Some Patients With Stage III Low-Risk Colon Cancer May Require Less Oxaliplatin Therapy

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Patients with stage III colon cancer considered at low risk for recurrence may be treated effectively—and incur less neurotoxicity—with 3 months of an oxaliplatin-based regimen as compared with the standard 6 months, according to the results of the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) trial, the largest prospective clinical trial ever conducted in colorectal cancer.1 In the study, the shorter course was associated with a dramatic reduction in neurotoxicity, with little to no compromise in disease-free survival at 3 years. 

There was three times more toxicity with 6 months compared to 3 months of chemotherapy, which was highly statistically significant.
— Axel Grothey, MD

“There was three times more toxicity with 6 months compared to 3 months of chemotherapy, which was highly statistically significant,” reported Axel Grothey, MD, of the Mayo Clinic Cancer Center, Rochester, at a press briefing. The findings were presented during the Plenary Session at the 2017 ASCO Annual Meeting by Qian Shi, PhD, also of the Mayo Clinic Cancer Center. 

But IDEA did not quite meet its statistical endpoint, as the investigators were unable to show the shorter duration is noninferior to 6 months of chemotherapy for all patients. Three months was deemed acceptable, however, for patients with T1–3, N1 tumors, according to the group’s consensus statement. 

For its primary objective, IDEA was designed as a noninferiority trial in which 3 months of an oxaliplatin-based regimen would not sacrifice more than 12% of the benefit of standard adjuvant therapy. In statistical terms, the upper 95% confidence interval (CI) of the hazard ratio (HR) of disease-free survival could not exceed 1.12, to prove noninferiority. The consideration of less oxaliplatin (and resulting reduction in neurotoxicity) was based on a post hoc analysis for low-risk patients, with the only study regimen that did fulfill the primary endpoint.

Differing Opinions

For stage III colon cancer patients with low-risk tumors, “We do not recommend more than 3 months of chemotherapy with an oxaliplatin-based regimen,” Dr. Grothey said. 

ASCO spokesperson Nancy Baxter, MD, PhD, of St. Michael’s Hospital in Toronto, told journalists, “Today, up to 60% of my patients with stage III colon cancer will be able to stop after 3 months of therapy and be able to get on with their lives and have a lower risk of permanent problems, such as numbness of their hands and feet. Less is more.”

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But not all colon cancer experts were ready to endorse this change completely. Invited discussant Cathy Eng, MD, FACP, the Sophie Caroline Steves Distinguished Professor in Cancer Research at The University of Texas MD Anderson Cancer Center, Houston, thought the failure to meet the primary endpoint was important. “The failure to meet the primary endpoint means that 6 months of adjuvant oxaliplatin-based therapy is still standard of care. Due to the differences in toxicity in the arms, a discussion with patients is necessary. For less toxicity, the detriment in cure rate is minimal for low-risk patients, but it is substantive in the high-risk patients; shortening the course of chemotherapy for these patients puts them at risk for recurrence,” she said. 

Big IDEA: 20 Countries, 12,834 Patients

IDEA was an international academic collaboration that began about 1 decade ago. Researchers from six separate trials pooled the results of 12,834 patients with stage III colon cancer, including TOSCA, SCOT, IDEA France, HORG, ACHIEVE, and -CALGB 80702. The first three individual studies were also presented at the ASCO meeting. The study asked whether a shorter course of oxaliplatin for stage III colon cancer would result in noninferiority for disease-free survival for 3 months of adjuvant oxaliplatin-based chemotherapy vs 6 months.

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Patients received 6 months or 3 months of FOLFOX (leucovorin, fluorouracil, oxaliplatin) or CAPOX (capecitabine, oxaliplatin), based on clinician and patient choices. Some countries used one or the other regimen exclusively (U.S. and Canadian physicians used FOLFOX). Altogether, 3,870 patients received FOLFOX for 3 months and 3,893 received it for 6 months, while 2,554 -received CAPOX for 3 months and 2,517 received it for 6 months. 

Details of the Findings

After a median follow-up of 39 months, the efficacy analysis, based on 3-year disease-free survival, failed to meet the prespecified noninferiority threshold—an upper hazard ratio limit of 1.12.

“When you do the math, … we potentially reduce disease-free survival by 0.9% at 3 years [with 3 months of treatment]. Statistical noninferiority was not achieved, but the difference in efficacy is very small. This is where clinical judgment comes in,” Dr. Grothey said. 

For all patients combined, the disease-free survival rate at 3 years was 74.6% for 3 months of chemotherapy and 75.5% for 6 months (HR = 1.07, 95% CI = 1.00–1.15). There were differences by regimen, however, with a greater compromise in efficacy (though still small) observed in FOLFOX-treated patients. For FOLFOX, the disease-free hazard ratio for 3 months’ duration was 1.16 (95% CI = 1.06–1.26), whereas for CAPOX, the hazard ratio was 0.95 (95% CI = 0.85–1.06). Level of recurrence risk also mattered. 

“The disease-free survival noninferiority of 3 months’ oxaliplatin-based adjuvant therapy was not established in overall stage III colon cancer. However, results comparing disease-free survival between 3 months and 6 months of treatment depend on risk groups and regimen,” said Dr. Shi, at the Plenary Session.


  • The IDEA trial, an international collaboration of 6 studies involving almost 13,000 stage III colon cancer patients, examined whether a shorter duration of oxaliplatin-based adjuvant chemotherapy (3 vs 6 months) would result in noninferiority for disease-free survival.
  • The study did not meet its primary endpoint (noninferiority of the 3-month regimen), with 3-year disease-free survival rates of 74.6% for 3 months of chemotherapy and 75.5% for 6 months (HR = 1.07, 95% CI = 1.00–1.15). Noninferiority could only be declared if the upper boundary of the 95% CI for disease-free survival did not exceed 1.12.
  • Post hoc analyses suggest that patients at low risk of recurrence with CAPOX, show noninferiority. The consensus recommendation from the IDEA investigators was to consider treating low-risk patients with 3 months of chemotherapy. 

A post hoc analysis was then pursued of patients with T1-3, N1 (low-risk) and T4, N2 (high-risk) disease. While IDEA was not designed to compare outcomes between the regimens, and patients were not randomized between them, the differences between FOLFOX and CAPOX were of interest, and their different outcomes are hard to explain, Dr. Grothey told journalists. “We all recognized that lower-risk patients need less treatment than high-risk patients, but the interaction between treatment effect and chemotherapy regimen in terms of duration is puzzling.” 

One hypothesis is that differences in schedule and delivery methods of the chemotherapy components may explain the difference, the investigators proposed. 

Of the three individual trials presented, only the SCOT trial fulfilled its primary endpoint for noninferiority. TOSCA and IDEA (France) were not able to establish noninferiority for 3 months of oxaliplatin-based chemotherapy.

The investigators’ consensus was that the duration of adjuvant chemotherapy for stage III patients should be risk-based. Patients with T1–3, N1 tumors are candidates for 3 months of treatment, whereas those with T4 and/or N2 tumors or other high-risk factors should have their treatment duration determined by tolerability of therapy, patient preference, assessment of recurrence risk, and regimen (FOLFOX vs CAPOX). ■

DISCLOSURE: Drs. Baxter and Eng reported no conflicts of interest.


1. Shi Q, Sobrero AF, Shields AF, et al: Prospective pooled analysis of six phase III trials investigating duration of adjuvant oxaliplatin-based therapy (3 vs 6 months) for patients with stage III colon cancer. 2017 ASCO Annual Meeting. Abstract LBA1. Presented June 4, 2017. 

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Expert Point of View: Cathy Eng, MD, FACP and Alfred Neugut, MD, PhD

Cathy Eng, MD, FACP, the Sophie Caroline Steves Distinguished Professor in Cancer Research at The University of Texas MD Anderson Cancer Center, Houston, said the trial demonstrates “the challenge of analyzing six individually conducted studies in a pooled analysis.” 

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