The PROSPECT study showed that neoadjuvant FOLFOX, with selective use of pelvic chemoradiation, is safe and effective for locally advanced rectal cancer.
Neoadjuvant pelvic chemoradiation with either 5FU or capecitabine, followed by surgery and subsequent adjuvant chemotherapy (CAPOX or FOLFOX) has been standard of care for the past two decades in patients with locally advanced rectal cancer. However, neoadjuvant pelvic chemoradiation comes with long-term toxicity: impaired bowel, bladder, and sexual function, increased risk for pelvic fracture, impaired marrow reserve, and infertility.
The PROSPECT trial (NCT01515787) was designed to evaluate the de-escalation of neoadjuvant chemoradiation in patients with locally advanced rectal cancer. The study compared standard-of-care pelvic chemoradiation with neoadjuvant FOLFOX (6 cycles) and chemoradiation only in case of poor response to neoadjuvant FOLFOX (<20% tumor shrinkage) or intolerability of FOLFOX. The primary endpoint was disease-free survival (DFS). The trial was designed as a non-inferior (non-inferiority upper limit HR, 1.29). Deborah Schrag, MD, MPH, presented the results at the 2023 ASCO Annual Meeting, held June 2-6 in Chicago.
Enrolled were 1,128 patients (T2N-positive, T3N-negative, T3N-positive) who were randomly assigned 1:1 to FOLFOX and selective chemoradiation or chemoradiation. After 5 years, DFS rates were similar in both arms: 80.8% in the FOLFOX arm versus 78.6% in the chemoradiation arm (HR, 0.92; 95% CI, 0.74-1.14). This means PROSPECT met its endpoint. Of note, only 9% of patients in the FOLFOX arm (53/585) received chemoradiation. In addition, local recurrence-free and overall survival were non-inferior (HR, 1.18 and 1.04, respectively).
Complete rectal resection (R0) was 99% in the FOLFOX arm compared with 97% in the chemoradiation arm, and 22% compared with 24% of patients had a pathologic complete response. More patients in the FOLFOX arm reported grade 3 or greater adverse events during neoadjuvant treatment (41% and 23%). Of note, the duration of neoadjuvant treatment was doubled in the FOLFOX arm (12 weeks vs 6 weeks). Grade 3 or greater adverse events during adjustment treatment were more common in the chemoradiation arm (39% vs 25%).
Based on these results, Dr. Schrag concluded that “neoadjuvant FOLFOX, with only selective use of pelvic chemoradiation, is a safe and effective treatment option for patients with locally advanced rectal cancer. However, other treatment approaches have advanced since the study began, and overtreatment associated with neoadjuvant rectal cancer therapy remains a concern.”
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