside of the context of a clinical trial. The main difference between the recommendation for the induction and adjuvant chemotherapy are primarily due to the number of the randomized trials in which there are few studies regarding the adjuvant chemotherapy in nasopharyngeal carcinoma. Thank you.

BRITTANY HARVEY: Thank you for reviewing each of those recommendations. So then, what is the importance of this guideline? And how will it impact clinical practice in patients with nasopharyngeal carcinoma?

JUN MA: For nasopharyngeal carcinoma, it has extremely uneven geographically global distribution. More than 70 percent of this new diagnosis worldwide in the 2018 year, occurred in the East and Southeast Asia. Therefore, nasopharyngeal carcinoma remains a significant public health problem in these regions, which emphasize the significance of this guideline for providers and patients from the endemic area.

From my point of view, one of the novel features of this joint deadline is that it was developed through the international collaboration with the regional groups. Experts from the CSCO and ASCO shared interpretation of the evidence while accounting for the organizing national or cultural diversity of different regions. In brief, the guideline provides the guidelines on how to plan radiotherapy and when and how to add chemotherapy. Through the interpretation protecting the guideline, care providers can avoid over or under-treatment. And providing the most suitable chemoradiotherapy for NPC patients.

Besides, for the patients, they could receive the most suitable treatment, which is the balance of the efficiency as a quantity of the life. Thank you.

BRITTANY HARVEY: Great. Definitely, we appreciate the collaboration between the American Society of Clinical Oncology and the Chinese Society of Clinical Oncology. So thank you so much for your work on these guidelines. And thank you for your time today, Dr. Ma.

JUN MA: Thank you.

BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/head-neck-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

An interview with Dr. John D. Gordan from the University of California, San Francisco, and Dr. Michal G. Rose from Yale Cancer Center and VA Connecticut Healthcare System on "Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline." This guideline addresses first-line and subsequent systemic therapy options for patients with unresectable hepatocellular carcinoma that is not amenable to local therapies. Read the full guideline at www.asco.org/gastrointestinal-cancer-guidelines.

Transcript

ASCO: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines Podcast Series, brought to you by the ASCO Podcast Network. A collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org

My name is Brittany Harvey, and today I'm interviewing Dr. John D. Gordon from the University of California, San Francisco, and Dr. Michal G. Rose from Yale Cancer Center, and VA Connecticut Health Care System, co-chairs on "Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline." Thank you for being here Dr. Gordon and Dr. Rose.

DR. MICHAL G. ROSE: Thank you.

DR. JOHN D. GORDON: Thank you.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Gordon, do you have any relevant disclosures that are related to this guideline topic?

DR. JOHN D. GORDON: I do not.

BRITTANY HARVEY: Thank you. And Dr. Rose, do you have any relevant disclosures that are related to this guideline topic?

DR. MICHAL G. ROSE: I do not, either.

BRITTANY HARVEY: OK, then thank you. Then Dr. Rose, can you first explain the general purpose and the scope of this guideline?

DR. MICHAL G. ROSE: Of course. Thank you for this opportunity. As people know, the incidence of liver cancer, hepatocellular carcinoma, is rising rapidly in the United States and worldwide. And although there are multiple local and potentially curable treatments for early stage disease, the medical oncologist does get involved when these fail or if the patient presents with metastatic disease. And over the last three years, or bit more than three years, we've gone from having only one agent for advanced disease, which is sorafenib, to having nine agents approved for either first or subsequent lines of treatment. So this has created a really good problem for medical oncologists, how to choose between these multiple options. So the purpose of our guideline is to help us select the best treatment for the individual patient based on the best current evidence.

BRITTANY HARVEY: Great. Then this guideline covers both first line and subsequent systemic therapy options for patients with advanced hepatocellular carcinoma. Dr. Gordon, what are the key recommendations for first line therapy?

DR. JOHN D. GORDON: Thanks, and it's also a great pleasure for me to be on this podcast and I appreciate the entire process of putting together this guideline. In the front line setting, a lot of what motivates the completion of this guideline is the approval of the first front line combination for advanced HCC, which is the combination of bevacizumab and atezolizumab. So this was approved based on a report in the New England Journal of Medicine back in May that specifically studied a first line population of patients with advanced HCC and relatively preserved liver function. And the key recommendation of this guideline is that the combination of atezolizumab and bevacizumab be adopted for patients that meet this description. Particular caution is recommended for patients who are at risk of specific side effects or adverse events with these agents.

So for patients receiving bevacizumab, there is a particular risk of bleeding complications and MI or other ischemic complications. And so for patients with a recent MI or with uncontrolled esophageal varices, we recommend either management of these or not using this combination. Similarly, there are a range of contraindications to use of PD1, PDL1 inhibitors, such as atezolizumab, including history of various autoimmune diseases. And so we do not recommend this combination for patients with those co-morbidities. For patients with either more advanced liver failure or the specific risks that I just outlined, we're recommending continuation when safe and appropriate, of what was the previous standard of care. Which is front line treatment with either the oral TKI lenvatinib or the oral TKI sorafenib.

BRITTANY HARVEY: Great. Thank you for that overview of the first line recommendations. And Dr. Rose, what are the recommendations for second line therapy?

DR. MICHAL G. ROSE: So our team had a harder time with second line recommendations. And mainly because there's a lack, currently, of published data on treatment outcomes in patients who've received atezolizumab plus bevacizumab front line or lenvatinib front line. So we debated a lot in our group, which was a very multidisciplinary and collaborative group. And we did agree that patients who are well enough to receive second line therapy, that is their Child-Pugh was still A, and they had a good performance status, they should be considered for sorafenib, oral lenvatinib, if they had received atezolizumab plus bevacizumab in the front line setting. But of course other options for the second line would be cabozantinib or regorafinib, are reasonable in the evidence based options.

In patients who received sorafenib oral lenvatinib front line, we also discussed that it was reasonable to treat them with atezo bev because we presume that these patients did not have access to that combination in the front line. Of course if they meet the criteria that John outlined in the discussion of front line treatment. In patients who received sorafenib or lenvatinib front line, of course that we have data on using other tyrosine kinase inhibitors, such as cabozantinib or regorafinib. We also have data on using ramucirumab in patients who have an alpha fetoprotein greater than 400. And those were the recommendations that we made.

The other discussion that we had in these guidelines was the use of the immune checkpoint inhibitors second line. And we made the recommendation that they should be considered for patients who received sorafenib or lenvatinib in the front line setting, especially if they have contraindications to the use of further tyrosine kinase inhibitors. Or if they could not tolerate tyrosine kinase inhibitors.

BRITTANY HARVEY: Got it. Thank you for reviewing those second line systemic therapy options. Then Dr. Gordon finally, what is the importance of this guideline and how will it impact clinical practice and affect patients with advanced hepatocellular carcinoma?

DR. JOHN D. GORDON: Thanks. And so I think this very much follows on Michal's initial introduction about the purpose of this guideline, which was to address the dramatic proliferation of approved agents for advanced HCC. And what we were attempting to do, and I think achieved to the best that the evidence would support, was provide some degree of guidance on how providers could select both their first line agent and then later lines of therapy to the extent that patients are able to receive it. We think that the availability of these multiple agents for HCC, as Michal alluded to, is really an embarrassment of riches and now we need to think about how to use them wisely.

And we hope that actually as these new combinations and just a greater set of options enter clinical practice, it will be possible to actually do some of the studies that would address the questions that right now remain unanswered around treatments sequencing and the like. I think that there remain some interesting questions in the management of HCC, both for patients with more impaired liver function and for patients at the threshold between localized HCC who are still candidates for local regional therapies such as TACE or selective internal radiotherapy, and requiring systemic therapy as the outcomes from systemic therapy are becoming more positive. But in aggregate we think that these guidelines now provide something of a sequence for the treatment of patients who do require systemic therapy and hopefully an outline for further development.

BRITTANY HARVEY: Great. Thanks. It sounds like this will be important for both practitioners, and patients. So I want to thank you both for joining me on the podcast today and for your leadership on the development of these guidelines, Dr. Rose and Dr. Gordon.

DR. MICHAL G. ROSE: Thank you. And thank you for the opportunity to discuss them.

DR. JOHN D. GORDON: Yeah, thanks as well. And thanks to the amazing team at ASCO and to the entire expert panel, which put in quite a bit of time over the several years that we developed this guideline as more and more data became available.

BRITTANY HARVEY: Great. And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast Series. To read the full guideline, go to www.asco.org/gastrointestinal-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app, available in iTunes or the Google Play store. If you've enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

An interview with Dr. Neelima Denduluri from Virginia Cancer Specialists, U.S. Oncology in Arlington, VA and Dr. Sharon Giordano from the University of Texas MD Anderson Cancer Center in Houston, TX on "Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Guideline Update." This update addresses the use of adjuvant trastuzumab emtansine and the use of biosimilar forms of trastuzumab. Read the full guideline at www.asco.org/breast-cancer-guidelines.

Transcript

ASCO: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast series brought to you by the ASCO podcast network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org. My name is Brittany Harvey, and today I'm interviewing Dr. Neelima Denduluri from Virginia Cancer Specialists, US Oncology in Arlington, Virginia, and Dr. Sharon Giordano from the University of Texas M.D. Anderson Cancer Center in Houston, Texas, co-chairs on "Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Guideline Update."

Thank you for being here, Dr. Denduluri and Dr. Giordano.

Dr. Neelima Denduluri: Thanks for having us.

Dr. Sharon Giordano: Yeah, we're delighted to be here. Thank you.

Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Denduluri, do you have any relevant disclosures that are related to this guideline topic?

Dr. Neelima Denduluri: Our institution has received research funding from companies including Genentech.

Brittany Harvey: Thank you. And Dr. Giordano, do you have any relevant disclosures that are related to this guideline topic?

Dr. Sharon Giordano: No, I don't have any relevant disclosures. Thank you.

Brittany Harvey: Thank you. Then let's get into the guideline content. Dr. Denduluri, what prompted this focused update of the selection of optimal adjuvant chemotherapy and targeted therapy for early breast cancer guideline?

Dr. Neelima Denduluri: There was an FDA meta analysis and several other studies that showed that patients that did not receive a pathologic complete response after preoperative therapy in the HER2-positive setting had a worse prognosis. In the past, we didn't have actionable findings to improve their outcome.

But there was a trial, the KATHERINE trial, that randomized patients that received chemotherapy and trastuzumab, plus or minus pertuzumab, that did not achieve a pathologic complete response to receive standard of care trastuzumab or 14 cycles of trastuzumab emtansine. And the patients that received trastuzumab emtansine had a significantly improved outcome over those that received standard of care trastuzumab. These were very impactful findings that changed care for women with early breast cancer. Therefore, we wanted to update the guideline.

Brittany Harvey: So Dr. Giordano, there are two new recommendations in this guideline update. First, what does the guideline say regarding the use of adjuvant trastuzumab emtansine following standard preoperative chemotherapy and HER2-targeted therapy for patients with HER2-positive breast cancer with residual invasive cancer in the breast or lymph nodes at surgery?

Dr. Sharon Giordano: So the first recommendation was based on the data from the KATHERINE trial that Dr. Denduluri just mentioned. And so their recommendation is that patients with HER2-positive breast cancer who have pathologic invasive residual disease at surgery to either in the breast or the lymph node after standard pre-op chemo with HER2-targeted therapy should be offered 14 cycles of adjuvant trastuzumab emtansine unless there's a recurrence or unworkable toxicity. So basically stating, based on the data from KATHERINE, that if patients have residual disease after their chemotherapy for HER2-positive breast cancer, they should get adjuvant trastuzumab emtansine. And the panel overall felt that the evidence behind this-- the quality of the evidence was very high, and it had a strong recommendation for this treatment.

Brittany Harvey: And then second, Dr. Denduluri, how does this guideline address the use of biosimilar forms of trastuzumab?

Dr. Neelima Denduluri: So biosimilars are increasingly being incorporated into clinical practice, and the guidance that we have from the FDA is that the efficacy of biosimilars compares well with standard trastuzumab. So, we said that patients that would receive trastuzumab are allowed to receive trastuzumab biosimilar without what we think will negatively impact their outcome.

Dr. Sharon Giordano: For that recommendation, we also had input from the Breast Cancer Guideline Advisory Group that helped us decide to expand the update to include the biosimilars. We think that at least five biosimilars have been approved by the FDA, and based on similar efficacy and similar safety data felt that it was appropriate to use them or trastuzumab in a setting where previously we had just used trastuzumab.

Brittany Harvey: Great. And then how will this guideline update impact clinical practice?

Dr. Sharon Giordano: I think that many practitioners have already adapted clinical practice to start to use adjuvant trastuzumab emtansine based on the KATHERINE data, but we certainly hope that this guideline update will reinforce the practice of providing adjuvant trastuzumab emtansine for patients with HER2-positive breast cancer with residual disease after preoperative treatment. The improvement in outcomes was really clinically meaningful for patients, so this does seem to be a significant step forward in the treatment of HER2-positive breast cancer.

Dr. Neelima Denduluri: Additionally, I think that it's important to remember, as clinicians, that we should think about preoperative therapy in those patients with higher-risk HER2-positive disease, because we know that we can impact their outcomes if they don't achieve a pathologic complete response. And hopefully this guideline will heighten the awareness that we need to do that. The other question that we commonly are asked is, even if there is a small amount of residual invasive carcinoma, should we switch to trastuzumab emtansine instead of trastuzumab plus or minus pertuzumab. And what the KATHERINE data did show is that patients that-- even if they had a small amount of residual cancer burden, they still derived benefit.

Obviously, we have to think about the safety, and we also wanted to outline that in this guideline that trastuzumab emtansine is associated with a higher risk of neuropathy and thrombocytopenia and liver function abnormalities. So we certainly need to worry about that. And those patients that do have poor tolerance, we can go back to their HER2-targeted backbone they received in the preoperative setting.

Dr. Sharon Giordano: Yeah, those are great additional points.

Brittany Harvey: Definitely. And you've both already touched on a bit of how adjuvant therapy impacts patients, but how will these guideline recommendations affect patients?

Dr. Neelima Denduluri: I think that really, as Dr. Giordano stated, this is an overwhelming benefit that we don't normally see in terms of impacting outcomes. So the addition of trastuzumab emtansine potentially has good efficacy for them and improves their outcomes.

Dr. Sharon Giordano: Yeah, I agree. I think this trial was associated with a really meaningful reduction in risk of recurrence and better outcomes. So this really is a step forward for treating HER2-positive breast cancer.

Dr. Neelima Denduluri: The other interesting thing about this trial is that it did not delay their local therapy. They allowed concurrent trastuzumab emtansine with radiation therapy. And they also, in terms of systemic therapy, allowed endocrine therapy with trastuzumab emtansine, similar to what we do with trastuzumab plus or minus pertuzumab in the adjuvant setting. So as Dr. Giordano stated, really impactful in terms of efficacy, well-tolerated in most situations, and pragmatic in terms of not holding up the local therapy and the systemic therapy that they may need additionally.

Brittany Harvey: Great, thank you so much for sharing that information about how it impacts patients. I appreciate you both coming on the podcast today and for all your work that you put into updating these guidelines. And thank you for your time today Dr. Giordano and Dr. Denduluri.

Dr. Sharon Giordano: Thank you so much. It was a pleasure.

Dr. Neelima Denduluri: Thank you both, and thank you Brittany for always working so hard to make sure that these guidelines help our patients.

Brittany Harvey: And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

An interview with Dr. Felasfa Wodajo from Virginia Cancer Specialists on "The Treatment of Metastatic Carcinoma and Myeloma of the Femur: Joint MSTS/ASTRO/ASCO Guideline." This guideline covers medical oncology, radiation oncology, and surgical recommendations regarding the management of patients with metastatic or myelomatous lesions of the femur. Read the full guideline at www.asco.org/supportive-care-guidelines.

Transcript

ASCO: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world's cancer care. You can find all the shows, including this one, at podcast.asco.org

My name is Brittany Harvey and today I'm interviewing Dr. Felasfa Wodajo from Virginia Cancer Specialists in Fairfax, Virginia, co-chair on the treatment of metastatic carcinoma and myeloma of the femur, joint Musculoskeletal Tumor Society, American Society for Radiation Oncology, and American Society of Clinical Oncology Guideline. Thank you for being here Dr. Wodajo.

Dr. Felasfa Wodajo: Thank you so much Brittany, I really appreciate the opportunity to talk about our joint guideline that is being published as we speak. It's a great opportunity to share the information with your members as well as hopefully patients and members of other societies.

Brittany Harvey: Great. Then first I'd like to note that ASCO takes care in the development of its guidelines in ensuring that the conflicts of interest are managed for each guideline. This guideline expert panel was assembled in accordance with the American Association of Orthopedic Surgeons conflict of interest policy implementation for clinical practice guidelines. And the full conflict of interest information for this guideline panel is available online in the full text of the joint guideline on the MSTS website.

Dr. Wodajo, do you have any relevant disclosures that are related to this guideline topic?

Dr. Felasfa Wodajo: There's one relevant, but not directly conflicting. I'm a consultant for ONKOS Surgical. That's a maker of implants, but mostly for patients who need sarcoma surgery, and they don't make implants for the types of conditions that are in the guideline.

Brittany Harvey: OK, well thanks for letting us know. First, can you give us a general overview of what this guideline covers?

Dr. Felasfa Wodajo: Sure. The guideline is focused on the effects of metastatic carcinoma or myeloma on the femur. And, as all medical oncologists are aware, metastatic disease to the bone and myeloma are often associated with skeletal pain and sometimes skeletal fractures. Those fractures can occur in any part of the body, spine, of course long bones, and ribs, and so on.

But in our world of orthopedic surgery-- I'm a representative from the Musculoskeletal Tumor Society-- the bones and then added complication are not all equal, and some areas have greater morbidity and effect on patient's outcome than others, the femur being a very important one. And we wanted to focus our efforts on discussing the causes and potential treatments of metastatic disease to the femur.

Brittany Harvey: And then what are the key recommendations of this guideline?

Dr. Felasfa Wodajo: Sure, I'm looking forward to discussing those. I do want to, of course, take a second to acknowledge the hard work that was done by my co-chairs, Dr. Patrick Getty, also from the MSTS, Dr. John Charlson, who was an ASCO co-chair, and Dr. Josh Petit, who is the ASTRO co-chair. And also this gives me a chance to say that this guideline was a joint effort between those three organizations which you already mentioned.

The initiative was led by our organization-- the Musculoskeletal Tumor Society, MSTS-- which is a mostly North American, but also international, society of musculoskeletal tumor surgeons, also known as orthopedic oncologists. And therefore, in almost every place that members of our group work, they're working in close association with medical oncologists and radiation oncologists.

So we wanted to make sure that the guideline reflects the input of all three specialties since all three specialists are often treating the same patients. And in developing the PICO questions-- which are the underlying questions in developing a guideline-- we made sure that we had co-chairs-- one from each of the societies-- agree on which PICO questions to include in the final literature search.

And then finally, the guideline as written, roughly breaks the recommendations down by specialty. It starts off with medical oncology topics, then radiation oncology topics, and then surgical topics. So that's a little bit of background that might be helpful.

I also wanted to mention that one of the meta level findings was the paucity or the dirth of literature that directly addressed the question at hand which is, what kinds of treatments can prevent femur fractures, and then which therapies are best for patients with disease in the femur that may or may not lead to fractures. And we started off with a fairly broad net. But as we focused down on the questions, our initial literature search-- which resulted in over 4,000 journal articles-- was winnowed down to a total of 23 papers which had the high enough level of evidence to be included in our guideline production. And therefore, that inevitably a good number of our questions-- not having strong enough evidence to make a strong evidence based recommendation-- and therefore more than half of our recommendations in the end had to be consensus or expert opinion.

So let me continue with your original question which is, what are the key recommendations. Well, questions that we were interested in were number one, to what extent can non-surgical treatments of metastatic disease to the femur, or myeloma in the femur, will reduce the risk of fracture.

So almost everybody listening to this podcast will know well that bone targeted agents such as the bisphosphonates and denosumab have a strong effect validated in multiple high level randomized and prospective studies in reducing Skeletal Related Events, SREs. As you know, as the listeners also know, Skeletal Related Events is a fairly broad umbrella term, and it includes fracture of any bone as well as hypercalcemia and need for surgery.

But like I said earlier on, a compression fracture of a vertebral body which causes back pain but is treated conservatively, and a fracture of the rib, which also causes pain, treated conservatively or nonoperatively, is a very different matter from a femur fracture which always requires surgery in order to allow the patient to ambulate and regain function.

Having said that, we were disappointed to find that in much of the literature around bone targeted agents-- of which there is plenty-- there's really very little of it that you can find where they stratify, or at least retort, which bones were fractured. So even though there is a strong literature base supporting reduction skeletal events, we can't really say for sure that the risk of a fracture of a femoral lesion is diminished by both targeted agents.

That came out as a consensus statement because this seems to reduce fractures overall, so we left this as a consensus and agreed that BMAs may assist in reducing the incidence of femur fractures.

The next item, number three, in our final report recommended that clinicians consider decreasing the frequency of zoledronic acid dosing to 12 weeks instead of the usual, and most common, four week interval.

There's actually a fair amount of literature supporting quarterly injections as equally efficacious. That's mostly focused on zoledronic acid. It may be true for [INAUDIBLE]. It may also even be true for denosumab, but the literature didn't support that as yet.

But we did make this strong recommendation on our part that clinicians consider reducing the frequency of dosing. If nothing else, because in addition to reducing costs to the patient and time of the patient, we think there may be-- and we put this in our rationale-- there's some chance that some of the unintended side effects of long-term treatment with these bisphosphonate and bismuth therapies such as aseptic necrosis of the jaw and atypical fractures, or brittle bone fractures, of the femur may be reduced with decreased frequency.

Extrapolating from the finding that the longer patients are treated, the higher the incidence of these conditions are, especially atypical fractures. So it could be that less frequent dosing is analogous to less length of treatment. So that was an evidence based and strong recommendation.

We also then looked at the effect of radiation on bone lesions and whether or not it does reduce risk of fracture. We found, not surprisingly, that the radiation oncology literature really focuses on pain. And it's been proven many times and in multiple studies across many decades that radiation therapy does reduce pain at 80% to 90%. And even re-treatment will reduce pain in up to 50% to 70% of patients. But surprisingly, there's actually very little data out there whether it reduces the risk of fracture.

Now we would presume that fracture risk is correlated to bone loss, and that would be radiolucency or loss of calcification on the X-ray. And there are some studies out there which attempt to measure density of bone before and after radiation therapy. And there seems to be some validation, or at least some measurement out there that radiodensity does increase with radiation therapy, and again, we went from that and extrapolated that fracture risk would best be reduced.

But that ended up being a consensus statement. And it's actually a fairly important topic. And hope that more studies would be forthcoming on this, because it would be very helpful for us to predict ahead of time whether this patient can avoid a fracture with radiation alone or do they need to go to surgery.

Next we talked about how effective or beneficial is radiation after somebody's had surgery. So whether or not they've had a fracture, is there a further benefit to radiation. And here the amount of data was even more disappointing.

There's really only two studies that attempt to address this question-- is there a benefit to additional radiation following surgery-- neither one of which was well controlled. They're way out of date and the criteria themselves used in measuring the benefit were not validated.

Now we felt, as a work group-- again consisting of medical oncologists, radiation oncologists, and surgical oncologists, in this case orthopedic oncologists-- that the additional morbidity from radiation after surgery is fairly low. So we left that recommendation as that it has some benefit, but that was the consensus only.

One item that we elevated from consensus to a moderate strength was the benefit of using multifraction radiotherapy to reduce the risk. There is some data-- again, it may be biased-- that patients who undergo single dose radiotherapy as opposed to multifraction radiotherapy for metastatic lesions have an increased risk of fracture. And it may be associated and it may be that those patients getting single dose radiation were at higher risk or had more rapidly progressing disease. But there may be some signal in that noise, and after evaluating the papers and with the help of our experts in radiation oncology, we elevated that to a moderate strength of recommendation.

Then there was a series of questions we tried to address, various surgical techniques and the management of pathology of fractures in the femur and prevention of, and those questions are really more about surgical technique. And these were addressed to our surgical colleagues in large part. I don't know, and I would suspect that the audience of this podcast probably won't be as interested in these questions as the ones we just discussed, so I'll leave those for another time. But I will say a large number of these ended up being also consensus driven evidence.

Brittany Harvey: Got it. Well, thank you so much for reviewing those highlights from the multidisciplinary group and the supporting level of evidence. That's very helpful. So in your view, why is this guideline so important and how will it impact clinical practice?

Dr. Felasfa Wodajo: So, thank you for the question. I'll answer that in two ways. I think the two items that might be of immediate clinical relevance, and therefore of help to patients and their physicians, is number one, further promulgation of the idea of less frequent dosing of bone targeted agents is equally efficacious.

We felt that, if based on our common experiences in our various practices and institutions, that still was not widespread practice. In other words, most patients were still receiving monthly injections of these medications. So we do believe that there is some net patient benefit available to us if those are reduced to quarterly injections for the reasons I mentioned above. So that's one potential immediate release and early improvement that we can expect for patients.

I think the other one, to some extent, may be that what I discussed a little while ago about and multifraction versus single fraction therapy. Again, we don't have nationwide survey data to tell us how often those techniques are used. Again, based on this sort of experience of the workup we thought that that may not be widely understood. So those are two immediate clinical benefits that may be there for patients.

The other way I would look at is at a meta level. Number one was that this is a cooperative venture in which the design and implementation of the guideline was across three organizations. And many times guidelines do incorporate the viewpoints of people of multiple specialties, and sometimes even patient representatives. But it's also, I think, further valuable to have multiple organizations involved because there's some cross-fertilization opportunities there, other products may arise from that, and then also you get what we hope is promulgation of that information to people of different specialties. In other words, these recommendations don't stay inside the ecosphere of one association.

Now when you have multiple organizations working on one project, necessarily it gets more complicated. And there is certainly a heavier administrative burden in getting this project initiated and completed. But hopefully the benefits of that will accrue.

The other thing which I'd like to mention is that I think the paucity of high level evidence for the questions we ask-- which we believe are important questions for physicians and patients-- I think hopefully should stimulate the researchers in these fields to accrue more data so that future researchers and clinicians have access to these information.

For example, I suspect that in future prospective studies of bone targeted agents-- those studies are ongoing-- new agents will be coming out. Pharma will be looking at how those work for their patients in the future. And we would like to ask that those future researchers include, at a minimum, anatomic data for fractures. In other words, they should unbundle Skeletal Related Events and tabulate fractures as occurring in which part of the bone, and if that resulted in surgery.

Those data are there in the records, but if they don't collate them as they go forward, they will not be available to us, and so therefore won't be as efficacious in helping our patients in the future.

Brittany Harvey: Definitely. Those are some important points and I like that you touched on the collaboration of the societies. We find that very important at ASCO to one, reduce the duplication of efforts, and then also to improve the clarity of the recommendations. So, I guess then, finally-- and you've addressed this a bit in terms of dosing of bone modifying agents-- what do these guideline recommendations mean for patients?

Dr. Felasfa Wodajo: Well, for the bone targeting agents, as I said, that might mean fewer doctors visits and maybe less expense, hopefully fewer side effects. For the hyperfractionated radiation, it may not be immediately apparent. I mean a lot of times when a patient's getting single fraction radiation they are fairly advanced in their cancer. But of course they'll get more fractions which means more time in the machine. But hopefully maybe some benefit If they survive longer, which of course, patients are now doing. So those are two potential patient benefits.

Brittany Harvey: Great. Well thank you for your work on these guidelines and for joining me on the podcast today Dr. Wodajo.

Dr. Felasfa Wodajo: I very much appreciate your invitation, and thank you.

Brittany Harvey: And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in iTunes or the Google Play store.

If you've enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

An interview with Dr. William P. Tew from Memorial Sloan Kettering Cancer Center on "PARP Inhibitors in the Management of Ovarian Cancer: ASCO Guideline." This guideline provides recommendations on the use of poly (ADP-ribose) polymerase inhibitors (PARPis) for management of epithelial ovarian, tubal, or primary peritoneal cancer. Read the full guideline at www.asco.org/gynecologic-cancer-guidelines.

Transcript

ASCO: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Brittany Harvey: Hello, and welcome to the ASCO guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org. My name is Brittany Harvey, and today, I'm interviewing Dr. William P. Tew from Memorial Sloan Kettering Cancer Center in New York, New York, lead author on PARP inhibitors and the management of ovarian cancer. Thank you for being here, Dr. Tew.

Dr. William Tew: Thank you, Brittany, for having me.

Brittany Harvey: First, I'd like to note the ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Tew, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. William Tew: No, I do not.

Brittany Harvey: OK, thank you. Then, can you give us a general overview of what this guideline covers?

Dr. William Tew: Sure. So my co-chair, Elise Kohn, and panel members, and ASCO staff put together a very comprehensive guideline on the use of PARP inhibitors in the management of women with ovarian cancer. And as many of your listeners may know, there has been a rapid speed of phase 3 practice changing trials that have been published and FDA approvals within the last year, and what we wanted to do was to put that all in one document and give guidance on how and when and which PARP inhibitor to use in your specific patient and at what point during the lifecycle of ovarian cancer of when to use it.

So we broke up the guideline into five sections. One is the use of PARP inhibitors as maintenance therapy after first line platinum based treatment in women with stage 3 and 4 ovarian cancer. Second, we looked at maintenance therapy after a second or higher platinum based treatment. Three, the use of PARP inhibitors as treatment for patients with recurrent epithelial ovarian cancer.

We then looked at different combinations of PARP inhibitors, whether it's with chemotherapy or biologics and the data that we have presently on those combinations. And then lastly, we looked at common side effects with PARP inhibitors and offering guidance on how to manage those toxicities.

Brittany Harvey: Great. Then you just mentioned that this covers several different sections, so I'd like to go through each of those sections and review those recommendations for our listeners. So first, what are the recommendations for PARP inhibitors for patients with newly diagnosed epithelial ovarian cancer?

Dr. William Tew: So for women with newly diagnosed ovarian cancer, there's been several studies that have been published in the last year and a half, and we broke this up into the different studies and the different patient populations. First and foremost, we wanted to stress that PARP inhibitors are not recommended for the use in the initial treatment of patients with early stage, meaning stage 1 or 2 ovarian cancer, because there really isn't sufficient evidence to support the use in this population. All of the trials looked at patients with stage 3 or 4 epithelial ovarian cancer and used primarily in the main setting, and what that basically means is that women that have had a complete or partial response to first line platinum based chemotherapy and have response by CT scan or CM 125, when do you use a PARP inhibitor?

Which are the women that you would say PARP inhibitor is going to benefit you with long-term outcome? So our first recommendation is based on a trial-- looking at a drug called olaparib. Olaparib was the first PARP inhibitor published in this population, and in that study, they included women with both germline or somatic pathogenic or likely pathogenic variants in the BRCA1 or BRCA2 gene. And so this is a group of women that you could offer olaparib for.

And generally, that is given at a dosage of 300 milligrams once every 12 hours for up to two years. The second study looked at a drug called niraparib, and in this trial, they included population of all women, regardless of BRCA status. And they offered it to women with high-grade serous or endometrial ovarian cancer. And the FDA has given approval for the use of niraparib for all patients, and that is at a dosage of 200 to 300 milligrams oral daily for three years, with the lower dose given for patients who have a low platelet count or low body weight to prevent the common toxicity of thrombocytopenia.

Then you could consider longer durations in select individuals, but generally, these drugs are given for a limited period of time and continued unless a patient has significant toxicity or progression. The other two studies in the newly diagnosed ovarian cancer population was a study that looked at olaparib with bevacizumab maintenance. This was a study that included patients with germline or somatic mutations and BRCA 1 or 2 and/or genomic instability or homologous repair deficiency, as determined by the myriad my choice test.

And again, this population, a partial or complete response to chemotherapy and their first line therapy should have included bevacizumab. And so if one is on bevacizumab with their platinum based therapy, they should have a response to treatment, one could continue bevacizumab and add the addition of olaparib as a PARP inhibitor. And then the final study that we addressed was called switch therapy, and that we don't really have enough data to support its use, specifically that's with the drug called veliparib, and veliparib was given in addition to the chemotherapy and then continued as a maintenance therapy.

We don't really have sufficient data to suggest this was superior, equal, or less toxic than the approaches discussed above, which is single agent PARP inhibitor or bevacizumab with PARP inhibitor. And it should be noted, also, veliparib is not yet an FDA approved drug and not commercially available.

Brittany Harvey: OK, then what are the recommendations for PARP inhibitors for patients with recurrent epithelial ovarian cancer?

Dr. William Tew: Yeah, and this data has been around a little bit longer, and I think any oncologists that treat them with ovarian cancer are more comfortable with the evidence with these studies. So what we're talking about here is that patients who were in clinical remission and then their ovarian cancer recurs. And the first group of women that we look at is patients that are then retreated with platinum based therapy. Those women that have platinum sensitive disease, and then whether to offer PARP maintenance in the second line or more remission settings.

And there is very good data to support the use of PARP monotherapy in second or greater maintenance. This has been shown with all three commercially available PARP inhibitors, olaparib, rucaparib, and niraparib. We do know that women who have a germline or somatic pathogenic or likely pathogenic variant in the BRCA 1 or 2 genes have the highest benefit of maintenance PARP inhibition, and those patients have the strongest evidence to receive those drug.

So the only other point I wanted to make with current ovarian cancer is if a patient has received a PARP inhibitor in the past, there is no evidence to give a second exposure to PARP inhibitor. Those studies are being developed now, but PARP inhibitor use once in the life cycle is what's recommended. And then there's also evidence to use PARP inhibitor as an actual treatment. So not in the maintenance setting, and the drug most commonly used as one called niraparib or olaparib, and these are patients that have measurable disease or generally have platinum sensitive disease, and those women that have homologous repair deficiency, as determined by the Myriad myChoice test, and again, have platinum sensitive to disease do have benefit for treatment with PARP inhibitors.

Brittany Harvey: OK, then, so you just mentioned this, but is it correct that PARPi therapy for epithelial ovarian cancer should not be repeated over the course of treatment?

Dr. William Tew: Right now, that is what we recommend. All of the studies that looked at the use of PARP inhibitors disqualified women who have had prior PARP inhibitors. So as of now, we don't have any evidence to support the use of repeated PARP inhibition.

Brittany Harvey: And what does the guidelines say about using PARP inhibitors in combination with chemotherapy or other targeted agents?

Dr. William Tew: There are many studies going on currently looking at the use of PARP inhibitors in combination with immunotherapy, chemotherapy, and other targeted agents, but currently, at least in the recurrent setting, there is no data to support its use in combination with another anti-cancer treatment. Now, of course, in the context of a clinical trial, this would be very reasonable, and we encourage clinical trial participation.

The only studies that looked at PARP in combination with other anti-cancer treatments are in the first line setting, as I discussed earlier, including PARP inhibitors with bevacizumab, as in the case with olaparib or PARP inhibitors with chemotherapy, as is often the case with veliparib.

Brittany Harvey: OK, thank you. And then how should clinicians manage the adverse effects associated with PARP inhibitors?

Dr. William Tew: I think the first and foremost thing is to be aware of the specific side effect profile of each PARP inhibitor, because they can vary slightly between parts. The most common side effects include fatigue, nausea, change in appetite, and effects on the blood counts, and we gave guidance on each of those specific side effects. As far as the effects on the blood counts, anemia, I'd say, is one of the more common side effects across all PARPi's, and the use of blood transfusions is generally recommended if patients are symptomatic and their hemoglobin is below 8 to 7.

And then for neutropenia, usually, this requires hold of dosing, and we did not encourage the use of growth support, although it may be used in certain settings when the drugs on hold. And then the final cytopenia issue is the issue with platelets, and this is unfortunately very common side effect with niraparib. And we discussed earlier about starting at a lower dose, 200 milligrams of niraparib based on a weight and platelet count to help temper the degree of thrombocytopenia. But with thrombocytopenia, clearly, the drugs sometimes need to be held or discontinued if it's significant.

And with cytopenias, we do recommend close observation of laboratory blood work, particularly in the first month of use of PARP inhibitors, and then always being mindful if patients are on PARP inhibitors for prolonged periods of time that there has been reports of treatment related myelodysplastic syndromes and leukemias and that should be further worked up if there is any evidence of dysplasia.

Brittany Harvey: So then, what is the importance of this guideline in your view, and how will its implementation affect clinical practice?

Dr. William Tew: Well, I think this is the most up-to-date and comprehensive guideline on PARP inhibitors and will help, both clinicians and patients, understand all the practice changing studies, the populations, and the settings they will use, and all these studies that were published over the last five years. I think this last year we've seen such a rapid growth of clinical trial results and FDA approvals that this manuscript, I think, successfully puts them all together in table form and brief recommendations to better treat and provide proper management to your patients with ovarian cancer.

Brittany Harvey: And then finally, how will these guideline recommendations impact patients with ovarian cancer?

Dr. William Tew: We were very fortunate to have two patient advocates as part of our panel, and what they told us was that these recommendations will help them understand the scientific trials, will put in context when to use PARP inhibitors, and also to prepare them for those conversations that they have with their clinicians in discussing if they're a good candidate for a PARP inhibitor now or in the future. So we're really proud of that, that we were able to get our patients perspective in developing these guidelines.

Brittany Harvey: Definitely. Well, thank you for your work on these important and timely guidelines and for taking the time to join me on the podcast today, Dr. Tew.

Dr. William Tew: My pleasure. Thank you so much, Brittany, for having me.

Brittany Harvey: And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast series. To read the full guideline, go to www.asco.org/gynecologic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app, available on iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

An interview with Dr. Davendra Sohal from the University of Cincinnati, and Dr. Daniel Laheru from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins on "Metastatic Pancreatic Cancer: ASCO Guideline Update." This update covers new information on targeted therapies for metastatic pancreatic cancer. Read the full guideline at www.asco.org/gastrointestinal-cancer-guidelines

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 brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org.

My name is Brittany Harvey, and today I'm interviewing Dr. Davendra Sohal from the University of Cincinnati, and Dr. Daniel Laheru from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, co-chairs on Metastatic Pancreatic Cancer, ASCO Guideline update. Thank you for being here, Dr. Sohal and Dr. Laheru.

Hi, Brittany. Thank you for inviting us.

Happy to be here. Thanks.

First, I'd like to note that ASCO takes great care in development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. But Doctor Sohal, do you have any relevant disclosures that are directly related to this guideline topic?

No, I do not have anything directly in conflict. Thank you.

And Dr. Laheru, do you have any relevant disclosures that are related to this guideline topic?

Thank you, Brittany. I do not either.

Great. Than delving into the guideline content, Dr. Laheru, can you tell us what prompted an update to this guideline?

Yeah, sure. So what has been seen in almost every cancer is that with careful understanding of the molecular alterations of individual cancers, that targeted therapies have been developed for almost every cancer. And so for pancreas cancer, we have not had an opportunity in the past to use targeted therapies. Because for pancreas cancer, many of the genetic alterations that are found in other cancers are not seen in pancreas cancer. And so the guidelines were updated based on new evidence of the use of certain targeted therapies for pancreas cancer.

Then Dr. Sohal, what are the key updates that were made to the recommendations in this guideline iteration?

So the key updates relate to the so-called targeted therapies, the genomic-driven therapies that have now come up with evidence that pertains to pancreatic cancer as well. The overarching update is that every patient with metastatic pancreatic cancer who is a candidate for treatment should have tumor or somatic, the so-called somatic genomic profiling, as well as germline genomic testing, because these can lead to treatment recommendations.

And those treatment recommendations include PD-1 checkpoint inhibitor therapies for microsat light instability high tumors, track the TRK fusion inhibitors, such as larotrectinib and entrectinib for track fusions in tumors. And PARP inhibitors, such as olaparib for germline BRCA1 or BRCA2 mutations to be used as maintenance therapy after stable disease on platinum-based therapy.

Then Dr. Laheru, can you speak to the importance of this guideline and how it will drive changes to clinical practice?

Yes. So as Dr. Sohal said, these specific genetic alterations, the mismatch repair deficiency, the use of PARP inhibitors for BRCA1, BRCA2 germline mutations or somatic mutations that are pathologically significant, and for the NTRK fusion transcripts, even though these mutations for pancreas cancer are quite unusual, less than 5%, for example, for NTRK fusion transcripts, 5% to 10% for BRCA1, BRCA2 germline mutations, and probably 1% or 2% for a mismatch repair deficient pancreas cancer, the committee felt that we should inform the larger cancer community that even though these mutations are uncommon, if they are found, they could be very important for individual treatment for pancreas cancer.

And so this is why we really felt that it was time to provide an update, because of the recent information with the olaparib maintenance and with the NTRK inhibitors for the NTRK fusion transcripts.

Great. And then finally, Dr. Sohal, how do you envision that this guideline update will affect patients?

I think it expands our armamentarium for pancreas cancer patient management. It affords opportunities for better treatments, targeted therapies, which have hopefully higher efficacy and lower toxicity than standard chemotherapy, even though, as Dr. Laheru said, the proportion of patients being eligible for these therapies may be only around 5%. Still, in a disease where there are not many options, every 1 in 20 patients can get these therapies based on tumor genomic profiling and/or germline testing.

And the other slightly different but associated topic is that if germline testing finds something in the patient, a bad gene, then obviously, that patient's blood relatives can be tested for that germline finding, and there may be implications for further testing and surveillance of family members.

Well, thank you both for your work on this metastatic pancreatic cancer guideline update. And thanks for taking the time to speak with me today, Dr. Sohal and Dr. Laheru.

It's our pleasure, Brittany. Thank you very much.

Certainly. Thank you so much.

And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast Series. To read the full guideline, go to www.asco.org/gastrointestinal-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available on iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.