Radiation therapy can be safely omitted in select patients with locally advanced rectal cancer

Although radiation with sensitizing fluoropyrimidine (5FUCRT) is a standard curative intent treatment for locally advanced rectal cancer (LARC), it comes at the cost of both short- and long-term toxicity. Results of the phase III PROSPECT trial now demonstrate that neoadjuvant FOLFOX with selective use of 5FUCRT is non-inferior to 5FUCRT prior to a low anterior resection with total mesorectal excision in patients with LARC.

Globally, approximately 800.000 new rectal cancers will be diagnosed in 2023, with roughly half of patients presenting with locally advanced disease. Pelvic chemoradiation with either 5FU or capecitabine can reduce local pelvic recurrence. Neoadjuvant pelvic chemoradiation has been the standard treatment for the past two decades. Unfortunately however, pelvic chemoradiation comes at the cost of many toxicities, both on short-term and on long-term. Therefore, the phase III PROSPECT trial hypothesized that neoadjuvant chemotherapy with FOLFOX and only selective use of pelvic chemoradiation will be non-inferior to routine use of pelvic chemoradiation for locally advanced rectal cancer.

Study design

Between June 2012 and December 2018, 1,194 patients were enrolled in the PROSPECT trial. Eligible patients had cT2N+, cT3N-, cT3N+ rectal cancers deemed appropriate for neoadjuvant therapy prior to low anterior resection with TME. Patients with distal, T4 tumors, threatened radial margins or >4 enlarged lymph nodes were ineligible. Patients were randomised 1:1 without blinding. Patients in the control group received 5FUCRT with 5040 cGy over 5.5 weeks with either capecitabine or 5FU. Patients in the intervention group had 6 cycles of mFOLFOX6 followed by restaging. If tumour regression was >20%, then TME was performed without radiation. However, if tumour regression was <20%, 5FUCRT was given before TME. Primary endpoint was disease-free survival (DFS) and secondary endpoints included overall survival (OS), local recurrence-free survival, R0 resection, pathologic complete response (CR), and toxicity.

Results

Between June 2012 and December 2018, 1,194 patients were enrolled in the PROSPECT trial. Median age of the patients was 57 years, 34.5% were women and 61.9% had clinically positive nodes. After a median follow-up of 58 months, DFS was 78.6% for patients in the chemoradiation group and 80.8% for patients in the mFOLFOX6 with selective chemoradiation group (HR[95%CI]: 0.92[0.74-1.14]), meeting the criterion for non-inferiority. The five-year OS rates were 90.2% and 89.5%, respectively (HR[95%CI]: 1.04[0.74-1.44]). Also in terms of surgical resection rates (complete removal of the tumour and surrounding tissue), there was no difference between both study arms (97.1% for chemoradiation and 98.8% for mFOLFOX6 with selective chemoradiation). The rates of local recurrence were very low, at less than 2% for both groups. Pathologic CR was 24% for patients in the chemoradiation group and 22% for patients in the experimental arm. Finally, only 9% of patients who received mFOLFOX6 with selective chemoradiation needed preoperative chemoradiation. This was either because restaging demonstrated a clinical response <20% or they did not tolerate at least five cycles of FOLFOX.

Neoadjuvant grade ≥3 adverse events were reported in 41% of patients in the experimental arm and in 23% of patients in the standard chemoradiation arm. During neoadjuvant treatment, there was more diarrhoea in the chemoradiation group and more neuropathy in the FOLFOX group. Furthermore, adjuvant grade ≥3 adverse events occurred in respectively 25% and 39% of patients. In terms of quality of life, there was a trend (although no statistical significance) in favour of the FOLFOX arm. In addition, bowel function and sexual function were significantly in favour of the FOLFOX group.

Conclusion

Neoadjuvant FOLFOX, with only selective use of pelvic chemoradiation, is a safe and effective treatment option for patients with cT2N+, cT3N-, cT3N+ rectal cancer.

Reference

Schrag D, et al. PROSPECT: A randomized phase III trial of neoadjuvant chemoradiation versus neoadjuvant FOLFOX chemotherapy with selective use of chemoradiation, followed by total mesorectal excision (TME) for treatment of locally advanced rectal cancer (LARC) (Alliance N1048). Presented at ASCO 2023; Abstract LBA2.