Patients with locally advanced rectal cancer with tumors that respond to chemotherapy may safely forgo radiation therapy before surgery, based on the findings of the PROSPECT trial. These data were presented by Deborah Schrag, MD, FASCO, MPH, at the 2023 ASCO Annual Meeting (Abstract LBA2) and simultaneously published in The New England Journal of Medicine (efficacy data) and the Journal of Clinical Oncology (patient-reported outcomes data). Omitting radiation therapy can reduce short- and long-term side effects that impact quality of life, while providing similar outcomes in disease-free survival and overall survival.
Deborah Schrag, MD, FASCO, MPH
About the Study
The phase III PROSPECT trial enrolled 1,194 patients from June 2012 to December 2018 with rectal cancer that had spread to nearby tissue or lymph nodes but had not spread to distant organs. Patients were randomly assigned to the chemoradiation therapy group (control) or to the modified FOLFOX6 (leucovorin, fluorouracil, oxaliplatin) chemotherapy with selective use of chemoradiation therapy group (intervention), and 1,128 patients went on to receive treatment through the study.
In the control group, 543 patients received chemoradiation with 28 radiation treatments over 5.5 weeks before a low anterior resection with total mesorectal excision. Chemoradiation consisted of a drug combination called 5FUCRT, a combination of radiation therapy and a sensitizing fluoropyrimidine (either intravenous fluorouracil or oral capecitabine).
In the intervention group, 585 patients received six cycles of modified FOLFOX6 followed by tumor restaging. If the tumor shrank by 20% or more based on follow-up magnetic resonance imaging of the pelvis, no radiation therapy was given before surgery. If tumors did not shrink by 20% or more, radiation therapy with fluorouracil or capecitabine was administered before surgery. In the intervention group, 53 people (9%) needed radiation therapy before surgery because the tumors did not shrink by 20% or more. After surgery, physicians and patients could choose to prescribe/receive additional chemotherapy. Most patients in both groups went on to have further postoperative modified FOLFOX6 chemotherapy.
Key Findings
After 5 years, there was no statistically significant difference between the two treatment groups in any of the endpoints studied, meaning that radiation therapy can be safely omitted before surgery if the tumor responds to treatment with modified FOLFOX6 chemotherapy.
Five years from random assignment, the results showed that:
- Disease-free survival was 78.6% in the chemoradiation group and 80.8% in the modified FOLFOX6 with selective chemoradiation group.
- Overall survival was 90.2% in the chemoradiation group and 89.5% in the modified FOLFOX6 with selective chemoradiation group.
- Surgical resection rates were 97.1% in the chemoradiation group and 98.8% in the modified FOLFOX6 with selective chemoradiation group.
- Local recurrence rates were very low and similar for both groups (2%).
- Pathologic complete response was 24.3% in the chemoradiation group and 21.9% in the modified FOLFOX6 with selective chemoradiation group.
- Only 9% of patients who received modified FOLFOX6 in the experimental group needed preoperative chemoradiation.
“This study establishes preoperative therapy with FOLFOX and only selective use of chemoradiation for patients with locally advanced rectal cancer,” said lead author Dr. Schrag, Chair of the Department of Medicine at Memorial Sloan Kettering Cancer Center. “Having this option is important for several reasons. First, in many parts of the world, radiation therapy is not readily accessible. An all-chemotherapy approach may make curative intent treatment accessible for patients in these 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.”
Radiation therapy can have significant short- and long-term toxicities that negatively impact quality of life, including infertility, ovarian failures, the need for a temporary ostomy, diarrhea, cramping, fecal incontinence, and bladder problems. Chemotherapy also has side effects including fatigue, nausea, vomiting, low white blood cell counts, infection, and neuropathy (numbness and tingling in the hands and feet). This study gives patients alternative treatment options.
Next Steps
The trial will continue to follow the participants and collect additional data on disease-free survival, overall survival, local recurrence–free survival, and other secondary endpoints for 8 years. Further studies will evaluate the biological specimens collected during this study to see if there are any tumor features that are associated with a higher likelihood of responding to chemoradiation or with a higher likelihood of responding to modified FOLFOX6 chemotherapy.
Disclosure: The study was funded by the National Cancer Institute of the National Institutes of Health. For full disclosures of the study authors, visit coi.asco.org.
