Longer median disease-free survival was observed in a multicenter, randomized, open-label, Phase III study of patients with locally advanced rectal cancer who had neoadjuvant chemotherapy with FOLFIRINOX (oxaliplatin, irinotecan, leucovorin, and fluorouracil) before standard chemoradiotherapy and total mesorectal excision. Patients were compared with a control group who had the standard therapy alone.
Findings reported in The Lancet Oncology also show that adverse risk factors-including distant metastasis-were favorably impacted by the neoadjuvant therapy, and that there was no increase in the incidence of serious toxicities (2021; https://doi.org/10.1016/S1470-2045(21)00079-6).
"This strategy of neoadjuvant chemotherapy, then chemo-radiation [and surgery], is a new option of care for all patients with T3 or T4 rectal cancer," said lead author Thierry Conroy, MD, Professor of the Department of Medical Oncology at Institut de Cancerologie de Lorraine. "This improved complete response rate and increased disease-free survival. And this should be discussed with the patients."
The study authors wrote: "Significantly improved disease-free survival in the neoadjuvant chemotherapy group, and reduced toxicity, indicate that the perioperative approach is more efficient and better tolerated than adjuvant chemotherapy. Therefore, these results could change clinical practice."
Conroy said the main reason for doing the study had been that for 20 years there had been no further survival benefits reported among patients with locally advanced rectal cancer treated with chemoradiotherapy followed by total mesorectal excision. There had been improvement in local recurrence rates-which had declined from 40 percent to about 5 percent, he said, but not in overall survival. He attributed this to the fact that there had still been a "substantial rate" of distant metastases-around 30 percent at 5 years.
Adjuvant chemotherapy had failed to improve survival. "There was no proof of efficacy of adjuvant chemotherapy," said Conroy, with no survival benefit in most trials-despite the fact that longer disease-free survival had been reported. "This may be due to the low compliance [with] adjuvant chemotherapy in all trials [around 50 percent]," he said.
Conroy explained that the idea of doing the Phase III study had been to determine whether using initial chemotherapy could reduce the rate of micrometastasis, and improve both disease-free and overall survival. He said the components of the regimen had been important: "[This was] polychemotherapy with FOLFIRINOX: Not [just] FOLFOX, but: FOLFOX with irinotecan," he emphasized.
All patients had chemoradiotherapy plus total mesorectal excision followed by 3 months adjuvant chemotherapy. "In both groups, patients received the same schedule of chemoradiation, the same surgery, and the same total duration of chemotherapy-6 months," he said.
Study Details
The study randomized adults aged up to 75 years who had newly diagnosed, biopsy-proven, rectal adenocarcinoma (stage cT3 or cT4 M0, and World Health Organization performance status of 0-1) to either the usual standard of care or the same preceded by neoadjuvant chemotherapy.
A total of 461 patients were randomly assigned to the French standard of care-with or without neoadjuvant chemotherapy. Patients in the investigational arm received FOLFIRINOX intravenously every 14 days for 6 cycles. After this, they had the standard chemoradiotherapy (50 gray for 5 weeks with concurrent oral capecitabine twice daily for 5 days per weeks), total mesorectal excision, and then adjuvant chemotherapy (3 months of modified FOLFOX6 (intravenous oxaliplatin and leucovorin, followed by intravenous fluorouracil bolus and then continuous infusion over 46 hours every 14 days for 6 cycles, or capecitabine orally twice daily on days 1-14 every 21 days).
Patients in the standard-of-care control arm received chemoradiotherapy, total mesorectal excision, and adjuvant chemotherapy (for 6 months). The primary endpoint was disease-free survival (assessed in the intention-to-treat population) at 3 years.
At a median follow-up of 46.5 months, 3-year disease-free survival rates were 76 percent in the neoadjuvant chemotherapy group and 69 percent in the standard-of-care group. The "stratified" hazard ratio was 0.69 with a p-value of 0.034.
Conroy said that, in addition to having significantly fewer recurrences, patients treated with neoadjuvant therapy had lower rates of distant metastasis and of unresectable tumors during surgery. Postoperative mortality and high-grade postoperative complications were also significantly reduced among patients who had neoadjuvant therapy. And the standard adjuvant chemotherapy was better tolerated in these patients-with lower rates of peripheral neuropathy.
Pathology findings after surgery had shown significant improvements in pathological complete response rate, tumor regression, and the number of metastatic regional lymph nodes among patients treated with neoadjuvant chemotherapy compared with controls. The neoadjuvant "rectal score" (described as "a strong surrogate endpoint" for disease-free survival) had also been significantly lower among patients treated with neoadjuvant chemotherapy. The authors wrote that the significant improvement in metastasis-free survival suggested that shifting systemic chemotherapy to an earlier time in the treatment sequence might control distant metastases without increasing locoregional failure.
At the time of reporting the study had not yet shown a survival benefit, Conroy conceded. He was hopeful the 5-year analysis would reveal one, but believed the study data already provided grounds for changing practice.
"On pathology specimens, we had a high rate of complete response, 28 percent in the new treatment versus 12 percent, and this may be important for future wait-and-watch strategy," he said.
The study found toxicity trade-offs. "During preoperative chemotherapy we had a moderate toxicity-with 2 percent of febrile neutropenia, 11 percent of grade 3/4 diarrhea-but at the same time with improved symptoms: disappearance of all rectal symptoms within 6 weeks. Looking at serious adverse events there was no difference," said Conroy. Serious adverse events had occurred in 63 (27%) of 231 participants in the neoadjuvant chemotherapy group and 50 (22%) of 230 patients in the standard-of-care group (p=0.167) during the whole treatment period.
Serious adverse events during adjuvant therapy occurred in 18 (11%) of 163 participants in the neoadjuvant chemotherapy group and 36 (23%) of 158 patients in the standard-of-care group (p=0.0049). There was a single treatment-related death out of 226 patients in the neoadjuvant chemotherapy group and two deaths from 227 patients in the standard-of-care group.
The report concluded: "To our knowledge, this is the first study to provide evidence of improved long-term disease-related outcomes with neoadjuvant chemotherapy in patients with locally advanced rectal cancer. Compliance with FOLFIRINOX in our study was very high, with more than 90 percent of patients completing 6 cycles of treatment, thus avoiding one of the major shortfalls of adjuvant chemotherapy."
Peter M. Goodwin is a contributing writer.