PC 02.03 PCI---YES

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Journal of Thoracic Oncology

received consolidation thoracic radiotherapy (30 Gy in 10 fractions) had significantly better 2-year OS rates than did those who did not receive thoracic radiotherapy (13% vs. 3%, P¼0.004). Thoracic radiotherapy further improved thoracic-only failure rates (19.8% vs. 46% without, P¼0.001) (Slotman B et al, Lancet Oncol 2015;385:3642). However, many patients with extensive-stage SCLC do not respond to the standard etoposide/cisplatin chemotherapy (Fig 1). Those patients may need to receive molecular-targeted therapies or immunotherapy with the consolidating thoracic radiotherapy. Several histologic and immunohistochemical markers have been evaluated for diagnosing or monitoring treatment response in SCLC, including transcription thyroid factor-1 (positive in >85% of SCLC cases); cytokeratin 7; deletions in chromosome 3; Leu-7; chromogranin A; synaptophysin; myc amplification; and p53 mutations (present in w75% of cases). Deletions in tumor-suppressor genes are also relatively common and include fragile histidine triad (FHIT) (80%); RAS effector homologue (RASSF1) (>90%); TP53 (>75%); retinoblastoma-1 (RB1) (>90%); and retinoic acid receptor-beta (72%). However, to date no biomarkers have been validated for use in diagnosing SCLC. Moreover, mutations that are often present in non-small cell lung cancer (such as epidermal growth factor receptor [EGFR] mutations and anaplastic lymphoma kinase [ALK]) are rare in SCLC. Several clinicopathologic features have been linked with worse prognosis, including poor performance status, significant weight loss, high lactate dehydrogenase levels, large numbers of metastatic sites, and the presence of paraneoplastic syndromes. Because SCLC has the among the highest rates of somatic driver mutations, and because more than 95% of patients with SCLC are former or current smokers, immunotherapy seems a reasonable approach, as high mutation burdens correlate with good response to chemoradiotherapy and sensitivity to immunomodulators (Peifer M et al., Nat Genet 2012;44(10):1104-10). At MD Anderson Cancer Center, an ongoing phase I/II study of patients with extensive-stage SCLC has been proposed to the NRG as a prospective randomized study (PI J Welsh) (Fig 2). Use of thoracic radiotherapy to consolidate a site at which SCLC is quite likely to recur is reasonable, given that recurrence considerably reduces quality of their life as well as OS. In summary, in most cases SCLC presents as extensive-stage disease, for which outcomes are very poor. Consolidation with thoracic radiotherapy for patients who achieve a complete response to chemotherapy can improve 2-year OS rates. However, less toxic and more effective systemic treatment is also required to derive the greatest benefit from consolidation thoracic radiotherapy. Keywords: thoracic radiotherapy extensive small-cell lung cancer, immunotherapy

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PC 02.03 PCI—YES A. Bezjak Radiation Oncology, Princess Margaret Cancer Centre, Toronto/CA Radiation therapy (RT) has an important role in both limited stage and extensive stage (M1) small cell lung cancer (SCLC), although more recent randomized trial results have led to increasing discussion and opposing views regarding the indications and type and degree of benefit conferred. This is one such debate, in which I am arguing in favor of recommending Prophylactic Cranial Irradiation (PCI) in extensive stage (ES) SCLC. There is no disagreement about the prevalence of brain metastases (BM) in SCLC. There is strong randomized trial evidence that delivery of modest doses of RT, such as 25 Gy in 10 fractions (fr) over 2 weeks, can reduce the incidence of BM. The simplistic explanation is that RT reduces the tumor cell burden and affects the ability of cancer cells to multiply, thus delaying or preventing the progression of microscopic intracranial metastases, and reducing the likelihood, that patient will develop symptomatic metastases e thus the term “prophylactic” brain RT. A meta-analysis1 of previously conducted randomized clinical trials (RCTs) in patients with limited stage (LS) or ES SCLC with response to chemotherapy demonstrated not only a reduction in symptomatic BM (from 58% to 33% at 3 yrs) but also a survival benefit (15.3% to 20.7%). A large RCT2 in LS SCLC confirmed that 25Gy/10 fr is the optimal dose fractionation, and described the potential negative neurocognitive and quality of life (QOL) impact of PCI.3 Other studies4 provided further data to inform patients regarding the potential risks and benefits of PCI. The EORTC group conducted a RCT in ES SCLC,5 randomizing 286 patients who had a response to 4-6 cycles of chemotherapy and had no clinical evidence of BM (but who did not have brain imaging to confirm absence of radiological metastases) to PCI vs observation. Their primary endpoint was time to symptomatic BM. A range of fractionation schedules was allowed; 62% of pts were treated with 20 Gy/5fr, 22% with 30 Gy/10-12 fr and only 4% with 25Gy/10 fr. There was a large reduction in symptomatic BM, 16.8% in the PCI group vs 41.3% in the control group (p < 0.001, hazard ratio (HR) 0.27 (95% confidence intervals (CI) 0.16-0.44). Disease-free survival (DFS) was significantly longer in the PCI group (median 14.7 weeks, vs 12 weeks, p ¼ 0.02, HR0.76 (95% CI 0.59-0.96), as was the overall survival (OS) (median 6.7 mo vs 5.4 mo, p ¼ 0.003). This study let to the more widespread recommendation of PCI to patients with ES SCLC who have responded to chemotherapy. Practice guidelines on management of ES SCLC include PCI in their recommendations. A more recent Japanese RCT6 randomized patients with ES SCLC who had a response

November 2017 to chemotherapy and no BM on MRI, to PCI (25 Gy/10 fr) vs observation. Follow up MRIs were mandated every 3 mo initially, then q6 mo. If patients were discovered to have radiological brain progression, whole brain RT was utilized regardless of whether they were symptomatic or not. Primary endpoint was OS. The study was closed after interim analysis, as the PCI group was not going to have a superior OS; 224 patients were enrolled in all. There was a reduction in BM in the PCI group, with the cumulative incidence at 6 mo15% vs 46% in the observation arm; at 12 months there was also a difference (33% and 59% respectively). PFS was identical, and there was no significant difference in OS (11.5 mo median OS in the PCI group vs 13.7, p ¼ 0.094, HR 1.27 (95% CI 0.96-1.68)). The study concluded that PCI doesn’t result in longer OS and is thus “not essential for patients with ES SCLC (..) and a confirmed absence of BM, if patients will be followed by periodic MRIs.” Those are indeed very fair conclusions of their data, although it is interesting that some, perhaps many, especially in the medical oncology community, after hearing the presentation at ASCO 2015, seem to have concluded that PCI may be detrimental to survival (given the small and statistically non-significantly longer survival in the observation group). Comments have been made that in the era of staging/ restaging MRIs, there may be no benefit to PCI in ES SCLC, and that perhaps the EORTC study showed improved survival because patients may have had clinically undetected gross metastatic disease (ie not just microscopic disease). That is clearly an incorrect interpretation of the Japanese data, and an assumption that has no proof in terms of the EORTC study. Every study that looked at local control ie ability of PCI to eradicate metastatic disease showed a benefit to RT, whether assessed radiologically or clinically. The incidence of BM in the control arms of the EORTC and Japanese trials was similar, suggesting that patients staged with MRIs did not have a different risk of brain disease than patients staged clinically. Even if restaging MRIs are routinely available in many parts of the world, close surveillance with regular MRIs is not routinely done for ES SCLC; it should be noted that Japan has the highest ratio of MRI to population. A very large proportion of patients in the observation arm of the Japanese study (83%) had whole brain RT for BM e no wonder there was no survival difference as it was really a comparison of early vs late RT. Finally, the risk of systemic disease in ES SCLC is high, so that a treatment that clearly has an impact in reducing brain relapse would be expected to have a relatively small OS benefit. Thus, Japanese study provides valuable data that continue to support the role of PCI in ES SCLC, and emphasize the need for a more realistic and holistic view of the expected role and benefit of RT e ie reducing BM, prolonging survival in some, and aiming to provide good neurological functioning and QOL. Rather than trying to argue against PCI as a strategy, we should continue with attempts to reduce its toxicity, such as through hippocampal sparing techniques7 and to identify groups of patients who are more or less likely to benefit in terms of survival.8,9 References: 1. Auperin A, Arriagada R, Pignon JP, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. N Engl J Med. 341(7):476-84, 1999. 2. Le Péchoux C, Dunant A, Senan S, et al. Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomized clinical trial. Lancet. 10(5):467-74, 2009. 3. Le Pechoux C, Laplanche A, Faivre-Finne 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 intergroup phase III trail (PC I00-01, EORTC 22003-08004, RTOG 0212 and IFCT 99-01). Annals of Oncology 22: 1154-1163, 2011. 4. Wolfson AH, Kyounghwa B, Ritsuko K, et al. Primary Analysis of a

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phase II randomized trial radiation therapy oncology group (RTOG) 0212: Impact of different total doses and schedules of prophylactic cranial irradiation of chronic neurotoxicity and quality of life for patients with limited-disease small-cell lung cancer. Int. J. Radiation Oncology Biol. Phys Vol 81 (1): 77-84, 2011. 5. Slotman B, FaivreFinn C, Kramer G, et al. EORTC Radiation Oncology Group and Lung Cancer Group. Prophylactic cranial irradiation in extensive smallcell lung cancer. N Engl J Med. 357(7):664-72, 2007. 6. Takahashi T, Takeharu Y, Takashi S, et al. Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell lung cancer: a multicenter, randomized, open-label, phase 3 trial. The Lancet Oncology, 18: 663-71, 2017. 7. Gondi V, Paulus R, Bruner DW et al. Decline in tested and self-reported cognitive functioning following prophylactic cranial irradiation for lunc cancer: Pooled secondary analysis of RTOG randomized trials 0212 and 0214. Int J. Radiat Oncol Biol Phys. 86(4): 656-664, 2013. 8. Rule WG, Foster NR, Meyers JP et al. Prophylactic cranial irradiation in elderly patients with small cell lung cancer: Findings from a North Central Cancer Treatment Group pooled analysis. Journal of Geriatric Oncology 6: 119-126, 2014. 9. Farooqi AS, Holliday EB, Allen PK et al. Prophylactic cranial irradiation after definitive chemoradiotherapy for limited-stage small cell lung cancer: Do all patients benefit? Radiotherapy and Oncology 122: 307-312, 2017. Keywords: small cell lung cancer, radiation therapy

PC 02.04 PCI—NO T. Seto Department of Thoracic Oncology, National Kyushu Cancer Center, Fukuoka/JP What does prophylactic cranial irradiation (PCI) prevent in ED-SCLC? Why isn’t the presence of brain metastasis evaluated before performing PCI? Background: In a European trial, prophylactic cranial irradiation (PCI) was performed on patients with extensive-disease small cell lung cancer (ED- SCLC). As a result, PCI was reported to reduce the incidence of symptomatic brain metastasis and to prolong patient survival. However, their treatments were completely different from our routine medical care. For example, they did not perform tests to examine whether there was a metastatic brain tumor before assignment to the PCI group or observation group and, after assignment, symptoms alone were observed and no imaging test was performed. For this reason, in Japan, we corrected this inconsistency of protocol and repeated the trial to determine whether PCI contributes to prolonged survival. Participants and Method: Included in the current trial were patients who underwent two or more cycles of platinum-based combination chemotherapy, had achieved at least stable disease (SD), and had no metastatic brain tumor on their MRI. They were randomly assigned to either the PCI group or observation group. Follow-up with brain, chest and abdominal diagnostic imaging tests was performed every three months in both groups. Results: In the first pre-specified interim analysis, it was found that there was no possibility of improving patient prognosis using PCI even if the trial were continued. An independent data monitoring committee therefore terminated the trial. At that time, 224 cases had already been enrolled, with 113 cases assigned to the PCI group and 111 cases to the observation group. Median survival period in the final analysis was 11.6 months for the PCI group and 13.7 months for the observation group (hazard ratio, 1.27; 95% CI, 0.96 to 1.68). There was no statistically significant difference between the groups, but PCI actually tended to make the prognosis somewhat worse or, at least, did not improve prognosis in