Patients with intermediate-risk rectal cancer who received neoadjuvant chemotherapy with selective use of pelvic chemoradiation therapy had disease-free survival that was noninferior to the standard approach using pelvic chemoradiation, according to findings from the randomized phase III PROSPECT trial (Alliance N1048), which were reported during the Plenary Session of the 2023 ASCO Annual Meeting.1 The study found that neoadjuvant chemotherapy with six cycles of FOLFOX, with only the selective use of chemoradiation, is a safe and effective treatment option for patients with cT2N-positive, cT3N-negative, or cT3N-positive tumors.
Deb Schrag, MD, MPH, FASCO, the George J. Bosl Chair of the Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, reported that reserving chemoradiation therapy for the 9% of patients whose tumors did not regress more than 20% after neoadjuvant chemotherapy did not increase the risk for distant recurrence, local recurrence or death. At a median follow-up of 58 months, the 5-year overall survival was 89.5% with selective chemoradiation therapy and 90.2% with chemoradiation therapy (hazard ratio [HR] = 1.04, 95% confidence interval [CI] = 0.74–1.44).
Deb Schrag, MD, MPH, FASCO
Julie R. Gralow, MD, FACP, FASCO
The efficacy results were published simultaneously in The New England Journal of Medicine.2 The patient-reported outcomes were published in the Journal of Clinical Oncology.3
“Having this option is important for several reasons…,” noted Dr. Schrag. “An all-chemotherapy approach may make curative-intent treatment accessible for patients in resource-constrained settings. Additionally, given the rising rates of colorectal cancer in young patients, this provides an option for patients who wish to preserve fertility or avoid early menopause.”
Julie R. Gralow, MD, FACP, FASCO, ASCO Chief Medical Officer and Executive Vice President, said the approach featured reliable patient selection and enabled treatment optimization. Investigators were able to de-escalate therapy in 91% of patients and identify the 9% who needed treatment escalation, she emphasized during a press briefing.
Chemoradiation Therapy Was Standard Approach
When PROSPECT was initiated in 2012, the prevailing approach to treatment of locally advanced rectal cancer involved 5.5 weeks of daily chemoradiation therapy (5,040 cGy with concurrent fluorouracil or capecitabine), surgery with total mesorectal excision, and adjuvant chemotherapy with eight cycles of FOLFOX (fluorouracil, leucovorin, oxaliplatin) or six cycles of CAPOX (capecitabine, oxaliplatin). “This approach achieves cure in approximately three-quarters of patients, and local recurrence rates are in the single-digit range, but it comes at a cost, as there is considerable long-term toxicity from pelvic chemoradiation,” Dr. Schrag said.
The many advances in chemoradiotherapy that have occurred since the study was started “led us to hypothesize that we could de-escalate treatment and use chemoradiation selectively without compromising outcomes,” she said, describing the intent of the noninferiority PROSPECT trial. “We asked the following question: Could we use radiation more selectively and give it only to people who do not respond to chemotherapy rather than giving the radiation to everyone as part of the standard? This is a theme of de-escalating or optimizing therapy.”
The trial enrolled 1,128 patients (mean age, 57) from 264 practice sites in the United States, Canada, and Switzerland. Patients had cT2N-positive, cT3N-negative, or cT3N-positive rectal cancer and were candidates for sphincter-sparing surgery. They were randomly assigned to one of the following two regimens:
A response was considered tumor regression of more than 20%. For this group, surgery was performed without radiation therapy. For patients with tumor regression of less than 20%, chemoradiation therapy (as in the control group) was given before surgery. The surgical approach was low anterior resection and total mesorectal excision. Postoperative adjuvant chemotherapy with six cycles in the modified FOLFOX group or eight cycles in the chemoradiotherapy group was suggested but not mandated.
The selective approach resulted in avoidance of neoadjuvant chemoradiation in 91% of patients in the intervention group of neoadjuvant modified FOLFOX. Based on lack of response or intolerance of the FOLFOX regimen, 53 of 585 randomly assigned to receive modified FOLFOX required neoadjuvant chemoradiation therapy. A total of 10.4% of those in the modified FOLFOX arm received chemoradiation therapy: 9.1% prior to surgery and 1.4% after surgery.
After a median follow-up of 58 months, modified FOLFOX was found to be noninferior to chemoradiotherapy for disease-free survival (HR = 0.92; P = .005 for noninferiority). The 5-year disease-free survival was 80.8% for the modified FOLFOX group and 78.6% for the chemoradiotherapy group; the 5-year overall survival was 89.5% vs 90.2% (HR = 1.04; nonsignificant), respectively; and the 5-year local recurrence–free survival was 98.2% and 98.4%, respectively (HR = 1.18; nonsignificant), Dr. Schrag reported.
Other endpoints showed no compromise with the optimized treatment in the control group. For the intervention vs control groups, respectively, rates were 99% and 97% for complete resection, 98% and 98% for low anterior resection, 22% and 24% for pathologic complete response, as well as 1.2% and 1.5% for radial margin positivity (≤ 1 mm). Adjuvant therapy after treatment was given to 82% and 83%, respectively.
Tolerability and Quality of Life
“We spent a lot of time evaluating toxicity, and what I’m proudest of is we measured toxicity based on what patients told us,” Dr. Schrag said. “That was a paradigm shift in how we conducted the trial. We created a system—the PRO-CTCAE—to report adverse symptom events, and patients did so. This system is soon to be available as a module in EPIC’s electronic health record and will enable a better, more efficient strategy for direct assessment of symptoms.
Notable patient-reported toxicities during neoadjuvant treatment included more diarrhea with chemoradiation therapy (20% vs 6%), but with modified FOLFOX, more appetite loss (22% vs 9%), constipation (27% vs 11%), fatigue (42% vs 20%), nausea (21% vs 7%), and neuropathy (19% vs 5%). The only notable difference at 12 months, however, was more neuropathy in the chemoradiation therapy arm (8% vs 3%). Most adverse events reported early with modified FOLFOX had disappeared, she noted.
Clinician-reported toxicities grade ≥ 3 with neoadjuvant therapy were reported in 41% of the modified FOLFOX arm and 23% of the chemoradiation therapy arm; with adjuvant therapy, grade ≥ 3 toxicities were observed in 25% and 39%, respectively. Although early toxicity was more common in the modified FOLFOX arm, the treatment duration was twice as long for these patients, Dr. Schrag added.
For the quality-of-life assessments, the investigators evaluated overall health-related quality of life, bowel function, male sexual function, and female sexual function. Most parameters did not significantly differ, but bowel function and sexual function significantly favored the modified FOLFOX group.
New Approaches Emerge
Dr. Schrag acknowledged that since the initiation of PROSPECT, several new approaches have emerged that are improving rectal cancer oncologic and tolerability outcomes. They include shorter courses of adjuvant FOLFOX, the use of FOLFIRINOX (fluorouracil, leucovorin, irinotecan, oxaliplatin), short-course radiation therapy, total neoadjuvant therapy, nonoperative management, and immune ablation therapy. “The next generation of trials is a priority and will further extend our ability to achieve high cure rates and optimal quality of life for patients with rectal cancer,” she concluded.
DISCLOSURE: Dr. Schrag has served as an editor for JAMA and has received institutional research funding from GRAIL. Dr. Gralow reported no conflicts of interest.
1. 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 for treatment of locally advanced rectal cancer (Alliance N1048). 2023 ASCO Annual Meeting. Abstract LBA2. Presented June 4, 2023.
2. Schrag D, Shi Q, Weiser MR, et al: Preoperative treatment of locally advanced rectal cancer. N Engl J Med. June 4, 2023 (early release online).
3. 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. June 4, 2023 (early release online).
Pamela L. Kunz, MD
Commenting at a press briefing, Pamela L. Kunz, MD, Director of the Center for Gastrointestinal Cancers and Chief of GI Medical Oncology at Smilow Cancer Hospital and Yale Cancer Center, New Haven, said the results of PROSPECT are “practice-changing” and “align incredibly...