In a randomised, controlled, non-inferiority PROSPECT study conducted in the US, Canada, and Switzerland in patients with locally advanced rectal cancer, compared with the current standard of neoadjuvant pelvic chemoradiation with 5-fluorouracil, patients receiving neoadjuvant FOLFOX followed by selected use of chemoradiation experienced significantly lower rates of diarrhoea and better overall bowel function, but higher rates of anxiety, appetite loss, constipation, depression, dysphagia, dyspnoea, oedema, fatigue, mucositis, nausea, neuropathy, and vomiting.
Once treatment was complete, 12 months after surgery, most acute treatment-related symptomatic adverse events had resolved in both groups, although significantly higher rates of fatigue, neuropathy, and sexual dysfunction persisted among patients assigned to receive neoadjuvant pelvic chemoradiation with 5-fluorouracil. These findings were similar at 18 months. Despite these differences in symptoms and functioning between groups, overall health-related quality-of-life (HRQoL) did not significantly differ between groups at any time point. The findings were presented in part at 2023 ASCO Annual Meeting in Chicago, IL, US and published by Dr. Ethan Basch of the Division of Oncology, University of North Carolina in Chapel Hill, NC, US, and colleagues on 4 June in the Journal of Clinical Oncology. Drs. Ethan Basch and Amylou C. Dueck contributed equally to this work.
The authors wrote in the background that since 1990, management for patients with locally advanced rectal cancer has included pelvic chemoradiation with fluorouracil administered in 28 fractions over 5.5 weeks to reduce the risk of pelvic recurrence, with neoadjuvant pelvic chemoradiation with fluorouracil demonstrating better local control and tolerability than given in the adjuvant setting. Pelvic chemoradiation with fluorouracil is associated with both short-term and long-term adverse events, in particular impaired bowel, and sexual function.
The PROSPECT (N1048) randomised study was designed to investigate whether neoadjuvant chemotherapy with FOLFOX regimen and chemoradiation reserved only for the subset of patients’ intolerant to chemotherapy or whose tumours do not respond well to chemotherapy (defined as less than 20% of radiographic response), is non-inferior to pelvic chemoradiation with fluorouracil for patients with clinical stage cT2N+, cT3N–, and cT3N+ tumours.
In the primary clinical efficacy outcomes of the PROSPECT study reported at 2023 ASCO Annual Meeting along with a simultaneous publication in The New England Journal of Medicine, neoadjuvant FOLFOX was found to be non-inferior to neoadjuvant pelvic chemoradiation with fluorouracil for the primary endpoint of disease-free survival (DFS), and there were no significant differences between treatment groups for secondary efficacy outcomes including overall survival, local recurrence, complete resection rate, and pathologic complete response.
To understand the comparative patient experiences with treatments in the PROSPECT study, the investigators evaluated patient-reported outcomes (PROs) according to the US National Cancer Institute’s PRO version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) and measures of HRQoL between those assigned to FOLFOX versus pelvic chemoradiation with fluorouracil before sphincter-sparing surgery.
In PROSPECT, a multicentre, unblinded, non-inferiority, randomised study, enroled patients were asked to provide PROs at baseline, during neoadjuvant treatment, and at 12 months after surgery. PROs included 14 symptoms from the PRO-CTCAE. Additional PRO instruments measured bowel, bladder, sexual function, and HRQoL.
From June 2012 to December 2018, in total 1194 patients were randomly assigned, of whom 1128 initiated treatment, and 940 provided PRO-CTCAE data, 493 in neoadjuvant FOLFOX group and 447 in neoadjuvant pelvic chemoradiation with fluorouracil group. During neoadjuvant treatment, patients reported significantly lower rates of diarrhoea and better overall bowel function with FOLFOX while anxiety, appetite loss, constipation, depression, dysphagia, dyspnoea, oedema, fatigue, mucositis, nausea, neuropathy, and vomiting were lower with pelvic chemoradiation with fluorouracil (all multiplicity adjusted p < 0.05).
At 12 months after surgery, patients randomly assigned to neoadjuvant FOLFOX reported significantly lower rates of fatigue and neuropathy and better sexual function versus those assigned to neoadjuvant pelvic chemoradiation with fluorouracil (all multiplicity adjusted p < 0.05). Neither bladder function nor HRQoL differed between groups at any time point.
The authors wrote that this study demonstrates the value of PROs to characterise how patients feel and function, especially in a non-inferiority trial. Given the non-inferiority between neoadjuvant FOLFOX and pelvic chemoradiation with fluorouracil for DFS and the similarity of other efficacy endpoints, these findings can inform decision making by patients and their clinicians. For those concerned about acute impairments in bowel function during presurgical treatment, or fatigue and sexual function a year or more after surgery, neoadjuvant FOLFOX may be preferable. For side effects beyond bowel function, neoadjuvant pelvic chemoradiation with fluorouracil resulted in fewer presurgical side effects and may remain preferable for some patients.
Treatment period for patients assigned to neoadjuvant FOLFOX was nearly twice as long as neoadjuvant pelvic chemoradiation with fluorouracil, which may explain the greater number of symptoms reported by this group.
The authors commented that since the PROSPECT study was conceived and began recruitment in 2012, a variety of other strategies for management of rectal cancer have emerged. For example, total neoadjuvant therapy with pelvic chemoradiation with fluorouracil and chemotherapy followed by non-operative management has potential to spare some patients the morbidity of surgery although this is offset by the need for close surveillance and high rates of recurrence in others. Other approaches include immune checkpoint blockade alone as a curative strategy for the subset of patients with mismatch repair-deficient rectal cancer. These approaches may further decrease adverse events and improve HRQoL, but there are not yet prospective studies comparing these strategies to neoadjuvant pelvic chemoradiation with fluorouracil.
This study was supported by US National Cancer Institute awards.
Basch E, Dueck AC, Mitchell SA, et al. Patient-Reported Outcomes During and After Treatment for Locally Advanced Rectal Cancer in the PROSPECT Trial (Alliance N1048). JCO; Published online 4 June 2023. DOI: 10.1200/JCO.23.00903.