Neoadjuvant chemotherapy regimen shows durable survival benefit in rectal cancer
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Key takeaways:
- Seven-year estimates favored the neoadjuvant FOLFIRINOX group vs. the standard-of-care group for all survival outcomes.
- Researchers also observed no increase in local relapses with total neoadjuvant therapy.
CHICAGO — Administering modified FOLFIRINOX chemotherapy before chemoradiation, surgery and adjuvant chemotherapy improved survival outcomes of patients with locally advanced rectal cancer, according to results of the PRODIGE 23 trial.
“The most important point of PRODIGE 23 is the overall survival benefit,” Thierry Conroy, MD, of the department of medical oncology at Institut de Cancérologie de Lorraine in France, told Healio. “Since the Swedish Rectal Cancer Trial of preoperative radiotherapy in 1997, no further long-term OS improvement had been reported in a trial.”
Background, methodology
Previously reported results of the randomized phase 3 PRODIGE 23 trial showed the total neoadjuvant therapy (TNT) approach significantly prolonged DFS and reduced neurotoxicity among patients with stage cT3 or cT4, M0 rectal cancer.
At ASCO Annual Meeting, Conroy presented 7-year results of the primary endpoint (DFS) and secondary endpoints, which included OS, pathologic complete response, metastases-free survival, quality of life and toxicity.
The study included 461 patients aged 18 to 75 years at 35 centers who had a WHO performance score of 1 or less. Researchers randomly assigned 230 patients (median age, 62 years) to preoperative chemoradiotherapy consisting of 50.4 Gy at 2 Gy/fraction for 25 fractions plus capecitabine, total mesorectal excision and adjuvant chemotherapy for 6 months. The other 231 patients (median age, 61 years) received neoadjuvant chemotherapy with modified FOLFIRINOX (85 mg/m2 oxaliplatin, 180 mg/m2 irinotecan, 400 mg/m2 leucovorin, and 2,400 mg/m2 fluorouracil via IV every 14 days for six cycles), followed by the same preoperative chemoradiotherapy regimen, surgery and adjuvant chemotherapy with modified FOLFOX6 or capecitabine for 3 months.
Researchers stratified randomization by center, T stage, N status, location of the tumor and tumor extramural spread. They used a stratified Cox proportional hazard model to estimate HRs and 95% CIs for survival outcomes. However, they observed nonproportional hazard, which may have made use of the HR estimate misleading, Conroy said. Therefore, they evaluated treatment effect using restricted mean survival time (RMST).
Median follow-up was 82.2 months (95% CI, 79.8-83.5).
Results
Fifty-five patients in the standard-of-care group died, compared with 42 patients in the neoadjuvant modified FOLFIRINOX group.
Seven-year estimates favored the TNT group vs. the standard-of-care group for all survival outcomes, including DFS (67.6% vs. 62.5%; stratified HR = 0.8; 95% CI, 0.58-1.11), metastasis-free survival (73.6% vs. 65.4%; stratified HR = 0.73; 95% CI, 0.51-1.02), OS (81.9% vs. 76.1%; stratified HR = 0.73; 95% CI, 0.48-1.09) and cancer-specific survival (84.9% vs. 79.6%; stratified HR = 0.66; 95% CI, 0.42-1.05).
Differences in RMST at 84 months of follow-up showed gains of 5.7 months (95% CI, 0.05-11.4) in DFS, 7.1 months (95% CI, 1.7-12.6) in metastasis-free survival, 4.3 months (95% CI, 0.4-8.4) in OS and 3.8 months (95% CI, -0.02 to 7.7) in cancer-specific survival with the TNT vs. standard-of-care regimen.
Conroy noted “the absence of increase in local relapses and the durable benefit in decrease in metastases in the experimental arm.”
Researchers did not observe the ATRESS (neoadjuvant therapy-related shortening of survival) phenomenon, with no decrease in survival after distant failure in the TNT group (median OS, 44.4 months vs. 39.4 months).
The neoadjuvant modified FOLFIRINOX group had a numerically lower 7-year cumulative incidence of locoregional relapse than the standard-of-care group (5.3% vs. 8.1%).
“TNT with induction modified FOLFIRONOX should now be considered as one of the best options of care for patients with locally advanced rectal cancers,” Conroy said during a presentation. “The strategy is now investigated in rectal cancer for tailored management according to response to induction modified FOLFIRINOX.”
References:
- Conroy T, et al. Abstract LBA3504. Presented at: ASCO Annual Meeting; June 2-6, 2023; Chicago.
- Conroy T, et al. Lancet Oncol. 2021;doi:10.1016/S1470-2045(21)00079-6.
Perspective
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A move toward total neoadjuvant therapy in rectal cancer has been driven by enhanced rates of therapy delivery, increased rates of pathologic response leading to potential nonoperative management in clinical complete responders, and the possibility of improved DFS and OS.
The initial report of PRODIGE 23 and the contemporarily reported RAPIDO trial using total neoadjuvant therapy both indicated neoadjuvant therapy was safe, feasible and resulted in an increase in pathologic complete response compared with conventional chemoradiotherapy. Both studies also showed improvement in [metastasis-free survival] with total neoadjuvant therapy.
The results of PRODIGE 23 at median follow-up of 82 months reinforce adoption of total neoadjuvant therapy as a care standard in rectal cancer for patients who require radiotherapy. The increase in pathologic complete response rate with total neoadjuvant therapy compared with conventional therapy supports this approach in candidates for nonoperative management who are clinical complete responders. Whether the benefits seen in PRODIGE 23 emerge purely from the earlier use of systemic chemotherapy or from the addition of irinotecan to FOLFOX remains to be established.
Memorial Sloan Kettering Cancer Center
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Conroy T, et al. Abstract LBA3504. Presented at: ASCO Annual Meeting; June 2-6, 2023; Chicago.
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