Patient-Reported Outcomes During and After Treatment for Locally Advanced Rectal Cancer in the PROSPECT Trial (Alliance N1048)

Abstract

Purpose: The standard of care for locally advanced rectal cancer in North America is neoadjuvant pelvic chemoradiation with fluorouracil (5FUCRT). Neoadjuvant chemotherapy with fluorouracil and oxaliplatin (FOLFOX) is an alternative that may spare patients the morbidity of radiation. Understanding the relative patient experiences with these options is necessary to inform treatment decisions.

Methods: PROSPECT was a multicenter, unblinded, noninferiority, randomized trial of neoadjuvant FOLFOX versus 5FUCRT, which enrolled adults with rectal cancer clinically staged as T2N+, cT3N-, or cT3N+ who were candidates for sphincter-sparing surgery. Neoadjuvant FOLFOX was given in six cycles over 12 weeks, followed by surgery. Neoadjuvant 5FUCRT was delivered in 28 fractions over 5.5 weeks, followed by surgery. Adjuvant chemotherapy was suggested but not mandated in both groups. Enrolled patients were asked to provide patient-reported outcomes (PROs) at baseline, during neoadjuvant treatment, and at 12 months after surgery. PROs included 14 symptoms from the National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Additional PRO instruments measured bowel, bladder, sexual function, and health-related quality of life (HRQL).

Results: From June 2012 to December 2018, 1,194 patients were randomly assigned, 1,128 initiated treatment, and 940 contributed PRO-CTCAE data (493 FOLFOX; 447 5FUCRT). During neoadjuvant treatment, patients reported significantly lower rates of diarrhea and better overall bowel function with FOLFOX while anxiety, appetite loss, constipation, depression, dysphagia, dyspnea, edema, fatigue, mucositis, nausea, neuropathy, and vomiting were lower with 5FUCRT (all multiplicity adjusted P < .05). At 12 months after surgery, patients randomly assigned to FOLFOX reported significantly lower rates of fatigue and neuropathy and better sexual function versus 5FUCRT (all multiplicity adjusted P < .05). Neither bladder function nor HRQL differed between groups at any time point.

Conclusion: For patients with locally advanced rectal cancer choosing between neoadjuvant FOLFOX and 5FUCRT, the distinctive PRO profiles inform treatment selection and shared decision making.

Trial registration: ClinicalTrials.gov NCT01515787.

FIG 1.

CONSORT diagram, patient enrollment and outcomes. ^aSites were not required to provide screening logs during recruitment; therefore, the number of patients assessed for eligibility is not available. ^bData at 12-month postsurgery time point is missing in these patients because the software system for electronic PRO-CTCAE data collection was discontinued in September 2019. 5FUCRT, chemoradiation with fluorouracil; c, clinical; FOLFOX, fluorouracil and oxaliplatin; N, node; PRO-CTCAE, Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events; T, tumor.

FIG 2.

PRO-CTCAE composite score distributions for each symptom during the neoadjuvant treatment period and 12 months after surgery, adjusted for baseline symptoms. Higher scores (represented by darker colors) are worse. The lightest color shading represents a score of zero. Column labels (n) show the number of subjects with an observed score. 5FUCRT, chemoradiation with fluorouracil; FOLFOX, fluorouracil and oxaliplatin; PRO-CTCAE, Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events.

FIG 3.

Mean changes from baseline between groups during neoadjuvant treatment (1-2 weeks before surgery) and at 12 and 24 months after surgery for (A) bladder function (bladder emptying question from the International Prostate Symptom Score, administered both to males and females); (B) bowel function (Memorial Sloan Kettering Bowel Function Instrument Aggregate Global Score); (C) male sexual function (International Index of Erectile Function Total Score, administered to males only); (D) female sexual function (Female Sexual Function Index Total Score, administered to females only); and (E) overall health-related quality of life (EuroQoL EQ-5D-5L Index). Positive values represent improvement compared with baseline for all scales. Means were estimated using a general linear mixed model for each scale. Between-group differences with raw P < .05 are demarcated with ^a and P < .01 with ^b. The results for all domain subscales are shown in the Data Supplement. ^aBetween-group difference raw P < .05. ^bBetween-group difference raw P < .01 (12 months only: multiplicity-adjusted P < .05). 5FUCRT, chemoradiation with fluorouracil; FOLFOX, fluorouracil and oxaliplatin.

FIG A1.

PRO-CTCAE composite score distributions at baseline, during neoadjuvant treatment (unadjusted for baseline scores), and 12 and 18 months after surgery (unadjusted for baseline scores). Higher scores indicate worse magnitude of a given symptom. Column labels (n) show the number of patients with an observed score. 5FUCRT, chemoradiation with fluorouracil; FOLFOX, fluorouracil and oxaliplatin; PRO-CTCAE, Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events.

FIG A2.

PRO-CTCAE individual attribute item score distributions for symptoms at baseline, during neoadjuvant treatment (unadjusted for baseline symptoms), and 12 months after surgery (unadjusted for baseline symptoms). Higher scores indicate worse magnitude of a given symptom. Column labels (n) show the number of patients with an observed score. 5FUCRT, chemoradiation with fluorouracil; FOLFOX, fluorouracil and oxaliplatin; PRO-CTCAE, Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events

FIG A3.

CONSORT diagram for HRQL measures evaluating bowel, bladder, sexual function, and overall HRQL. ^aSites were not required to provide screening logs during recruitment; therefore, the number of patients assessed for eligibility is not available. c, clinical; HRQL, health-related quality of life; N, node; T, tumor.