Adding Oxaliplatin in Neoadjuvant CTRT for Rectal Cancer

From the JCO this week:

The ACCORD trial is a randomized phase III trial looking at two CTRT regimens for T3-T4 rectal tumors: 45Gy/25fx + Capecitabine vs 50Gy/25fx + Capecitabine and Oxaliplatin. It is a bit perplexing as to why the investigators decided to add a slightly different RT regimen to the randomization, as it makes the more important question (that of the addition of oxaliplatin) more difficult to evaluate. Nonetheless, their primary endpoint was pCR, and they powered the study to detect an increase from 11% in the control arm to 20% in with oxalipatin (and 5 more Gy).

Results demonstrate a non-significant difference in pCR of 13.9% in the control arm, and a 19.2% with oxaliplatin and 5 additional Gy (p=0.09). G3-4 toxicities were increased at 10.9% 45Gy + capecitabine vs 25.4% 50Gy + capox. The investigators state in their conclusions that oxaliplatin should not be used, and 50Gy with capcitabine should be explored. I would not necessarily be so quick to dismiss oxaliplatin, as the absolute difference in pCR was 5.3%, a result which might not be stasticaly significant, but may be clinical relevant, given the other interventions we pursue for a 5% benefit.

I think at the end of the day, we are left in the same position as before, with oxaliplatin being unproven but potentially worthwhile, and waiting for the NSABP-R04 trial to accrue and report (goal of 1,606 patient accrual, 2x2 randomization of capecitabine vs 5-FU and oxaliplatin vs no-oxaliplatin).

Link and abstract -

Comparison of Two Neoadjuvant Chemoradiotherapy Regimens for Locally Advanced Rectal Cancer: Results of the Phase III Trial ACCORD 12/0405-Prodige 2 [Gastrointestinal Cancer]: "Purpose

Neoadjuvant chemoradiotherapy is considered a standard approach for T3-4 M0 rectal cancer. In this situation, we compared neoadjuvant radiotherapy plus capecitabine with dose-intensified radiotherapy plus capecitabine and oxaliplatin.

Patients and Methods

We randomly assigned patients to receive 5 weeks of treatment with radiotherapy 45 Gy/25 fractions with concurrent capecitabine 800 mg/m² twice daily 5 days per week (Cap 45) or radiotherapy 50 Gy/25 fractions with capecitabine 800 mg/m² twice daily 5 days per week and oxaliplatin 50 mg/m² once weekly (Capox 50). The primary end point was complete sterilization of the operative specimen (ypCR).

Results

Five hundred ninety-eight patients were randomly assigned to receive Cap 45 (n = 299) or Capox 50 (n = 299). More preoperative grade 3 to 4 toxicity occurred in the Capox 50 group (25 v 1%; P < .001). Surgery was performed in 98% of patients in both groups. There were no differences between groups in the rate of conservative surgery (75%) or postoperative deaths at 60 days (0.3%). The ypCR rate was 13.9% with Cap 45 and 19.2% with Capox 50 (P = .09). When ypCR was combined with yp few residual cells, the rate was respectively 28.9% with Cap 45 and 39.4% with Capox 50 (P = .008). The rate of positive circumferential rectal margins (between 0 and 2 mm) was 19.3% with Cap 45 and 9.9% with Capox 50 (P = .02).

Conclusion

The benefit of oxaliplatin was not demonstrated and this drug should not be used with concurrent irradiation. Cap 50 merits investigation for T3-4 rectal cancers."