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• W3083480767 abstract "Small cell lung cancer (SCLC) outcomes remain poor. Approximately, 40–60% of SCLC patients develop brain metastases (BMs) [1Lukas R.V. Gondi V. Kamson D.O. Kumthekar P. Salgia R. State-of-the-art considerations in small cell lung cancer brain metastases.Oncotarget. 2017; 8: 71223Crossref PubMed Scopus (36) Google Scholar, 2Hirsch F.R. Paulson O.B. Hansen H.H. Larsen S.O. Intracranial metastases in small cell carcinoma of the lung Prognostic aspects.Cancer. 1983; 51: 529-533Crossref PubMed Scopus (68) Google Scholar, 3Nugent J.L. Bunn Jr., P.A. Matthews M.J. et al.CNS metastases in small cell bronchogenic carcinoma: increasing frequency and changing pattern with lengthening survival.Cancer. 1979; 44: 1885-1893Crossref PubMed Scopus (427) Google Scholar] and less than 15% survive beyond two years [4Howlader N. Forjaz G. Mooradian M.J. et al.The effect of advances in lung-cancer treatment on population mortality.N Engl J Med. 2020; 383: 640-649Crossref PubMed Scopus (499) Google Scholar, 5Robin T.P. Jones B.L. Amini A. et al.Radiosurgery alone is associated with favorable outcomes for brain metastases from small-cell lung cancer.Lung Cancer. 2018; 120: 88-90Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar]. In lung cancer management, contemporary advances in systemic therapies and focal radiation techniques have also tended to improve outcomes more in non-small cell lung cancer (NSCLC) than SCLC over the last decade [[4]Howlader N. Forjaz G. Mooradian M.J. et al.The effect of advances in lung-cancer treatment on population mortality.N Engl J Med. 2020; 383: 640-649Crossref PubMed Scopus (499) Google Scholar]. For patients with brain metastases, whereas upfront SRS has become the preferred treated for limited brain metastases arising from most solid tumor histologies [[6](NCCN) NCCN. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Central Nervous System Cancers v2.2020; 2020.Google Scholar], whole brain radiotherapy (WBRT) remains the standard of care for SCLC [[7](NCCN) NCCN. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) – Small Cell Lung Cancer v1.2021; 2020.Google Scholar]. Although WBRT has demonstrated efficacy in controlling both local and distant intracranial disease there is now increasing concern about its acute and late toxicities particularly with respect to cognitive function and quality of life [[8]Li J. Brown P.D. The diminishing role of whole-brain radiation therapy in the treatment of brain metastases.JAMA Oncol. 2017; 3: 1023-1024Crossref PubMed Scopus (30) Google Scholar]. Stereotactic ablative radiation techniques such as radiosurgery (SRS) and fractionated stereotactic treatment (FSRT) are standard options for metastatic NSCLC and other solid tumor histologies with multiple randomized trials demonstrating similar overall survival and improvement in cognitive outcomes and quality of life (QoL) compared to WBRT [[9]Tsao M.N. Xu W. Wong R.K. et al.Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases.Cochrane Database Syst Rev. 2018; 1: Cd003869PubMed Google Scholar]. However, SCLC patients were excluded from these landmark trials due to multiple factors including concerns for short interval, multi-lesion central nervous system (CNS) progression specific to patients with SCLC histology, as well as the prevalent policy of prophylactic cranial irradiation (PCI) which has limited both the ability to study SRS without prior brain radiation and to randomize patients to arms that included WBRT [10Nussbaum E.S. Djalilian H.R. Cho K.H. Hall W.A. Brain metastases. Histology, multiplicity, surgery, and survival.Cancer. 1996; 78: 1781-1788Crossref PubMed Scopus (571) Google Scholar, 11Rusthoven C.G. Camidge D.R. Robin T.P. Brown P.D. Radiosurgery for small-cell brain metastases: challenging the last bastion of preferential whole-brain radiotherapy delivery.J Clin Oncol. 2020; : Jco2001823Crossref PubMed Scopus (10) Google Scholar]. Due to the paucity of data on SRS, WBRT has endured as the preferred treatment strategy for SCLC patients with one or more brain metastasis. Today almost half of the world’s population is online and growing exponentially by 8% per year [[12]Data OWI. Number of Internet Users by Country; 2020.Google Scholar]. Among these, over 2.8 billion people use social media. With nearly 79% of Twitter users outside the US [[12]Data OWI. Number of Internet Users by Country; 2020.Google Scholar], this modality offers a unique platform for global engagement. We have previously shown how this tool may be used to enable rapid dissemination of specialty-specific knowledge [[13]Simcock R. Thomas T.V. Estes C. et al.COVID-19: global radiation oncology’s targeted response for pandemic preparedness.Clin Transl Radiat Oncol. 2020; 22: 55-68Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar]. To inspect the neglected condition of SCLC with BMs we used the global lens of the Radiation Oncology Journal Club (#RadOnc #JC) to critically review a large international cohort who received upfront SRS as an emerging option for patients (FIRE-SCLC). This #RadOnc #JC occurred on Twitter™ from Saturday, June 21st 8AM to Sunday, June 22nd 4PM Central Standard Time (CST) in accordance with our usual protocol. The online journal club included limited-time open-access of the publication [[14]Rusthoven C.G. Yamamoto M. Bernhardt D. et al.Evaluation of first-line radiosurgery vs whole-brain radiotherapy for small cell lung cancer brain metastases: the FIRE-SCLC Cohort Study.JAMA Oncol. 2020; Crossref Scopus (71) Google Scholar] and an asynchronous online discussion followed by a live-hour to reduce barriers to participation, targeted online invitations to encourage diverse perspectives across disciplines and regions, moderation by a resident (IP) and diverse faculty (MK, RS, HS), and attendance by the study’s lead author (CR). Structured discussion topics (T1, T2, T3…) included an introduction for more general audiences then critical appraisal of the cohort study for application locally and globally by patients and providers. Natural evolution of these topics was allowed to draw out new lines of inquiry. Throughout, tweets were summarized using the social media content organization platform Wakelet [[15]Simcock R. SABR in SCLC – The FIRE Study. https://wke.lt/w/s/YQgshb. Published 2020. Accessed August 23 2020.Google Scholar] for easier access to the knowledge-base generated by the discussion. Following the journal club, tweets were further reviewed, systematically organized into themes, and checked against existing literature to form the basis of the collated findings presented in this paper. Over 80 individuals from 10 countries participated in the journal club with up to 120 participants responding to the anonymous polls (Table 1). These included radiation oncologists, medical oncologists, family physicians, residents, and a patient advocate. There was a total of 496 tweets, 205 retweets, 128 tweets with links and over 2.9 million impressions (Table 1). The Altmetric Attention Score, one composite measure of scholarly impact and online engagement with research output, was 227 (top 5%) as of July 24, 2020 [[16]Erdt M. Nagarajan A. Sin S.-C.J. Theng Y.-L. Altmetrics: an analysis of the state-of-the-art in measuring research impact on social media.Scientometrics. 2016; 109: 1117-1166Crossref Scopus (129) Google Scholar]. Thematic analysis resulted in four themes: limitations of the study, the changing role of PCI, emerging alternatives and adjunct treatments, and the impact on patients including informed consent. A slim majority of participants had already offered SRS as first-line treatment for SCLC BMs (50.6%, n = 77). Radiation oncologists mainly prompted the clinical consideration of upfront SRS (72%, 15.6% medical oncologists, 3.1% patients; n = 32). Locally ablative treatments were usually done by the central nervous system (CNS) team (46.7%, 25.8% by anyone, 24.2% by an SRS/FSRT specialist; 3.3% or the lung cancer team; n = 120).Table 1Journal Club Participants.Period: June 20 – 21, 2020Countries: 10Total Tweets:496North America:2366% Unique Tweets20541% US2263%Impressions:2.9 million Canada13%Total Participants:86Europe:720% Active Participants3541% UK411%Physicians:3394% Spain13% Radiation Oncologists2571% Italy13% Clinical Oncologists13% Germany13% Medical Oncologists13%South America: Residents617% Columbia13%Patients:13%Iceland:13%Southeast Asia:26% Thailand13% South Korea13%Article Altmetric Score:227(top 5%)Participant demographics from the June 2020 #RadOnc #JC. Active participants were defined as those who contributed to the discussion (i.e. excluding retweets or introductions). Unique tweets were total tweets minus retweets. Demographics only includes active participants. Open table in a new tab Participant demographics from the June 2020 #RadOnc #JC. Active participants were defined as those who contributed to the discussion (i.e. excluding retweets or introductions). Unique tweets were total tweets minus retweets. Demographics only includes active participants. Our global journal club discussion suggests that occasional use of upfront SRS (delivered as a single fraction or fractionated locally ablative therapy) for carefully selected cases of SCLC BMs in combination with MRI active surveillance is not uncommon among the #RadOnc community; however, patterns of care analyses suggest that upfront WBRT is used in the vast majority of SCLC cases [5Robin T.P. Jones B.L. Amini A. et al.Radiosurgery alone is associated with favorable outcomes for brain metastases from small-cell lung cancer.Lung Cancer. 2018; 120: 88-90Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 17Jiang W. Haque W. Verma V. Butler B. Teh B.S. Stereotactic radiosurgery for brain metastases from newly diagnosed small cell lung cancer: practice patterns and outcomes.Acta Oncol. 2019; 58: 491-498Crossref PubMed Scopus (23) Google Scholar]. Although consideration of upfront SRS is likely to be prompted more often by radiation oncologists, medical oncologists and patients are becoming increasingly aware of this potential option. The majority of participating radiation oncologists’ respondents indicated that their centers have a dedicated CNS team to perform SRS, which was followed by individual SRS specialists. In a minority of places, lung teams are involved in SRS. Earlier SRS studies for BMs were limited to treating 3 to 4 intracranial lesions. However, technological advancement, increasing expertise, and encouraging results have paved the way for trials evaluating treatment for a larger number of intracranial lesions [[18]Yamamoto M. Serizawa T. Shuto T. et al.Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study.Lancet Oncol. 2014; 15: 387-395Abstract Full Text Full Text PDF PubMed Scopus (872) Google Scholar]. Additionally, the increased training in SRS and desire to decrease toxicity is helping to drive increased study and early adoption of SRS in this setting [[19]Canadian Cancer Trials G, Alliance for Clinical Trials in O, Oncology NRG. Stereotactic Radiosurgery Compared With Hippocampal-Avoidant Whole Brain Radiotherapy (HA-WBRT) Plus Memantine for 5-15 Brain Metastases; 2020.Google Scholar]. The First-Line Radiosurgery for Small Cell Lung Cancer (FIRE-SCLC) study is the largest analyses for upfront SRS (without prior PCI or WBRT) for SCLC BMs (n = 710). Compared to a WBRT cohort (n = 219) it concluded a similar median overall survival (mOS, 6.5 for upfront SRS vs 5.2 months for WBRT; p = .003) against a trade-off of shorter time to central nervous system progression (TTCP, 9.0 months vs not reached for WBRT; hazard ratio 0.38; p < .001). The trade-offs observed with SRS without WBRT in this study, including inferior CNS disease control without a decline in OS, appear similar to other histologies where upfront SRS is already well established by multiple randomized trials [[9]Tsao M.N. Xu W. Wong R.K. et al.Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases.Cochrane Database Syst Rev. 2018; 1: Cd003869PubMed Google Scholar]. However, our journal club highlighted some of the significant barriers to recommending upfront SRS as a standard option at this time. Despite a trend in literature, regulatory bodies, and some practices to accept lower-level evidence as practice-changing, there are key limitations of non-randomized data. Although propensity score analyses can help mitigate confounding variables, they are not a substitute for randomization and cannot guarantee balanced confounders or statements of causality [[20]Lalani N. Jimenez R.B. Yeap B. Understanding propensity score analyses.Int J Radiat Oncol Biol Phys. 2020; 107: 404-407Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar]. In light of the clinical reality that SCLC patients treated with SRS would often be highly selected, even after propensity score matching it is likely that that biases from uncontrolled and unmeasured confounding would remain. Moreover, the rate of post-treatment MRIs differed between study groups. In the WBRT cohort they were recommended only in symptomatic patients after radiation and only 46% had at least one follow-up MRI. This increased to 89% in the SRS cohort and could have increased the differences in time to CNS progression (TTCP) observed between SRS and WBRT patients. The differences in follow up MRIs may have also allowed for more disease-altering salvage interventions among the SRS patients. Indications for modality of salvage therapy (16% salvage with WBRT and 33.5% with SRS in the upfront SRS cohort) were also not collected in the study. Lack of information on systemic therapies and the delivery of SRS largely in the pre-immunotherapy era (last year of treatment 2018 in FIRE-SCLC) could limit contemporary interpretations. Newer immune checkpoint inhibitors (ICIs) in combination with platinum-based chemotherapy have become a standard first-line treatment options for extensive stage-SCLC [[21]Ganti AKP, Loo BW, Bassetti M, et al. NCCN Guidelines Version 1.2021 Small Cell Lung Cancer. NCCN; 2020.Google Scholar] following the results of the IMpower 133 in 2018 and CASPIAN in 2019 [22Paz-Ares L. Dvorkin M. Chen Y. et al.Durvalumab plus platinum–etoposide versus platinum–etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial.Lancet. 2019; 394: 1929-1939Abstract Full Text Full Text PDF PubMed Scopus (827) Google Scholar, 23Paz-Ares L.G. Dvorkin M. Chen Y. et al.Durvalumab ± tremelimumab + platinum-etoposide in first-line extensive-stage SCLC (ES-SCLC): updated results from the phase III CASPIAN study.J Clin Oncol. 2020; 38 (9002–9002)Crossref PubMed Google Scholar, 24Slotman B. Faivre-Finn C. Kramer G. et al.Prophylactic cranial irradiation in extensive small-cell lung cancer.N Engl J Med. 2007; 357: 664-672Crossref PubMed Scopus (858) Google Scholar, 25Horn L. Mansfield A.S. Szczęsna A. et al.First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer.N Engl J Med. 2018; 379: 2220-2229Crossref PubMed Scopus (1564) Google Scholar]. However, most studies on ICIs have not included SCLC patients with untreated brain metastases. Widespread use of upfront SRS is also limited by current practice patterns including standards of care, availability and accessibility. FIRE-SCLC omitted patients who received PCI, which is the standard of care for limited-stage SCLC and a standard treatment option in extensive-stage SCLC with global variation in utilization [7(NCCN) NCCN. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) – Small Cell Lung Cancer v1.2021; 2020.Google Scholar, 26Simone II, C.B. Bogart J.A. Cabrera A.R. et al.Radiation therapy for small cell lung cancer: an ASTRO clinical practice guideline.Practical Radiat Oncol. 2020; 10: 158-173Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 27Taremi M. Vella E.T. Cheng S. et al.Recommendations for prophylactic cranial irradiation and consolidative radiation for patients with small cell lung cancer.Endorsement of the 2019 National Institute for Health and Care Excellence Guidance. 2019Google Scholar, 28(UK) NIfHCaE. Lung cancer: diagnosis and management. NICE guideline [NG122].Google Scholar, 29Früh M. De Ruysscher D. Popat S. Crinò L. Peters S. Felip E. Small-cell lung cancer (SCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2013; 24 (vi99-105)PubMed Google Scholar]. The majority of patients in its upfront SRS group (540/710; 76%) were from Japan, which has the largest concentration of MRIs in the world (52 MRI units per million capita) and guidelines strongly recommending against PCI with near consensus from 34/35 of its subcommittee members [30Society JLC. Treatment policy for small cell lung cancer; 2018.Google Scholar, 31OECD. Magnetic resonance imaging (MRI) exams (indicator); 2020.Google Scholar]. For low-to-middle income countries (LMICs), while it may be an aspiration to opt for MRI surveillance this may not always be realistic. Although NCCN guidelines for Africa suggest both PCI and MRI surveillance as standard options [[32]Network NCC. NCCN Harmonized Guidelines for Sub-Saharan Africa – Small Cell Lung Cancer v1.2019; 2019Google Scholar], the latter will be hard to achieve when its populations have among the lowest levels of access (0.5 MRI units and 0.26 treatment units per million capita with less than 4% of its radiation needs covered). In many parts of the world the financial toxicity of upfront SRS and MRI active surveillance is the major limitation for patients and their healthcare systems who must prioritize their costs of care. Furthermore, it is important to realize the decreased sensitivity of a standard MRIs for detecting small BMs compared with high resolution thin slice, double or triple dose MRI [[33]Pope W.B. Brain metastases: neuroimaging.Handb Clin Neurol. 2018; 149: 89-112Crossref PubMed Scopus (90) Google Scholar]. For others that allow either CT or MRI surveillance, given the significantly lower sensitivity for CT [[34]Seute T. Leffers P. ten Velde G.P. Twijnstra A. Detection of brain metastases from small cell lung cancer: consequences of changing imaging techniques (CT versus MRI).Cancer. 2008; 112: 1827-1834Crossref PubMed Scopus (125) Google Scholar], it is unclear if brain CT surveillance is an effective strategy [[21]Ganti AKP, Loo BW, Bassetti M, et al. NCCN Guidelines Version 1.2021 Small Cell Lung Cancer. NCCN; 2020.Google Scholar]. Each of these issues can limit outcome comparisons between SRS vs. WBRT, the feasibility of trials, and applicability for practice while carrying risk of widening global disparities unless examined and deployed carefully. The evolving role of more standard radiation options was also debated. PCI was as an exclusion criteria of FIRE-SCLC’s upfront SRS, and it could be argued that the encouraging outcomes with first line SRS without PCI offer an additional challenge to routine PCI administration. Although most participants still regarded PCI as the standard of care for LS and a standard treatment option for ES-SCLC [[35]Gjyshi O. Ludmir E.B. Pezzi T.A. et al.Evolving practice patterns in the use of prophylactic cranial irradiation for extensive-stage small cell lung cancer.JAMA Netw Open. 2019; 2Crossref PubMed Scopus (12) Google Scholar], some participants were warmer to the idea of its omission. In support of PCI in LS-SCLC, a landmark meta-analysis of 987 patients across 7 randomized trials from 1977 to 1994 suggested a 5.4% OS benefit at 3 years with PCI over observation [[36]Aupérin A. Arriagada R. Pignon J.-P. et al.Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission.N Engl J Med. 1999; 341: 476-484Crossref PubMed Scopus (1409) Google Scholar], but some participants felt that its older methods including imaging in the pre-MRI era may no longer apply in the era of brain MRI staging and surveillance [[37]Rusthoven C.G. Kavanagh B.D. Prophylactic cranial irradiation (PCI) versus active MRI surveillance for small cell lung cancer: the case for equipoise.J Thorac Oncol. 2017; 12: 1746-1754Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar]. The landmark EORTC trial [[24]Slotman B. Faivre-Finn C. Kramer G. et al.Prophylactic cranial irradiation in extensive small-cell lung cancer.N Engl J Med. 2007; 357: 664-672Crossref PubMed Scopus (858) Google Scholar] showed a benefit in OS for patients receiving PCI after a good response to systemic therapy whereas a recent Japanese trial by Takahashi et al. [[38]Takahashi T. Yamanaka T. Seto T. et al.Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell lung cancer: a multicentre, randomised, open-label, phase 3 trial.Lancet Oncol. 2017; 18: 663-671Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar] showed no survival difference. A key difference was the frequency of brain imaging. Most patients in the EORTC trial did not have any baseline brain imaging (63%) whereas all patients in Takahashi trial had baseline and surveillance MRIs every 3 months for year 1 and every 6 months for year 2. In the Japanese study, despite a reduction in CNS progression events (33% vs 59% at 1 year; P < .001) with PCI, no significant differences in OS were observed in the setting of MRI surveillance which may have allowed for earlier and more effective salvage therapy. However, the CNS control benefit observed with PCI in the Japanese study has also allowed PCI to remain a preferred option for some providers and healthcare systems. Management of the thorax where failures traditionally occur has also evolved. Jeremic et al. [[39]Jeremic B. Shibamoto Y. Nikolic N. et al.Role of radiation therapy in the combined-modality treatment of patients with extensive disease small-cell lung cancer: a randomized study.J Clin Oncol. 1999; 17: 2092-2099Crossref PubMed Google Scholar] showed an improvement in survival with consolidative thoracic radiation treatment (TRT) for patients with ES-SCLC in an older era, and the more recent CREST [[40]Slotman B.J. van Tinteren H. Praag J.O. et al.Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial.Lancet. 2015; 385: 36-42Abstract Full Text Full Text PDF PubMed Scopus (349) Google Scholar] phase 3 randomized trial showed an OS benefit with consolidative thoracic RT in a secondary analysis at 2-years. Subgroup analyses from the CREST trial also suggested improved outcomes with decreased disease burden (less than three metastases) and potential consideration of dose escalation in select cases [[40]Slotman B.J. van Tinteren H. Praag J.O. et al.Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial.Lancet. 2015; 385: 36-42Abstract Full Text Full Text PDF PubMed Scopus (349) Google Scholar]. Similar to changing paradigms for other histologies and sites [41Gomez D.R. Tang C. Zhang J. et al.Local Consolidative therapy vs. maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer: long-term results of a multi-institutional, phase II, randomized study.J Clin Oncol. 2019; 37: 1558-1565Crossref PubMed Scopus (598) Google Scholar, 42Parker C.C. James N.D. Brawley C.D. et al.Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial.Lancet. 2018; 392: 2353-2366Abstract Full Text Full Text PDF PubMed Scopus (664) Google Scholar, 43Palma D, Olson R, Harrow S, et al. Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers: Long-Term Results of the SABR-COMET Phase II Randomized Trial. medRxiv. 2020:2020.2003.2026.20044305.Google Scholar], identification of a select patient group to benefit from consolidative radiation in SCLC may suggest a relative oligometastatic state where a combination of aggressive local management of the thoracic disease with modern systemic therapy may yield better outcomes. Another theme centered on alternatives to the traditional standard of WBRT as patients may be living longer and focus shifts to patient-centered care. Although only one patient advocate participated, many physicians held strong views on offering options to patients that minimize toxicity. Neurotoxicity from CNS directed radiation can be difficult to assess due to several factors such as sequelae of the intracranial disease, other treatments, and comorbidities. However, adverse effects on memory and quality-of-life have been described within the first year of patients receiving cranial irradiation with increased rates in older patients and those receiving higher doses [44Le Péchoux C. Laplanche A. Faivre-Finn C. et al.Clinical neurological outcome and quality of life among patients with limited small-cell cancer treated with two different doses of prophylactic cranial irradiation in the intergroup phase III trial (PCI99-01, EORTC 22003–08004, RTOG 0212 and IFCT 99–01).Ann Oncol. 2011; 22: 1154-1163Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar, 45Brown P.D. Jaeckle K. Ballman K.V. et al.Effect of radiosurgery alone vs radiosurgery with whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases: a randomized clinical trial.JAMA. 2016; 316: 401-409Crossref PubMed Scopus (937) Google Scholar]. Hippocampal-avoidance radiation treatment (HA-RT) has emerged as a standard option to preserve neurocognitive function without compromising intracranial failures in NSCLC [[46]Brown P.D. Gondi V. Pugh S. et al.Hippocampal avoidance during whole-brain radiotherapy plus memantine for patients with brain metastases: phase III trial NRG oncology CC001.J Clin Oncol. 2020; 38: 1019-1029Crossref PubMed Scopus (313) Google Scholar]. Although to this point hippocampal avoidance techniques have not been firmly established by trials specifically in SCLC patients, some participants already declared the demise of any conventional whole brain radiation delivery techniques and apply HA to both PCI and WBRT for SCLC when all metastatic lesions are away from the hippocampus. Hopefully the open question regarding the role of hippocampal avoidance in PCI will be settled by ongoing trials (Table 2). Another option that may improve both local and distant brain control could be adding a simultaneous integrated boost with WBRT, although recent trials have excluded SCLC [[47]Popp I. Rau S. Hintz M. et al.Hippocampus-avoidance whole-brain radiation therapy with a simultaneous integrated boost for multiple brain metastases.Cancer. 2020; 126: 2694-2703Crossref PubMed Scopus (15) Google Scholar]. ICIs with CNS efficacy either alone or in combination with RT were also discussed, although existing data is mainly from preclinical and NSCLC studies and ongoing SCLC trials are limited (Table 2).Table 2Pending Relevant Clinical Trials in ES-SCLC Globally.Clinical TrialPhaseArmsStatus1* EndpointHA-PCINCT01780675 [50]van Meerbeeck J. De Ruysscher D. Belderbos J. et al.Neuro-cognitive (HVLT-R total recall) functioning in localized vs. metastatic small-cell lung cancer with or without hippocampus sparing PCI: Results from a phase III trial.Eur Respirat J. 2019; 54: OA5103Google ScholarNetherlandsP3PCI ± HAActive, Not RecruitingNCF @4mosNCT01849484 [51]University of Erlangen-Nürnberg Medical S. Enhancement of Neurocognitive Functions by Hippocampal Sparing Radiotherapy; 2020.Google ScholarHIPPO-SPARE 01-GermanyP3PCI ± HARecruitingQoL & NCFNCT02635009 [52]Oncology NRG, National Cancer I, Radiation Therapy Oncology G. Whole-Brain Radiation Therapy With or Without Hippocampal Avoidance in Treating Patients With Limited Stage or Extensive Stage Small Cell Lung Cancer; 2020.Google ScholarNRGCC003/NCI-North AmericaP2/3PCI ± HARecruitingHVLT-R@6mos, Brain Relapse@12mosPCI vs. No PCINCT04155034 [53]Southwest Oncology G, National Cancer I. SWOG S1827 (MAVERICK) Testing Whether the Use of Brain Scans Alone Instead of Brain Scans Plus Preventive Brain Radiation Affects Lifespan in Patients With Small Cell Lung Cancer; 2020.Google ScholarMAVERICK- SWOG/NCI-USAP3MRI Surveillance ± HA-PCIRecruitingOS @6mosBrain RT vs. SRSNCT03297788 [48]Juergen D, Heidelberg U, University Hospital H. Whole Brain Radiation Therapy Alone vs. Radiosurgery for SCLC Patients With 1-10 Brain Metastases; 2020.Google ScholarENCEPHALON-GermanyP31-10BMs, WBRT vs. SRSRecruitingNCF@ 3mosNCT03391362 [49]Dana-Farber Cancer I. Stereotactic Radiation in Patients With Small Cell Lung Cancer and 1-6 Brain Metastases; 2020.Google ScholarDana Farber-USAP21-6BMsRecruitingNCF@3mosPendingNRG CC009P31-10BMs, HA-WBRT vs. SRSPendingTTCF@6mosNCT03550391 [19]Canadian Cancer Trials G, Alliance for Clinical Trials in O, Oncology NRG. Stereotactic Radiosurgery Compared With Hippocampal-Avoidant Whole Brain Radiotherapy (HA-WBRT) Plus Memantine for 5-15 Brain Metastases; 2020.Google ScholarCCTG/ACTO/NRG-North AmericaP35-15BMs, SRS vs HA-WBRT + MemantineRecruitingOS, NCFImmunoRTNCT02589522 [54]National Cancer. Testing the Safety of M6620 (VX-970) When Given With Standard Whole Brain Radiation Therapy for the Treatment of Brain Metastases from Non-small Cell Lung Cancer, Small Cell Lung Cancer, or Neuroendocrine Tumors; 2020.Google ScholarNCI-USAP1M6620 (VX-970) + WBRTRecruitingMTDNCT02978404 [55]Centre hospitalier de l'Université de M, Bristol-Myers S. Combining Radiosurgery and Nivolumab in the Treatment of Brain Metastases; 2020.Google ScholarMontrealP2SRS + NivolumabActive, Not RecruitingIPFS @1yrNCT03971214 [56]Chinese Academy of Medical S. PD-1 Inhibitors Consolidation in Extensive-stage Small Cell Lung Cancer; 2020.Google ScholarChinese Academy of Medical SciencesP1JS 001 (PDL1i) after standard tmt or SRSNot yet recruitingSafety & ORRNCT03043599 [57]Center HLMC, Research I, Bristol-Myers S. Ipilimumab + Nivolumab w/Thoracic Radiotherapy for Extensive-Stage Small Cell Lung Cancer; 2018.Google ScholarMoffitt-USAP1/2Ipi/Nivo + cTRTActive, Not RecruitingSafety, PFS, OSNCT04472949[58]Swiss Group for Clinical Cancer R. Thoracic Radiotherapy Plus Maintenance Durvalumab After First Line Carboplatin and Etoposide Plus Durvalumab in Extensive-stage Disease Small Cell Lung Cancer (ED-SCLC); 2020.Google ScholarSAKK 15/19-SwitzerlandP2Durva + CE -> cTRT + DurvaNot yet recruitingProgressionNCT04462276 [59]Institut für Klinische Krebsforschung IKFGaKN, Thoraxklinik-Heidelberg gGmb H. Thoracic RadiothErapy With Atezolizumab in Small Cell lUng canceR Extensive Disease; 2020.Google ScholarTREASURE-GermanyP2CE + Atezo -> cTRT + AtezoNot yet recruitingOS, PFSNCT04314297 [60]Wuhan Union Hospital C. Anlotinib In Combination With Durvalumab As Sequential Therapy of Thoracic Radiotherapy After Induction Chemotherapy For Extensive-Stage Small Cell Lung Cancer:A Single Arm Study; 2020.Google Scholar, NCT04313660 [61]Xiaorong D, Wuhan Union Hospital C. Anlotinib In Combination With PD-1/L1 Inhibitor As Sequential Therapy of Thoracic Radiotherapy After Induction Chemotherapy For Extensive-Stage Small Cell Lung Cancer:A Single Arm Study; 2020.Google ScholarChinaP2cTRT -> Anlotinib + Durva or TetraNot yet recruitingPFSNCT03532880 [62]Memorial Sloan Kettering Cancer C. A Study of Olaparib and Low Dose Radiotherapy for Small Cell Lung Cancer; 2020.Google ScholarMSKCC-USAP1Olaparib + lcTRTRecruitingMTD, SafetyNCT02934503 [63]Health NYUL, Merck S, Dohme C. 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Amsterdam University Medical Centre VS, British Columbia Cancer – Centre for the N, Beaston West of Scotland Cancer C, London Health Sciences C, Lawson Health Research I. Stereotactic Ablative Radiotherapy for Comprehensive Treatment of 4-10 Oligometastatic Tumors; 2020.Google ScholarSABR-COMET10-CanadaP3Palliative RT vs. SBRT/SRTRecruitingOSNCT01345539 72Steven B, University of P. Radiosurgery for Patients With Oligometastatic Disease at Initial Presentation; 2020.Google Scholar, 73UPMC. Phase II Study for Curative Intent Treatment for Patients With Oligometastatic Disease at Initial Presentation (UPCI #10-027); 2024.Google ScholarU PittsburghP2SBRT/SRTRecruitingFeasibilityThe above trials may influence the management and outcomes of brain metastases in this setting.Brain RT = WBRT or HA-WBRT (excluding PCI), TTCF = Time to cognitive failure, HVLT-R = Hopkins Verbal Learning Test – Revised, Brain RT = WBRT or HA-WBRT (excluding PCI), MTD = Maximum Tolerated Dose, IPFS = Intracranial Progression Free Survival, ORR = Objective Remission Rate, cTRT = Consolidative Thoracic Radiation Treatment, Ipi = Ipililumab, Nivo = Nivolumab, PDL1i = PD-L1 Inhibitor, Durva = Durvalumab, Atezo = Atezolizumab, Tetra = Tetraprizumab, Trem = Tremilimumab, Ola = Olaparib, Tala = Talazopari Open table in a new tab The above trials may influence the management and outcomes of brain metastases in this setting. Brain RT = WBRT or HA-WBRT (excluding PCI), TTCF = Time to cognitive failure, HVLT-R = Hopkins Verbal Learning Test – Revised, Brain RT = WBRT or HA-WBRT (excluding PCI), MTD = Maximum Tolerated Dose, IPFS = Intracranial Progression Free Survival, ORR = Objective Remission Rate, cTRT = Consolidative Thoracic Radiation Treatment, Ipi = Ipililumab, Nivo = Nivolumab, PDL1i = PD-L1 Inhibitor, Durva = Durvalumab, Atezo = Atezolizumab, Tetra = Tetraprizumab, Trem = Tremilimumab, Ola = Olaparib, Tala = Talazopari The importance of patient-centered care in any decision-making was also discussed, especially for newer techniques with more uncertainty. Participants agreed that the risks and benefits of all available options in the context of their level of evidence should be discussed with patients when eliciting informed consent. This is especially true for HA brain radiation approaches, SRS, and MRI surveillance without PCI, even when these strategies are included in common guidelines [[21]Ganti AKP, Loo BW, Bassetti M, et al. NCCN Guidelines Version 1.2021 Small Cell Lung Cancer. NCCN; 2020.Google Scholar]. Where available, patients should be offered clinical trials to decrease this uncertainty. Less clear was the interpretation of the “best available evidence.” Some participants more strictly adhered to the standard options that were based on high levels of evidence than others. This journal club highlighted the key findings and implications of the FIRE-SCLC study, a large cohort comparing SRS to WBRT that has brought much attention to the management of SCLC with BMs." @default.
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• W3083480767 title "Stereotactic radiosurgery (SRS) – A new normal for small cell lung cancer?" @default.
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