SUMMARY: The American Cancer Society estimates that 45,230 new cases of rectal cancer will be diagnosed in the US in 2021. Based on the information from the SEER database, the 5-year relative survival rates for rectal cancer, all SEER stages combined, is 67%. The current standard of care for patients with locally advanced rectal cancer (Stages T3, T4, or N+) consists of Chemoradiation followed by Total Mesorectal Excision (TME), which provides good local disease control, although distant metastases can still occur. Adjuvant chemotherapy after preoperative Chemoradiation remains controversial, as it has not shown an improvement in Overall Survival (OS). This has been attributed in part to poor treatment compliance. Phase II trials of total neoadjuvant therapy have yielded promising results but there is presently no data from Phase III trials.
The Phase III PRODIGE 23 trial sponsored by the French UNICANCER GI group, investigated the role of neoadjuvant modified FOLFIRINOX before standard preoperative chemoradiotherapy, in patients with locally advanced rectal cancer. The aim of the study was to assess whether administering neoadjuvant chemotherapy before preoperative Chemoradiation could reduce the risk of distant recurrences. In this study, 461 patients were randomly assigned 1:1 to either the neoadjuvant chemotherapy group (N=231) or the standard-of-care Chemoradiation group (N=230). Eligible patients had newly diagnosed, biopsy-proven, rectal adenocarcinoma staged cT3 or cT4 M0, with a Performance Status of 0-1. The neoadjuvant chemotherapy group received preoperative chemotherapy with FOLFIRINOX (Oxaliplatin 85 mg/m2 IV, Irinotecan 180 mg/m2 IV, Leucovorin 400 mg/m2 IV, and Fluorouracil 2400 mg/m2 IV as a continuous infusion over 46 hours every 14 days for 6 cycles), followed by Chemoradiation (50 Gy over 5 weeks along with concurrent Capecitabine 800 mg/m2 orally twice daily for 5 days per week), followed by Total Mesorectal Excision, and adjuvant chemotherapy which consisted of modified FOLFOX6 (Oxaliplatin 85 mg/m2 IV and Leucovorin 400 mg/m2 IV, followed by Fluorouracil 400 mg/m2 IV bolus and then Fluorouracil 2400 mg/m2 continuous infusion over 46 hours) every 14 days for six cycles or Capecitabine 1250 mg/m2 orally twice daily on days 1-14 every 21 days.
The Chemoradiotherapy group received preoperative Chemoradiation (50.4 Gy over 5 weeks along with Capecitabine 800 mg/m2 orally twice daily for 5 days per week), followed 7 weeks later by Total Mesorectal Excision and adjuvant chemotherapy, which consisted of 6 months (12 cycles) of modified FOLFOX or 6-8 cycles of Capecitabine. It should be noted that patients received the same schedule of Chemoradiation, the same surgery, and the same total duration of chemotherapy (6 months) in both groups.
The Primary endpoint was Disease Free Survival (DFS) at 3 years. Secondary endpoints included Overall Survival (OS), Metastasis-Free Survival (MFS), and Cancer-Specific Survival (CSS). Safety analyses were performed on treated patients. More than 90% of patients received all planned cycles of FOLFIRINOX.
At a median follow-up of 46.5 months, the 3-year DFS rates were 76% in the neoadjuvant chemotherapy group and 69% in the standard-of-care group (HR=0.69; P=0.034). This represented a 31% reduction in the DFS hazard in the neoadjuvant group. Metastasis-Free-Survival at 3 years was significantly improved in the neoadjuvant group (79% vs 72%, P=0.017) and the pathologic Complete Responses were also significantly higher in the neoadjuvant group (28% versus 12%; P<0.001).
FOLFIRINOX was reported to be well tolerated with 92% compliance rate with this regimen. There were significantly more grade 3 or 4 adverse events in the Chemoradiation group, especially neutropenia and neuropathy. There were significantly more Grade 3 or 4 adverse events associated with adjuvant chemotherapy in the Chemoradiation control group (79% versus 45%, P<0.0001). Grade 3 or 4 neutropenia, thrombocytopenia, lymphopenia and neuropathy, all occurred significantly more often in the patients who received 6 months of adjuvant therapy (Chemoradiation group), suggesting that for the same duration of chemotherapy, the perioperative approach was better tolerated than adjuvant chemotherapy.
The authors concluded that chemotherapy intensification using FOLFIRINOX before preoperative Chemoradiation significantly improved outcomes, with better tolerance and decreased neurotoxicity, compared with standard-of-care preoperative Chemoradiation, among patients with cT3 or cT4 M0 rectal cancer.
Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial. Conroy T, Bosset J-F, Etienne P-L, et al. Lancet Oncol. 2021;22:702-715.