Abstract
Background/Aim: This phase 1 study aimed to evaluate the safety and tolerability of S-1 plus oxaliplatin (SOX) as consolidation chemotherapy following chemoradiotherapy (CRT) in total neoadjuvant therapy (TNT) for locally advanced lower rectal cancer.
Patients and Methods: Patients with stage II/III lower rectal adenocarcinoma received long-course CRT followed by two cycles of SOX therapy. A standard 3+3 dose-escalation design was used to determine the recommended dose. The primary endpoint was the incidence of dose-limiting toxicity (DLT) during the first chemotherapy cycle. Secondary endpoints comprised pathological complete response, adverse events, treatment completion, and surgical outcomes.
Results: The DLT was evaluated in 12 patients. One DLT was observed at dose level 1, while no DLTs were observed at dose level 2. This established the recommended dose as 130 mg/m2 of oxaliplatin and 40-60 mg/time of S-1 (based on body surface area). Grade 3 hematologic toxicities (leukopenia, neutropenia) occurred in three patients at dose level 2; there were no non-hematologic adverse events with a grade ≥3. Twelve patients underwent surgery within the planned timeframe. Among these 12 patients, one achieved a pathological complete response (8.3%) and one experienced a postoperative complication of Clavien-Dindo grade ≥2.
Conclusion: SOX therapy as consolidation chemotherapy after CRT was safe and well tolerated as part of the TNT for lower rectal cancer. To our knowledge, this is the first study to report the use of SOX in TNT. Further trials are warranted to evaluate the efficacy of SOX as consolidation therapy after CRT in larger populations.
Introduction
Colorectal cancer (CRC) remains one of the most common cancers worldwide. Despite advances in surgical techniques and the development of molecularly targeted therapies and immune checkpoint inhibitors, CRC continues to be the second leading cause of cancer-related death globally (1).
Due to its anatomical location within the narrow pelvis, rectal cancer presents unique surgical challenges and has a significantly higher rate of local recurrence compared with colon cancer (2, 3). In particular, lower rectal cancer is associated with a greater incidence of distant metastases and poorer overall survival (OS) and disease-free survival (DFS) compared with tumors located in the upper or middle rectum (4, 5). Therefore, it is critical to control both local recurrence and distant metastases in the management of advanced lower rectal cancer.
In Western countries, preoperative chemoradiotherapy (CRT) followed by total mesorectal excision has been established as the standard treatment for locally advanced rectal cancer, primarily owing to its efficacy in reducing local recurrence. However, CRT alone has limited effectiveness in controlling distant metastases, and its impact on long-term outcomes such as OS and DFS remains uncertain (6, 7). To address these limitations of CRT, total neoadjuvant therapy (TNT), which integrates both CRT and systemic chemotherapy prior to surgery, has been introduced. Several trials have demonstrated that TNT significantly improves pathological complete response (pCR) rates compared with CRT alone (8-10) and increases organ preservation rates (11). Furthermore, the PRODIGE-23 trial revealed that TNT significantly improves both OS and DFS during long-term follow-up (12). Based on these findings, TNT has rapidly become a standard treatment option for locally advanced rectal cancer in recent years.
Previous TNT trials have commonly used systemic chemotherapy regimens such as FOLFOX, CAPOX, and FOLFIRINOX. In Japan, a combination of S-1 and oxaliplatin (SOX therapy) is widely used as a standard regimen for unresectable advanced colorectal cancer. However, no studies have evaluated the feasibility of incorporating SOX into a TNT strategy, and its safety and efficacy in this context remain unclear.
In this phase 1 study, we aimed to evaluate the safety and preliminary efficacy of SOX chemotherapy following CRT as part of TNT for locally advanced lower rectal cancer.
Patients and Methods
Patient selection. Participants were eligible for inclusion if they met all of the following criteria: 1) age 20 to 80 years, 2) histologically confirmed stage II or III lower rectal adenocarcinoma, 3) Eastern Cooperative Oncology Group performance status of 0 or 1, 4) completion of preoperative CRT for stage II or III locally advanced lower rectal cancer, 5) received S-1 with a dose intensity of ≥70% during CRT, 6) white blood cell count ≥3,000/μl, absolute neutrophil count ≥1,500/μl, hemoglobin ≥9.0 g/dl, platelet count ≥100,000/μl, aspartate aminotransferase and alanine aminotransferase <2× the upper limit of normal, total bilirubin ≤1.5 mg/dl, and estimated glomerular filtration rate ≥60 ml/min/1.73 m2, and 7) provision of informed consent.
Patients were excluded if they met any of the following criteria: 1) prior pelvic radiotherapy, 2) tumor invasion into adjacent organs, 3) receipt of chemotherapy for any malignancy within the past six months, 4) known hypersensitivity or contraindications to S-1 or oxaliplatin, 5) presence of serious comorbidities, including but not limited to interstitial pneumonia, pulmonary fibrosis, uncontrolled diabetes, poorly controlled hypertension, heart failure, renal failure, liver cirrhosis, or hepatic failure, 6) pregnant or lactating women, or those with the potential or intent to become pregnant, 7) participation in another clinical trial or use of unapproved/uninsured investigational drugs within three months prior to enrollment, 8) deemed unsuitable for participation by the investigator.
Study design and endpoints. This single-center, non-randomized, prospective phase 1 trial was conducted at Tottori University Hospital, Japan, to evaluate the safety and tolerability of SOX therapy following long-course CRT for stage II or III lower rectal cancer. All patients initially received CRT consisting of 45 Gy in 25 fractions and two cycles of oral S-1 (administered twice daily for 14 days followed by a 7-day rest). Approximately two weeks after CRT completion, SOX therapy was initiated. Two cycles of SOX therapy (each lasting 21 days) were planned. The second cycle was administered only if the first cycle was tolerated and laboratory criteria were met at the scheduled time. If treatment could not be initiated due to adverse events or laboratory abnormalities, it was postponed for one week; if delays persisted, the case was considered to meet the definition of dose-limiting toxicity (DLT).
Dose escalation followed a standard 3+3 design to determine the recommended dose of SOX therapy. Patients were enrolled in three cohorts with predefined dose levels. If no DLTs occurred, escalation to the next dose level proceeded; if one DLT occurred, three additional patients were enrolled at the same dose level. If two or more DLTs occurred in six or more patients, dose escalation was halted and de-escalation was considered. The recommended dose was determined based on the incidence of DLTs across dose levels. Dose levels and doses of SOX are shown in Table I. All adverse events were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Dose levels of S-1 and oxaliplatin.
The primary endpoint was the incidence of DLT during the first course of SOX therapy. Secondary endpoints comprised the pCR rate, treatment completion rate, time from initiation of SOX therapy to surgery, postoperative complications, and adverse events. Surgery was scheduled for 8-10 weeks after the initiation of SOX therapy. The interval from the end of SOX therapy to surgery was defined as the waiting period, and the observation period continued for four weeks postoperatively.
Ethics approval. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the ethics committee of Tottori University Hospital (21C001). Informed consent was obtained from all patients prior to enrollment. This study was registered in the Japan Registry of Clinical Trials (jRCT) under the identifier jRCTs061210016.
Results
Patient characteristics. Table II summarizes the baseline characteristics of the 13 patients enrolled in this study. The median age was 61 years (range=44-73 years), and the cohort comprised 10 men and three women. All patients had an Eastern Cooperative Oncology Group performance status of 0. One patient was diagnosed with cT4 disease, while the remaining 12 had cT3 tumors. Clinically positive lymph node metastasis was observed in 12 patients, and seven of these 12 patients were also diagnosed with suspected lateral lymph node metastasis. One patient received an excessive dose of S-1 after completing the first course of SOX therapy and was excluded from the DLT evaluation and efficacy analysis.
Patient characteristics (n=13).
Study treatment. Three patients were incorporated into the dose level 1 group. One patient had an elevated hepatitis B virus DNA and was considered to have reached DLT because of the time required for management, including the induction of antivirals; therefore, treatment was postponed for more than one week from the scheduled start date of the second course. The patient did not receive the second course and refused surgery, which was not performed. The remaining two patients had no DLT expression, so three more patients were enrolled in the dose level 1 group. These three patients did not develop DLT, but the third patient was found to have an excessive dose of S-1 after the completion of SOX therapy. The Effectiveness and Safety Committee of our institution reviewed the case and decided to exclude this patient from the DLT evaluation and efficacy evaluation; however, safety was to be evaluated in the same way as for other included patients. One additional patient was enrolled and treated with SOX therapy but did not develop DLT. Therefore, DLT occurred in one of six patients, and the dose was increased to level 2 and the study continued.
Three patients were enrolled in the dose level 2 group. None of these three patients showed DLT. Thus, three additional patients were enrolled in the dose level 2 group. These three additional patients also did not show DLT. Based on these findings, dose level 2 was determined to be the optimal dose.
Surgical and postoperative findings. The surgical and postoperative outcomes of the 12 patients who underwent surgery (excluding one patient who refused surgery) are summarized in Table III. All patients underwent robot-assisted surgery using five or six ports, depending on the case. Low anterior resection or abdominoperineal resection was performed based on tumor location. In cases where lateral lymph node metastasis was suspected on pre-treatment computed tomography (CT) or magnetic resonance imaging (MRI), lateral lymph node dissection was performed using the robotic approach (excluding the patient who refused surgery). In one patient, a large uterine fibroid was simultaneously resected robotically. There were no conversions to open surgery. Postoperative complications with a Clavien-Dindo grade of ≥2 occurred in only one patient. Tumor exposure was noted at the dissection plane in one case. The median postoperative hospital stay was 13 days (range=7-19 days). A pCR was observed in one of 12 patients (8.3%).
Surgical and postoperative outcomes (n=12).
Safety. Safety was evaluated in 12 patients, excluding one who received an excessive dose of S-1. Treatment was completed in 11 patients (91.7%), as one patient did not receive the second course of chemotherapy due to the occurrence of DLT. The median interval from the start of SOX therapy to surgery was 64 days (range=57-185 days). The prolonged interval in the case requiring 185 days was due to the patient initially refusing surgery after completing SOX therapy, although the surgical procedure was eventually performed at the patient’s request.
Adverse events by dose level are presented in Table IV. At dose level 1, there were no adverse events with a CTCAE grade of ≥3. At dose level 2, CTCAE grade 3 leukopenia and neutropenia were observed in two and one patients, respectively. All affected patients recovered, and the second course of chemotherapy was administered without issue. There were no non-hematologic toxicities with a CTCAE grade of ≥3 and no adverse events with a CTCAE grade of 4.
Adverse events.
Discussion
This phase 1 study demonstrated that the appropriate dose of SOX following CRT is 130 mg/m2 of oxaliplatin combined with 40-60 mg/m2 of S-1, adjusted for body surface area. These doses are consistent with standard clinical practice. Although SOX has been established as an effective first-line therapy for unresectable or recurrent colorectal cancer with demonstrated non-inferiority to CAPOX and a higher objective response rate (13), its role in the TNT setting has not previously been investigated. We therefore conducted this trial to evaluate the safety and feasibility of SOX as consolidation chemotherapy.
S-1 is an oral fluoropyrimidine composed of tegafur (a 5-FU prodrug), gimeracil (a dihydropyrimidine dehydrogenase inhibitor), and oteracil potassium (which reduces gastrointestinal toxicity). S-1 has demonstrated efficacy both as monotherapy and in combination with oxaliplatin or irinotecan and has shown non-inferiority to capecitabine in CRT with a favorable toxicity profile (14). To further enhance therapeutic efficacy, chemoradiotherapy regimens combining S-1 with additional agents such as oxaliplatin or irinotecan have also been investigated. In particular, preoperative CRT with S-1 plus irinotecan has demonstrated clinical feasibility and favorable response rates in patients with locally advanced rectal cancer (15). Moreover, CRT using S-1 in combination with oxaliplatin has also been reported and may contribute to improved local control in anorectal cancer (16). Given its widespread use in Asia and our prior institutional experience, SOX was considered a reasonable consolidation regimen. Compared with intravenous fluoropyrimidine-based regimens, SOX provides greater convenience and may improve treatment adherence, which could be particularly advantageous in the TNT setting where treatment duration is prolonged.
The primary endpoint in the present study was DLT during the first SOX cycle. Only one DLT was observed in a patient with chronic hepatitis B who required antiviral therapy, thereby precluding administration of the second SOX cycle. No further DLTs occurred at dose level 1 or after escalation to dose level 2, establishing level 2 as the recommended dose. Hematologic toxicities were limited to CTCAE grade 3 leukopenia and neutropenia in a few patients at dose level 2, while no CTCAE grade ≥3 non-hematologic events were recorded. Peripheral neuropathy was confined to CTCAE grade 2 events, which contrasts with the higher incidence of severe neuropathy reported in other studies (8, 9), likely reflecting the limited oxaliplatin exposure (two cycles only). These findings indicate that SOX can be delivered at full dose in the consolidation setting without unexpected safety concerns.
Except for one patient with DLT and one who declined surgery, all patients completed treatment and underwent resection. The postoperative outcomes were favorable, with only one case (8.3%) of CTCAE grade 2 complications and no CTCAE grade ≥3 events, supporting the tolerability of SOX in the TNT setting. This contrasts with meta-analytic data suggesting a higher incidence of postoperative morbidity following TNT compared with CRT alone (17), reinforcing the acceptable safety profile of SOX observed in the present study. However, only one patient (8.3%) achieved a pCR, which is a lower incidence than in previous TNT trials (8, 9). This may reflect both the small number of SOX cycles administered (two cycles versus four to six cycles of CAPOX or FOLFOX/FOLFOXIRI in other trials) and the advanced disease stage of our cohort. More than half of our patients were suspected to have lateral lymph node metastasis before treatment, and pathological confirmation was obtained in two of six patients undergoing dissection. These findings suggest that it may be necessary to extend the number of SOX cycles or stratify patients according to risk features to optimize efficacy.
Recent randomized trials such as the RAPIDO, PRODIGE 23, and OPRA trials have confirmed the benefits of TNT by demonstrating improved systemic control, DFS, and organ preservation, albeit primarily using intravenous fluoropyrimidine-based regimens associated with substantial toxicity and treatment burden (8, 9, 18). The advantage of our treatment is that SOX therapy, like CAPOX, is a regimen that combines an oral anticancer drug and does not require the construction of a port, making it highly convenient. Furthermore, S-1 is widely used in Asia, including Japan, and is easily applicable to actual clinical practice in Japan. The present study findings suggest that TNT using SOX therapy has a favorable safety profile and may become an alternative to FOLFOX and CAPOX as a TNT treatment for rectal cancer in the future.
In conclusion, full-dose SOX therapy (40-60 mg of S-1 twice daily and 130 mg/m2 of oxaliplatin) is safe and well tolerated as consolidation chemotherapy following CRT for advanced lower rectal cancer. This is the first report to evaluate TNT incorporating SOX therapy. While limited by the small sample size, this phase 1 study provides a foundation for future phase 2/3 trials to confirm the efficacy of SOX therapy, define the optimal number of treatment cycles, and clarify its role in organ preservation and long-term disease control.
Acknowledgements
The Authors would like to thank Kelly Zammit, BVSc, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.
Footnotes
Authors’ Contributions
MY: conceptualization; methodology; formal analysis; investigation; writing – original draft; visualization. KU: investigation; writing – review and editing. KO: investigation; writing – review and editing. CY: investigation; resources; writing – review and editing. TY: data curation; methodology; writing – review and editing. YK: data curation; methodology; writing – review and editing. KK: methodology; supervision; writing – review and editing. TM: project administration; writing – review and editing. NT: data curation; writing – review and editing. ST: resources; writing – review and editing. TS: conceptualization; supervision; writing – review and editing. YF: conceptualization; methodology; writing – review and editing; project administration; funding acquisition.
Conflicts of Interest
The Authors declare that they have no conflicts of interest in relation to this study.
Funding
No grants, equipment, or funding were received for this study.
Artificial Intelligence (AI) Disclosure
During the preparation of this manuscript, a large language model (ChatGPT, OpenAI) was used solely for language editing and stylistic improvements in select paragraphs. No sections involving the generation, analysis, or interpretation of research data were produced by generative AI. All scientific content was created and verified by the authors. Furthermore, no figures or visual data were generated or modified using generative AI or machine learning-based image enhancement tools.
- Received January 10, 2026.
- Revision received March 7, 2026.
- Accepted March 10, 2026.
- Copyright © 2026 The Author(s). Published by the International Institute of Anticancer Research.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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