Neoadjuvant FOLFIRINOX Improves Disease Control in Advanced Rectal Cancer


FOLFIRINOX initiated before standard therapy may offer better disease-free survival for patients with rectal cancer.

Adding neoadjuvant leucovorin, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) before preoperative chemoradiotherapy produced a marked improvement in disease-free survival among patients with locally advanced rectal cancer compared with the current standard of care, according to findings recently published in The Lancet Oncology.

“The current standard of care for patients with locally advanced rectal cancer (stages T3, T4, or N+) includes chemoradiotherapy followed by total mesorectal excision. This multidisciplinary approach confers excellent local disease control, but distant recurrence rates remain high (about 30%),” Thierry Conroy, MD, of Institut de Cancérologie de Lorraine, France, and colleagues wrote. “We decided to assess a novel strategy based on the intensification of chemotherapy and its administration in the neoadjuvant setting.”

The investigators performed a multicenter, open-label, randomized phase 3 trial (NCT01804790) of patients aged 18 to 75 years with newly diagnosed stage cT3 or cT4 M0 rectal adenocarcinoma treated at 35 hospitals in France who were randomly assigned to receive either neoadjuvant FOLFIRINOX, followed by chemoradiotherapy, total mesorectal excision, and adjuvant chemotherapy (n = 231) or standard care consisting of chemoradiotherapy, resection, and adjuvant chemotherapy (n = 230). The main outcome was disease-free survival at 3 years.

Patients assigned to the neoadjuvant therapy group demonstrated a 3-year disease-free survival rate of 76% (95% CI, 69%-81%) compared with 69% (95% CI, 62%-74%) in the standard-of-care group after a median follow-up of 46.5 months (HR, 0.69; 95% CI, 0.49-0.97; P = .034).

The most common grade 3/4 adverse effects (AEs) during FOLFIRINOX therapy were diarrhea (11%) and neutropenia (17%).

Lymphopenia, the most common grade 3/4 AE of chemoradiotherapy, occurred in 28% of patients in the neoadjuvant therapy group and in 30% of the standard-of-care group. During adjuvant chemotherapy, grade 3/4 events included peripheral sensory neuropathy (12% vs 21%, respectively) and neutropenia (6% vs. 18%).

Over the entire treatment period, serious AEs occurred in slightly more than one-fourth of the neoadjuvant group (27%) compared with slightly less in the standard-of-care group (22%; P = .167). Eighteen of 163 (11%) patients in the neoadjuvant group and 36 of 128 (23%) in the standard-of-care group experienced these serious adverse events during adjuvant therapy (P = .0049). There were 3 treatment-related deaths: 1 sudden death in the neoadjuvant group (<1%), and 1 sudden death and 1 death from myocardial infarction in the standard-of-care group (1%).

“...Neoadjuvant chemotherapy with FOLFIRINOX followed by chemoradiotherapy, surgery, and adjuvant chemotherapy significantly improved outcomes in patients with locally advanced rectal cancer compared with patients who received standard chemoradiotherapy, surgery, and adjuvant chemotherapy,” the investigators wrote. “The significantly improved disease-free survival in the neoadjuvant chemotherapy group and the reduced toxicity indicate that the perioperative approach is more efficient and better tolerated than adjuvant chemotherapy is. Therefore, these results could change clinical practice.”

Future studies, “should also logically address the possibility of risk-adapted therapy, including further evaluation of non-operative management and organ-preserving strategies in selected patients following neoadjuvant chemotherapy,” in response to the high rate of complete response among patients assigned to neoadjuvant therapy.


Conroy T, Bosset J-E, Etienne P-L, et al. 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. Lancet Oncol. 2021;22(5): 702-715. doi:10.1016/S1470-2045(21)00079-6.

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