TOSCA Supports Shorter Adjuvant CT Duration for Resected Colon Cancer

TOSCA Supports Shorter Adjuvant CT Duration for Resected Colon Cancer

Dr. Alberto F. Sobrero presents Abstract 3501.
Results of the large Italian TOSCA trial narrowly failed to meet the primary endpoint but still offer great value to patients with high-risk stage II or stage III colon cancer slated to receive oxaliplatin-based treatment after surgery. The findings, presented on June 5, showed that the relapse-free survival (RFS) rate for a 3-month course of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin), compared with 6 months, differed by less than 2% at 3 years and elicited far fewer adverse events (Abstract 3501).

“Because the difference in RFS is so limited … but the toxicity so much better, 3 months of oxaliplatin-based chemotherapy can be considered another standard option for the adjuvant treatment of resected colon cancer,” presenter Alberto F. Sobrero, MD, of the Ospedale San Martino, in Italy, said.

Six months of adjuvant oxaliplatin-based therapy represents the worldwide standard of care for stage III colon cancer, and it is often used for many patients with high-risk stage II disease. However, the cumulative neurotoxicity associated with oxaliplatin makes it difficult for many patients to complete the full course of therapy.

TOSCA represents the Italian component of the six-trial IDEA collaboration that was designed to determine whether oxaliplatin-based adjuvant therapy can be decreased from 6 to 3 months without compromising efficacy but while improving tolerability, treatment burden, and costs. Pooled IDEA results for more than 10,000 patients across all six trials were presented at the Plenary Session (Abstract LBA1) on June 4.

TOSCA, like its sister studies, was a randomized, open-label, phase III, noninferiority trial and was conducted from June 2007 to March 2013 at 130 sites across Italy. A total of 3,759 patients with high-risk stage II or stage III radically resected colon cancer were randomly assigned to either 3 or 6 months of adjuvant FOLFOX or CAPOX—a choice left up to the treating physician. In the overall study population, 66% of patients received FOLFOX, and 34% received CAPOX. The primary endpoint was RFS, defined as the time from random assignment to first relapse or death as a result of any cause.

After a median follow-up of 62 months, the 3-year RFS rate reached 81.1% with 3 months of treatment and 83% with 6 months—a difference of 1.9%. The hazard ratio for relapse or death with the shorter course of treatment was 1.14 (95% CI [0.99, 1.32]). The stickler was the upper bound of the 95% confidence interval.

“Because this is beyond the 1.20 level that we set as the noninferiority margin, we could not reject the null hypothesis of noninferiority. In other terms, 3 months is not as good as 6 months—that’s the message coming from statistics,” Dr. Sobrero explained.

Dr. Jeffrey A. Meyerhardt discusses Abstract 3501.
Subgroup analysis of RFS yielded two intriguing findings. As in the larger IDEA analysis, there was a signal that CAPOX yields better RFS outcomes than FOLFOX when delivered for 3 months. Unexpectedly, patients with stage II disease, but not those with stage III disease, had poorer RFS results with the shorter course of treatment—a finding that counters observations in the larger IDEA analysis and one that Dr. Sobrero and others are still trying to understand.

Three months of adjuvant chemotherapy produced much less toxicity than 6 months. Most notably, grades 3 to 4 neurologic toxicity occurred in 9% of patients assigned to 3 months of treatment compared with 31% of patients assigned to the standard 6 months (p < 0.0001). Significant reductions in febrile neutropenia, thrombocytopenia, diarrhea, and allergic reactions also were observed with the shorter treatment course.

To put the TOSCA findings—and the IDEA results as a whole—into context, discussant Jeffrey A. Meyerhardt, MD, MPH, FASCO, of the Dana-Farber Cancer Institute, explained that only 22 of 100 patients with stage III colon cancer are cured by adjuvant chemotherapy, but all experience toxic adverse effects of treatment, including lasting neuropathy.

“The last 24 hours, with the Plenary Session and today’s talks, will change the lives of hundreds of thousands of [patients with] colorectal cancer each year worldwide,” Dr. Meyerhardt said.

On the basis of the results of TOSCA, SCOT, IDEA France, and other IDEA trials, Dr. Meyerhardt plans to offer 6 months of FOLFOX to his patients with T4 or N2 disease. For those with T1-3N1 disease, he will offer 3 months of CAPOX or FOLFOX to reduce toxicity and alleviate the logistical burden of treatment; he cited his preference for CAPOX because of its slightly more preferable efficacy data.  

–Kara Nyberg, PhD