Phase 2 feasibility study of adjuvant chemotherapy with cisplatin (CDDP) and TS-1, followed by alternate-day TS-1 maintenance therapy, in patients with completely resected pathological stage II-IIIA non-small cell lung cancer

Introduction

Perioperative management for lung cancer has significantly improved in recent years (1). Lung cancer remains the leading cause of cancer-related mortality worldwide (1,2). For patients with completely resected stage II–IIIA non-small cell lung cancer (NSCLC), platinum-based doublet chemotherapy is recommended as the standard adjuvant treatment by several clinical trials (3-8). Among these, cisplatin plus vinorelbine (CDDP + VNR) demonstrated survival benefits in large randomized trials and was widely adopted, particularly in Japan (6,9,10). Overall, adjuvant chemotherapy improves 5-year survival by approximately 5% compared with surgery alone (3-7). However, the completion rate of four cycles of CDDP + VNR remains unsatisfactory at approximately 50%, mainly due to frequently observed treatment-related toxicities. Therefore, there is a continuing need for effective and sustainable adjuvant chemotherapy regimens with improved tolerability.

In recent years, molecular targeted therapies and immune checkpoint inhibitors (ICIs) have been incorporated into the standard of care in the adjuvant setting. Osimertinib for EGFR-mutated NSCLC, as demonstrated in the ADAURA trial, and atezolizumab for resected stage II–IIIA NSCLC, as shown in the IMpower010 trial, have significantly improved disease-free survival and have changed the current therapeutic landscape (11-13). These advances underscore the importance of re-evaluating the role of conventional platinum-based chemotherapy.

TS-1 is an oral fluoropyrimidine consisting of tegafur, gimeracil, and oteracil potassium, designed to enhance the antitumor activity of 5-fluorouracil while reducing gastrointestinal toxicity (14,15). TS-1 has been established as a standard postoperative adjuvant therapy for gastric cancer, and is also recommended in the Japanese clinical practice guidelines for pancreatic and breast cancers based on the results of randomized clinical trials (16-21). In advanced NSCLC, TS-1 in combination with platinum agents has shown activity and acceptable safety (22,23). Moreover, several Japanese trials have evaluated TS-1 as postoperative adjuvant chemotherapy, either as monotherapy or in combination regimens (24-29). Although TS-1 is available in other Asian countries, postoperative adjuvant chemotherapy studies have been conducted exclusively in Japan.

Historically, TS-1 has been administered using a 4-week on/2-week off or 2-week on/1-week off schedule. However, prolonged administration was often hindered by gastrointestinal and hematologic toxicities. Recent studies have suggested that alternate-day or modified intermittent dosing schedules may reduce toxicity while maintaining efficacy, thereby improving treatment compliance (25,29).

To further improve tolerability, we designed a regimen in which the CDDP dose and number of cycles were reduced, followed by alternate-day TS-1 maintenance to maximize treatment continuity. This strategy was expected to enhance the overall completion of adjuvant therapy and ultimately improve survival outcomes in patients with resected NSCLC.

Based on these considerations, we conducted a phase II feasibility study of three cycles of CDDP plus TS-1 (CDDP + TS-1) (2 weeks on, 1 week off) followed by one year of alternate-day TS-1 monotherapy as adjuvant chemotherapy in patients with completely resected pathological stage II–IIIA NSCLC [tumor-node-metastasis (TNM) 7th edition]. The primary endpoint was the completion rate of the entire protocol, while secondary endpoints included 3-year relapse-free survival (RFS), 3-year overall survival (OS), completion rates of each treatment component, and adverse events (AEs). We present this article in accordance with the TREND reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1518/rc).

Methods

Patients

This study included patients with NSCLC who were diagnosed with pathologic stage II–IIIA according to the TNM 7th edition classification and underwent curative (R0) resection. Patients were enrolled according to the inclusion and exclusion criteria (Table S1). Patients were enrolled from August 1, 2013, to October 31, 2018, across eight institutions (Department of Thoracic Surgery, Kumamoto University Hospital, Kumamoto, Japan; Department of Thoracic Surgery, Omuta Tenryo Hospital, Fukuoka, Japan; Department of Thoracic Surgery, Kumamoto Chuo Hospital, Kumamoto, Japan; Division of Respiratory Surgery, Saiseikai Kumamoto Hospital, Kumamoto, Japan; Department of General Thoracic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan; Department of Pulmonary Medicine, Sendai Medical Association Hospital, Kagoshima, Japan; Second Department of Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan; and Department of Thoracic Surgery, National Hospital Organization Minamikyushu Hospital, Kagoshima, Japan). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This clinical study was approved by the Institutional Review Board of Kumamoto University Hospital under the Japanese Clinical Trials Act (approval No. 6). Written informed consent was obtained from all patients prior to their participation in the study. Patient confidentiality was maintained throughout the study. The other institutions were informed of and agreed to participate in this study. This study was registered with the Japan Registry of Clinical Trials (jRCT) under the registration number jRCTs071180083.

Study design and treatment

The adjuvant chemotherapy regimen was initiated within 8 weeks of surgery using a combination of CDDP and TS-1. The CDDP + TS-1 combination therapy was administered in three cycles, each lasting either 3 or 4 weeks (Figure 1).

Figure 1 Treatment protocol flowchart. This figure depicts the treatment protocol for patients with completely resected stage II–IIIA NSCLC, staged according to TNM version 7. The patients were 20–74 years of age with an ECOG PS 0 or 1. The treatment regimen involved an induction phase consisting of three cycles of CDDP and TS-1 combination therapy, with TS-1 administered orally from days 1 to 14 of each cycle. This was followed by TS-1 monotherapy as maintenance therapy, administered every other day for a duration of one year post-surgery. The flowchart outlines the sequence and timing of the treatment phases. CDDP, cisplatin; ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small cell lung cancer; PS, performance status; TNM, tumor-node-metastasis.

CDDP was administered at a dose of 60 mg/m² via intravenous infusion on day one of each cycle. TS-1 was administered according to body surface area (BSA): for patients with a BSA of <1.25 m², 40 mg per dose (80 mg/day); for those with a BSA of 1.25–1.5 m², 50 mg per dose (100 mg/day); and for those with a BSA of ≥1.5 m², 60 mg per dose (120 mg/day). TS-1 was administered orally twice daily for 14 consecutive days (from days 1 to 14) in each cycle.

Following the completion of CDDP + TS-1 combination therapy, TS-1 monotherapy was initiated within 3 weeks and continued for one year as maintenance therapy. TS-1 monotherapy was administered orally every other day. The criteria for dose reduction and treatment discontinuation are outlined in Tables S1-S3.

The primary endpoint of the study was the completion rate of the treatment protocol, defined as the completion of TS-1 monotherapy administered every other day. The secondary endpoints included the completion rates for three courses of CDDP + TS-1 combination therapy, completion rate of TS-1 monotherapy, 3-year RFS, 3-year OS, and incidence of AEs. OS was defined as the interval from surgery to death from any cause, and RFS as the interval from surgery to recurrence or death. Patients without an event were censored at the date of last follow-up.

Survival analysis was performed using Kaplan-Meier curves created with IBM SPSS Statistics (ver. 29.0.1, IBM Corp., Armonk, NY, USA). AEs were evaluated according to the Common Terminology Criteria for AEs (CTCAE) version 5.0, and the severity of each event was graded accordingly.

Statistical analysis and sample size calculation

In the ANITA trial, which established CDDP + VNR as one of the standard adjuvant chemotherapy regimens, the completion rate for four courses was reported to be 50%. In contrast, the feasibility of postoperative adjuvant chemotherapy incorporating TS-1 was reported in the TORG0809 trial presented at American Society of Clinical Oncology (ASCO) 2012. This trial involved the combination of docetaxel and CDDP (DTX + CDDP) for 3–4 weeks cycles followed by TS-1 (2 weeks on and 1 week off for 8 cycles). While the completion rate for the three courses of DTX + CDDP was 84.5%, the completion rate for TS-1 monotherapy after eight cycles was 51.2% [95% confidence interval (CI): 42.54–57.79%]. In the WJOG4107 trial, which compared CDDP + TS-1 combination therapy with TS-1 monotherapy for adjuvant chemotherapy in lung cancer, the completion rate for 4 courses of CDDP + TS-1 was 74.7%, while the 1-year completion rate for TS-1 monotherapy was 52.6% (24). The relatively poor compliance with TS-1 was attributed to a high incidence of patient refusal owing to toxicities that did not meet the discontinuation criteria (grade ≤3 or grade ≤2 or lower non-hematologic toxicities), which accounted for 50% of TS-1 discontinuations in the TORG0809 trial (30). Gastrointestinal toxicities and oral mucositis, which are typical side effects of TS-1, have been suggested to significantly reduce long-term patient compliance. Considering these findings, the expected completion rate for TS-1 monotherapy administered every other day was set at 60%, with a minimum acceptable completion rate of 40% based on the results of the TORG0809 trial. Under these conditions, a sample size of 53 patients was required to achieve 90% power, at a one-sided significance level of 0.05. Considering the estimated 10% ineligibility rate, the target sample size was set to 58 patients. OS and RFS were estimated using the Kaplan-Meier method. Median follow-up time was estimated using the reverse Kaplan-Meier method. Ninety-five percent CIs were determined for survival rates and completion rates. Analyses were performed using IBM SPSS Statistics (ver. 29.0.1, IBM Corp., Armonk, NY, USA).

Results

Patient characteristics

A total of 59 patients were enrolled in this study across eight institutions. The median follow-up was 58.0 months (95% CI: 52.4–63.6; cutoff date: October 31, 2021). The median age was 64.9 (range, 42–74) years. Of the 59 patients, 42 were male (71.2%) and 17 were female (28.8%). The majority of patients had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 (91.5%), while 8.5% of patients had an ECOG PS of 1. Regarding pathological staging, the patients were initially staged according to the 7th edition of the TNM classification at the start of the study. However, during the clinical trial period, the TNM 8th edition was adopted and both staging systems were presented. According to the 7th edition, the distribution of stages was as follows: stage IIA, 17 patients (28.8%); stage IIB, 21 patients (35.6%); and stage IIIA, 21 patients (35.6%). In the 8th edition, the distribution was stage IIA in 5 patients (8.5%), stage IIB in 33 patients (55.9%), stage IIIA in 19 patients (32.2%), and stage IIIB in 2 patients (3.4%), indicating that 54 out of 59 patients had lymph node metastases. Histologically, adenocarcinoma was the most common subtype, occurring in 46 patients (78.0%). The other subtypes included squamous cell carcinoma (10 patients, 16.9%), adenosquamous carcinoma (two patients, 3.4%), and pleomorphic carcinoma (one patient, 1.7%). EGFR mutation testing was not mandatory for this study; however, it was performed in 50 patients. Among those tested, 35 patients (59.3%) had wild-type EGFR and 15 patients (25.4%) had EGFR mutations. Nine patients (15.3%) had an unknown EGFR mutation status. The patient characteristics are summarized in Table 1.

Completion rate of protocol treatment

The primary endpoint of this study was the completion rate of the entire treatment protocol, defined as the completion of three cycles of CDDP + TS-1 combination therapy followed by one year of alternate-day TS-1 monotherapy. Based on this definition, the overall protocol completion rate was 57.6% (34 of 59 patients; 95% CI: 44.9–69.4%) (Figure 2). As secondary endpoints, the completion rates of each treatment component were also assessed. The completion rate for the three cycles of CDDP + TS-1 combination therapy was 72.8% (43 of 59 patients; 95% CI: 60.4–82.6%). Among the 43 patients who proceeded to TS-1 monotherapy, 79.1% (34 of 43 patients; 95% CI: 64.8–82.6%) successfully completed the 1-year regimen. Reasons for treatment discontinuation included AEs in five patients during CDDP + TS-1 therapy, disease recurrence in three patients, and other factors such as patient refusal or complications. The details of treatment discontinuation are shown in Figure 2, and the associated AEs with their severity grades are summarized in Tables 2,3.

Figure 2 Treatment completion rates. The treatment progression in the 59 patients enrolled in this study is shown. The completion rate for the induction phase, consisting of three cycles of CDDP + TS-1 combination therapy, was 72.9%, with discontinuations occurring due to AEs, disease recurrence, or other factors. Following the induction phase, 41 patients proceeded to the maintenance phase, with TS-1 monotherapy administered every other day. Ultimately, 34 patients successfully completed the protocol, resulting in an overall completion rate of 57.6%. AE, adverse event; CDDP, cisplatin.

OS and RFS

As secondary endpoints, 3-year overall survival (OS) and 3-year RFS were evaluated. Kaplan-Meier survival curves for OS and RFS were generated for all 59 patients enrolled in this study (Figure 3). The 2-year OS rate was 88.1%, and the 3-year OS rate was 82.9%. The 2-year RFS rate was 67.8%, and the 3-year RFS rate was 62.5%.

Figure 3 Kaplan-Meier curves for OS and RFS. (A) OS. The 2- and 3-year OS rates were 88.1% and 82.9%, respectively. (B) RFS. The 2- and 3-year RFS rates were 67.8% and 62.5%, respectively. The median follow-up was 58.0 months (95% CI: 52.4–63.6; cutoff date: October 31, 2021). CI, confidence interval; OS, overall survival; RFS, relapse-free survival.

AEs

AEs were evaluated in accordance with the CTCAE version 5.0, and the severity of each event was graded accordingly. The AEs observed during the CDDP + TS-1 induction phase are summarized in Table 2. No Grade 5 events were reported. The most frequent grade 3 or 4 AEs were neutropenia (8.5%), leukopenia (6.8%), and oral mucositis (3.4%). These AEs contributed to treatment discontinuation in 5 patients, with neutropenia being the primary cause. All these events were managed with G-CSF and resolved; however, they still resulted in protocol deviation. In the grade 1 or 2 category, the most common AEs were anorexia (45.8%), fatigue (25.4%), and nausea (13.6%). However, these events did not meet the treatment discontinuation criteria. During the TS-1 monotherapy maintenance phase, only one patient experienced grade 3 neutropenia (2.3%), with no grade 4 or 5 AEs reported. The most common grade 1 or 2 AEs during the maintenance phase were anorexia (7%) and fatigue (7%), shown in Table 3, both of which occurred at relatively low frequencies.

Discussion

In the present study, we conducted a multicenter, phase II, prospective single-arm trial to evaluate the feasibility, safety, and efficacy of a postoperative adjuvant chemotherapy regimen for completely resected stage II–III NSCLC. The protocol consisted of three courses of CDDP + TS-1, followed by one year of TS-1 maintenance therapy administered orally on alternate days. The primary endpoint was the overall treatment completion rate, including both the CDDP + TS-1 induction phase and the TS-1 monotherapy maintenance phase. Secondary endpoints included the completion rates of the CDDP + TS-1 and TS-1 monotherapy phases, AEs, 3-year OS, and 3-year RFS. The choice of overall treatment completion rate as the primary endpoint was based on the known challenges of treatment discontinuation with platinum-based regimens and TS-1, and was considered the most appropriate measure of feasibility.

Currently, the most widely used standard treatment is CDDP + VNR, as demonstrated in a meta-analysis of the LACE trial, which has been shown to improve survival outcomes (6). Furthermore, osimertinib is now used for EGFR mutation-positive cases and ICIs are widely administered to programmed death ligand-1 (PD-L1)-positive cases (12,31,32). However, nearly half of the patients undergoing these treatments are unable to complete postoperative adjuvant therapy owing to AEs (4,6,7). This underscores the importance of developing postoperative adjuvant therapies that reduce side effects and minimize patient burden, while maintaining efficacy.

In Japan, several clinical trials have been conducted since the 2010s using TS-1 for the treatment of NSCLC, both for advanced cancer and postoperative adjuvant therapy (22-29,33). These results demonstrate that the combination of TS-1 and platinum-based agents is comparable to or superior to traditional platinum-based regimens, and that TS-1 monotherapy results in fewer AEs while maintaining relatively good efficacy. Notably, TS-1 is associated with a low incidence of treatment-related interstitial lung disease, is considered cost-effective from a healthcare resource perspective, and has been suggested to be a feasible option even in elderly patients. Our study investigated a protocol involving three courses of CDDP + TS-1, followed by a maintenance regimen with TS-1 monotherapy administered on alternate days, which differs from the conventional 2-weeks-on-1-week-off or 4-weeks-on-2-weeks-off dosing schedules. The objective of this study was to maintain treatment efficacy while reducing side effects, as indicated in previous trials.

In our study, we initially administered three courses of CDDP + TS-1 as the induction phase. The treatment completion rate was 72.8%, which is consistent with the WJOG4107 study, where a 74.7% completion rate was reported for four courses of CDDP + TS-1 and TS-1 (15). As shown in Figure 2, 16 patients discontinued the study protocol. The most common reasons for discontinuation were grade ≥3 neutropenia in four patients, patient refusal in four patients, and other medical conditions in four patients. Five patients (8.5%) were unable to transition to TS1 monotherapy due to grade ≥3 hematological toxicity, which prevented them from continuing treatment. These results are significantly lower than those observed in the JIPANG trial, which reported grade ≥3 neutropenia in 81.1% of patients receiving CDDP + VNR and 22.8% of those receiving CDDP + pemetrexed (PEM), suggesting that CDDP + TS-1 therapy remains a safe and well-tolerated treatment option (10). Of the 41 patients who transitioned to the TS1 monotherapy maintenance phase, 79.1% successfully completed the treatment, which was notably higher than the completion rates observed in the TORG0809 study (51.2% with TS1 monotherapy) and the WJOG4107 study (52.6%) (24,30). Only one patient experienced grade 3 neutropenia as an AE, and there were no cases of protocol discontinuation due to AEs. Although the completion rate in our study was slightly lower than the expected rate of 60% (57.6%), it remained relatively good and within the acceptable range.

In secondary efficacy analyses, the 2- and 3-year survival rates were 88.1% and 82.9%, respectively, while the 2- and 3-year RFS rates were 67.8% and 62.5%, respectively. The 59 patients enrolled in this study were classified according to TNM version 8, with 54 cases presenting with lymph node metastasis. When comparing the results of this study with those of the ADAURA trial (pStage II–III; osimertinib group: 3-year RFS 78.3%, 3-year OS 94%; placebo group: 3-year RFS 34%, 3-year OS 86%) and the Impower010 trial (all randomized population, pStage II–IIIA; atezolizumab group: 3-year RFS 59.3%, 3-year OS 78.7%; placebo group: 3-year RFS 49.4%, 3-year OS 79.7%), our findings demonstrated comparable efficacy (12,13,31). Furthermore, TS-1 is used as a standard treatment for postoperative adjuvant therapy in various cancers, including gastric, pancreatic, and breast cancers, in Japan, indicating that its effectiveness may not be limited to specific tissue types (16-18,34).

An exploratory subgroup analysis according to EGFR mutation status did not demonstrate statistically significant differences in OS or RFS, likely due to the limited number of patients tested (n=50) and the small number of mutation-positive cases (n=15) (Figure S1). While these results should be interpreted with caution, they suggest that the feasibility of this regimen may not be strongly influenced by EGFR mutation status. In addition, although adenocarcinoma was the predominant histological subtype in this study, with smaller proportions of squamous cell carcinoma and other types, no obvious differences in RFS were observed across histological subtypes. However, the sma295-ll sample size of non-adenocarcinoma cases limited the statistical power to detect differences. Larger studies are needed to clarify the impact of molecular profiles on treatment outcomes.

Limitations

The treatment completion rate in this study was 57.6%, which is slightly below the expected value of 60%. Therefore, patient selection and treatment scheduling require further refinement in future studies. In addition, the small sample size of 59 patients limited the statistical reliability of our findings. Larger studies with larger numbers of patients are needed to increase the generalizability of the results. Furthermore, while the completion rate for TS-1 monotherapy is relatively high, the role of alternate-day dosing in reducing side effects and its potential impact on treatment efficacy has not been fully analyzed. This warrants further investigation through comparative studies.

Another limitation is that publication of the study results was delayed. The trial period coincided with a time when multiple postoperative adjuvant clinical trials were actively being conducted, which made patient enrollment slower than expected. In addition, event rates were lower than anticipated, necessitating an extended follow-up period. The coronavirus disease 2019 (COVID-19) pandemic also disrupted routine clinical practice and delayed data collection and verification. These factors contributed to the prolonged time before final analysis and reporting.

Strengths

A key strength of this study is the favorable RFS and OS outcomes, despite the inclusion of a substantial proportion of patients with higher pathological stages: stage IIB in 33 patients (55.9%), stage IIIA in 19 (32.2%), and stage IIIB in 2 (3.4%) according to the TNM 8th edition. These results suggest that CDDP + TS-1 followed by TS-1 maintenance may be a promising postoperative adjuvant treatment option, even in populations not typically expected to have a favorable prognosis. Additionally, this regimen offers a significant reduction in side effects compared to the traditional CDDP + VNR regimen, making it a safer and more tolerable choice, particularly for elderly patients or those with comorbidities. The ability to minimize toxicity while maintaining treatment adherence provides valuable insight into future treatment strategies.

Conclusions

This study confirmed that CDDP + TS1 followed by TS1 is a promising postoperative adjuvant therapy. It effectively reduced side effects while maintaining favorable OS and RFS outcomes. Despite the challenges with treatment completion rates and patient selection, this treatment regimen demonstrates potential as a viable option for postoperative adjuvant therapy, with promising results that should be further explored in larger trials. Additionally, evaluation of PD-L1 and osimertinib in future studies will be essential for understanding their role in the context of postoperative adjuvant therapy.

Acknowledgments

The findings of this study were presented as a poster session at the 2023 World Conference on Lung Cancer (WCLC) in Singapore. We express our sincere gratitude to the patients who participated in this study and their families for their cooperation. This study was conducted with the support of the following eight institutions: Kumamoto University Hospital, Omuta Tenryo Hospital, Kumamoto Chuo Hospital, Saiseikai Kumamoto Hospital, Kagoshima University, Sendai Medical Association Hospital, University of Occupational and Environmental Health, and the National Hospital Organization Minamikyushu Hospital. Patient enrollment occurred from 2013 to 2018, and the final data were locked in 2022. This study was a prospective phase 2 trial, and we are deeply appreciative of the clinical staff at each institution for their contribution to patient recruitment and data collection. We also extend our gratitude to the research teams at all participating hospitals for their efforts in ensuring the success of this study.

Footnote

Reporting Checklist: The authors have completed the TREND reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1518/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1518/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1518/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-2025-1518/coif). The 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. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Ethical approval was obtained from the Institutional Review Board of Kumamoto University Hospital under the Japanese Clinical Trials Act (approval No. 6). Written informed consent was obtained from all patients prior to their participation in the study. Patient confidentiality was maintained throughout the study. The other institutions were informed of and agreed to participate in this study.

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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