A retrospective study on the prognosis of patients with small cell lung cancer with or without interstitial pneumonia treated with postoperative chemotherapy

Introduction

In patients with limited-disease small cell lung cancer (LD-SCLC), the goal of treatment is cure using chemotherapy, thoracic radiotherapy, and/or curative surgery. Surgery and postoperative chemotherapy are recommended for patients with stage I–IIA (1). Previous reports had shown that the overall survival (OS) of patients with SCLC who received postoperative chemotherapy or chemoradiotherapy was longer than that of patients who received surgery alone (2). Preexisting interstitial pneumonia (IP) is one of the most common complications associated with smoking and is related to a poor prognosis of lung cancer (3). In addition, treatments for lung cancer, such as surgery, chemotherapy, and radiotherapy, are associated with the risk of acute exacerbation of IP, which is a fatal complication (4). Previous reports have shown that patients with usual IP (UIP) pattern IP have a higher frequency of acute exacerbations in natural history and higher frequency of chemotherapy-induced acute exacerbations compared to those with non-UIP IP pattern patients (5-7). Several studies have demonstrated the safety and efficacy of chemotherapy in extensive-disease SCLC (ED-SCLC) with IP (8-10).

However, there is no data on patients with early-stage SCLC and IP treated with surgery and postoperative chemotherapy. In this retrospective observational study, we aimed to compare the prognosis of patients with early-stage SCLC and IP treated with surgery and postoperative chemotherapy with that of patients without IP. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2056/rc).

Methods

Study design and patients enrollment

This retrospective study included consecutive patients with SCLC who underwent surgery between April 2011 and September 2021. Patients who did not receive postoperative chemoradiotherapy, postoperative chemotherapy with platinum and irinotecan, those who underwent diagnostic surgery or had incomplete resection, and those who did not receive postoperative chemotherapy were excluded. We used the 8^th edition of the tumor-node-metastasis (TNM) classification for staging of SCLC (11). We obtained data from Chiba University Hospital’s database and reviewed their medical records. The study received approval from the institutional ethics review board for Observational Studies of Chiba University Hospital (No. HK202303-14), and individual consent for this retrospective analysis was waived. Given the study’s retrospective nature and anonymized design, patients were given the option to opt out via Chiba University Hospital’s website rather than through written informed consent. The study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN ID 000051612). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Perioperative management strategies

At Chiba University Hospital, we implement the following perioperative management strategies for managing patients with lung cancer and IP during the perioperative period. Pirfenidone and sivelestat may be administered during the perioperative period (12-14). Anesthesiologists are advised to maintain low oxygen concentrations and airway pressures to minimize pulmonary stress during surgery. Postoperatively, we aim to discontinue oxygen therapy as early as clinically feasible. For thoracic drainage, we utilize the Topaz drainage system set at 5 cmH₂O and actively employ water-seal management. To reduce operative time and bleeding, we avoid robotic surgery. Additionally, postoperative pleurodesis is minimized whenever possible.

Diagnosis of IP and acute exacerbation of IP

Respirologists, radiologists, and pathologists discussed with all patients to diagnose and evaluate IP. IP diagnosis was based on the criteria listed in Table 1. All patients were classified into two groups: those with and without IP. Patients with IP were further classified into UIP and non-UIP-IP subgroups. Respirologists and radiologists discussed the patients who developed pneumonia between surgery and 10 weeks after the last administration of chemotherapy to diagnose acute exacerbation of IP. The pathologists participated in discussions with patients who underwent lung biopsies for pneumonia. We collected data on grade 3 or higher adverse events, including acute exacerbation of IP, from medical records. The severity of adverse events was evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) grade version 5.0. Acute exacerbation of IP was diagnosed based on a previous international working group report on idiopathic pulmonary fibrosis (IPF). Acute exacerbations of IP that were not IPF were diagnosed using the same criteria as those used for IPF. We defined the observation period as the duration from the date of surgery until 10 weeks after the final administration of postoperative chemotherapy (9,10).

Statistical analysis

The primary endpoint was the 3-year OS rate based on previous phase III trials of postoperative chemotherapy for resected SCLC (15). Secondary endpoints included the 3-year disease-free survival (DFS) rate, median OS and DFS, adverse events equal to or higher than grade 3, and frequency and severity of acute exacerbation of IP. Statistical analysis was performed using R. Survival analysis was performed using the Kaplan-Meier method and log-rank analysis. The survival period was defined as the number of days from the date of surgery. No patients had missing data.

Results

Baseline characteristics

Forty-one patients with SCLC underwent surgery between April 2011 and September 2021. We excluded four patients who received postoperative chemoradiotherapy, two patients who received postoperative chemotherapy with platinum and irinotecan, and one patient who did not receive postoperative chemotherapy because of IP.

A patient flowchart is shown in Figure 1. The pretreatment characteristics of the patients are shown in Table 2. Among the 34 patients, 10 were diagnosed with IP, including six with UIP and four with non-UIP-IP (Figure 2). A number of patients whose diagnosis of SCLC was confirmed preoperative tissue biopsy preoperative tissue was confirmed in 16 overall, including three patients with IP. Among these three patients with IP, one patient belonged to the UIP subgroup. The median age was 72.5 (range, 46–80) years, and the median preoperative lung capacity percentage to the predicted value was 92.4% (range, 59.9–115.9%). The median serum pro-gastrin-releasing peptide (proGRP) levels was 67.6 pg/mL in patients without IP and 74.0 pg/mL in patients with IP. Median serum Krebs von den Lungen-6 (KL-6) was 241 U/mL in patients without IP and 512 U/mL in patients with IP, and 874 U/mL in UIP subgroup. The most common comorbidities were chronic obstructive pulmonary disease (COPD), observed in 15 patients overall. Two patients in the UIP subgroup and one patient without IP had rheumatoid arthritis, and all three were receiving oral steroid, which were continued throughout the perioperative period. No patients had been receiving pirfenidone before diagnosis. Three patients in the UIP subgroup started on 600 mg of pirfenidone 1 month before surgery, with the dose increased to 1,200 mg. Pirfenidone treatment was continued postoperatively. The other three patients in the UIP subgroup received sivelestat for 7 days after surgery. There were no patients with a history of acute exacerbation of IP among those with IP. There were five patients in the UIP subgroup with pathological findings of IP with surgery specimen. Regarding clinical stage, 30 patients (88%) were at stage I, 3 (9%) at stage IIB, and 1 (3%) at stage IIIA. One patient with stage IIIA disease had enlarged mediastinal lymph nodes and lung nodules. Despite undergoing lung and lymph node biopsies via endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), a definitive diagnosis was not achieved. Surgery was performed for diagnostic and therapeutic purposes, revealing SCLC on postoperative pathological examination. Subsequently, the patient underwent postoperative chemotherapy. Regarding the pathological stage, 27 patients (79%) were at stage I, 5 (15%) at stage II, and 2 (6%) at stage IIIA. In the UIP subgroup, all 6 patients (100%) were diagnosed with clinical stage IA SCLC, but 4 of them (67%) had an upstaged pathological stage. Lymph node metastases were found in two of the four patients who had an upstaged pathological stage with UIP. Among the two patients with lymph node metastasis, one had mediastinal and hilar lymph nodes that were symmetrically enlarged on preoperative imaging. A biopsy with EBUS-TBNA was performed on the mediastinal lymph node before surgery, which showed no malignancy. A biopsy of the hilar lymph nodes was not performed. However, the pathological examination of the surgical specimen revealed metastasis to the hilar lymph nodes. In the other patient, preoperative imaging revealed no enlarged mediastinal or hilar lymph nodes. A biopsy with EBUS-TBNA was performed on both sides of the hilar and mediastinal lymph nodes, which showed no malignancy before surgery. However, the pathological findings from the surgical specimen showed metastasis to the mediastinal lymph nodes. In the surgical specimens of the other two patients with UIP who were pathologically upstaged, metastasis to the visceral pleura was observed. Preoperative computed tomography (CT) showed tumors adjacent to the pleura, but no obvious pleural metastasis was detected on imaging.

Figure 1 Patients flow. We included 34 of the 41 patients who underwent surgery at Chiba University Hospital between April 2011 and September 2021. Ten patients have IP, including six in the UIP subgroup and four in the non-UIP-IP subgroup. IP, interstitial pneumonia; SCLC, small cell lung cancer; UIP, usual IP.

Figure 2 CT images of patients of UIP and non-UIP-IP subgroups. Chest CT scans of two patients with IP (UIP and non-UIP-IP). (A-D) CT images of a patient in the non-UIP-IP subgroup. (E-H) CT images of a patient in the UIP subgroup. The arrows in (A,G) indicate lung cancer. CT, computed tomography; IP, interstitial pneumonia; UIP, usual IP.

Treatment details

Table 3 provides details of the treatments. All 10 patients with IP and 22 of the 24 patients without IP (92%) underwent lobectomy. There were no patients who underwent diagnostic surgery or incomplete resection. Seven of the 10 patients with IP (70%) and 21 of the 24 patients (88%) without IP received four courses of postoperative chemotherapy. Five patients with IP (50%) and 6 patients without IP (25%) were treated with carboplatin and etoposide.

OS

The median follow-up period for all patients was 35.3 (range, 7–143) months. Figure 3 shows OS. The 3-year OS rate of all patients was 67% [95% confidence interval (CI): 47–81%]. The 3-year OS rate was 68% (95% CI: 31–89%) in patients with IP and 69% (95% CI: 44–84%) in those without IP. The median OS was 85.5 months [95% CI: 35.5–not evaluated (NE)] for all patients. Median OS was not reached in patients without IP (95% CI: 35.4–NE), and was 85.4 months (95% CI: 7.0–NE) in patients with IP. The three-year OS rate was 50% (95% CI: 11–80%) in patients with UIP and 100% (95% CI: NE) in those with non-UIP-IP. Median OS was 50.2 months (95% CI: 7.0–NE) in patients of the UIP subgroup and not reached (95% CI: NE) in the non-UIP-IP subgroup. The causes of death are listed in Table 4. The deaths of 13 of the 34 patients (38%) were observed, including 4 patients with IP (40%) and nine patients without IP (38%). Three patients with IP (30%) and 5 patients without IP (21%) died because of disease progression of SCLC. None of the patients died of acute exacerbation or progression of IP.

Figure 3 OS curve. (A) The 3-year OS rate of all patients is 67%, with a median OS of 85.5 months. (B) The 3-year OS rate of patients without IP is 69%, and for patients with IP, it is 68%. The median OS is not reached in patients without IP, while it is 85.4 months in patients with IP. (C) The 3-year OS rate in the UIP subgroup is 50%, while it is 100% in the non-UIP-IP subgroup. The median OS is not reached for patients in the non-UIP-IP subgroup, while it is 50.2 months in the UIP subgroup. IP, interstitial pneumonia; OS, overall survival; UIP, usual IP.

DFS

Figure 4 shows DFS. The 3-year DFS rate for all patients was 54% (95% CI: 33–67%). The 3-year DFS rate was 36% (95% CI: 10–65%) in patients with IP and 57% (95% CI: 35–73%) in those without IP. The median DFS was 71.3 months (95% CI: 13.7–NE) for all patients. Median DFS was 71.3 months (95% CI: 16.1–NE) in patients without IP and 13.9 months (95% CI: 3.4–NE) in patients with IP. The 3-year DFS rate was 17% (95% CI: 1–52%) in patients in the UIP subgroup and 68% (95% CI: 5–95%) in patients in the non-UIP-IP subgroup. The median DFS was 7.13 months (95% CI: 3.4–NE) in patients in the UIP subgroup and 85.4 months (95% CI: 13.7–NE) in patients in the non-UIP-IP subgroup. The recurrence sites are shown in Table 5. Three of the four recurrences in patients with IP occurred in the lymph nodes.

Figure 4 DFS curve. (A) The 3-year DFS rate of all patients is 54%, with a median DFS of 71.2 months. (B) The 3-year DFS rate of patients without IP is 57%, and for patients with IP, it is 36%. The median DFS is 71.3 months for patients without IP, and 13.9 months for patients with IP. (C) The 3-year DFS rate of the UIP subgroup is 17%, while it is 68% for the non-UIP-IP subgroup. The median DFS is 7.1 months for patients in the UIP subgroup, while it is not reached for the non-UIP-IP subgroup. DFS, disease-free survival; IP, interstitial pneumonia; UIP, usual IP.

Adverse events

Table 6 shows adverse events. Adverse events of grade 3 or higher occurred in 22 of 34 patients (65%). The frequency was 60% with IP and 67% without IP. Grade 3 or higher hematologic toxicity was observed in 5 patients with IP (50%) and 11 patients without IP (46%). Non-hematological toxicity of grade 3 or higher occurred in 3 patients with IP (30%) and 9 patients (38%) without IP. One patient with UIP died during chemotherapy on day 17 of the third course from an unknown cause.

Acute exacerbation of IP was not observed in the patients with IP (95% CI: 0–30.8%). One patient without IP developed pneumonia 41 days after the last dose of chemotherapy. A multidisciplinary discussion with respirologists, radiologists, and pathologists concluded that the pneumonia was a drug-induced lung injury with an organizing pneumonia pattern. Among patients with IP, one developed pneumonia 57 days after the first administration of chemotherapy during the treatment of grade 4 febrile neutropenia and colon perforation. A multidisciplinary discussion with respirologists, radiologists, and pathologists concluded that the patient had developed aspiration pneumonia.

Discussion

To our knowledge, this is the first report of patients with IP treated with postoperative chemotherapy for early-stage SCLC. The 3-year survival rates were 67% overall, 68% in patients without IP, and 68% in those with IP. These 3-year survival rates are comparable with those of previous studies reporting the survival of patients with LD-SCLC who underwent surgery and postoperative chemotherapy (15-17). However, the OS of patients with UIP was poor. Acute exacerbations were not observed in 10 patients with IP. The frequency of adverse events of grade 3 or higher was 60% with IP and 67% without IP.

Trials of chemotherapy for patients with SCLC began in the 1960s, such as trials comparing cyclophosphamide and placebo (18). A meta-analysis showed the benefit of chemotherapy including platinum in 2000 (19), and platinum-based chemotherapy has been the standard treatment for patients with SCLC. In contrast, the benefits of surgery and postoperative chemotherapy for early-stage SCLC were first reported in the 1980s (20), and several retrospective observational and prospective studies exploring the efficacy of postoperative chemotherapy in patients with resected SCLC have been conducted over the past four decades (15-18). In a single-arm phase II trial of postoperative chemotherapy with cisplatin and etoposide in patients with completely resected SCLC, the 3-year OS rate was 61% and the 5-year OS rate was 57% (16). A population-based retrospective study showed that the prognosis of patients treated with postoperative chemotherapy or postoperative chemoradiotherapy was better than that of surgery alone, with a 5-year OS rate of 40.4% for surgery alone and 52.7% for postoperative chemotherapy or chemoradiotherapy (17). In addition, a trial comparing postoperative chemotherapy regimens of cisplatin and etoposide with cisplatin and irinotecan showed no superiority of cisplatin plus irinotecan over cisplatin and etoposide (15). Moreover, in an observational study conducted in Japan, the 1-year survival rate for patients with SCLC who underwent surgery was 81.7%, the 3-year survival rate was 55.7%, and the 5-year survival rate was 45.4% (21,22). Based on these data, postoperative chemotherapy with platinum and etoposide is recommended as the standard therapy for resected SCLC according to clinical guidelines (2,3). Although the evidence remains limited, a previous observational study mentioned above found no significant difference in prognosis between the chemoradiotherapy group (n=190) and the chemotherapy group (n=354) (17). Consequently, chemotherapy is recommended by both the American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) guidelines, while chemoradiotherapy is only recommended for patients with incomplete resection or lymph node metastasis in the NCCN guidelines (1,2).

In our study, the OS and DFS of patients with SCLC, with or without IP, were comparable to those reported in previous studies, suggesting the benefits of postoperative chemotherapy in patients with SCLC and IP and who were eligible for surgery. However, since our study was a single-center study with a limited number of patients, the benefits and tolerability of postoperative chemotherapy in patients with IP need to be further evaluated in a larger cohort.

The frequency of adverse events equal to or higher than grade 3 was 67% without IP and 60% with IP in our study. Minegishi et al. reported on 17 patients with SCLC and IP who were treated with chemotherapy containing platinum and etoposide. Among the 17 patients, one developed acute exacerbation of IP (grade 5) (9). Several observational studies have also reported the safety of chemotherapy in patients with ED-SCLC and IP, showing that the incidence of acute exacerbation of IP ranges from 1.9% to 16% (4,8). In our study, no acute exacerbation of IP was observed in 10 patients with IP, although one patient with IP died from an unknown cause 17 days after the third administration of chemotherapy. Our perioperative management strategies may contribute to fewer frequencies of acute exacerbation of IP. These results suggest that patients with SCLC and IP who are eligible for surgery can tolerate postoperative chemotherapy.

Several reports have suggested that IPF has a negative prognostic impact on patients with lung cancer undergoing surgery (23-25). In these reports, the poor prognosis is attributed to the poor prognosis of IPF. However, as shown in Table 4, the most frequent cause of death in patients with IP in our cohort was not the exacerbation or progression of IP, but the disease progression of SCLC. Several patients with IP experienced recurrence in the mediastinal lymph nodes (Table 5). Four of the six patients in the UIP subgroup (67%) experienced pathological upstaging, with two patients showing lymph node metastases in surgical specimens. A previous study showed that enlarged mediastinal lymph nodes are observed in 70% of patients with IPF (26), and the diagnostic accuracy of positron emission tomography (PET)/CT in patients with lung cancer and IP is lower than in those without IP (27). Although the mechanism of mediastinal lymph node enlargement in IPF is unknown, reports suggest that inflammation and immune reactions in IPF are related. Mediastinal lymph node enlargement has been reported to be associated with fibrosis progression (28). Secondly, the frequency of mediastinal lymph node enlargement was lower in patients recently treated with systemic corticosteroids (29). Lymph node biopsy with EBUS-TBNA is the gold standard for diagnosing lymph node metastases in patients with NSCLC without IP (30). However, no report has detailed the diagnostic accuracy of EBUS-TBNA in patients with IP. In our study, the prognosis of patients with UIP was poor, and there was a discrepancy in staging accuracy for patients with SCLC and UIP. These results suggest that close attention should be paid to the preoperative diagnosis of SCLC and UIP.

Limitation

This study had several limitations. First, it was conducted at a single institution, and only a few patients with IP underwent postoperative chemotherapy for SCLC. However, there are no other reports on perioperative chemotherapy for patients with SCLC and IP. Therefore, this report is important because it is the first to show the benefits of postoperative chemotherapy for patients with SCLC and IP, even in a small number of patients. Second, the diagnosis of IP was limited because lung specimens were not obtained specifically for the diagnosis of IP. However, we aimed to make the diagnosis as accurate as possible using a multidisciplinary approach.

Conclusions

In conclusion, the 3-year OS rates were 68% with IP and 69% without IP, suggesting benefits of postoperative chemotherapy following the resection of SCLC in patients with IP and who are eligible for surgery. The 3-year OS rates of patients with and without IP were comparable to those in a previous phase III trial of postoperative chemotherapy for resected SCLC (15). However, the prognosis of patients in the UIP subgroup was poor because of SCLC progression. Further studies with larger cohorts are necessary to clarify the efficacy and safety of postoperative chemotherapy in patients with IP.

Acknowledgments

We would like to thank Editage (http://www.editage.jp/) for the English language editing.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2056/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2056/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2056/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2056/coif). G.S. received honoraria from Ono Pharmaceutical, Chugai Pharmaceutical, Novartis, Pfizer, Taiho Pharmaceutical, AstraZeneca, Merck Sharp & Dohme, Daiichi Sankyo. M.A. received grants and honoraria for lectures from Boehringer Ingelheim. M.O. received honoraria from Novartis, AstraZeneca, Chugai pharmaceutical. I.Y. received Grants from Chugai Pharmaceutical, AstraZeneca and consulting fees from AstraZeneca, Medicaroid, Chugai Pharmaceutical, Coviden, and Johnson and Johnson. I.Y. received honoraria from Daiichi Sankyo, Shionogi, Chugai Pharmaceutical, Taiho Pharmaceutical, AstraZeneca, CSL Behring, Tsumura, Eli Lilly, Johnson and Johnson, Covidien, and Intuitive surgical. Y.T. received grants from Taiho Pharmaceutical, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Boehringer Ingelheim, Eisai and consulting fees from Ono Pharmaceutical, Bristol Myers Squibb, AstraZeneca, Takeda Pharmaceutical, Merck Sharp & Dohme, Oncolys BioPharma. Y.T. received honoraria from Ono Pharmaceutical, Bristol Myers Squibb, Taiho Pharmaceutical, Chugai Pharmaceutical, AstraZeneca, Pfizer, Merck Sharp & Dohme, Novartis, Daiichi Sankyo, Eli Lilly, Boehringer Ingelheim, Kyowa Kirin Pharmaceutical, and Takeda Pharmaceutical. T.S. received honoraria from AstraZeneca, Boehringer Ingelheim. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study received approval from the institutional ethics review board for Observational Studies of Chiba University Hospital (No. HK202303-14), and individual consent for this retrospective analysis was waived. Given the study’s retrospective nature and anonymized design, patients were given the option to opt out via Chiba University Hospital’s website rather than through written informed consent.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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