Duration of Adjuvant Doublet Chemotherapy (3 or 6 months) in Patients With High-Risk Stage II Colorectal Cancer

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PURPOSE:

As oxaliplatin results in cumulative neurotoxicity, reducing treatment duration without loss of efficacy would benefit patients and healthcare providers.

PATIENTS AND METHODS:

Four of the six studies in the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) collaboration included patients with high-risk stage II colon and rectal cancers. Patients were treated (clinician and/or patient choice) with either fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPOX) and randomly assigned to receive 3- or 6-month treatment. The primary end point is disease-free survival (DFS), and noninferiority of 3-month treatment was defined as a hazard ratio (HR) of < 1.2- v 6-month arm. To detect this with 80% power at a one-sided type one error rate of 0.10, a total of 542 DFS events were required.

RESULTS:

3,273 eligible patients were randomly assigned to either 3- or 6-month treatment with 62% receiving CAPOX and 38% FOLFOX. There were 553 DFS events. Five-year DFS was 80.7% and 83.9% for 3-month and 6-month treatment, respectively (HR, 1.17; 80% CI, 1.05 to 1.31; P [for noninferiority] .39). This crossed the noninferiority limit of 1.2. As in the IDEA stage III analysis, the duration effect appeared dependent on the chemotherapy regimen although a test of interaction was negative. HR for CAPOX was 1.02 (80% CI, 0.88 to 1.17), and HR for FOLFOX was 1.41 (80% CI, 1.18 to 1.68).

CONCLUSION:

Although noninferiority has not been demonstrated in the overall population, the convenience, reduced toxicity, and cost of 3-month adjuvant CAPOX suggest it as a potential option for high-risk stage II colon cancer if oxaliplatin-based chemotherapy is suitable. The relative contribution of the factors used to define high-risk stage II disease needs better understanding.

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Most cited references 15

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Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer.

Daniel Sargent, Silvia Marsoni, Geneviève Monges … (2010)

Prior reports have indicated that patients with colon cancer who demonstrate high-level microsatellite instability (MSI-H) or defective DNA mismatch repair (dMMR) have improved survival and receive no benefit from fluorouracil (FU) -based adjuvant therapy compared with patients who have microsatellite-stable or proficient mismatch repair (pMMR) tumors. We examined MMR status as a predictor of adjuvant therapy benefit in patients with stages II and III colon cancer. MSI assay or immunohistochemistry for MMR proteins were performed on 457 patients who were previously randomly assigned to FU-based therapy (either FU + levamisole or FU + leucovorin; n = 229) versus no postsurgical treatment (n = 228). Data were subsequently pooled with data from a previous analysis. The primary end point was disease-free survival (DFS). Overall, 70 (15%) of 457 patients exhibited dMMR. Adjuvant therapy significantly improved DFS (hazard ratio [HR], 0.67; 95% CI, 0.48 to 0.93; P = .02) in patients with pMMR tumors. Patients with dMMR tumors receiving FU had no improvement in DFS (HR, 1.10; 95% CI, 0.42 to 2.91; P = .85) compared with those randomly assigned to surgery alone. In the pooled data set of 1,027 patients (n = 165 with dMMR), these findings were maintained; in patients with stage II disease and with dMMR tumors, treatment was associated with reduced overall survival (HR, 2.95; 95% CI, 1.02 to 8.54; P = .04). Patient stratification by MMR status may provide a more tailored approach to colon cancer adjuvant therapy. These data support MMR status assessment for patients being considered for FU therapy alone and consideration of MMR status in treatment decision making.

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Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer.

Thierry André, Corrado Boni, Lamia Mounedji-Boudiaf … (2004)

The standard adjuvant treatment of colon cancer is fluorouracil plus leucovorin (FL). Oxaliplatin improves the efficacy of this combination in patients with metastatic colorectal cancer. We evaluated the efficacy of treatment with FL plus oxaliplatin in the postoperative adjuvant setting. We randomly assigned 2246 patients who had undergone curative resection for stage II or III colon cancer to receive FL alone or with oxaliplatin for six months. The primary end point was disease-free survival. A total of 1123 patients were randomly assigned to each group. After a median follow-up of 37.9 months, 237 patients in the group given FL plus oxaliplatin had had a cancer-related event, as compared with 293 patients in the FL group (21.1 percent vs. 26.1 percent; hazard ratio for recurrence, 0.77; P=0.002). The rate of disease-free survival at three years was 78.2 percent (95 percent confidence interval, 75.6 to 80.7) in the group given FL plus oxaliplatin and 72.9 percent (95 percent confidence interval, 70.2 to 75.7) in the FL group (P=0.002 by the stratified log-rank test). In the group given FL plus oxaliplatin, the incidence of febrile neutropenia was 1.8 percent, the incidence of gastrointestinal adverse effects was low, and the incidence of grade 3 sensory neuropathy was 12.4 percent during treatment, decreasing to 1.1 percent at one year of follow-up. Six patients in each group died during treatment (death rate, 0.5 percent). Adding oxaliplatin to a regimen of fluorouracil and leucovorin improves the adjuvant treatment of colon cancer. Copyright 2004 Massachusetts Medical Society

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Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial.

Thierry André, Corrado Boni, Matilde Navarro … (2009)

PURPOSE Three-year disease-free survival (DFS) was significantly improved in patients who had undergone resection with curative intent for stage II or III colon cancer who received bolus plus continuous-infusion fluorouracil plus leucovorin (LV5FU2) with the addition of oxaliplatin (FOLFOX4). Final results of the study, including 6-year overall survival (OS) and 5-year updated DFS, are reported. PATIENTS AND METHODS A total of 2,246 patients were randomly assigned to receive LV5FU2 or FOLFOX4 for 6 months. The primary end point was DFS. Secondary end points were OS and safety. Results Five-year DFS rates were 73.3% and 67.4% in the FOLFOX4 and LV5FU2 groups, respectively (hazard ratio [HR] = 0.80; 95% CI, 0.68 to 0.93; P = .003). Six-year OS rates were 78.5% and 76.0% in the FOLFOX4 and LV5FU2 groups, respectively (HR = 0.84; 95% CI, 0.71 to 1.00; P = .046); corresponding 6-year OS rates for patients with stage III disease were 72.9% and 68.7%, respectively (HR = 0.80; 95% CI, 0.65 to 0.97; P = .023). No difference in OS was seen in the stage II population. The incidence of second noncolorectal cancers was 5.5% and 6.1% in the FOLFOX4 and LV5FU2 groups, respectively. Among patients receiving oxaliplatin, the frequency of grade 3 peripheral sensory neuropathy was 1.3% 12 months after treatment and 0.7% at 48 months. CONCLUSION Adding oxaliplatin to LV5FU2 significantly improved 5-year DFS and 6-year OS in the adjuvant treatment of stage II or III colon cancer and should be considered after surgery for patients with stage III disease.

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Author and article information

Journal

Journal ID (nlm-ta): J Clin Oncol

Journal ID (iso-abbrev): J Clin Oncol

Journal ID (hwp): jco

Journal ID (pmc): jco

Journal ID (publisher-id): JCO

Title: Journal of Clinical Oncology

Publisher: American Society of Clinical Oncology

ISSN (Print): 0732-183X

ISSN (Electronic): 1527-7755

Publication date (Print): 20 February 2021

Publication date (Electronic): 13 January 2021

Volume: 39

Issue: 6

Pages: 631-641

Affiliations

[ ¹ ]University of Southampton, Southampton, United Kingdom

[ ² ]Ospedale Policlinico San Martino IRCCS, Genova, Italy

[ ³ ]National Cancer Center Hospital East, Kashiwa, Japan

[ ⁴ ]Department of Medical Oncology, University Hospital of Heraklion, Iraklio, Greece

[ ⁵ ]Mayo Clinic, Rochester, MN

[ ⁶ ]West Cancer Center and Research Institute, Germantown, TN

[ ⁷ ]Christie Hospital, Manchester, United Kingdom

[ ⁸ ]Cancer Center, Ospedale Papa Giovanni XXIII Bergamo, Bergamo, Italy

[ ⁹ ]Department of Biostatistics, Yokohama City University School of Medicine, Kanagawa, Japan

[ ¹⁰ ]Bioclinic Thessaloniki, Thessaloniki, Greece

[11] ¹¹Department of Oncology, Zealand University Hospital, Køge, Denmark

[ ¹² ]IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy

[ ¹³ ]Shizuoka Cancer Center, Shizuoka, Japan

[ ¹⁴ ]Hellenic Oncology Research Group, Athens, Greece

[ ¹⁵ ]University of Oxford, Oxford, United Kingdom

[ ¹⁶ ]Kyushu University, Fukuoka, Japan

[ ¹⁷ ]Veneto Institute of Oncology IRCCS, Padua, Italy

[ ¹⁸ ]University of Glasgow, Institute of Cancer Sciences, Scotland, United Kingdom

[ ¹⁹ ]San Carlo Hospital, Potenza, Italy

Author notes

Timothy J. Iveson, MD, FRCP, Southampton University Hospital NHS Foundation Trust, Tremona Road, Southampton SO16 0YD, United Kingdom; e-mail: tim.iveson@ 123456uhs.nhs.uk .