Long-Term Survival in Extensive Disease Small Cell Lung Cancer Patients Treated Without Immune Checkpoint Inhibitors

Background: Immune checkpoint inhibitors (ICIs) combined with chemotherapy have been approved as rst-line treatment for patients with untreated extensive disease-small cell lung cancer (ED-SCLC). However, there are few reports about the long-term survival in patients with ED-SCLC treated without ICIs. Thus, we analyzed the long-term survival in patients with ED-SCLC. Methods: We retrospectively examined the medical records of patients with SCLC who were treated at our hospital between September 2002 and September 2019. The main inclusion criteria were as follows: (1) histological or cytological conrmation of SCLC, (2) diagnosed with ED-SCLC, and (3) received chemotherapy, not including ICIs, as the rst-line treatment. To assess the trends of treatment outcomes, we compared the survival outcomes between 2002–2010 (early) and 2011–2019 (late) groups. Results: A total of 314 patients were included in this study. Patient characteristics at the time of rst-line treatment were as follows: median age was 69 years; 82% of the patients were male; and 70% had a performance status of 0 or 1. The median follow-up time of overall survival (OS) was 7.4 years, and 89% of the patients died. The median progression-free survival and survival time were 4.9 months and 12.1 months, respectively. Five-year survival rate was 2%. There was no signicant difference in survival between the early and late groups. Conclusion: We found that the long-term survival in ED-SCLC patients treated without ICIs was poor. Prior to the approval of ICI treatment for ED-SCLC, there was no improvement in the OS for approximately 20 years.

between the early and late groups.
Conclusion: We found that the long-term survival in ED-SCLC patients treated without ICIs was poor. Prior to the approval of ICI treatment for ED-SCLC, there was no improvement in the OS for approximately 20 years.

Background
Lung cancer is the most common cause of cancer-related deaths worldwide. Small-cell lung cancer (SCLC) is one of the major histological types of lung cancers and accounts for 10%-15% of all lung cancers [1]. Approximately 60%-70% of patients have extensive disease (ED)-SCLC, with a poor prognosis. Although SCLC shows high sensitivity to chemotherapy and radiotherapy, the median survival time (MST) for ED-SCLC is 8-13 months, and the two-year survival rate is only 5% [2]. In the recent decades, no drug has shown promising results in improving the prognosis of patients with ED-SCLC.
Consequently, four drugs, nivolumab, pembrolizumab, atezolizumab, and durvalumab, have been currently approved for patients with NSCLC. In case of SCLC, the e cacy of ICIs has not been reported by many trials in several years. However, the IMpower 133 trial, conducted in 2018 [10], compared carboplatin, etoposide, and atezolizumab with carboplatin, etoposide, and placebo for patients with previously untreated ED-SCLC, with investigator-assessed progression-free survival (PFS) and overall survival (OS) as the primary endpoints. The median PFS (mPFS) was 5.2 months in the atezolizumab group and 4.3 months in the placebo group (hazard ratio [HR]: 0.77, 95% con dence interval [CI]: 0.62-0.96, p = 0.02), and the MST was 12.3 months and 10.3 months, respectively (HR: 0.70, 95% CI: 0.54-0.91, p = 0.007). IMpower 133 showed that the addition of atezolizumab to chemotherapy signi cantly prolonged PFS and OS compared with chemotherapy alone. The CASPIAN study, a phase III study of durvalumab conducted in 2019, was designed similar to the IMpower 133 trial and reproducibly showed that the addition of ICI to chemotherapy was also effective in patients with ED-SCLC. Based on these two studies, many guidelines recommend atezolizumab or durvalumab combined with chemotherapy as rstline treatment for patients with ED-SCLC.
Recently, clinical trials that compared ICI monotherapy with docetaxel for NSCLC patients [11][12][13] reported long-term survival results, which were represented by a plateau in the right tail of the survival curve. However, the median follow-up period of the trial that evaluated the e cacy of ICI combined with cytotoxic chemotherapy in patients with NSCLC or ED-SCLC was approximately 2 years, and it is unclear whether ICI combined with cytotoxic chemotherapy shows a plateau in the right tail of the survival curve. Although the data on long-term survival in patients with ED-SCLC treated without ICIs are necessary to assess the e cacy of ICIs combined with chemotherapy, there are limited reports documenting these data.

Patients
We retrospectively analyzed data on consecutive patients with ED-SCLC treated with rst-line chemotherapy between September 2002 and June 2019 from the medical records of Shizuoka Cancer Center. The recruitment criteria for this study were as follows: (1) histological or cytological con rmation of SCLC, (2) diagnosis of ED-SCLC, (3) received chemotherapy, not including ICIs, as the rst-line treatment, and (4) no history of interstitial lung disease. We de ned sensitive relapse as treatment-free interval ≥ 90 days.
To assess the trends of treatment outcomes, we divided the patients with ED-SCLC into two groups according to the year of the rst-line treatment. The "early group" included patients treated during 2002-2010 and the "late group" included patients treated during 2011-2019.

Evaluation and statistical analysis
We evaluated the tumor response to chemotherapy in accordance with the Response Evaluation Criteria in Solid Tumors by performing chest and abdomen computed tomography, head magnetic resonance imaging, bone scintiscan, or positron emission tomography-computed tomography [14]. All categorical variables were analyzed using the chi-square test or Fisher's exact test, as appropriate. Clinical evaluation of PFS and OS after the initiation of rst-line chemotherapy was conducted using the Kaplan-Meier method to assess the time of recurrence or death, respectively. Survival analyses were performed using the log-rank test. The follow-up period was also estimated using the Kaplan-Meier method. All tests were two-sided, and p-values < 0.05 were considered signi cant. Statistical analyses were performed using the JMP software version 9.0 (SAS Institute Inc., Cary, NC) and EZR. The data cutoff date was June 30, 2020. Our study was approved by the Institutional Review Board of the Shizuoka Cancer Center. (range, 43-89) years; 82% of the patients were males, 70% had a performance status (PS) of 0 or 1, 97% were past or current smoker, 98% had stage IV disease, and 34% of the patients had brain metastasis (Table 1). amrubicin was most frequently administered drug.

E cacy
The overall response rate (ORR) of rst-line treatment was 80% in all patients with ED-SCLC (Table 2). In total, 127 and 187 patients were grouped into the early and late groups, respectively. There was no signi cant difference in gender, PS at rst-line treatment, and smoking status between the two groups (Table 3). Although the proportion of patients over 75 years old was not signi cantly different, more older patients were included in the late group. The proportion of patients with stage IV disease or lung metastasis was greater in the late group. Subsequent chemotherapy was administered in 75 patients (75%) of the early group and 127 patients (68%) of the late group.

Discussions
In this study, we retrospectively analyzed the long-term survival of rst-line treatment in patients with ED-SCLC. Our study showed that the MST of rst-line treatment was 12. Only a few drugs for SCLC patients have been approved in the last 20 years and cisplatin plus etoposide or irinotecan have been the standard treatment until recently. ICIs, such as atezolizumab and durvalumab, were approved as rst-line treatment for ED-SCLC patients in 2019. The follow-up period of the studies that led to the approval of ICIs for patients with ED-SCLC were short, and there are limited reports on the long-term survival of ED-SCLC patients treated without ICIs. In 1995, the long-term survival of 1714 patients with SCLC were reported from nine trials [15]. This report included 886 ED-SCLC patients, and the ve-year survival rate was 2.3%; these results were comparable with our results. Schabath et al. In case of NSCLC, studies have revealed that ICI monotherapy shows a plateau in the right tail of the survival curve. However, cytotoxic chemotherapy did not show a plateau, and the survival rate was close to zero. When ICI was combined with chemotherapy, it was unclear whether it shows a plateau in the right tail of the survival curve because of the short follow-up period of the study, while our study showed the long-term survival of patients with ED-SCLC without treatment with ICIs. We believe our study will be an important reference for future studies on ICIs combined with chemotherapy for patients with ED-SCLC.
Our study had several limitations. First, the sample size was small and this study was the result of a single-center analysis. However, our study included only patients with ED-SCLC, and there are only a few reports on ED-SCLC patients. Moreover, our study had a follow-up time of almost 7 years, which was longer than the average time-period of previous clinical trials. Based on these factors, we believe our study is very worthwhile. Second, the timing of response assessment was decided by each physician; although, this might have introduced variance of ORR and PFS, we also assessed OS, which was a reliable endpoint. Finally, this study was retrospective analysis. However, a prospective study assessing the long-term survival of patients with ED-SCLC treated without ICI is di cult. We though our results were important as real-world date of those patients. For more reliable date of long-term survival in patients with ED-SCLC, multi institutional study of ED-SCLC was warranted in the future.

Conclusion
In conclusion, this study revealed that the long-term survival in patients with ED-SCLC treated without ICI was poor. Analysis of the survival trend for patients with ED-SCLC prior to the approval of ICI treatment revealed no improvement in patient survival. We believe our study will be an important reference for future studies evaluating the e cacy of ICIs combined with chemotherapy in ED-SCLC patients. Ethics approval and consent to participate: Our study was approved by the Institutional Review Board of the Shizuoka Cancer Center. The need to obtain informed consent to participate was waived due to the retrospective design of this study.