Adjuvant chemotherapy following chemoradiation therapy and surgery
Many academic oncologists recommend that FOLFOX be considered the standard for adjuvant chemotherapy in rectal cancer. However, there are no data in rectal cancer to support this consideration. FOLFOX has become the standard arm in the latest Intergroup study evaluating adjuvant chemotherapy in rectal cancer. An Eastern Cooperative Oncology Group trial (ECOG-E5202 [NCI-2009-00562]) randomly assigned patients with stage II or III rectal cancer who have received preoperative or postoperative chemoradiation therapy to 6 months of FOLFOX with or without bevacizumab.
Oxaliplatin with chemoradiation therapy
Oxaliplatin has also been shown to have radiosensitizing properties in preclinical models; and phase II studies combining this agent with fluoropyrimidine-based chemoradiation have reported pathologic complete response (pCR) rates ranging from 14% to 30%.[28,29,30,31,32] Data from multiple studies have demonstrated a correlation between rates of pCR and endpoints including distant metastasis-free survival, DFS, and OS.[33,34,35]
pCR was the primary endpoint (albeit never validated as a true surrogate of OS) in the ACCORD 12/0405-Prodige 2 trial, which randomly assigned 598 patients with clinically staged T2 or T3 or resectable T4 rectal cancer accessible to digital rectal examination to either preoperative radiation (45 Gy in 25 fractions over 5 weeks) with capecitabine (800 mg/m2 twice daily five of every 7 days) or to a higher dose of radiation (50 Gy in 25 fractions over 5 weeks) with the same dose of capecitabine and oxaliplatin (50 mg/m2 weekly). TME was performed in 98% of both groups at a median interval of 6 weeks after chemoradiation was completed. Although a higher percentage of patients achieved a pCR in the oxaliplatin-treated group (19.2% vs. 13.9%), the difference did not reach statistical significance (P = .09). Moreover, the rate of grade 3 or 4 toxicity was significantly higher in the oxaliplatin-treated group (25% vs. 11%, P < .001), and there was no difference in sphincter-sparing surgery (75% vs. 78%). Therefore, there is no current role for off-trial use of concurrent oxaliplatin and radiation in the treatment of patients with rectal cancer.
The STAR-01 trial similarly investigated the role of oxaliplatin combined with 5-FU chemoradiation for locally advanced rectal cancer. This Italian study randomly assigned 747 patients with resectable, locally advanced, clinically staged T3 or T4 and/or clinical N1 to N2 adenocarcinoma of the mid- to low-rectum to receive either continuous-infusion 5-FU with radiation or to receive the same regimen in combination with oxaliplatin (60 mg/m2). Although the primary endpoint was OS, a protocol-planned analysis of response to preoperative therapy has been preliminarily reported. The rate of pCR was equivalent at 16% in both arms (OR 0.98; 95% CI, 0.66–1.44, P = .904). Additionally, there was no difference noted in the rate of pathologically positive lymph nodes, tumor infiltration beyond the muscularis propria, or the rate of circumferential margin positivity. Again, an increase in grades 3 to 4 treatment-related acute toxicity was noted with the addition of oxaliplatin (24% vs. 8%, P <.001). Longer-term outcomes including OS have not yet been reported.[Level of evidence: 1iiA]