Oxaliplatin Has Few Benefits, High Toxicity in Rectal Cancer

Barbara Boughton

January 31, 2012

January 31, 2012 (San Francisco, California) — Long-term results from the French ACCORD 12 trial indicate that the addition of oxaliplatin to capecitabine plus radiotherapy provides no additional survival benefit and increases toxicity in patients with resectable rectal adenocarcinoma, according to research reported here at the 2012 Gastrointestinal Cancers Symposium.

Presenting author Eric François, MD, from the Centre Antoine Lacassagne in Nice, France, noted that the long-term results of ACCORD 12 and similar recent randomized trials, such as STAR 01 and NSABP 04, indicate that oxaliplatin should not be included in neoadjuvant treatment for resectable rectal adenocarcinoma.

From our results "and those of other recent trials, we can propose a new regimen for neoadjuvant treatment for resectable rectal adenocarcinoma — the CAP50 regimen," Dr. François said.

The CAP50 regimen consists of radiotherapy 50 Gy in 25 fractions over 5 weeks, plus capecitabine 1600 mg/m² per day and 800 mg² twice per day on radiotherapy days, he explained.

In ACCORD 12 trial, 598 patients from 56 different French institutions were randomized to either CAP45 (radiotherapy 45 Gy weekly for 5 weeks plus capecitabine 1600 mg/m² per day) or CAPOX50 (radiotherapy 50 Gy for 5 weeks plus capecitabine 1600 mg/m² per day plus oxaliplatin).

"After 3 years of follow-up, there was no significant difference in overall survival with the addition of oxaliplatin to radiotherapy and capecitabine," Dr. François explained. In addition, there was no significant difference in disease-free survival at 3 years between the CAP45 and CAPOX50 groups (71% vs 73%).

Early grade 3 and 4 toxicities were significantly more common in the CAPOX50 group than in the CAP45 group (25% vs 11%; P < .001). "Oxaliplatin increases toxicity, particularly diarrhea, without any clear impact on complete response rate," Dr. François added.

He added that increasing the radiotherapy dose to 50 Gy with chemotherapy improved the complete response rate without increasing toxic effects.

The French team assessed quality of life for the patients who had undergone each regimen. At 3 years, there was no significant difference between the 2 regimens in terms of bowel function, erectile dysfunction, or social life disturbance, Dr. François reported.

Compared with other recent trials of neoadjuvant treatments in rectal adenocarcinoma, ACCORD 12 found that capecitabine plus radiotherapy is as effective as fluorouracil (5-FU) plus radiotherapy.

"It's clear from the results of this trial that oxaliplatin does not appear to lead to greater benefit for patients with resectable anal cancer, and is more toxic," said Gail Eckhardt, MD, from the University of Colorado in Denver.

Dr. Eckhardt noted, however, that the results of the trial could have been muddled by the number of changes that the investigators made to standard neoadjuvant therapy for resectable anal cancer. "The enthusiasm of the investigators led to 3 changes: using oxaliplatin instead of 5-FU, intensifying the dosage of capecitabine, and increasing the radiotherapy dose," she said.

The most relevant findings for clinical practice from the ACCORD 12 trial are those on local recurrence and distant metastases 3 years after treatment, which indicate that there is no significant difference in these results with the addition of oxaliplatin, Dr. Eckhardt said.

"It's also clear from these results that we can substitute capecitabine for 5-FU infusion without compromising results," Dr. Eckhardt said.

The radiotherapy dose recommended by the investigators — 50 Gy — is one that most clinicians feel comfortable with in treating resectable anal cancer, Dr. Eckhardt noted.

As research continues into treatment for rectal cancer, it's likely that patients will benefit, not only from the regimen tested in the ACCORD 12 trial, but also from novel ways of delivering radiotherapy and the integration of biologics into adjuvant therapy.

"We will be using imaging to guide therapy, and the potential is there to find biomarkers of response or resistance to therapy," Dr. Eckhardt said. "We should be able to look at these markers of response and resistance to guide us in developing future therapies for this disease," she added.

Dr. François reports being a consultant or advisor to Merck and Roche. Dr. Eckhardt reports being a consultant or advisor to Genentech, Millennium, Onconova, Oncothyreon, and Sanofi-aventis.

2012 Gastrointestinal Cancers Symposium (GICS): Abstract 389. Presented January 21, 2012.


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