Total neoadjuvant therapy with mFOLFIRINOX as a new option of care for the initial management of patients with locally advanced rectal cancer

The multi-centre, open-label randomised phase III PRODIGE 23 trial compared neoadjuvant chemotherapy with mFOLFIRINOX followed by preoperative chemoradiotherapy (CRT) versus preoperative CRT in patients with locally advanced rectal cancer. Final results of the trial demonstrate that upfront chemotherapy with mFOLFIRINOX significantly increased the probability of achieving a pathological complete response and increased the chance for curative-intent surgery. In addition, neoadjuvant chemotherapy was also shown to significantly improve the disease-free (DFS) and metastasis-free survival (MFS) of patients.

Introduction

Since 2004, preoperative chemoradiotherapy (CRT) followed by total mesorectal excision (TME) has been the standard of care for patients with stage II/III rectal cancer (T3-4, N0 or N+). We even have to go back in time to 1997 to find the last clinical trial that was able to demonstrate a significant improvement in MFS and overall survival (OS) in this setting. Nevertheless, the medical need in patients with stage II/III rectal cancer remains high, with distant metastases developing in 25-30% of patients enrolled in recently published clinical trials. Although controversial (except for ypN+), adjuvant chemotherapy after CRT and TME is increasingly being used, but feasibility and compliance are usually poor (43-70%). Superior tolerability and compliance have been reported with neoadjuvant chemotherapy before CRT (total neoadjuvant therapy, TNT). In addition, the FOLFIRINOX regimen has a high response rate (66-86%) in metastatic colorectal cancer. Therefore, TNT with mFOLFIRINOX versus preoperative chemoradiation in patients with locally advanced rectal cancer was studied in the phase III PRODIGE 23 trial.

Eligible patients for the multicentre, randomised PRODIGE 23 trial had cT3 or cT4, M0 rectal adenocarcinomas <15 cm from the anal verge, were 18 to 75 years of age, and had a WHO performance status of 0-1. Patients randomised to CRT (N=230) received preoperative CRT (50 Gy, 2 Gy/fraction [fr]; 25 fr + capecitabine), surgery and then adjuvant chemotherapy for 6 months. Patients in the TNT arm (N=231) received 6 cycles of mFOLFIRINOX (oxaliplatin 85 mg/m², leucovorin 400 mg/m², irinotecan 180 mg/m² D1, and 5-FU 2.4 g/m² over 46h) every 14 days, followed by the same preoperative CRT, surgery and 3 months of adjuvant chemotherapy. Adjuvant chemotherapy consisted of mFOLFOX6 or capecitabine, depending on the treating centre. Randomisation was stratified by centre, T-stage, N-status, tumour location, and perirectal fat extramural extension. The primary endpoint of the trial was disease-free survival (DFS).

Results

At ASCO 2020, the final results of the PRODIGE 23 trial were presented, after a median follow-up of 46.5 months. Neoadjuvant mFOLFIRINOX was generally well tolerated and patient compliance was high (91.6% completed 6 cycles). The most common grade 3/4 adverse events were neutropenia (16.9%) and diarrhea (11.1%). In addition, the compliance with chemoradiotherapy was high with 98% of patients in both arms receiving at least 48 Gy of radiotherapy. The capecitabine discontinuation rate was 8.3% in the mFOLFORINOX arm and 3.1% in the CRT arm (p< 0.02). The postoperative surgical morbidity did not differ between the two arms (29.3% in the TNT arm versus 31.2% in the CRT arm). Importantly, the rate of complete or near-complete tumour regression, a good predictor of survival, was significantly increased in the mFOLFORINOX arm (p= 0.003) with also more than twice as much patients having a tumour that was classified as ypT0N0 (12.1 versus 27.8% in the CRT and TNT arms, respectively (p< 0.001). In total, 80.4% of patients in the TNT arm completed all the adjuvant treatment cycles and this was also the case for 75.3% of patients randomized to CRT (in most patients [+80%], the adjuvant therapy consisted of mFOLFOX6). With respect to the safety of the adjuvant therapy it is important to note that per protocol patients in the CRT arm received adjuvant therapy for 6 months, while this was only 3 months in the TNT arm. As such it is no surprise to see a higher rate of grade 3/4 adverse events in the CRT arm compared to TNT (74.1% versus 44.4%; p<0.001). The rate of grade 3/4 peripheral neuropathy was 11.7% in the TNT arm as compared to 20.7% with CRT. To facilitate a more direct comparison of the toxicity the investigators made a comparison between the adverse events during adjuvant therapy only taking into account the first 3 months. During the first 3 months of adjuvant therapy in the CRT arm, the incidence of grade 3/4 adverse events was 52.5%, which is still higher than the 44.4% reported with TNT. As such, it is safe to say that for the same duration of chemotherapy, the perioperative approach is better tolerated than the adjuvant chemotherapy.

The three-year DFS-rate for patients in the TNT arm was reported at 75.7%, which is significantly better than the 68.5% seen in the CRT arm (HR [95%CI]: 0.69 [0.49-0.97], p=0.034). In addition, also the three-year metastases-free survival rate was significantly increased from 71.7% for patients in the CRT group, to 78.8% for patients in the TNT group (HR [95%CI]: 0.64 [0.44-0.93], p=0.017). Of note, 54.2% of the patients with relapse were alive at the time of the analysis and no difference in overall local relapse rates (4.8% versus 7%) was observed. Finally, there were no statistical differences in baseline health-related quality of life (HRQoL) between arms and the overall Global Health Status/ QoL improved over time in both arms (p< 0.001), with a trend in favour of the TNT regimen (p=0.076). Over time, some symptoms scores were significantly lower in the TNT group, including less impotence (evolution of scores of time: p=0.077, time to deterioration 10-points MCID: p=0.006).

Conclusions

This trial demonstrates that mFOLFIRINOX is a safe regimen with manageable toxicities without impairing the overall treatment feasibility and tolerance in stage II/III rectal cancer. Upfront chemotherapy with mFOLFIRINOX significantly increases the probability of achieving pathological complete response and the probability of curative-intent surgery as well as improved the DFS and MFS. Global quality of life scores are not significantly different between groups but support mFOLFIRINOX over time. Total neoadjuvant therapy with mFOLFIRINOX should therefore now be considered as a new option of care for the initial management of patients with T3-4 rectal cancers.

Reference

Conroy T, Lamfichekh N, Etienne PL, et al. Total neoadjuvant therapy with mFOLFIRINOX versus preoperative chemoradiation in patients with locally advanced rectal cancer: Final results of PRODIGE 23 phase III trial, a UNICANCER GI trial. Presented at ASCO 2020; Abstract 4007.