Adjuvant Therapy with Edrecolomab versus Observation in Stage II Colon Cancer: A Multicenter Randomized Phase III Study*

4052 Background: Whereas several studies showed adjuvant chemotherapy to improve survival of patients with stage III colon cancer, survival benefit from adjuvant treatment in patients with stage II disease is a matter of controversy. Methods: Patients with curatively resected stage II colon cancer (T3–4, N0, M0) according to UICC were randomized to either adjuvant chemotherapy with 5-FU/LV (100 mg/m2 LV + 450 mg/m2 5-FU weekly, w 1–6, in 8 w cycles x 7) or surveillance only. Primary endpoint was overall survival (OS) with 636 patients originally planned to demonstrate a difference in OS of 10% with 85% power and alfa =0.05 in a final analysis 7 years after study initiation. After accrual of 535 patients between 11/1993 and 6/2003, recruitment was stopped ahead of schedule for low accrual rates. Results: 505 patients were eligible and evaluable for analyses. After a median follow-up of 96 months, 56 (21.8%) patients have died in the 5-FU/LV arm and 58 (23.4%) in the surveillance arm. There was no statistically significant difference in OS between the two treatment arms (HR 1.137, 95% CI 0.787–1.641, p=0.4947, chi square), thus the primary endpoint of the study was not met. Disease relapse was documented in 35 (13.6%) patients of the chemotherapy arm and in 48 (19.4%) patients of the control arm. The relative risk for disease relapse was higher for patients in the surveillance arm compared to patients in the 5-FU/LV arm, however, this difference was statistically not significant (HR 1.506, 95% CI 0.974–2.328, p=0.0657, chi square). Subgroup analysis including in the chemotherapy arm only patients who received at least one cycle of 5-FU/LV (n=250), showed a statistically significantly lower risk for relapse in patients treated with 5- FU/LV (HR 1.559, 95% CI 1.001–2.429, p=0.0477, chi square). Conclusions: Results of this trial demonstrate a trend to a lower risk for relapse in patients treated with adjuvant 5-FU/LV for stage II colon cancer. However, adjuvant chemotherapy did not significantly improve DFS and OS. No significant financial relationships to disclose.

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Cochrane systematic review and meta-analysis of adjuvant therapy for stage II colon cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.15_suppl.3513 ◽

2015 ◽

Vol 33 (15_suppl) ◽

pp. 3513-3513

Author(s):

Brandon Matthew Meyers ◽

Humaid Obaid Al-Shamsi ◽

Alvaro Tell Figueredo

Keyword(s):

Systematic Review ◽

Colon Cancer ◽

Adjuvant Therapy ◽

Meta Analysis ◽

Stage Ii ◽

Cochrane Systematic Review ◽

Stage Ii Colon Cancer

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Adjuvant Therapy for Stage II Colon Cancer: A Systematic Review From the Cancer Care Ontario Program in Evidence-Based Care’s Gastrointestinal Cancer Disease Site Group

Journal of Clinical Oncology ◽

10.1200/jco.2004.03.087 ◽

2004 ◽

Vol 22 (16) ◽

pp. 3395-3407 ◽

Cited By ~ 218

Author(s):

Alvaro Figueredo ◽

Manya L. Charette ◽

Jean Maroun ◽

Melissa C. Brouwers ◽

Lisa Zuraw

Keyword(s):

Systematic Review ◽

Colon Cancer ◽

Overall Survival ◽

Adjuvant Therapy ◽

Meta Analysis ◽

Disease Free Survival ◽

Stage Ii ◽

Free Survival ◽

Stage Ii Colon Cancer ◽

Disease Free

Purpose To develop a systematic review that would address the following question: Should patients with stage II colon cancer receive adjuvant therapy? Methods A systematic review was undertaken to locate randomized controlled trials comparing adjuvant therapy to observation. Results Thirty-seven trials and 11 meta-analyses were included. The evidence for stage II colon cancer comes primarily from a trial of fluorouracil plus levamisole and a meta-analysis of 1,016 patients comparing fluorouracil plus folinic acid versus observation. Neither detected an improvement in disease-free or overall survival for adjuvant therapy. A recent pooled analysis of data from seven trials observed a benefit for adjuvant therapy in a multivariate analysis for both disease-free and overall survival. The disease-free survival benefits appeared to extend to stage II patients; however, no P values were provided. A meta-analysis of chemotherapy by portal vein infusion has also shown a benefit in disease-free and overall survival for stage II patients. A meta-analysis was conducted using data on stage II patients where data were available (n = 4,187). The mortality risk ratio was 0.87 (95% CI, 0.75 to 1.01; P = .07). Conclusion There is preliminary evidence indicating that adjuvant therapy is associated with a disease-free survival benefit for patients with stage II colon cancer. These benefits are small and not necessarily associated with improved overall survival. Patients should be made aware of these results and encouraged to participate in active clinical trials. Additional investigation of newer therapies and more mature data from the presently available trials should be pursued.

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Association between ColDx assay result and recurrence-free interval in stage II colon cancer patients on CALGB (Alliance) 9581.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.455 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 455-455 ◽

Cited By ~ 3

Author(s):

Donna Niedzwiecki ◽

Wendy Frankel ◽

Alan Paul Venook ◽

Xing Ye ◽

Paula N. Friedman ◽

...

Keyword(s):

Colon Cancer ◽

Prognostic Factors ◽

Gene Expression Signature ◽

Stage Ii ◽

Phase Iii ◽

Eligibility Criteria ◽

Accurate Identification ◽

Free Interval ◽

Assay Result ◽

Stage Ii Colon Cancer

455 Background: Only 15-25% of pts with stage II colon cancer (CC) experience recurrence and conventional staging methods neither allow accurate identification of low (L) and high-risk (H) subgroups nor predict benefit of adjuvant chemotherapy. The ColDx assay (Almac Diagnostics) is a 634-probeset gene expression signature shown to be independently prognostic for recurrence-free interval (RFI). The objective of this study was to assess the ability of ColDx to classify stage II CC pts at L- and H-risk of relapse. Methods: This validation study was conducted using formalin fixed paraffin embedded biospecimens and clinical data from CALGB 9581, a phase III trial of edrecolomab v. observation in pts with normal risk, stage II CC. 1,454 CALGB 9,581 pts met eligibility criteria. A case-cohort sampling design was used to randomly select (RS) 514 pts from 901 eligible pts with available tissue; supplemented by 49 non-RS recurrent pts (total 563). Risk status for each pt was based on a positive or negative ColDx score using a pre-specified cutpoint, 0.4377. The Self Prentice method was used to test the association between ColDx categories and RFI (distant recurrence or death due to primary disease). Results: Initial results in 563 pts were erroneous due to a quality failure in a batch of reagent. 524 samples were re-labeled, re-ordered, and re-assayed using reagents that passed quality control (36 samples had insufficient material; 95 failed ColDx QC). Final analysis comprised 393 pts, 360 RS (58 events; 16%); 33 non-RS events. 216 pts (55%) were predicted H (62 events); 177 (45%) pts were predicted L (29 events). H pts exhibited significantly worse RFI (univariable hazard ratio (HR), 2.0; 95% CI, 1.3-3.3; p < 0.01). ColDx remained significant after adjustment for prognostic factors; HR, 2.1 (95% CI, 1.3-3.4; p < 0.01). Conclusions: The ColDx assay result is associated with RFI in the CALGB 9,581 sub-sample and is independent from other prognostic factors, including MSI. Further investigation is needed to establish the role of this classifier in guiding treatment decisions in this patient population.

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