Patients with locally advanced rectal cancer with tumours that respond to chemotherapy can safely forego radiation therapy before surgery based on the findings of federally funded research that were presented at the 2023 Annual Meeting of the American Society of Clinical Oncology (ASCO) and simultaneously published in the New England Journal of Medicine (efficacy) and the Journal of Clinical Oncology (patient-reported outcomes).
Omitting radiation therapy can reduce short- and long-term side effects that impact the quality of life while providing similar outcomes in disease-free survival and overall survival.
Patients were randomly assigned to receive one of two treatments before a sphincter-sparing low anterior resection with a total mesorectal excision, which is surgery to remove tumours in the rectum and surrounding lymph nodes.
The control group received the standard treatment of chemoradiation (a combination of radiation therapy and either 5FU or capecitabine) prior to surgery. This was the standard of care at the time of study design. The experimental group received the chemotherapy combination mFOLFOX6. If the tumour responded well to mFOLFOX6 and shrank by 20% or more, patients immediately had surgery. If the tumour did not shrink by 20% or more or the patient was unable to continue with mFOLFOX6, they received the same chemoradiation as the control group prior to surgery.
After five 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 tumour responds to treatment with mFOLFOX6 chemotherapy. Five years after randomisation, the results showed that:
Disease-free survival was 78.6% in the chemoradiation group and 80.8% in the mFOLFOX6 with the selective chemoradiation group.
Overall survival was 90.2% in the chemoradiation group and 89.5% in the mFOLFOX6 with the selective chemoradiation group.
Surgical resection rates (complete removal of the tumour and surrounding tissue) were 97.1% in the chemoradiation group and 98.8% in the mFOLFOX6 with the selective chemoradiation group.
Local recurrence rates were very low and similar for both groups (2%).
Pathologic complete response (no sign of cancer cells in tissue during surgery after treatment) was 24.3% in the chemoradiation group and 21.9% in the mFOLFOX6 with the selective chemoradiation group.
Only 9% of patients who received mFOLFOX6 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 Deb Schrag, MD, FASCO, MPH, 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.”
In 2023, an estimated 46,050 people will be diagnosed with rectal cancer in the United States. Advances in treatment and early detection for colorectal cancer have led to a steady decrease in mortality rates, with the 5-year relative survival rate for locally advanced rectal cancer at 74%.1
Despite declining mortality rates, however, the incidence is increasing among younger patients. Radiation therapy can have significant short- and long-term toxicities that negatively impact the quality of life, including infertility, ovarian failures, the need for a temporary ostomy, diarrhoea, cramping, faecal 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.
“We’ve reached a tipping point in treating patients with rectal cancer. As we develop new therapies, we are also exploring where we can eliminate toxic therapies for our patient’s well-being. The findings of this study allow us to do just that, showing we can omit radiation therapy for some patients, improving quality of life without compromising efficacy. These practice-changing findings are significant, even as the treatment landscape for these patients continues to evolve,” said Pamela L. Kunz, MD, ASCO expert.
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 mFOLFOX6 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, which involves removing part of the rectum and surrounding lymph nodes. The chemoradiation was a drug combination called 5FUCRT, a combination of radiation therapy and a sensitising fluoropyrimidine (either intravenous 5FU or oral capecitabine).
In the intervention group, 585 patients received six cycles of a chemotherapy combination called mFOLFOX6, followed by tumour restaging. If the tumour shrank by 20% or more based on a follow-up MRI of the pelvis, no radiation therapy was given before surgery. If tumours did not shrink by 20% or more, radiation therapy with 5FU or capecitabine was administered before surgery. In the intervention group, 53 people (9%) needed radiation therapy before surgery because the tumours did not shrink by 20% or more. After surgery, physicians and patients could choose to have additional chemotherapy. Most patients in both groups went on to have further postoperative mFOLFOX6 chemotherapy.
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 eight years. Further studies will evaluate the biological specimens collected during this study to see if there are any tumour features that are associated with a higher likelihood of responding to chemoradiation or with a higher likelihood of responding to mFOLOFOX6 chemotherapy.
The study was funded by the National Cancer Institute of the National Institutes of Health.
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