S-1 and Oxaliplatin Versus Tegafur-uracil and Leucovorin as Postoperative Adjuvant Chemotherapy in Patients With High-risk Stage III Colon Cancer (ACTS-CC 02): A Randomized, Open-label, Multicenter, Phase III Superiority Trial

Sunami, Eiji; Kusumoto, Tetsuya; Ota, Mitsuyoshi; Sakamoto, Yoshiyuki; Yoshida, Kazuhiro; Tomita, Naohiro; Maeda, Atsuyuki; Teshima, Jin; Okabe, Masaru; Tanaka, Chihiro; Yamauchi, Junichiro; Itabashi, Michio; Kotake, Kenjiro; Takahashi, Keiichi; Baba, Hideo; Boku, Narikazu; Aiba, Keisuke; Ishiguro, Megumi; Morita, Satoshi; Takenaka, Naruhito; Okude, Ryota; Sugihara, Kenichi

doi:10.1016/j.clcc.2019.10.002

Cited by 11 publications

(7 citation statements)

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“…Alternatively, patients assessed with DPD overexpression commonly associated with incidence DYPD*2A polymorphisms may consider the use of 5-FU together with JTE-013 to effectively inhibit S1PR2 as the upstream regulator of DPD expression [ 236 ]. Gimeracil is another reversible inhibitor of DPD, known to be combined alongside oteracil potassium and tegafur as prodrug 5-FU, in a preparation simply termed as S-1 [ 284 ]. Stage III colon cancer patients receiving S-1 plus oxaliplatin reported a slight improvement in 3-year DFS when compared to patients receiving only tegafur-uracil plus leucovorin.…”

Section: Reversal Strategiesmentioning

confidence: 99%

Recent Updates on Mechanisms of Resistance to 5-Fluorouracil and Reversal Strategies in Colon Cancer Treatment

Azwar

Seow

Abdullah

et al. 2021

Biology

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5-Fluorouracil (5-FU) plus leucovorin (LV) remain as the mainstay standard adjuvant chemotherapy treatment for early stage colon cancer, and the preferred first-line option for metastatic colon cancer patients in combination with oxaliplatin in FOLFOX, or irinotecan in FOLFIRI regimens. Despite treatment success to a certain extent, the incidence of chemotherapy failure attributed to chemotherapy resistance is still reported in many patients. This resistance, which can be defined by tumor tolerance against chemotherapy, either intrinsic or acquired, is primarily driven by the dysregulation of various components in distinct pathways. In recent years, it has been established that the incidence of 5-FU resistance, akin to multidrug resistance, can be attributed to the alterations in drug transport, evasion of apoptosis, changes in the cell cycle and DNA-damage repair machinery, regulation of autophagy, epithelial-to-mesenchymal transition, cancer stem cell involvement, tumor microenvironment interactions, miRNA dysregulations, epigenetic alterations, as well as redox imbalances. Certain resistance mechanisms that are 5-FU-specific have also been ascertained to include the upregulation of thymidylate synthase, dihydropyrimidine dehydrogenase, methylenetetrahydrofolate reductase, and the downregulation of thymidine phosphorylase. Indeed, the successful modulation of these mechanisms have been the game plan of numerous studies that had employed small molecule inhibitors, plant-based small molecules, and non-coding RNA regulators to effectively reverse 5-FU resistance in colon cancer cells. It is hoped that these studies would provide fundamental knowledge to further our understanding prior developing novel drugs in the near future that would synergistically work with 5-FU to potentiate its antitumor effects and improve the patient’s overall survival.

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Section: Reversal Strategiesmentioning

confidence: 99%

Recent Updates on Mechanisms of Resistance to 5-Fluorouracil and Reversal Strategies in Colon Cancer Treatment

Azwar

Seow

Abdullah

et al. 2021

Biology

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“…The adjuvant SOX treatment has not yet been established for colon cancer. SOX treatment was compared with UFT/ LV in adjuvant setting in ACTS‐CC 02 trial, 23 which was ongoing when our trial was planned and started. This study showed the 3‐year DFS was 62.7% (95% CI, 58.1–66.9) in the SOX group, compared to 60.6% (95% CI, 56.0–64.9) in the UFT/LV group.…”

Section: Discussionmentioning

confidence: 99%

Exploratory randomized phase II trial for optimizing treatment dosage and duration of adjuvant S‐1 plus oxaliplatin in patients with stage III colon cancer: YCOG1402 (SOAP trial)

Suwa

Watanabe

Suwa

et al. 2023

Annals of Gastroent Surgery

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IntroductionConventionally, the recommended duration of adjuvant chemotherapy of colon cancer had been 6 months. The IDEA Collaboration suggested that shortening capecitabin and oxaliplatin (CAPOX) adjuvant chemotherapy may be possible. S‐1 and oxaliplatin (SOX) treatment is standard treatment in metastatic colorectal cancer in Japan. The aim of this study was to optimize treatment dosage and duration of adjuvant SOX in stage III colon cancer.MethodsThis trial was as open‐label multi‐center randomized phase II study. Patients with stage III colon cancer were randomly assigned to 3 months or 6 months of adjuvant SOX treatment in different doses: 130 mg/m2 (3 months) or 100 mg/m2 (6 months) of oxaliplatin. The primary endpoint was 3‐year disease‐free survival (DFS) and the null hypothesis for the primary endpoint was that the 3‐year DFS was ≤72% in each arm and was tested with a one‐sided significance level of 10%.ResultsEighty‐two patients were assigned to the 6 months arm and 81 to the 3 months arm. The 3‐year DFS was 75.0% (80% CI 67.95–80.72, p = 0.282) in the 6 months arm and 76.9% (80% CI 70.1–82.38, p = 0.171) in the 3 months arm. Treatment completion rate and relative dose intensity (RDI) were higher in 3 months than 6 months arm. The adverse events (AE) were similar in both arms.ConclusionsThe 3‐year DFS was not significantly superior to null hypothesis in both 3 months and 6 months arms for the stage III colon cancer. Primary endpoint was not achieved. The SOX regimen was not feasible in long‐term outcomes.

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“…In the ACTS-CC02 study, S-1 plus oxaliplatin therapy (SOX) was not superior to UFT/LV in terms of OS and disease-free survival (DFS) in patients with high-risk stage III colon cancer of any T, N2, or positive nodes around the origin of the feeding arteries (18,20). SOX was efficacious in patients with T4N2b disease.…”

Section: Discussionmentioning

confidence: 99%

“…In the ACTS-CC trial (15)(16)(17), S-1 was not inferior to UFT/LV for stage III disease. Furthermore, S-1 plus oxaliplatin (SOX) was not superior to UFT/LV as adjuvant chemotherapy in the ACTS-CC02 trial (18)(19)(20). This latter trial focused on patients with high-risk stage III colon cancer, which is defined as N2 with any T or positive nodes around the origin of the feeding arteries.…”

Section: Introductionmentioning

confidence: 99%

Real impact of oxaliplatin in adjuvant chemotherapy for patients with stage III colon cancer based on the Multi-Institutional Registry of Large Bowel Cancer in Japan

Yamada

Kobayashi

Nagashima

et al. 2022

GHM

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Although fluoropyrimidine plus oxaliplatin is the standard of care for stage III colon cancer, fluoropyrimidine alone is also recommended for stage III patients in Japanese and other practice guidelines. We assessed efficacy of adjuvant fluoropyrimidine with or without oxaliplatin across a population of patients with stage III colon cancer in the Multi-Institutional Registry of Large Bowel Cancer in Japan. From the registry, we analyzed 6,834 stage III colorectal cancer patients. Approximately 70% of colorectal cancer patients received some form of chemotherapy. Of these, we analyzed those who received adjuvant chemotherapy between 2008 and 2011. Based on the TNM classification, the 5-year overall survival rates of colon and rectal cancer after the covariate adjustment by regimens of adjuvant chemotherapy were 95.7% with fluoropyrimidines and 90.6% with oxaliplatin-combined therapy at stage IIIA (Stratified log-rank P < 0.001), 86.5% and 80.8% at stage IIIB (P < 0.001), and 72.1% and 70.7% at stage IIIC (P < 0.001), respectively. Oxaliplatin did not enhance efficacy with regard to relapse-free survival as well as overall survival. Adjuvant fluoropyrimidine monotherapy and fluoropyrimidine plus oxaliplatin show comparable efficacy benefits for the treatment of stage III of Japanese colon cancer patients. This supports the use of fluoropyrimidine alone as a standard option for this patient group in Japan.

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S-1 and Oxaliplatin Versus Tegafur-uracil and Leucovorin as Postoperative Adjuvant Chemotherapy in Patients With High-risk Stage III Colon Cancer (ACTS-CC 02): A Randomized, Open-label, Multicenter, Phase III Superiority Trial

Cited by 11 publications

References 14 publications

Recent Updates on Mechanisms of Resistance to 5-Fluorouracil and Reversal Strategies in Colon Cancer Treatment

Recent Updates on Mechanisms of Resistance to 5-Fluorouracil and Reversal Strategies in Colon Cancer Treatment

Exploratory randomized phase II trial for optimizing treatment dosage and duration of adjuvant S‐1 plus oxaliplatin in patients with stage III colon cancer: YCOG1402 (SOAP trial)

Real impact of oxaliplatin in adjuvant chemotherapy for patients with stage III colon cancer based on the Multi-Institutional Registry of Large Bowel Cancer in Japan

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