Additional Advances in Small Cell Lung Cancer Radiotherapy With Henry Park, MD, MPH
Recently, Dr. Henry Park, Chief of Thoracic Radiotherapy at Smilow Cancer Network of Yale School of Medicine, served as faculty for i3 Health's CME/NCPD/CPE–approved podcast, Optimizing Treatment Selection, Sequencing, and Tolerability in Small Cell Lung Cancer (SCLC). This month, numerous updates in the use of radiotherapy for SCLC were presented at the American Society for Therapeutic Radiology and Oncology (ASTRO) Annual Meeting. In this interview, Dr. Park outlines the most significant updates presented at ASTRO and how he plans to incorporate them into the treatment of patients with SCLC.
Oncology Data Advisor: Welcome to Oncology Data Advisor. Today, I'm joined by Dr. Henry Park, who is the Chief of Thoracic Radiotherapy at Yale School of Medicine, Smilow Cancer Network. Last year, Dr. Park served as faculty for i3 Health's CME/NCPD/CPE–approved activity on Optimizing Treatment Selection, Sequencing, and Tolerability in Small Cell Lung Cancer (SCLC). Today, he's here to share some updates that have occurred in the field since then, including data presented just this month at the American Society for Therapeutic Radiology and Oncology (ASTRO) Annual Meeting. Dr. Park, thanks so much for coming on today.
Henry Park, MD, MPH: Thanks very much for having me.
Oncology Data Advisor: Would you like to introduce yourself and share what your work and your research focus on?
Dr. Park: Sure, my name is Henry Park. I'm an Associate Professor, the Vice Chair for Clinical Research, and the Chief of Thoracic Radiation Therapy at Yale. My research focuses is on comparative effectiveness research and clinical trials to study the value of radiation therapy and the nuances of treatment planning, with the goal of improving outcomes for patients with lung cancer.
Oncology Data Advisor: I'm excited to hear about the updates that were presented at the ASTRO Annual Meeting recently. To start off, what were some of the notable abstracts in SCLC that were presented?
Dr. Park: Yes, this year was a very exciting year for advancing small cell lung cancer treatment at ASTRO. There were two plenary talks, a clinical trial session, and two oral presentations tackling the issue of using radiation dose escalation for limited-stage disease; hippocampal avoidance techniques for prophylactic cranial irradiation when patients don't have brain metastases yet; stereotactic radiosurgery for those who do have brain metastases; and also consolidative thoracic radiation for extensive-stage disease.
For limited-stage small cell lung cancer, a phase 3 trial from China was presented by Dr. Yu, it and studied the value of escalating the dose of twice-daily radiation to the involved primary tumor and lymph nodes. Either way, patients received three weeks of twice daily radiation. Overall survival and progression-free survival were both improved in patients receiving the higher-dose treatment, without an increase in side effects. The primary critiques were that the overall survival differences were much more impressive than progression-free survival, mirroring the earlier study from Norway from Grønberg et al. Also, patients had to be 70 years or younger, and 40% of patients were non-smokers, and this is not representative of the small cell lung cancer patient population in the US. That being said, using 54 Gy in 30 fractions twice daily did seem to have a benefit over 45 Gy in 30 fractions twice a day.
For prophylactic cranial irradiation for small cell lung cancer, the phase 3 trial called NRG-CC003 was presented by Dr. Gondi, and this compared hippocampal avoidance techniques versus standard techniques of prophylactic cranial irradiation (PCI). There was no statistically significant difference in the primary neurocognitive end point called the Hopkins Verbal Learning Test, but there did appear to be a benefit in the secondary end point of neurocognitive function overall. Memantine paradoxically trended towards increased neurocognitive failure, which is an interesting finding that was somewhat surprising.
For those with brain metastases from small cell lung cancer, a German phase 2 study called ENCEPHALON was presented by Dr. Bernhardt comparing stereotactic radiosurgery (SRS) versus standard whole-brain radiotherapy. While not all patients had neurocognitive function values recorded, the authors concluded that there was a greater risk of significant decline in neurocognitive function three months after baseline for patients receiving whole-brain radiation compared to SRS. What's unclear is whether or not this difference persists and whether or not the outcomes will be different when comparing to hippocampal avoidance whole-brain radiation rather than standard whole-brain radiation.
Then there were two additional Chinese oral presentations focused on retrospective analyses of patients receiving versus not receiving consolidative thoracic radiation along with maintenance immunotherapy following upfront chemoimmunotherapy in extensive-stage small cell lung cancer. The first one was presented by Dr. Li, and they observed higher survival for those undergoing consolidative thoracic radiation. The second one noted that dose-escalating radiation therapy from 30 Gy in 10 fractions, up to 45 gray in 15 fractions, did not appear to have a beneficial effect.
Oncology Data Advisor: Thank you so much for sharing all these results. That was a really comprehensive overview, and it's exciting to hear about all the new updates. How do you think that these new results will begin to affect SCLC practice?
Dr. Park: In my practice, I think limited-stage patients will continue to have the option of twice-daily radiation over three weeks in 30 fractions versus once-daily radiation over six to seven weeks in 30 to 35 fractions. Either way, I plan to push the dose to the primary and nodal tumors themselves a bit higher than I may have done in the past, based on results of this ASTRO presentation of the phase 3 trial from China, in addition to similar findings from the Norway phase 2 trial, while still respecting the normal organ constraints as much as I've done before. We know from the CONVERT study, as well as the RTOG 053 study, that using 70 Gy, while not superior to 45 Gy, twice daily may still be fairly similar in terms of outcomes. Now we're seeing that 54 Gy in 30 twice-daily fractions may be better than 45 Gy in twice-daily fractions. I think either way, I would inch more towards the higher end of those ranges as much as possible.
In the near future, we're also looking forward to results of the ADRIATIC and the NRG LU005 studies in defining the role of concurrent or consolidative radiation for limited-stage disease. Now, if immunotherapy becomes a standard of care after these trials show their results, then we should consider acting right away in conducting clinical trials that are based on improved combinations of systemic therapies that are being added to the backbone of chemoradiation.
Now, for other questions regarding PCI, consolidative radiation, and brain metastasis stereotactic radiosurgery, I'll continue to encourage patients to enroll on our three active small cell lung cancer cooperative group clinical trials. The first one for PCI is the MAVERICK S1827 trial, and this randomizes both limited-stage and extensive-stage patients without brain metastases between getting PCI versus no PCI, but either way, having regular MRI surveillance. For patients on this study, I will feel better about offering hippocampal avoidance techniques based on these NRG CC003 results that were presented at ASTRO. Hippocampal avoidance was allowed, but not required, on this MAVERICK trial. I think in the era of routine magnetic resonance imaging (MRI) surveillance, immunotherapy, and hippocampal avoidance techniques, it's really critical to have updated prospective data on this question regarding the impact of PCI on both survival and neurocognitive outcomes.
The RAPTOR NRG-LU007 study, looking at consolidative radiation for extensive-stage patients, randomizes those who get chemo and immunotherapy and maintenance immunotherapy, between getting radiation to up to five sites versus not getting radiation afterwards. It's also important to have prospective data on the value of consolidative radiation to see if the recent retrospective evidence, presented at this year's ASTRO, as well as prior prospective evidence from the CREST trial that favor consolidated radiation, still applies in this current era of immunotherapy. I do not plan to dose escalate beyond 30 Gy in 10 fractions except in very unusual circumstances, based on this ASTRO study.
Of note, these extensive-stage patients without brain metastases can actually co-enroll on both the MAVERICK and the RAPTOR studies. If they have no brain metastases and they have extensive-stage disease, they can be randomized to PCI or no PCI and also consolidative radiation versus no consolidative radiation. Finally, the NRG CC009 triali s randomizing patients with up to 10 brain metastases to either hippocampal avoidance whole-brain versus SRS, which is a highly relevant question in light of the ENCEPHALON results, which only compared SRS to standard whole-brain radiation.
Oncology Data Advisor: Awesome, it's great to hear about all the ways that these trials are already beginning to affect practice. What are some of the additional research directions, either for these trials or others, that you're looking forward to seeing in the next months or years?
Dr. Park: This is really a very exciting time in small cell lung cancer, which has seen relatively few major and even incremental therapeutic advances over the past several decades. I look forward to the publication of these ASTRO presentations so we can learn more details about who these patients were and exactly who may benefit most from these interventions. I'm also looking forward to seeing the results of other completed trials recently like ADRIATIC and LU005, looking at the value of immunotherapy in limited-stage disease, in addition to chemoradiation. I'm looking forward to seeing if immunotherapy and dose escalation at the same time of the radiation may be helpful as well for these patients.
I'm also excited about ongoing trials like MAVERICK, RAPTOR, and CC009, which are tackling optimal multidisciplinary treatments in both limited-stage and extensive-stage small-cell lung cancer. The more that we can work together among medical oncology, radiation oncology, and surgery in terms of figuring out the best combinations of these treatments for our small cell lung cancer patients, the better off we'll be.
Oncology Data Advisor: Fantastic. Well, it's so great to hear about all of these new advances in SCLC, so thank you so much for coming on today to explain all of them.
Dr. Park: Thank you for your time. Take care now.
About Dr. Park
Henry Park, MD, MPH, is an Associate Professor of Therapeutic Radiology, Vice Chair for Clinical Research and Therapeutic Radiology, and Chief of Thoracic Radiotherapy at the Smilow Cancer Network of the Yale School of Medicine. He specializes in radiation therapy for small cell lung cancers and head and neck cancer. Dr. Park is actively involved in clinical trials, having participated in over 120 peer-reviewed research articles. In addition, Dr. Park shows passion for his research by staying involved in and distilling the importance of patient care and medical education.
For More Information
Yu J, Jiang L, Zhao L, et al (2023). High dose hyperfractionated thoracic radiotherapy vs. standard dose for limited stage small-cell lung cancer: a multicenter, open-label randomized, phase 3 trial. Int J Radiot Oncol Biol Phys (ASTRO Annual Meeting Abstracts), 117(2):suppl_1. DOI:10.1016/j.ijrobp.2023.06.205
Bernhardt D, Shafie RE, Thomas M, et al (2023). Stereotactic radiotherapy vs. whole brain radiation therapy for patients with 1-10 brain metastases from small cell lung cancer: results of the randomized ENCEPHALON (ARO 2018-9) trial. Int J Radiot Oncol Biol Phys (ASTRO Annual Meeting Abstracts), 117(4):E5. DOI:10.1016/j.ijrobp.2023.08.031
Gondi V, Pugh S, Mehta MP, et al (2023). Primary endpoint results of NRG CC003: phase IIR/III trial of prophylactic cranial irradiation (PCI) with or without hippocampal avoidance (HA) for small cell lung cancer (SCLC). Int J Radiot Oncol Biol Phys (ASTRO Annual Meeting Abstracts), 117(4):E3. DOI: 10.1016/j.ijrobp.2023.08.028
Senan S, Okamoto I, Lee GW, et al (2020). Design and rationale for a phase III, randomized, placebo-controlled trial of durvalumab with or without tremelimumab after concurrent chemoradiotherapy for patients with limited-stage small-cell lung cancer: the ADRIATIC study. Clinical Lung Cancer, 21(2):84-88. DOI:10.1016/j.cllc.2019.12.006
Ross HJ, Hu C, Higgins KA, et al (2020). NRG Oncology/Alliance LU005: a phase II/III randomized clinical trial of chemoradiation versus chemoradiation plus atezolizumab in limited stage small cell lung cancer. J Clin Oncol (ASCO Annual Meeting Abstracts), 38(suppl_15). Abstract TPS9082. DOI:10.1200/JCO.2020.38.15_suppl.TPS9082
Yale Medicine (2023). MRI brain surveillance alone versus MRI surveillance and prophylactic cranial irradiation (PCI): a randomized phase III trial in small-cell lung cancer (MAVERICK). Available at: https://www.yalemedicine.org/clinical-trials/brain-scans-vs-brain-scans-with-preventative-brain-radiation-in-patients-with-small-cell-lung-cancer
Clinicaltrials.gov (2023). Testing the addition of radiation therapy to the usual immune therapy treatment (atezolizumab) for extensive stage small cell lung cancer, the RAPTOR trial. NLM identifier: NCT04402788.
Clinicaltrials.gov (2023). Testing if high dose radiation only to the sites of brain cancer compared to whole brain radiation that avoids the hippocampus is better at preventing loss of memory and thinking ability. NLM identifier: NCT04804644.
Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of Oncology Data Advisor.