PRO Analysis of PROSPECT Trial Reveals Distinct Toxicity Profiles With FOLFOX vs Chemoradiation in Rectal Cancer


FOLFOX was associated with lower rates or diarrhea and bowel dysfunction, but higher rates of fatigue, anxiety, nausea, and neuropathy, in data from the phase 2/3 PROSPECT trial.

 Ethan Basch, MD, MSc, FASCO

Ethan Basch, MD, MSc, FASCO

Neoadjuvant treatment with fluorouracil and oxaliplatin (FOLFOX) was associated with significantly lower rates of diarrhea and overall bowel dysfunction in patients with locally advanced rectal cancer compared with neoadjuvant pelvic chemoradiation with fluorouracil (5FCURT), according to an analysis of patient-reported outcomes (PROs) from the phase 2/3 PROSPECT trial (NCT01515787). However, patients who received 5FUCRT reported superior scores across other symptoms.1

The findings were reported in the Journal of Clinical Oncology. Responses were collected using the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), which were completed by a total of 940 patients.1

Overall, patients who received neoadjuvant FOLFOX (n = 493) achieved lower rates of diarrhea and better overall bowel function (P < .05). However, patients who underwent 5FUCRT (n = 447) achieved lower rates of anxiety, appetite loss, constipation, depression, dysphagia, dyspnea, edema, fatigue, mucositis, nausea, neuropathy, and vomiting (P < .05).1

An analysis of severe adverse events (AEs), which was defined as a composite score of 3, showed that the most common severe AEs in the FOLFOX arm were severe appetite loss (22%), constipation (27%), fatigue (42%), nausea (21%), neuropathy (19%), and pain (22%). In the control arm, these severe AEs were reported at the following rates: 9%, 11%, 20%, 7%, 5%, and 18%. In the 5FUCRT arm, the most common severe AEs were diarrhea (20%), fatigue, and pain. Patients receiving FOLFOX reported severe diarrhea at a rate of 6%.1

In the preoperative setting, patients receiving FOLFOX reported superior bowel function. Longer follow-up revealed that 12 months following surgery, the rates of fatigue and neuropathy were lower in the FOLFOX population than in the 5FUCRT population (P < .05). The FOLFOX population also reported significantly better sexual function at this time point (P < .05). AE reports were similar between both groups at 6 months postsurgery, according to the PRO-CTCAE assessments, and at 18 months postsurgery, according to a post hoc analysis.1

Of note, 12 months following surgery, more than 15% of patients in the 5FCURT group reported high diarrhea frequency. No other symptom was reported by more than 15% of patients, in either treatment group, at this timepoint.1

Bladder function and health-related quality-of-life (HRQOL) scores were consistent between the 2 both groups throughout treatment.1

“For those concerned about acute impairments in bowel function during presurgical treatment, or fatigue and sexual function a year or more after surgery, FOLFOX may be preferable,” Ethan Basch, MD, MSc, FASCO, Richard M. Goldberg Distinguished Professor in Medical Oncology at UNC-Chapel Hill, and co-investigators, wrote in the study. “For [AEs] beyond bowel function, 5FUCRT treatment resulted in fewer presurgical [AEs] and may remain preferable for some patients.”1

5FUCRT, which includes 28 fractions over the course of 5.5 weeks, has been an established standard of care for patients with locally advanced rectal cancer since the 1990s. Unfortunately, patients who receive 5FUCRT often experience short- and long-term AEs, including bowel and sexual dysfunction.2

Investigators designed the PROSPECT trial to assess whether neoadjuvant chemotherapy could replace 5FUCRT in most patient cases—potentially minimizing the proportion of patients who receive radiation to those whose tumors remonstrate less than a 20% radiographic response to chemotherapy and those who have a chemotherapy intolerance. During the 2023 American Society of Clinical Oncology Annual Meeting, findings from the PROSPECT trial showed that neoadjuvant FOLFOX induced an 80.8% 5-year disease-free survival (DFS) rate in this patient population. Standard pelvic chemoradiation elicited a 78.6% 5-year DFS rate, suggesting that FOLFOX is a noninferior option for patients eligible for sphincter-sparing surgery.3

The trial enrolled patients with clinically staged T2N, cT3N-, or cT3N+ rectal cancer who were candidates for sphincter-sparing surgery. In the FOLFOX arm, patients received 6 cycles over the course of 12 weeks. In the control arm, patients received standard-of-care 5FUCRT. Patients in both groups proceeded to undergo surgery. In both treatment cycles, adjuvant chemotherapy was suggested but not required.1

The trial was designed to assess noninferiority and DFS was the primary end point. Overall survival, surgical and pathologic outcomes, and PROs were the prespecified secondary end points.1

The protocol asked patients to fill out PROs at baseline, during neoadjuvant treatment, and 12 months after surgery. The PRO-CTCAE was leveraged to evaluate the following 14 symptoms: anxiety, appetite loss, constipation, depression, diarrhea, dysphagia, dyspnea, edema, fatigue, mucositis, nausea, neuropathy, pain, and vomiting. Investigators also queried about bowel, bladder, and sexual functions, as well as HRQOL, through additional PRO instruments.1

Patients were able to complete these items remotely between clinic visits. If patients did not complete the assessments, they received automated reminders at 24 hours and 48 hours after the anticipated completion time.1

Among respondents, the median age was 57 years (range, 19-86); 13.2% of patients were less than 45 years of age; 34.3% of respondents were female (n = 322); 86.6% were White (n = 814); and 39.4% (n = 370) had continued in school until high school.

According to investigators, the baseline symptoms were balanced between the 2 cohorts. At enrollment, approximately half of patients were experiencing fatigue and diarrhea, and a quarter of respondents were experiencing appetite loss, constipation, depression, dyspnea, nausea, neuropathy, and pain.

Treatment completion rates were comparable. A total of 94.9% of patients in the FOLFOX arm received at least 5 treatment cycles and 9.1% of patients in this arm proceeded to undergo neoadjuvant chemoradiation. In 5FUCRT arm, the full dose of 50.4 Gy radiation was administered to 95.0% of patients. The percentage of patients who received adjuvant chemotherapy, in the FOLFOX and 5FUCRT arms, respectively, were 74.8% vs 77.9%. Moreover, in the FOLFOX arm, 1.4% of patients received radiation after surgery.

The study authors acknowledged a number of limitations. Since 2012, additional rectal cancer therapies have been introduced as treatment options. 5FUCRT neoadjuvant therapy plus chemotherapy followed by nonoperative management has allowed certain patients to avoid morbid surgery, although the investigators state that this is offset by a need for close surveillance and risk of recurrence. Immunotherapy alone is another potentially curative strategy which may improve HRQOL, but these have not yet been compared with 5FUCRT.

Moreover, patients with high-risk disease were omitted because clinicians were concerned about the effect of omitting radiation. Therefore, the findings pertain only to patients with moderate-risk locally advanced tumors.

Nevertheless, the study authors maintained that understanding the PROs associated with these treatments may help patients and providers with treatment-selection and shared decision making.


  1. 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). J Clin Oncol. Published online June 4, 2023. doi:10.1200/JCO.23.00903.
  2. NIH consensus conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA. 1990;264(11):1444-50.
  3. Schrag D, Shi Q, Weiser MR, et al. PROSPECT: a randomized phase III trial of neoadjuvant chemoradiation versus neoadjuvant FOLFOX chemotherapy with selective use of chemoradiation, followed by total mesorectal excision (TME) for treatment of locally advanced rectal cancer (LARC) (Alliance N1048). J Clin Oncol. 2023;41(suppl 17):LBA2. doi:10.1200/JCO.2023.41.17_suppl.LBA2
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