The Fellow on Call: The Heme/Onc Podcast

We strongly recommend you listen to our previous episodes metastatic lung cancer (Episodes 0032 and 0033) to better be able to follow along with this conversation. Key trials mentioned in this episode include:CHECKMATE 227KEYNOTE 024Q:Do you send molecular testing (PDL1 and NGS) on the biopsy, peripheral blood or both?* Yield is highest from the tissue sample* Peripheral blood (circulating DNA) samples are dependent on the burden of disease and so often the yield is lower ** One of the benefits is that it can be sent quickly and having a fast turn-around; Tissue samples are dependent on being able to schedule a biopsy* Dr. West says he definitely sends this on a non-smoker with non-squamous lung cancer, as they are more likely to have molecular targets* Dr. West has not personally adopted the idea of sending peripheral and tissue samples for NGS testing for everyoneQ: Do you ever use Ipi/Nivo in patients with PDL1 <50% (ref: CHECKMATE 227)?* There are a lot of other options so he does not use this, as it is harder to predict the side effects with therapy like this * “Chemo-free does not mean side-effect free”Q: We understand there is a lack of randomized trial data on the use of consolidative radiation after IO based treatment in the metastatic setting. If patients have a good response to systemic treatment, when do you consider using consolidative radiation for cure?* A systemic therapy that is effective that leaves you with oligo-residual disease, radiation can be considered for the right patient** We need to balance what a radiation oncologist says he/she can radiate vs. what is actually the right thing to do** Sometimes, it’s best to give the cancer some time to “declare itself”. * A nuanced discussed, but it may be worth considering especially in patients who have disease that is ** (a) growing at a clinically meaningful rate ** (b) in patients with a few sites of disease, but otherwise great control * This is much more effective in patients with driver mutations being treated with TKIs with oligo-residual disease Q: Do you ever give chemo along with IO in patients with PDL1 >50%?* KEYNOTE 024: First study to show that IO was superior to chemo in high PDL1 patients lead to an instant change in our approach* More recent data suggests that there are differences between patients with PDL1 90% vs. someone at like 50, 60, or 70% (not all PDL1 >50% is created equal!)* If there is a patient with a lot of cancer burden, a lot of symptoms, and rapid progression of disease, you don’t want to miss an opportunity to do what is best for the patient. There is always a chance that IO may not work as monotherapy. This is a case-by-case discussion, but in cases like this, he discusses with his patient about using chemo + IO** Essentially attacking the cancer from multiple anglesQ: In patients with positive driver mutations who are initially stable on treatment, but then progress, do you repeat molecular testing at the time of progression? Do you ever treat with two TKIs at the same time?* Dr. West referenced recent abstract at ESMO 2022 by Dr. Julien Mazieres from CHU de Toulouse in France who presented data regarding the use of MET inhibitor tepotinib with osimertinib:** In the study, when screening for MET amplification, about 36% of patients were positive; at 9 months, the response rate was 54%** One limitation of this study is that every company that tests for MET amplification has a different definition of what constitutes “amplification”* Otherwise, there is mixed data about this* Molecular testing is often done on repeat biopsies in many academic centers, but that is not universally true and not the standard of careQ: TKIs have great CNS penetration. Let’s say a patient achieved a CR of CNS metastasis, but has progression of disease elsewhere. Do you continue the TKI? * He prefers, in general, to continue TKI given great CNS penetration while adding chemotherapy for other systemic metastatic sites** This is more expert opinion, not well-studied* Flare phenomenon can happen, meaning that abruptly stopping TKI may allow a clone of the cancer to begin rapidly growing if this subset of disease is responsive of treatment* Remember: Not all mutations are created equally** You DO NOT want to give EGFR and/or ALK IO even if they have a high PDL1** On the other hand, patients with KRAS and BRAFV600E do respond to IO treatmentAbout our guest:Dr. Jack West is an internationally-renowned Thoracic Oncologist. Associate Professor in the Department of Medical Oncology & Therapeutics Research at City of Hope Comprehensive Cancer Center. He is also the Clinical Executive Director of AccessHope. He completed his medical education at Harvard Medical School, and then trained at Brigham and Women’s Hospital before heading to Fred Hutchinson at the University of Washington. Twitter: @JackWestMD References:https://www.nejm.org/doi/full/10.1056/nejmoa1606774 - KEYNOTE024https://www.nejm.org/doi/full/10.1056/nejmoa1910231 - CHECKMATE227https://oncology.medicinematters.com/esmo-2022/non-small-cell-lung-cancer/insight-2-tepotinib-osimertinib-advanced-nsclc/23480600 - ESMO 2022 abstract on tepotinib with osimertinibhttps://www.thefellowoncall.com/tfocpodcast/jt7mmp342rn85wy - Episode 032https://www.thefellowoncall.com/tfocpodcast/jt7mmp342rn85wy-stczg - Episode 033Please visit our website (TheFellowOnCall.com) for more information Twitter: @TheFellowOnCallInstagram: @TheFellowOnCallListen in on: Apple Podcast, Spotify, and Google PodcastLove what you hear? Tell a friend and leave a review on our podcast streaming platforms!

Lung cancer is one of the most commonly diagnosed type of cancer and so it is fitting that we start the first of our disease-specific oncology series with this diagnosis. This week, we begin to round out our NSCLC series with the first of two episodes where we interview Dr. Jack West from City of Hope!We strongly recommend you listen to our previous episodes on early stage lung cancer (Episodes 026 and 029) to follow along in this discussion. Key trials mentioned in this episode include:ADAURA Trial IMPOWER010CHECKMATE816Q: We’ve previously discussed that adjuvant cisplatin doublet chemotherapy is used for tumors > 4cm and/or nodal involvement. Given that PD-L1 status and EGFR status can also potentially change adjuvant therapy choices, how do you employ these tests in your practice?* Different approaches at every center/with different thoracic oncologists. * Dr. West does NOT recommend sending broad NGS testing on everyone if it is not going to change management. * It it may influence management, at the very least, PDL1 and EGFR should be performed because of implications on adjuvant treatment options (See Episode 026 for treatment discussions): ** ADAURA Trial: Adjuvant Osimertinib x3 years for EGFR+ patients** IMPOWER010: In patients with PDL1 >50%, patients did better with 1 year of immunotherapy (atezolizumab) after adjuvant therapy* In patients with higher risk disease, can consider sending broad NGS, particularly looking for ALK and other mutations; remember that EGFR and ALK+ patients do NOT respond to immunotherapy well. This is important because we don’t want to give someone side effects that they would not otherwise had (these patients are getting treatment adjuvantly AKA after their disease is already resected!)Q: What are limitations of the ADUARA Trial? * The ADUARA suggested disease-free survival advantage with use of osimertinib, but we don’t know final overall survival data yet.*Limitations:** Three years of therapy** Very expensive drug** More data presented at ESMO 2022 on efficacy; Dr. West stated that there appears to be drop off in survival after stopping drug. Overall survival data not yet available * Just because patients can get osimertinib does NOT mean that they are not eligible for chemotherapy**Adjuvant chemotherapy for patients provides long-term benefit** JBR.10 Trial: Older trial, but showed that patients who got adjuvant treatment (in this case vinorelbine plus cisplatin) had prolonged disease-free and overall survival in early-stage non–small-cell lung cancer.** Follow up study suggested that EGFR+ patients trended towards longer survival Q: What are your thoughts on Checkmate 816 with the use of neoadjuvant nivolumab in addition to the platinum doublet? Do you think pathologic CR was an appropriate surrogate endpoint for the trial?* Complete path CR is a new end-point, but it does correlate with PFS. We cannot always for traditional endpoints, such as overall survival data, to mature because doing so may result in us withholding therapy that may be very beneficial. * Biggest benefit to neoadjuvant treatment is that more patients are able to get the full regimen. Many have complications after surgery and never are able to then get/benefit from chemotherapy. Supported by data from NATCH trial Q: What are your thoughts on induction chemoradiation vs. chemotherapy alone?* Dr. West prefers to not use radiation pre-operatively, with some exception (for instance, pancoast tumor) Tune in next week for part 2 of this discussion!About our guest:Dr. Jack West is an internationally-renowned Thoracic Oncologist. Associate Professor in the Department of Medical Oncology & Therapeutics Research at City of Hope Comprehensive Cancer Center. He is also the Clinical Executive Director of AccessHope. He completed his medical education at Harvard Medical School, and then trained at Brigham and Women’s Hospital before heading to Fred Hutchinson at the University of Washington. Twitter: @JackWestMD References:https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02098-5/fulltext - IMPOWER 010 Trial https://www.nejm.org/doi/full/10.1056/NEJMoa2027071- ADAURA Trial https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4032958/ - NATCH Trial https://www.nejm.org/doi/pdf/10.1056/NEJMoa043623 - JBR.10 Trialhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3033998/ - Follow up to JBR.10 Trial looking at influence of EGFR status on chemotherapy responsehttps://www.nejm.org/doi/10.1056/NEJMoa2202170 - CHECKMATE 816 https://www.thefellowoncall.com/tfocpodcast/episode-001disclaimer-wfhgf-ml3b6-9m66a-8rrc4-k8w87-x7xdd-wrzye-4xg8x-t73gt-cxc5s-nmg8f-cfyd6-hgs35-5pcwx-tf6dh-trggt-xzkt7-923gg-rpjzx-6s36p-hk27n-bbpgx-jymml-9lfam-76m4s - Episode 026https://www.thefellowoncall.com/tfocpodcast/episode-001disclaimer-wfhgf-ml3b6-9m66a-8rrc4-k8w87-x7xdd-wrzye-4xg8x-t73gt-cxc5s-nmg8f-cfyd6-hgs35-5pcwx-tf6dh-trggt-xzkt7-923gg-rpjzx-6s36p-hk27n-bbpgx-jymml-9lfam-76m4s-6xae9-ws6nt-ntn8g - Episode 029Please visit our website (TheFellowOnCall.com) for more information Twitter: @TheFellowOnCallInstagram: @TheFellowOnCallListen in on: Apple Podcast, Spotify, and Google PodcastLove what you hear? Tell a friend and leave a review on our podcast streaming platforms!

Lung cancer is one of the most commonly diagnosed type of cancer and so it is fitting that we start the first of our disease-specific oncology series with this diagnosis. This week, we continue our discussion on metastatic non-small cell lung cancer, focusing on NSCLC with driver mutations. * The approach to treatment of a patient with widespread metastatic NSCLC (mNSCLC) is very different than a patient without distant disease, which highlights why we do what we do:- Important to complete staging (discussed in prior episodes) to determine the extent of disease- Important to check molecular testing (looking for mutations in the cancer cells) and IHC for tumor proportion score (TPS) helps determine treatment options - If your molecular testing is identified in a driver mutation gene, there are targeted options for this! *Driver mutations are predictive of response to an oral therapy and a LACK of response to immune therapy (particularly in EGFR and ALK mutated patients) * EGFR Mutation:- Pay attention to the types of mutation in EGFR (not all are the same):-- Exon 19 deletion -- Exon 19 L858R-- Exon 21 T790M-- Exon 20 Insertion (Osimertinib [see below] cannot be used for this mutation)- Osimertinib is first-line standard of care for patients with EGFR-- Used to be a second-line agent. Many patients with EGFR mutations receiving earlier generation TKIs would develop resistance and when these tumors were sequenced, they would have Exon 21 T790M mutations. Osimertinib was effective even with this mutation and had superior overall survival data compared to chemotherapy (AURA3 Trial)--Now it is used in first-line setting for patients with EGFR mutation based on the FLAURA trial --- In this study, patients received osimertinib as first line vs. older generation EGFR-targeting TKIs (erlotinib or gefitib) and Osimertinib had better outcomes: ---- Showed that the median OS was 38.6 months with Osi vs. 31.8 months; also improved brain penetration! ---- Also effective in patients with metastatic disease to the brain: ----- Only 6% of patients had CNS progression with Osi vs. 15% with others- What if a patient is on Osi and later develops new brain mets?-- If there is progression within just the brain (and good control in other sites of the body) you can refer patient to Radiation Oncology for SRS-- Remember, based on discussion with Dr. Osmundson in our RadOnc lectures (Episode 028), it is important to HOLD Osimertinib if patient is going to get radiation to minimize the side effects- What is patient had progression of disease in several sites throughout the body?-- Management is less straightforward. -- In many of these cases, you can consider:--- Consolidative radiation - If small amounts of disease--- Changing therapy - If there has been widespread progression; likely would change to chemotherapy (without IO, since lower predictive response to IO with EGFR mutation)---- No clear guidelines if you should continue the TKI---- Remember that IO + TKIs can cause increased risk of side effects, such as pneumonitis and hepatitis. DO NOT DO THIS!* ALK Mutation:- There are many options for ALK mutations-- The first generation drug is crizotinib--- Lots of side effects —> “It is crazy to start with crizotinib”--- Studies for later generation TKIs were compared to crizotinib -- Many people today will use third generation ALK-inhibitor alectinib (Important trials: ALEX Trial and J-ALEX Trial)--- With alectinib, PFS 34.8 months, RR 83%, less CNS progression (12% vs 45%)--- 5 year OS rate 62.5%- What to do with disease progression while on ALK inhibitor?-- In ALK, you can actually switch to another ALK inhibitor and many will respond well--- Of course, with each change, you may expect not as great of a response * Lots of other mutations!- TFOC recommends just looking these up!-- Link to NCCN Guidelines on NSCLC; Page 41 has full list!- Another way to think about this, when do we NOT do TKIs as first line: -- KRAS G12C-- EGFR Exon 20 Insertion-- HER2- How do you counsel a patient when considering/starting a TKI? -- Patients with highest chance of having a targeted mutation are younger non-smokers with adenocarcinoma-- Set expectations: great outcomes overall, but still not a cure. -- Remembering the drugs: All TKIs usually end in “-nib” -- In general, the way we recommend remembering this: “Fatigue, GI, Derm (skin/nail changes)”; rarely pneumonitis References:* AURA3 Trial - https://www.nejm.org/doi/full/10.1056/NEJMoa1612674Established osimertinib was better than chemo for patients with EGFR mutation and acquired Exon 21 T790M resistance mutation* FLAURA Trial - https://www.nejm.org/doi/full/10.1056/nejmoa1713137 Established osimertinib as first-line agent for patients with EGFR mutation * ALEX Trial - https://www.nejm.org/doi/full/10.1056/nejmoa1704795Helped establish alectinib as superior for ALK mutations compared to crizotinib * J-ALEX Trial - https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)30565-2/fulltextHelped establish alectinib as superior for ALK mutations compared to crizotinib * NCCN Guidelines on NSCLC - https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450 Please visit our website (TheFellowOnCall.com) for more information Twitter: @TheFellowOnCallInstagram: @TheFellowOnCallListen in on: Apple Podcast, Spotify, and Google PodcastLove what you hear? Tell a friend and leave a review on our podcast streaming platforms!

Lung cancer is one of the most commonly diagnosed type of cancer and so it is fitting that we start the first of our disease-specific oncology series with this diagnosis. This week, we start our discussion on metastatic non-small cell lung cancer, focusing on NSCLC without driver mutations. * The approach to treatment of a patient with widespread metastatic NSCLC (mNSCLC) is very different than a patient without distant disease, which highlights why we do what we do:- Important to complete staging (discussed in prior episodes) to determine the extent of disease- Important to check molecular testing (looking for mutations in the cancer cells) and IHC for tumor proportion score (TPS) helps determine treatment options * Choosing a treatment is based on:- Histology - cannot use pemetrexed or bevacizumab in squamous cell - Platinum - Carboplatin is usually used (as opposed to our prior discussions about using Cisplatin because of LACE pooled analysis data)-- Why is Cisplatin not a great idea? Cisplatin should not be used if patients have (***high yield to know cisplatin eligibility criteria!!***): --- Poor performance status--- Patients with eGFR <60--- If a patient has baseline hearing loss--- If a patient has baseline neuropathy--- Patients with NYHF class III+--If patient is getting “palliative” / non-curative setting, you want to spare patients these terrible potential side effects -Immunotherapy - All patients with mNSCLC should have IO considered for treatment, unless they have contraindications. Considerations include: -- Patients with EGFR and ALK mutations - patients with these mutations do NOT respond well to IO so should not use-- TPS score:--- Patients with score >50% can get IO monotherapy (spared chemotherapy)---- KEYNOTE 024: approval for pembrolizumab monotherapy in patient with PDL1>50%----- Study compared pembro to platinum doublet----- OS 70% vs. 50% at one year---- IMPOWER110: approval for atezolizumab monotherapy----- Study compared atezo to chemotherapy----- OS 64.9% vs 50% at 12 months--- Patients with score <50% can get IO + chemotherapy---- KEYNOTE 189: Showed that the addition of Pembrolizumab to carboplatin/pemetrexed followed by pembro/pemetrexed maintenance in mNSCLC with adenocarcinoma histology had impressive benefits---- Carbo/taxol/pembro for squamous histology--- Lots of other trials, check out NCCN for a comprehensive list * Putting this all together: - In PDL1 >50% WITHOUT SYMPTOMS: IO alone- In PDL1 >50% WITH SYMPTOMS: Chemo + IO- In PDL1 <50%: -- Lots of options, but usually some combination of chemotherapy + IO-- Many people use Pembro, as it was first to market* Management of mNSCLC to the brain: - Recommend discussion with radiation oncology about role of SRSPlease visit our website (TheFellowOnCall.com) for more information Twitter: @TheFellowOnCallInstagram: @TheFellowOnCallListen in on: Apple Podcast, Spotify, and Google PodcastLove what you hear? Tell a friend and leave a review on our podcast streaming platforms!

Lung cancer is one of the most commonly diagnosed type of cancer and so it is fitting that we start the first of our disease-specific oncology series with this diagnosis. This week, we sit down with Thoracic Surgeon, Dr. Jane Yanagawa to discuss surgical considerations in treatment of NSCLC. * How do you choose what type of surgical resection to do?- Considerations: --Lung anatomy --Location of the nodule within lung--Lymph node involvement-Options: --Pneumonectomy: removal of whole lung --Lobectomy: remove a whole lobe--Segmentectomy/sublobar resection: part of a lobe* What does “adequate margins” mean? And how do you know if it’s enough?- If you’re removing the whole lobe, it does not matter as much - If you’re doing a segmentectomy, you want to have samples evaluated while in the OR because if there is signs of more disease that initially thought, you would take this one step further and do a lobectomy. - Need to consider the patient’s situation - how good is their status * Why does preoperative workup matter?- Pulmonary function tests: Surgeons are looking at the %FEV1 and %DLCO to then predict what their function would be AFTER surgery. After surgery, they want to ensure patient has %FEV1 or %DLCO >40%. - Lung anatomy: In patients with COPD and endobronchial lesions, sometimes they also get V/Q scans to evaluate ratio- Cardiac echo: Important in pneumonectomy where removal of lung tissue will also remove a significant amount of blood vessels. Want to rule out pulmonary hypertension pre-operatively. - Pulmonary hypertension can also affect someone’s survival while they’re ventilating with only one lung during the procedure (“single lung ventilation”). - Smoking status: Smoking can increase complications by ~60%. - Pre-habilitation: Encouraging patients to be fit prior to surgery with walking, nutrition, +/- pulmonary rehabilitation* What is “VATS”?- VATS stands for video-assisted thoracoscopic surgery; it is not, in itself, a procedure. But a VATS allows for minimally invasive surgery through the use of a camera. - It involves three incisions (axilla, lowest part of mid-axillary line, one posterior)* In what scenario is a mediastinoscopy warranted? - Needed after EBUS if there is still high index of suspicion for cancer involvement in lymph nodes, even if lymph nodes are negative from EBUS* What is “systematic lymph node sampling”?- An organized way to sample lymph nodes, including all lymph nodes that are along the way, not just the ones that may be involved * As a surgeon, how do you determine if a patient is okay for surgery if the mass is invading another structure?- Need to take the anatomy into consideration - are there major blood vessels or nerves there, for instance, which can impact outcome and recovery.* When should we consider induction chemotherapy from a surgeon’s perspective?- Lots of changes in this sphere coming; lots of discrepancy between institutions when there is N2 disease - In Dr. Yanagawa’s opinion, anyone with N2 disease should get neoadjuvant therapy * If there is neoadjuvant chemoradiation given, how does that effect your surgery?- Radiation increases scar tissue in the lung tissue. But what is worse is that radiation neoadjuvantly may make wound healing more difficult. She does not prefer radiation pre-operatively- Chemotherapy also adds scar tissue*How does neoadjuvant IO therapy affect scar tissue formation?- The hilum and lymph nodes are more swollen, but does not translate to more complications - She has even seen patients who had gotten IO for another cancer and then get lung cancer, she can still appreciate swollen nodes!* How long after surgery is it safe to start adjuvant therapy?- If patient has a complication from surgery, would not start right away. It is important to discuss with the surgeon about when it is okay to proceed with adjuvant therapy. - If patient has good recovery/without complications, okay to start about 4 weeks after- There is no good guidance yet about when it is safe to start IO after surgery About our guest: Jane Yanagawa, MD is an Assistant Professor of Thoracic Surgery at the UCLA David Geffen School of Medicine and the UCLA Jonsson Comprehensive Cancer Center. She completed medical school at Baylor College of Medicine, after which she went to UCLA for her surgical residency. She went onto Memorial Sloan-Kettering for her Thoracic Surgery Fellowship. In addition to her practice as a thoracic surgeon at UCLA, Dr. Yanagawa also sits on the NCCN NSCLC guidelines committee! We are so grateful she was able to join us despite her very busy schedule! Please visit our website (TheFellowOnCall.com) for more information Twitter: @TheFellowOnCallInstagram: @TheFellowOnCallListen in on: Apple Podcast, Spotify, and Google Podcast

If you’ve been with us since the beginning, thank you! But we've had a lot of new friends join the party so we thought we'd interrupt our regular programming to re-introduce ourselves! So if you’re new here, welcome to the Fellow on Call! We are so glad you’re here.

Lung cancer is one of the most commonly diagnosed type of cancer and so it is fitting that we start the first of our disease-specific oncology series with this diagnosis. This week, we round out our discussion of early stage lung cancer treatment!* When deciding if a patient can get surgery upfront or not, remember the three “Fellow on Call” criteria for early stage lung cancer:  - Mass invading other structures or mediastinum- Central lymph nodes (single digit)- Tumor >7 cm* If surgery is NOT an option at this time, where do we go from here?- Treat with upfront concurrent definitive chemoradiation- Treat with “induction” chemotherapy or induction concurrent chemoradiation**If surgery is/may be possible***What are the goals of “induction” treatments? - Eradicate microscopic disease- Improved local control, possibly shrinkage- Adding radiation may allow you to downstage tumor or lymph nodes to have a possible improvement in surgical outcomes* What sorts of discussions are being had a thoracic tumor board in patients with newly diagnosed early stage NSCLC? - Is the patient a surgical candidate?- If the patient is not a surgical candidate, then what are the options:--Definitive concurrent chemoradiation (usually) followed by immunotherapy---Pearl 1: Always choose this if surgeon thinks the patient is unresectable in general even with an induction approach---Pearl 2: Always choose this if 2 out of 3 criteria we discussed above are met---Pearl 3: Always choose this if N3 disease- “Induction” regimen with either chemotherapy alone or concurrent chemoradiation followed by surgery * What’s the idea behind “induction” chemo or chemoradiation? - There is a chance that patients with these high risk features may already have micrometastatic disease, so treatment upfront can help address that- There is a chance that after surgery, patient may suffer deconditioning, which may preclude the use of chemo +/- radiation (up to 90% of patients are often eligible for chemoradiation before surgery; this drops to ~60% after surgery)- Local disease control to achieve the best possible surgical outcome (R0 resection) and also prevent any microscopic residual disease from then having the opportunity to spread systemically, especially in areas where the mass may be adjacent to many blood vessels or lymph nodes* What to treat with in the neoadjuvant setting?- Platinum containing regimens (“platinum doublets”):-- Carboplatin + paclitaxel-- Cisplatin + etoposide-- Cisplatin + gemcitable-- Cistplain + pemetrexed- Can combine this with radiation* How does the data about chemotherapy+IO in the neoadjuvant setting fit in here (CHECKMATE 816)?- In patients with Stage IIB to IIIA (8th edition) WITHOUT EGFR or ALK mutation, treatment with NEOADJUVANT chemotherapy q3w x3 cycles (most got cisplatin based therapy) + nivolumab 360mg q3w x3 cycles resulted in improved event free survival (31.6 months vs. 20.8 months) AND pathological complete response was 24.0% vs. 2.2%- Current NCCN guidelines state that if nivolumab is used in neoadjuvant setting, it should not be used in adjuvant setting- There is still uncertainty about how this fits into treatment compared to “traditional” neoadjuvant approaches with chemo+/-radiation*So after neoadjuvant treatment, does everyone go to surgery?- Always re-assess the status of the disease; if there is progression of disease, then will go to definitive chemoradiation- Discuss with surgeons to confirm if the patient is still a surgery candidate* If patient undergoes surgery, then what?- If patient got neoadjuvant therapy and an R0, then they are done with treatment- If R0 resection was not able to achieved, then either radiation “boost” to the area (if they previously got radiation), a course of radiation (if they just got induction chemo) or re-resection- We discuss the adjuvant setting in more detail in Episode 026 (https://www.thefellowoncall.com/tfocpodcast/episode-001disclaimer-wfhgf-ml3b6-9m66a-8rrc4-k8w87-x7xdd-wrzye-4xg8x-t73gt-cxc5s-nmg8f-cfyd6-hgs35-5pcwx-tf6dh-trggt-xzkt7-923gg-rpjzx-6s36p-hk27n-bbpgx-jymml-9lfam-76m4s)** If surgery is not possible*** If patient cannot go through to surgery Definitive chemoradiation:- Same chemotherapy agents as above, but treatment course is longer.- For instance, for NSCLC, total 60Gy in 2Gy divided fractions (5 days/week, 6 weeks of treatment) with chemotherapy* Additional therapy after chemoradiation (PACIFIC Trial) - Found that “consolidation” durvalumab 44% PFS 18 months vs 20% 5year survival benefit 40% vs. ~30% without treatmentReferences:https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450 - NCCN Lung Cancer guidelines https://www.nejm.org/doi/full/10.1056/nejmoa1709937 - PACIFIC Trial (NEJM 2017)https://www.nejm.org/doi/10.1056/NEJMoa2202170 - CHECKMATE 816 (NEJM 2022) Please visit our website (TheFellowOnCall.com) for more information Twitter: @TheFellowOnCallInstagram: @TheFellowOnCallListen in on: Apple Podcast, Spotify, and Google Podcast

Lung cancer is one of the most commonly diagnosed type of cancer and so it is fitting that we start the first of our disease-specific oncology series with this diagnosis. An important component of treatment in lung cancer (and many other cancers) is the use of radiation. This week, we continue our discussion about the fundamentals of Radiation Oncology with our guest, Dr. Evan Osmundson. *We hear the terms “hypo-fractioned” and “hyper-fractionated” radiation. What do those mean?- Fractionation, that is breaking up the total dose of radiation into smaller ones, has allowed patients to tolerate the radiation better. The repeat exposure allows the healthy tissue to repair, whereas the tumor is not able to heal as well- Standard fractionation involves keeping the maximum dose per session at 1.8-2Gy/fraction. - Hyper-fractionation is when a patient gets multiple doses per day, each less than 2Gy. This is important in small cell lung cancer, where the standard dose of radiation is 1.5Gy twice daily- Hypo-fractionation os when larger doses are given in each session, typically larger than 2.5-3Gy, often 4-5Gy per fraction. This is analogous to SBRT. *With regards to SBRT, how do you determine the number of sessions? - Typically 3-5 sessions, and this is based on data run through their computer algorithm that allows the dose to be tumoricidal. - More sessions (more likely 5 sessions) if central tumor (<2cm central proximal bronchial tree) or ultra-central tumor (directly abutting bronchial tree/major vessel) or abutting the chest well. Poor outcomes in some studies with fewer sessions; 5 sessions seem to work well in central tumors, based on recent data. - Logistically speaking, five sessions is also typically the maximum that insurance will pay for. *What’s the max size of the tumor that is amenable to SBRT?- Most clinical trials have limited size to 5cm or less, but he has done SBRT to larger tumors. This is a case-by-case basis.* How do you calculate the duration of treatment when we are going to do concurrent chemo-radiation?- Treatment is usually 5 days a week, with the weekends off for patients- In NSCLC, total 60Gy appears to be the standard of care, based on RTOG 0617 study. (J Clin Oncol 2020 Mar 1;38(7):706-714. doi: 10.1200/JCO.19.01162. Epub 2019 Dec 16.); practically this means about 6 weeks of treatment.- In SCLC, Target 45Gy broken up into 1.5Gy TWICE daily OR 66Gy broken up into 2Gy ONCE daily is the standard of care based on CONVERT trial (Lancet Oncol. 2017 Aug;18(8):1116-1125. doi: 10.1016/S1470-2045(17)30318-2. Epub 2017 Jun 20.)* What is your guidance to avoid brain toxicity, for instance with using SRS to the brain for a brain met? - There is a risk of brain necrosis from the synergism between certain chemotherapies/targeted agents that penetrate the blood-brain barrier with SRS that can cause radiation necrosis to the brain. This is particularly an issue with TKIs, such as osimertinib. Dr. Osmundson recommends holding TKIs about 5-7 days, if possible.*What is proton therapy and how does it differ than “traditional” radiation therapy?- With x-rays/photon therapy, the beam is attenuated and there is an exit dose that can affect the neighboring tissues. - With proton beams, there is a “Bragg-Peak” effect, whereby you can specify how deep you want to radiation to deposit with little exit dose. - Per Dr. Osmundson, we are not currently in a position to recommend proton therapy AT THIS TIME, but this may be changing. Research is being done to better be able to maneuver the beam angles. - Proton therapy is also very expensive at this timeA special thank you to our guest, Evan Osmundson, MD, PhD, Associate Professor in the Department of Radiation Oncology and serves as the Medical Director of Radiation Oncology at Vanderbilt University Medical Center in Nashville, TN!Please visit our website (TheFellowOnCall.com) for more information Twitter: @TheFellowOnCallInstagram: @TheFellowOnCallListen in on: Apple Podcast, Spotify, and Google Podcast

Lung cancer is one of the most commonly diagnosed type of cancer and so it is fitting that we start the first of our disease-specific oncology series with this diagnosis. An important component of treatment in lung cancer (and many other cancers) is the use of radiation. Here, we discuss the fundamentals of Radiation Oncology with our guest, Dr. Evan Osmundson. Basic vocabulary: - Fraction/Fractionation: The total dose of radiation divided into smaller doses - Grey: Unit of measure of radiation being delivered in each session - Bragg-Peak effect: Specific to proton therapy (as opposed to photon therapy). It describes the sharp increase in concentration of the energy when hitting the tumor, while minimizing the effects to surrounding tissue. - Radiosensitizing chemotherapy: small doses of chemotherapy used to make the cells more responsive to the deleterious effects of radiation Fundamentals of radiation oncology: *When we make a referral to RadOnc, what happens then? - Send over any available imaging that is available - Team reviews the imaging to ensure that staging is completed - Simulation scan: Uses a CT scan to “simulate” the treatment; specifically map out the tumor and the surrounding organs/structures. Multidisciplinary team reviews the scan to maximize the dose to the tumor and minimizes damage to surrounding structures. - Based on the scans, they test run the treatment on a model to ensure that the simulation on the computer is able to be replicated on a model. - The above is why it can take a while for treatment planning to take place*What sorts of imaging modalities are important to have for patients prior to getting to Rad Onc? - Send prior CT imaging - If planning for radiation to the brain, should get thin-sliced MRI w/ and w/o contrast - If prostate cancer, also consider getting MRI*Many patients express concern about the “mask fitting” - what is that? - To ensure that the same dose of radiation is administered each time, it is important for the patient to remain very still and/or the same position every session. The mask is custom fit to ensure patient is in the correct position. *How do you determine the “maximum dose” of radiation in the mediastinal area is? - The maximum dose tolerance is dependent on the structure in question. A structure “in series” such as the bronchial tree would have profound effects if tissue is injured compared to lung parenchymal tissue (If you damage some, there is plenty more that is able to compensate) - Always concern for spinal cord when radiating the mediastinum *What are side effects you counsel patients on, specifically in thoracic radiation? - Fatigue (usually not debilitating), radiation esophagitis, pericarditis (rare) - Radiation pneumonitis (usually 6-8 weeks, but can be up to one year), presents with cough, shortness of breath; likelihood of this is dependent on duration of treatment, dose of radiation, location A special thank you to our guest, Evan Osmundson, MD, PhD, Associate Professor in the Department of Radiation Oncology and serves as the Medical Director of Radiation Oncology at Vanderbilt University Medical Center in Nashville, TN!Please visit our website (TheFellowOnCall.com) for more information Twitter: @TheFellowOnCallInstagram: @TheFellowOnCallListen in on: Apple Podcast, Spotify, and Google Podcast

How do we think about treatment of lung cancer? Recap on staging (see Episode 025) * Pro-tip: Highly recommend that you “forget” about the actual staging and focus more on the individual T, N, and M status * Tumor size:**T1a <1 cm **T1b <2 cm **T1c <3 cm **T2a <4 cm **T2b <5 cm **T3 5-7 cm**T4 cm *Nodal status: **Double digit nodes = hilar or intrapulmonary (peripheral) = N1**Single digit nodes = mediastinal (central ) = N2**Contralateral nodes or supraclavicular = N3*Sites of metastatic diseaseApproach to treatment in a stepwise approach: *Goal: Whenever feasible, we want to consider getting the patient to surgery to remove the cancer. *Surgery or no surgery?**How do we decide if someone is appropriate for surgery: ***Do they want surgery?***Do they have the pulmonary reserve if they were to get surgery ?***Do they have the cardiac reserve to withstand surgery?***Is the tumor size too big? (Usually >7cm)***Is the tumor invading other structures?****If invading other structures, surgery may not be possible; highly consider tumor board discussion***Mediastinal lymph node involvement?****Central lymph node involvement usually requires definitive chemotherapy + radiation (not surgery up-front)***Supraclavicular lymph node or contralateral lymph node?****This would be treated with chemotherapy and radiationSpeaking of surgery, what are the options for types of surgeries for lung cancer?*Sub-lobar:**Wedge (smallest resection)**Segmentecomy - ideally we want to do at least a segmentectomy*Lobar resection:**Lobectomy**PneumonectomyWhat if a patient’s tumor is amenable to surgery, but the patient’s underlying co-morbid conditions preclude him from getting a surgical intervention? *This is where we consider using radiation for treatment, specifically Stereotactic body radiation therapy (SBRT)Characteristics of surgical report?*The “R” status is if there is residual tumor after the surgery. This is a combination of evaluation by a pathologist AND by gross inspection by the surgeon**R0: No evidence of disease**R1: Microscopic sites of disease**R2: Macroscopic sites of disease (visible tumor)*Why does this matter?**If there is residual disease, there may be a role for further resection and/or systemic therapy*When a tumor is >4cm, patients are higher risk for recurrence, even without nodal disease or metastatic disease. We will give these patients chemotherapy in the adjuvant setting.  Approach to adjuvant chemotherapy:*In NSCLC, it is often a two-drug regimen, including a platinum-based therapy*Cisplatin is important**Based on LACE Pooled Analysis (https://ascopubs.org/doi/10.1200/jco.2007.13.9030) ***Cisplatin-based adjuvant therapy vs. placebo showed >5% improvement in survival when using cisplatin-based therapy***For adenocarcinoma:****Give cisplatin with pemetrexed****ALWAYS start patient on B12 and folate at least 1 week before starting pemetrexed and continue this throughout treatment, up to and including 3 weeks after their treatment course***For squamous cell caricnoma:****Give cisplatin with gemcitabine OR docetaxol (taxotere)*Nodal involvement (N1): Give two-drug regimen, as noted above*Additions to two-drug regimen:**IMPOWER 010 Trial: In patients with PDL1 >50%, patients did better with 1 year of immunotherapy (atezolizumab) after adjuvant therapy (https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02098-5/fulltext; https://ascopost.com/issues/november-10-2021/impower010-adjuvant-atezolizumab-improves-disease-free-survival-and-nsclc-relapse-in-patients-whose-tumors-express-pd-l1/)**Mutations matter! ADAURA Trial: EGFR with exon 19 deletion or L858R can get osimertinib, which had an improved outcomes (https://www.nejm.org/doi/full/10.1056/NEJMoa2027071)References: https://ascopubs.org/doi/10.1200/jco.2007.13.9030 - LACE Pooled analysis https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02098-5/fulltext - IMPOWER 010 Trial https://www.nejm.org/doi/full/10.1056/NEJMoa2027071- ADAURA Trial Please visit our website (TheFellowOnCall.com) for more information Twitter: @TheFellowOnCallInstagram: @TheFellowOnCallListen in on: Apple Podcast, Spotify, and Google Podcast