Jury Still Out on Oxaliplatin for Early-Stage Colon, Rectal Cancers

Claus Rödel, MD

According to late-breaking results presented at the 2011 ASCO conference in Chicago, adding oxaliplatin to 5-fluorouracil (5-FU) before and after surgery for the treatment of locally advanced rectal cancer is demonstrating significant benefit. However, a meta-analysis presented in the same session showed no benefit for stage II/III colorectal cancer patients who received oxaliplatin and 5-FU/leucovorin (Lv).

Claus Rödel, MD, from the Department of Radiation Therapy at the University of Frankfurt, Germany, delivered the first results of the German Rectal Cancer Study Group CAO/ ARO/AIO-04 randomized phase III trial.

“Our primary endpoint was disease-free survival [DFS],” stated Rödel. “We hypothesized that the three-year disease-free survival would improve from 75% to 82% in the experimental arm.”

The study enrolled 1265 patients (7/2006- 2/2010) to receive preoperative chemoradiation (CRT), surgery, and adjuvant chemotherapy with 5-FU (624 patients; control) or preoperative CRT with 5-FU and oxaliplatin, surgery, and adjuvant chemotherapy with a modified FOLFOX6 (folinic acid [leucovorin], fluorouracil, and oxaliplatin) regimen (613 patients).

In the experimental arm of the study, 50 mg/m2 of oxaliplatin was given on days 1, 8, 22, and 29 preoperatively together with 250 mg/m2 of 5-FU on days 1-14 and 22-25. Radiation therapy (RT) consisted of 50.4 Gy in 28 fractions, with a 1-week break from chemotherapy during the third week of RT.

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A long-term follow-up is necessary to determine if the inclusion of oxaliplatin into combined modality treatment for rectal cancer translates to a significantly higher three-year disease-free survival rate. ”

—Claus Rödel, MD

Rödel stated that this regimen was established by phase I/II testing prior to embarking on a large phase III trial and was associated with lower toxicity. The full-dose RT regimen was completed as scheduled by 95% of the control group and 94% of the experimental arm, while full-dose CRT was able to be completed by 80% and 85% of the patients, respectively. Both arms had a median 42-day interval from CRT to surgery, with low anterior resection being the preferred technique (64%-66%) with an abdominoperineal technique in 23% to 24% of the patients.

“An important part of our protocol was dedicated to quality control,” Rödel noted.

Pathology was used to determine the quality of surgery; complete resection was reported in 92% of patients in the control arm and 90% of patients in the experimental arm. The number of lymph nodes examined following preoperative CRT and surgery was deliberately high in order to ensure quality pathology. Rödel said that a median of 15 and 14 lymph nodes were examined in patients in the control and experimental arms of the study, respectively. Although not a predefined endpoint, pathologic complete response (pCR) was significantly higher in patients receiving oxaliplatin (16.5% vs 12.8% for the control arm; P = .045).

“I’d like to emphasize that this is the only phase III trial worldwide, apart from the ongoing German PETACC 6 trial, which is still recruiting and accruing patients, that included oxaliplatin preoperatively and postoperatively for treating locally advanced rectal cancer. A long-term follow-up is necessary to determine if the inclusion of oxaliplatin into combined modality treatment for rectal cancer translates to a significantly higher 3-year disease-free survival rate,” Rödel said.

Robert Glynne-Jones, MD, from the Mount Vernon Cancer Centre in London, praised the study for its quality assurance components. However, he noted that although the study indicated better compliance and less toxicity, determining the component of the treatment regimen responsible for DFS may prove problematic.

“If the study does show an impact on diseasefree survival, you’re not going to know which component improved [DFS],” he observed. “You’re not going to know if it was due to the chemoradiation component, the oxaliplatin component, or the postoperative adjuvant FOLFOX; you’re going to have to buy into the whole package.”

“The relative benefit of oxaliplatin is likely positive in stage II, but smaller than stage III.”

—Greg A. Yothers, PhD

A meta-analysis of 4 studies based on a pooled analysis of 4 National Surgical Adjuvant Breast and Bowel Project (NSABP) studies (C-05, C-06, C-07, and C-08) was presented by Greg A. Yothers, PhD, a research assistant professor in the department of biostatistics at the University of Pittsburgh Graduate School of Public Health. The research encompassed 4883 patients with stage II/III colorectal cancer (2009, stage II) who received 5-FU/Lv and 3788 patients (991, stage II) who received oxaliplatin and 5FU/Lv.

Yothers said the meta-analysis was performed to determine if oxaliplatin conferred benefits on patients with stage II disease, as well as to determine the benefits of oxaliplatin in high- and low-risk subsets in stage II disease. High-risk, as defined by the researchers, is perforation, T4 disease, or fewer than 12 lymph nodes examined.

He noted that the benefits of combining oxaliplatin with 5-FU/Lv were seen for overall survival (OS), DFS, and time-to-recurrence (TTR) in the overall population. However, the researchers found the hazard ratios for OS (0.95; 95% confidence interval [CI] 0.75-1.21; P = .67), DFS (0.86; 95% CI, 0.71-1.04; P = .11), and TTR (0.81; 95% CI, 0.62-1.05; P = .10) demonstrated that there is no definitive evidence that oxaliplatin is effective in stage II disease.

“The relative benefit of oxaliplatin is likely positive in stage II, but smaller than stage III,” Yothers said. However, he did observe that “The development of biomarkers to identify individual patients likely to benefit from oxaliplatin would aid in clinical decisionmaking and should be a high research priority.”

Rödel C, Becker H, Fietkau R, et. al. Preoperative chemoradiotherapy and postoperative chemotherapy with 5-fluorouracil and oxaliplatin versus 5-fluorouracil alone in locally advanced rectal cancer: first results of the German CAO/ARO/AIO-04 randomized phase III trial. J Clin Oncol. 2011;29(suppl; abstr LBA3505).

Yothers GA, Allegra CJ, O’Connell MJ, et. al. The efficacy of oxaliplatin when added to 5-fluorouracil/leucovorin in stage II colon cancer. J Clin Oncol. 2011;29(suppl; abstr 3507).