De-escalation of neoadjuvant treatment of locally advanced rectal cancer is non-inferior

The 5-year results of the PROSPECT trial showed that pre-operative chemotherapy (FOLFOX) with selective pelvic chemoradiation is non-inferior to neoadjuvant pelvic chemoradiation.

Neoadjuvant pelvic chemoradiation with either 5FU or capecitabine, followed by surgery and subsequent adjuvant chemotherapy (CAPOX or FOLFOX) has been the standard-of-care for the past 2 decades in patients with locally advanced rectal cancer. However, neoadjuvant pelvic chemoradiation comes with long-term toxicity which may lead to impaired bowel, bladder, and sexual function, increased risk of 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% tumour shrinkage) or intolerability of FOLFOX. The primary endpoint was disease-free survival (DFS). The trial was designed as a non-inferiority trial (non-inferiority upper limit HR 1.29). Dr Deborah Schrag (Memorial Sloan Kettering Cancer Center, NY, USA) presented the results [1].

Enrolled were 1,128 patients (T2N⁺, T3N^-, T3N⁺) who were randomised 1:1 to FOLFOX and selective chemoradiation or chemoradiation only. After 5 years, DFS rates were similar in both arms: 80.8% in the FOLFOX arm versus 78.6% in the chemoradiation-only arm (HR 0.92; 95% CI 0.74–1.14; P=0.0051). 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-only arm, and 22% compared with 24% of patients had a pathologic complete response. More patients in the FOLFOX arm reported grade ≥3 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 adverse events during adjuvant 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.”

1. Schrag D, et al. Preoperative chemotherapy with selective chemoradiation versus chemoradiation for locally advanced rectal cancer: the PROSPECT trial (Alliance N1048). Abstract LBA2, ASCO Annual Meeting 2023, 2–6 June, Chicago, USA.
2. Schrag D, et al. N Engl J Med 2023;Jun 4. DOI: 10.1056/NEJMoa2303269.

 

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Posted on 2 August, 202328 March, 2024