Globally, rectal cancer is a major health issue, with about 800,000 new cases diagnosed in 2023 alone, of which around half have been proven to be locally advanced.¹ Neoadjuvant pelvic chemoradiation (CRT) in combination with either fluorouracil (5FU) or capecitabine followed by a total mesorectal excision (TME) has become the accepted standard of care for the past 2 decades.¹ Although it is effective in providing curative intent, there is a plethora of toxicities that come from pelvic CRT including impaired bowel, bladder, and sexual function, in addition to an increased risk of pelvic fracture and secondary malignancies, impaired marrow reserves, as well as links to infertility and premature menopause.¹ Advancement in chemotherapy regimens has given birth to other options over the last 2 decades such as FOLFOX (i.e., leucovorin calcium, 5FU, and oxaliplatin).¹ In ASCO 2023, Professor Deborah Schrag from Weill Cornell Medicine, the United States (US), shared her team’s results of the PROSPECT trial.¹

The PROSPECT study was designed to investigate whether neoadjuvant chemotherapy with FOLFOX and only the selective use of pelvic CRT is non-inferior to the routine use of pelvic CRT in the management of locally advanced rectal cancer.¹ Patients from the US, Canada, and Switzerland at clinical staging of T2N+, T3N-, and T3N+ rectal cancer indicated for CRT from 2012-2018 were enrolled in the study with the exclusion of those who had distal, T4 tumors, threatened radial margins, or >4 enlarged lymph nodes.¹

Patients were randomized 1:1 to receive pelvic CRT (n=543) or 6 cycles of the FOLFOX regimen (n=585).¹ The mean age of the participants was 57 years old in both groups.¹ The baseline staging of both groups was also similar with T2N+ (11% vs. 7%), T3N- (39% vs. 37%), and T3N+ (50% vs. 56%) in the FOLFOX regimen group and the pelvic CRT group, respectively.¹ Patients in the pelvic CRT arm received 5,040cGy of radiation in 5.5 weeks together with either capecitabine or 5FU.¹ Patients in the intervention group received 6 cycles of FOLFOX and underwent restaging at the end of the 6 cycles.¹ If tumor regression was >20%, TME was performed without radiation, otherwise, pelvic CRT was given prior to TME.¹ Ultimately, 9% of patients (n=53) in the FOLFOX group received neoadjuvant CRT.¹

The primary endpoint was disease-free survival (DFS), which was defined as the time from randomization to any recurrence or death.¹ Non-inferiority margin was defined as hazard ratio (HR) <1.29.¹ Data were analyzed after 227 events with a median follow-up of 58 months.¹ The 5-year DFS in the pelvic CRT group was 78.6% (90.2% CI: 75.4-81.8) and 80.8% (90.2% CI: 77.9-83.7) in the FOLFOX group.¹ Non-inferiority was achieved with an HR of 0.92 (90.2% CI: 0.74-1.14; p=0.0051).¹ HR was 0.90 (90.2% CI: 0.73-1.13) after adjusting for age and staging, which also met the non-inferiority criterion.¹

The secondary endpoints included overall survival (OS), local recurrence free survival (RFS), complete rectal resection (R0), pathologic complete response (CR), and toxicity.¹ The 5-year local RFS was 98.4% (95% CI: 97.3-99.6) in the CRT group and 98.2% (95% CI: 97.1-99.4) in the FOLFOX group.¹ The 5-year OS was 90.2% (95% CI: 87.6%-92.6) in the CRT group and 89.5% (95% CI: 87.0-92.2) in the FOLFOX group.¹ Superiority of the FOLFOX group over the CRT group was achieved in 5-year OS (HR=1.04; 95% CI: 0.74-1.44; p=0.84) and 5-year local RFS (HR=1.18; 95% CI: 0.44-3.16; p=0.74).¹ Superiority was also achieved in R0 resection (97.1% vs. 98.9%; p=0.094) and pathologic CR (24.3% vs. 21.9%; p=0.35) among patients who had TME in the CRT group and the FOLFOX group, respectively.¹ During the neoadjuvant treatment, more cases of diarrhea were reported in the CRT group, whereas more cases of neuropathy were reported in the FOLFOX group.¹ With regard to the adjuvant treatment, more cases of diarrhea and neuropathy were reported in the CRT group.¹ There was no significant difference between the quality of life of the 2 groups.¹

In conclusion, neoadjuvant FOLFOX with selective pelvic CRT is a safe and effective alternative for patients with locally advanced rectal cancer.¹