Phase II trial evaluating the long-term efficacy and peripheral sensory neuropathy of adjuvant XELOX in Japanese patients 

Phase II trial evaluating the long-term efficacy and peripheral sensory neuropathy of adjuvant XELOX in Japanese patients | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Phase II trial evaluating the long-term efficacy and peripheral sensory neuropathy of adjuvant XELOX in Japanese patients Taishi Hata, Mamoru Umemura, Katsuki Danno, Shinichi Yoshioka, and 16 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4520888/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Nov, 2024 Read the published version in Scientific Reports → Version 1 posted 10 You are reading this latest preprint version Abstract Adjuvant oxaliplatin plus capecitabine (XELOX) therapy is recommended for patients with curatively resected colon cancer. However, prospective data on its practical application in Japanese patients are limited. Therefore, this study aims to conduct a long-term clinical evaluation of the efficacy and safety of adjuvant XELOX in patients with curatively resected stage III colon cancer (MCSCO-1024). This prospective, multicenter, open-label, single-arm phase II study enrolled patients with curatively resected stage III colon cancer. The treatment protocol comprised a 120-minute intravenous infusion of oxaliplatin (130 mg/m 2 ) on day 1 and two divided doses of oral capecitabine (2000 mg/m 2 /day) for 14 days in a 3-week cycle, totaling eight cycles (24 weeks). The primary endpoint was 3-year disease-free survival (DFS), and the secondary endpoints were 5-year overall survival and long-term prognosis of peripheral sensory neuropathy. In total, 196 patients were enrolled between November 2011 and August 2014 (34 months). The 3-year DFS rate was 73%, and the 5-year overall survival rate was 87%. The overall incidence of peripheral sensory neuropathy was 17%, with a 1% rate of grade 3 neuropathy after 5 years. Adjuvant XELOX demonstrated utility and safety in the clinical management of Japanese patients with stage III colon cancer. XELOX Adjuvant Chemotherapy Japanese peripheral sensory neuropathy Figures Figure 1 Figure 2 Figure 3 Introduction Although studies have assessed the safety and tolerability of adjuvant oxaliplatin plus capecitabine (XELOX) therapy in Asian patients with curatively resected colon cancer [ 1 , 2 ], there are limited reports on long-term outcomes, including peripheral neuropathy, in Japanese individuals. We previously published interim safety data from this study [ 3 ]. Therefor The aim of this study is to present the long-term efficacy of adjuvant XELOX therapy and peripheral sensory neuropathy (PSN) associated with it for Japanese patients who underwent curative resection for stage III colon cancer (MCSCO-1024). Patients and Methods Eligibility Criteria Eligible patients were aged ≥ 20 years with a histologically confirmed diagnosis of colon adenocarcinoma, specifically stage III colon cancer, which included cancers of the rectosigmoid region. They underwent colectomy with D2 or D3 lymph node dissection and achieved curative resection (curative level A) without macroscopic or microscopic residual tumors. Other eligibility criteria included an Eastern Clinical Oncology Group (ECOG) performance status of 0 or 1, no prior chemotherapy or radiotherapy, adequate oral food intake, and proper functioning of vital organs (e.g., white blood cell count ≥ 3000/mm 3 , neutrophil count ≥ 1500/mm 3 , platelet count ≥ 100,000/mm 3 , serum creatinine ≥ 1.5 × the institutional upper limit of normal (ULN), serum total bilirubin ≥ 2.5 × ULN, and serum aspartate aminotransferase and alanine aminotransferase ≥ 2.5 × ULN). Written informed consent was obtained from all patients before enrollment. Patients were excluded if they had watery diarrhea, a synchronous or metachronous (within 5 years) malignancy other than carcinoma in situ, Common Terminology Criteria for Adverse Events (CTCAE) v 4.0, grade > 1 of PSN, regularly used insulin, uncontrollable congestive heart failure, angina, hypertension, arrhythmia, severe mental disorders, active infections, pregnancy or lactation, or sexually active patients unwilling to use contraception. Inadequate physical conditions diagnosed by primary physicians also led to exclusion. These criteria are consistent with that in our previous study [ 3 ]. Study Design and Treatment The study protocol for this multicenter, open-label, single-arm, phase II study was approved by the review board of each participating institution and registered in the University Hospital Medical Information Network (UMIN) registry system (UMIN ID: 000006742). The first case was registered on 11/Jan/2011. Patients were enrolled, and XELOX therapy was initiated within 8 weeks of surgery. The treatment protocol comprised a 120-minute intravenous infusion of oxaliplatin (130 mg/m 2 ) on day 1 and oral capecitabine (2000 mg/m 2 /day) in two divided doses for 14 days in a 3-week cycle for a total of eight cycles (24 weeks), or until unacceptable toxicity occurred. The study adheres to the ethical principles of the Declaration of Helsinki and relevant guidelines, ensuring maximum protection of participant rights, welfare, and safety. The treatment protocol mirrors that in our previous study [ 3 ]. Dose Modification If the following criteria for the initiation of treatment were not met on the day of or the day before the start of each course, treatment was postponed for a maximum of 42 days: neutrophil count ≥ 1500/mm 3 , platelet count ≥ 75,000/mm 3 , PSN persistent grade ≥ 1, grade ≥ 1 hand-foot syndrome (HFS), and other parameters at the attending physician's discretion. Dose modifications were based on the most severe adverse events observed during the previous treatment cycle. If any of the following adverse events occurred (except PSN and HFS), oxaliplatin and capecitabine doses were reduced to 100 or 85 mg/m 2 and 1500 or 1000 mg/m 2 , respectively: grade ≥ 2 leukopenia, neutropenia, or thrombocytopenia, and any other grade ≥ 3 hematological or grade ≥ 2 non-hematological adverse events. Oxaliplatin dose was reduced to 100 mg/m 2 or 85 mg/m 2 if the patient developed persistent grade 2 PSN or grade 3 PSN, respectively. Oxaliplatin was discontinued if the patient developed a second occurrence of grade 2/3 or 4 PSN and if grade ≥ 3 adverse events occurred. Capecitabine monotherapy was permitted in patients who refused or discontinued oxaliplatin due to drug-induced PSN. Capecitabine dose was adjusted for adverse events of grade ≥ 2 HFS. At the first occurrence of grade ≥ 2 HFS, treatment was interrupted and resumed at a reduced dose of 1500 mg/m 2 after resolution to grade 1 or better. For second occurrences of grade ≥ 2 HFS, treatment was interrupted and resumed at a reduced dose of 1000 mg/m 2 after resolution to grade 1 or better. These modifications are consistent with those of our previous study [ 3 ]. Staging Criteria The Japanese Classification of Colorectal Carcinoma, 7th edition (Second English edition) [ 4 ], and the Union against Cancer (UICC) TNM Classification of Malignant Tumors 7th edition [ 5 ] were used for tumor staging. Statistical Analysis The primary endpoint was the 3-year disease-free survival (DFS). The 3-year DFS rate was 70.9% in the XELOXA/NO16968 trial [ 6 ]. In total, 165 patients were required to test the null hypothesis versus the alternative hypothesis with a one-sided α level of 0.05 and β level of 0.1 when the critical value of the 3-year DFS was 60%, and the expected value of 3-year DFS was 71%. In total, 195 patients were recruited for this study. The safety population was defined as patients who received at least one dose of the treatment protocol. PN was assessed using a patient-reported treatment diary and dictation and evaluated by a doctor according to CTCAE v. 4.0. Adherence to capecitabine was verified using a patient-reported treatment diary. Tumor assessments with abdominal computed tomography, ultrasonography, and chest radiography were performed at baseline and every 6 months for 5 years after the primary surgery. Tests for carcinoembryonic antigen and carbohydrate antigen 19–9 were conducted every 3 months for the first 3 years and every 6 months thereafter. The Kaplan–Meier method was used to evaluate the 3-year DFS and 5-year overall survival. The JMP® 10 software (SAS Institute Inc., Cary, NC, USA) was used for all statistical analyses. Results Patient characteristics. In total, 196 patients were enrolled at 25 institutions belonging to the Multi-center Clinical Study Group of Osaka, Colorectal Cancer Treatment Group (MCSGO). Among the 196 patients, one did not start the study protocol, and one violated protocol. Of the remaining 194 patients, four were excluded from the safety analysis of the per protocol set (PPS) (Fig. 1 ). Thus, a total of 190 patients were included in the safety analysis. The median patient age was 64 years (range: 29–78). There were 90 males and 100 females. The tumor invasion depth was T1 in six patients, T2 in 16 patients, T3 in 98 patients, and T4 in 70 patients. Lymph node status was N1 in 99 patients and N2 in 90 patients (Table 1). This result has already been reported in an earlier paper [ 3 ] but is included again because it is necessary to understand the contents of this paper. Efficacy The 3-year and the 5-year DFS were 73% and 70%, respectively (Fig. 2 ). The 5-year overall survival (OS) was 87% (Fig. 3 ). Safety Short-term safety has already been reported [ 3 ]. So, this study primarily focused on the long-term prognosis of peripheral neuropathy. However, data were available for only 141 patients (72%) after 5 years. The overall incidence of PSN was 17%, with grade 3 cases accounting for 1% after 5 years. The grade and timing of PSN onset during XELOX treatment were investigated in 24 patients with residual PSN for up to 5 years but found no correlation with onset at 5 years (Table 2). Discussion In our previous study, the short-term outcomes of adjuvant XELOX therapy in Japanese patients with curatively resected colon cancer were discussed [ 3 ]. Therefore, the primary focus of this study was to determine the long-term safety of this regimen in Japanese patients. The primary endpoint of 3-year DFS and the long-term outcomes of 5-year DFS and OS were assessed. The ACHIEVE Trial was a prospective investigation of the prognosis of Japanese patients [ 7 ] to assess the safety and efficacy of different dosing periods. Their results showed 5-year DFS rates of 75.2% and 74.2% for the 3-month and 6-month doses, respectively. In our study, this value was slightly lower (70%). Conversely, our 5-year OS was 87%, consistent with the 87% for the 3-month treatment and 86% for the 6-month treatment in their study. Compared to the results of the IDEA study, which included data from other countries, our 3-year DFS rates were 72.9% and 74.1% for the 3-month and 6-month doses, respectively [ 8 ]. These results are consistent with previously reported data. The MOSAIC Trial by Thierry et al. reported a 5-year DFS rate of 73.3% in patients with Stage III FOLFOX4 disease [ 9 ]. They found no significant difference in efficacy between FOLFOX and XELOX therapies, and the 5-year DFS rate for oxaliplatin-based adjuvant chemotherapy was 70–75%. In European countries, Andre et al. reported that peripheral neuropathy at four years occurred in 15.4% of cases overall, with 0.7% experiencing grade 3 and 2.8% experiencing grade 2. In our study, after 5 years, the overall incidence was 17%, and grade 3 was observed in 1% of the patients. Although there were no significant differences in the values, the frequency of residual peripheral neuropathy was the same or slightly higher in Japanese patients than in Western individuals. Although the reasons for this discrepancy are unknown, it may be due to racial differences. We evaluated 24 cases in which peripheral neuropathy persisted after 5 years of treatment and examined whether there was a correlation between the timing and severity of peripheral nerve symptoms during treatment. However, no clear correlation was observed. One reason for this could be that the assessment of numbness is subjective, as it relies on self-evaluation and varies in resistance among individuals, making it difficult to assign a specific grade. Therefore, the results may have been different if they were assessed using objective criteria for peripheral nerve symptoms. Nonetheless, this study had some limitations. First, data on peripheral neuropathy were available for only 72% of patients. Second, regarding the 5-year OS rate, chemotherapy treatment affected the survival rate in recurrent cases; however, there were no data on which chemotherapeutic agents were used or when they were administered in this study. Although the number of cases was small, and the results cannot be considered definitive, the number of Japanese patients with long-term grade 3 persistence was slightly higher than that of Western patients, possibly reflecting racial differences [ 10 ]. In conclusion, in real clinical practice, the 5-year DFS and 5-year OS after XELOX adjuvant chemotherapy in Japan were similar to those in previous clinical trials. Thus, adjuvant XELOX is useful and safe for the treatment of patients with Stage III colon cancer in Japan. To the best of our knowledge, this is the first report on long-term peripheral neuropathy in Asian patients. Declarations Acknowledgments This study was supported by the Multicenter Clinical Study Group of the Osaka Colorectal Cancer Treatment Group. Author contributions K.D. designed this study, T.H. drafted the manuscript. All authors have read and approved the final manuscript. Data availability statement The supporting data are available from the corresponding author on reasonable request. Ethics declarations Competing interests The authors declare no competing interests. Additional Information Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. References Osawa, H., Handa, N., Minakata, K. Efficacy and safety of capecitabine and oxaliplatin (CapOX) as an adjuvant therapy in Japanese for stage II/III colon cancer in a group at high risk of recurrence in retrospective study. Oncol Res 22 , 325–331 (2014). Chiu, J. et al. Efficacy and tolerability of adjuvant oral capecitabine plus intravenous oxaliplatin (XELOX) in Asian patients with colorectal cancer: 4-year analysis. Asian Pac J Cancer Prev 14 , 6585–6590 (2014). Danno, K. et al. Interim analysis of a phase II trial evaluating the safety and efficacy of capecitabine plus oxaliplatin (XELOX) as adjuvant therapy in Japanese patients with operated stage III colon cancer. Cancer Chemother Pharmacol 80 , 777–785(2017). Japanese Society for Cancer of the Colon and RectumJapanese classification of colorectal carcinoma, Second, English ed. Kanehara Shuppan, Tokyo (2009) Sobin LH, Gospodarowicz MKWC (eds) Union against cancer (UICC) TNM classification of malignant tumours, 7th ed. Wiley, Oxford (2009) Haller, D. G. et al. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol 29 , 1465–1471 (2011). Yoshino, T. et al. Final analysis of 3 versus 6 months of adjuvant oxaliplatin and fluoropyrimidine-based therapy in patients with stage III colon cancer: The randomized phase III ACHIEVE Trial. J Clin Oncol 40 ,3419–3429 (2022). Souglakos, J. et al. Three- versus six-month adjuvant FOLFOX or CAPOX for high-risk stage II and stage III colon cancer patients: The efficacy results of Hellenic Oncology Research Group (HORG) participation to the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) project. Ann Oncol 30 , 1304–1310 (2019). André, T. et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the Mosaic trial. J Clin Oncol 27 , 3109–3116 (2009). Kamei, K. et al. A new monitoring tool CLIP test for progression of oxaliplatin-induced peripheral neuropathy: A multicenter prospective study. Asia Pac J Clin Oncol 16 , e257–e262 (2020). Tables Tables are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files JapaneseXELOXHatatable.docx Cite Share Download PDF Status: Published Journal Publication published 02 Nov, 2024 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 06 Aug, 2024 Reviews received at journal 04 Aug, 2024 Reviewers agreed at journal 25 Jul, 2024 Reviews received at journal 09 Jul, 2024 Reviewers agreed at journal 04 Jul, 2024 Reviewers invited by journal 27 Jun, 2024 Editor assigned by journal 27 Jun, 2024 Editor invited by journal 21 Jun, 2024 Submission checks completed at journal 20 Jun, 2024 First submitted to journal 03 Jun, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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studies have assessed the safety and tolerability of adjuvant oxaliplatin plus capecitabine (XELOX) therapy in Asian patients with curatively resected colon cancer [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], there are limited reports on long-term outcomes, including peripheral neuropathy, in Japanese individuals. We previously published interim safety data from this study [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Therefor The aim of this study is to present the long-term efficacy of adjuvant XELOX therapy and peripheral sensory neuropathy (PSN) associated with it for Japanese patients who underwent curative resection for stage III colon cancer (MCSCO-1024).\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eEligibility Criteria\u003c/h2\u003e \u003cp\u003eEligible patients were aged\u0026thinsp;\u0026ge;\u0026thinsp;20 years with a histologically confirmed diagnosis of colon adenocarcinoma, specifically stage III colon cancer, which included cancers of the rectosigmoid region. They underwent colectomy with D2 or D3 lymph node dissection and achieved curative resection (curative level A) without macroscopic or microscopic residual tumors. Other eligibility criteria included an Eastern Clinical Oncology Group (ECOG) performance status of 0 or 1, no prior chemotherapy or radiotherapy, adequate oral food intake, and proper functioning of vital organs (e.g., white blood cell count\u0026thinsp;\u0026ge;\u0026thinsp;3000/mm\u003csup\u003e3\u003c/sup\u003e, neutrophil count\u0026thinsp;\u0026ge;\u0026thinsp;1500/mm\u003csup\u003e3\u003c/sup\u003e, platelet count\u0026thinsp;\u0026ge;\u0026thinsp;100,000/mm\u003csup\u003e3\u003c/sup\u003e, serum creatinine\u0026thinsp;\u0026ge;\u0026thinsp;1.5 \u0026times; the institutional upper limit of normal (ULN), serum total bilirubin\u0026thinsp;\u0026ge;\u0026thinsp;2.5 \u0026times; ULN, and serum aspartate aminotransferase and alanine aminotransferase\u0026thinsp;\u0026ge;\u0026thinsp;2.5 \u0026times; ULN). Written informed consent was obtained from all patients before enrollment. Patients were excluded if they had watery diarrhea, a synchronous or metachronous (within 5 years) malignancy other than carcinoma in situ, Common Terminology Criteria for Adverse Events (CTCAE) v 4.0, grade\u0026thinsp;\u0026gt;\u0026thinsp;1 of PSN, regularly used insulin, uncontrollable congestive heart failure, angina, hypertension, arrhythmia, severe mental disorders, active infections, pregnancy or lactation, or sexually active patients unwilling to use contraception. Inadequate physical conditions diagnosed by primary physicians also led to exclusion. These criteria are consistent with that in our previous study [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Treatment\u003c/h2\u003e \u003cp\u003e The study protocol for this multicenter, open-label, single-arm, phase II study was approved by the review board of each participating institution and registered in the University Hospital Medical Information Network (UMIN) registry system (UMIN ID: 000006742). The first case was registered on 11/Jan/2011. Patients were enrolled, and XELOX therapy was initiated within 8 weeks of surgery. The treatment protocol comprised a 120-minute intravenous infusion of oxaliplatin (130 mg/m\u003csup\u003e2\u003c/sup\u003e) on day 1 and oral capecitabine (2000 mg/m\u003csup\u003e2\u003c/sup\u003e/day) in two divided doses for 14 days in a 3-week cycle for a total of eight cycles (24 weeks), or until unacceptable toxicity occurred. The study adheres to the ethical principles of the Declaration of Helsinki and relevant guidelines, ensuring maximum protection of participant rights, welfare, and safety. The treatment protocol mirrors that in our previous study [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eDose Modification\u003c/h2\u003e \u003cp\u003eIf the following criteria for the initiation of treatment were not met on the day of or the day before the start of each course, treatment was postponed for a maximum of 42 days: neutrophil count\u0026thinsp;\u0026ge;\u0026thinsp;1500/mm\u003csup\u003e3\u003c/sup\u003e, platelet count\u0026thinsp;\u0026ge;\u0026thinsp;75,000/mm\u003csup\u003e3\u003c/sup\u003e, PSN persistent grade\u0026thinsp;\u0026ge;\u0026thinsp;1, grade\u0026thinsp;\u0026ge;\u0026thinsp;1 hand-foot syndrome (HFS), and other parameters at the attending physician's discretion. Dose modifications were based on the most severe adverse events observed during the previous treatment cycle. If any of the following adverse events occurred (except PSN and HFS), oxaliplatin and capecitabine doses were reduced to 100 or 85 mg/m\u003csup\u003e2\u003c/sup\u003e and 1500 or 1000 mg/m\u003csup\u003e2\u003c/sup\u003e, respectively: grade\u0026thinsp;\u0026ge;\u0026thinsp;2 leukopenia, neutropenia, or thrombocytopenia, and any other grade\u0026thinsp;\u0026ge;\u0026thinsp;3 hematological or grade\u0026thinsp;\u0026ge;\u0026thinsp;2 non-hematological adverse events. Oxaliplatin dose was reduced to 100 mg/m\u003csup\u003e2\u003c/sup\u003e or 85 mg/m\u003csup\u003e2\u003c/sup\u003e if the patient developed persistent grade 2 PSN or grade 3 PSN, respectively. Oxaliplatin was discontinued if the patient developed a second occurrence of grade 2/3 or 4 PSN and if grade\u0026thinsp;\u0026ge;\u0026thinsp;3 adverse events occurred. Capecitabine monotherapy was permitted in patients who refused or discontinued oxaliplatin due to drug-induced PSN. Capecitabine dose was adjusted for adverse events of grade\u0026thinsp;\u0026ge;\u0026thinsp;2 HFS. At the first occurrence of grade\u0026thinsp;\u0026ge;\u0026thinsp;2 HFS, treatment was interrupted and resumed at a reduced dose of 1500 mg/m\u003csup\u003e2\u003c/sup\u003e after resolution to grade 1 or better. For second occurrences of grade\u0026thinsp;\u0026ge;\u0026thinsp;2 HFS, treatment was interrupted and resumed at a reduced dose of 1000 mg/m\u003csup\u003e2\u003c/sup\u003e after resolution to grade 1 or better. These modifications are consistent with those of our previous study [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003eStaging Criteria\u003c/h2\u003e \u003cp\u003eThe Japanese Classification of Colorectal Carcinoma, 7th edition (Second English edition) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], and the Union against Cancer (UICC) TNM Classification of Malignant Tumors 7th edition [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] were used for tumor staging.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eThe primary endpoint was the 3-year disease-free survival (DFS). The 3-year DFS rate was 70.9% in the XELOXA/NO16968 trial [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In total, 165 patients were required to test the null hypothesis versus the alternative hypothesis with a one-sided α level of 0.05 and β level of 0.1 when the critical value of the 3-year DFS was 60%, and the expected value of 3-year DFS was 71%. In total, 195 patients were recruited for this study. The safety population was defined as patients who received at least one dose of the treatment protocol. PN was assessed using a patient-reported treatment diary and dictation and evaluated by a doctor according to CTCAE v. 4.0. Adherence to capecitabine was verified using a patient-reported treatment diary. Tumor assessments with abdominal computed tomography, ultrasonography, and chest radiography were performed at baseline and every 6 months for 5 years after the primary surgery. Tests for carcinoembryonic antigen and carbohydrate antigen 19\u0026ndash;9 were conducted every 3 months for the first 3 years and every 6 months thereafter. The Kaplan\u0026ndash;Meier method was used to evaluate the 3-year DFS and 5-year overall survival. The JMP\u0026reg; 10 software (SAS Institute Inc., Cary, NC, USA) was used for all statistical analyses.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e \u003cb\u003ePatient characteristics.\u003c/b\u003e \u003c/p\u003e \u003cp\u003eIn total, 196 patients were enrolled at 25 institutions belonging to the Multi-center Clinical Study Group of Osaka, Colorectal Cancer Treatment Group (MCSGO). Among the 196 patients, one did not start the study protocol, and one violated protocol. Of the remaining 194 patients, four were excluded from the safety analysis of the per protocol set (PPS) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Thus, a total of 190 patients were included in the safety analysis. The median patient age was 64 years (range: 29\u0026ndash;78). There were 90 males and 100 females. The tumor invasion depth was T1 in six patients, T2 in 16 patients, T3 in 98 patients, and T4 in 70 patients. Lymph node status was N1 in 99 patients and N2 in 90 patients (Table\u0026nbsp;1). This result has already been reported in an earlier paper [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] but is included again because it is necessary to understand the contents of this paper.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eEfficacy\u003c/h2\u003e \u003cp\u003eThe 3-year and the 5-year DFS were 73% and 70%, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The 5-year overall survival (OS) was 87% (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eSafety\u003c/h2\u003e \u003cp\u003eShort-term safety has already been reported [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. So, this study primarily focused on the long-term prognosis of peripheral neuropathy. However, data were available for only 141 patients (72%) after 5 years. The overall incidence of PSN was 17%, with grade 3 cases accounting for 1% after 5 years. The grade and timing of PSN onset during XELOX treatment were investigated in 24 patients with residual PSN for up to 5 years but found no correlation with onset at 5 years (Table\u0026nbsp;2).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn our previous study, the short-term outcomes of adjuvant XELOX therapy in Japanese patients with curatively resected colon cancer were discussed [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Therefore, the primary focus of this study was to determine the long-term safety of this regimen in Japanese patients. The primary endpoint of 3-year DFS and the long-term outcomes of 5-year DFS and OS were assessed.\u003c/p\u003e \u003cp\u003eThe ACHIEVE Trial was a prospective investigation of the prognosis of Japanese patients [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] to assess the safety and efficacy of different dosing periods. Their results showed 5-year DFS rates of 75.2% and 74.2% for the 3-month and 6-month doses, respectively. In our study, this value was slightly lower (70%). Conversely, our 5-year OS was 87%, consistent with the 87% for the 3-month treatment and 86% for the 6-month treatment in their study. Compared to the results of the IDEA study, which included data from other countries, our 3-year DFS rates were 72.9% and 74.1% for the 3-month and 6-month doses, respectively [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. These results are consistent with previously reported data.\u003c/p\u003e \u003cp\u003eThe MOSAIC Trial by Thierry et al. reported a 5-year DFS rate of 73.3% in patients with Stage III FOLFOX4 disease [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. They found no significant difference in efficacy between FOLFOX and XELOX therapies, and the 5-year DFS rate for oxaliplatin-based adjuvant chemotherapy was 70\u0026ndash;75%.\u003c/p\u003e \u003cp\u003eIn European countries, Andre et al. reported that peripheral neuropathy at four years occurred in 15.4% of cases overall, with 0.7% experiencing grade 3 and 2.8% experiencing grade 2. In our study, after 5 years, the overall incidence was 17%, and grade 3 was observed in 1% of the patients. Although there were no significant differences in the values, the frequency of residual peripheral neuropathy was the same or slightly higher in Japanese patients than in Western individuals. Although the reasons for this discrepancy are unknown, it may be due to racial differences.\u003c/p\u003e \u003cp\u003eWe evaluated 24 cases in which peripheral neuropathy persisted after 5 years of treatment and examined whether there was a correlation between the timing and severity of peripheral nerve symptoms during treatment. However, no clear correlation was observed. One reason for this could be that the assessment of numbness is subjective, as it relies on self-evaluation and varies in resistance among individuals, making it difficult to assign a specific grade. Therefore, the results may have been different if they were assessed using objective criteria for peripheral nerve symptoms.\u003c/p\u003e \u003cp\u003eNonetheless, this study had some limitations. First, data on peripheral neuropathy were available for only 72% of patients. Second, regarding the 5-year OS rate, chemotherapy treatment affected the survival rate in recurrent cases; however, there were no data on which chemotherapeutic agents were used or when they were administered in this study. Although the number of cases was small, and the results cannot be considered definitive, the number of Japanese patients with long-term grade 3 persistence was slightly higher than that of Western patients, possibly reflecting racial differences [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn conclusion, in real clinical practice, the 5-year DFS and 5-year OS after XELOX adjuvant chemotherapy in Japan were similar to those in previous clinical trials. Thus, adjuvant XELOX is useful and safe for the treatment of patients with Stage III colon cancer in Japan. To the best of our knowledge, this is the first report on long-term peripheral neuropathy in Asian patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the Multicenter Clinical Study Group of the Osaka Colorectal Cancer Treatment Group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eK.D.\u0026nbsp;designed this study, T.H. drafted the manuscript. All authors have read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe supporting data are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics declarations\u003c/strong\u003e\u003c/p\u003e\n\u003ch3\u003eCompeting interests\u003c/h3\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional Information\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ch3\u003ePublisher\u0026apos;s note\u003c/h3\u003e\n\u003cp\u003eSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eOsawa, H., Handa, N., Minakata, K. Efficacy and safety of capecitabine and oxaliplatin (CapOX) as an adjuvant therapy in Japanese for stage II/III colon cancer in a group at high risk of recurrence in retrospective study. \u003cem\u003eOncol Res\u003c/em\u003e \u003cstrong\u003e22\u003c/strong\u003e, 325\u0026ndash;331 (2014).\u003c/li\u003e\n\u003cli\u003eChiu, J. et al. Efficacy and tolerability of adjuvant oral capecitabine plus intravenous oxaliplatin (XELOX) in Asian patients with colorectal cancer: 4-year analysis. \u003cem\u003eAsian Pac J Cancer Prev\u003c/em\u003e \u003cstrong\u003e14\u003c/strong\u003e, 6585\u0026ndash;6590 (2014).\u003c/li\u003e\n\u003cli\u003eDanno, K. et al. Interim analysis of a phase II trial evaluating the safety and efficacy of capecitabine plus oxaliplatin (XELOX) as adjuvant therapy in Japanese patients with operated stage III colon cancer. \u003cem\u003eCancer Chemother Pharmacol\u003c/em\u003e \u003cstrong\u003e80\u003c/strong\u003e, 777\u0026ndash;785(2017).\u003c/li\u003e\n\u003cli\u003eJapanese Society for Cancer of the Colon and RectumJapanese classification of colorectal carcinoma, Second, English ed. Kanehara Shuppan, Tokyo (2009)\u003c/li\u003e\n\u003cli\u003eSobin LH, Gospodarowicz MKWC (eds) Union against cancer (UICC) TNM classification of malignant tumours, 7th ed. Wiley, Oxford (2009)\u003c/li\u003e\n\u003cli\u003eHaller, D. G. et al. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. \u003cem\u003eJ Clin Oncol\u003c/em\u003e \u003cstrong\u003e29\u003c/strong\u003e, 1465\u0026ndash;1471 (2011).\u003c/li\u003e\n\u003cli\u003eYoshino, T. et al. Final analysis of 3 versus 6 months of adjuvant oxaliplatin and fluoropyrimidine-based therapy in patients with stage III colon cancer: The randomized phase III ACHIEVE Trial. \u003cem\u003eJ Clin Oncol\u003c/em\u003e \u003cstrong\u003e40\u003c/strong\u003e,3419\u0026ndash;3429 (2022).\u003c/li\u003e\n\u003cli\u003eSouglakos, J. et al. Three- versus six-month adjuvant FOLFOX or CAPOX for high-risk stage II and stage III colon cancer patients: The efficacy results of Hellenic Oncology Research Group (HORG) participation to the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) project. \u003cem\u003eAnn Oncol\u003c/em\u003e \u003cstrong\u003e30\u003c/strong\u003e, 1304\u0026ndash;1310 (2019).\u003c/li\u003e\n\u003cli\u003eAndr\u0026eacute;, T. et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the Mosaic trial. \u003cem\u003eJ Clin Oncol\u003c/em\u003e \u003cstrong\u003e27\u003c/strong\u003e, 3109\u0026ndash;3116 (2009).\u003c/li\u003e\n\u003cli\u003eKamei, K. et al. A new monitoring tool CLIP test for progression of oxaliplatin-induced peripheral neuropathy: A multicenter prospective study. \u003cem\u003eAsia Pac J Clin Oncol\u003c/em\u003e \u003cstrong\u003e16\u003c/strong\u003e, e257\u0026ndash;e262 (2020).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"XELOX, Adjuvant Chemotherapy, Japanese, peripheral sensory neuropathy","lastPublishedDoi":"10.21203/rs.3.rs-4520888/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4520888/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAdjuvant oxaliplatin plus capecitabine (XELOX) therapy is recommended for patients with curatively resected colon cancer. However, prospective data on its practical application in Japanese patients are limited. Therefore, this study aims to conduct a long-term clinical evaluation of the efficacy and safety of adjuvant XELOX in patients with curatively resected stage III colon cancer (MCSCO-1024). This prospective, multicenter, open-label, single-arm phase II study enrolled patients with curatively resected stage III colon cancer. The treatment protocol comprised a 120-minute intravenous infusion of oxaliplatin (130 mg/m\u003csup\u003e2\u003c/sup\u003e) on day 1 and two divided doses of oral capecitabine (2000 mg/m\u003csup\u003e2\u003c/sup\u003e/day) for 14 days in a 3-week cycle, totaling eight cycles (24 weeks). The primary endpoint was 3-year disease-free survival (DFS), and the secondary endpoints were 5-year overall survival and long-term prognosis of peripheral sensory neuropathy. In total, 196 patients were enrolled between November 2011 and August 2014 (34 months). The 3-year DFS rate was 73%, and the 5-year overall survival rate was 87%. The overall incidence of peripheral sensory neuropathy was 17%, with a 1% rate of grade 3 neuropathy after 5 years. Adjuvant XELOX demonstrated utility and safety in the clinical management of Japanese patients with stage III colon cancer.\u003c/p\u003e","manuscriptTitle":"Phase II trial evaluating the long-term efficacy and peripheral sensory neuropathy of adjuvant XELOX in Japanese patients ","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-18 16:10:53","doi":"10.21203/rs.3.rs-4520888/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-08-06T15:54:01+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-04T17:14:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"109917319434183013823521287454943388382","date":"2024-07-25T13:23:12+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-10T03:22:37+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"187982095950642058994483446073661507728","date":"2024-07-04T11:00:23+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-06-27T15:45:08+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-27T15:37:46+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-06-21T14:24:09+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-20T05:02:07+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-06-03T09:42:57+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"152bf7e6-e4df-482e-88c8-8a78cdce27f4","owner":[],"postedDate":"July 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-11-04T16:27:16+00:00","versionOfRecord":{"articleIdentity":"rs-4520888","link":"https://doi.org/10.1038/s41598-024-73222-0","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2024-11-02 16:20:20","publishedOnDateReadable":"November 2nd, 2024"},"versionCreatedAt":"2024-07-18 16:10:53","video":"","vorDoi":"10.1038/s41598-024-73222-0","vorDoiUrl":"https://doi.org/10.1038/s41598-024-73222-0","workflowStages":[]},"version":"v1","identity":"rs-4520888","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4520888","identity":"rs-4520888","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}