UPDATED June 5, 2023 // Editor's note: This story has been updated with additional comments from Dr Corrie Marijnen.
CHICAGO — Many patients with locally advanced rectal cancer who do not have high-risk disease can skip radiotherapy to the pelvic area, and instead be treated with chemotherapy alone and then surgery, say researchers reporting results from the PROSPECT trial.
"This study establishes preoperative therapy with FOLFOX and only selective use of chemoradiation for patients with locally advanced rectal cancer," commented principal investigator Deborah Schrag, MD, MPH, gastrointestinal oncologist at Memorial Sloan Kettering Cancer Center, New York City.
"Having this option is important for several reasons," she said.
"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," she said.
Reacting to the findings, Pamela Kunz, MD, leader of the Gastrointestinal Cancers Program at Yale Cancer Center, New Haven, Connecticut, commented: "What's important here is that radiation can be safely omitted in many patients with clinically advanced rectal cancer — this is really 'less is more.' "
"We can spare select patients from receiving radiation without compromising efficacy," she said. "This leads to improved quality of life, and reduced side effects, including things like early menopause and infertility."
Kunz spoke at a press briefing where the results were highlighted prior to being presented today at a plenary session here at the American Society of Clinical Oncology annual meeting.
She said the trial was "practice changing, and it aligns incredibly well with the theme at this year's annual meeting around de-escalation of therapy and partnering with patients."
Julie R. Gralow, MD, ASCO chief medical officer and executive vice president, added that the theme may be de-escalation, but in this case it is "really more accurately optimization, because you were able to de-escalate in 91%, but you found the 9% who really needed that escalation, if you will."
Discussing the results, Corrie Marijnen, MD, PhD, chair, Department of Radiation Oncology, Amsterdam Cancer Institute, Amsterdam, the Netherlands, commented that the trial was well conducted, and congratulated the team for including patient-reported outcomes.
There are two ways of looking at the results, she continued, with oncologic outcomes viewed differently from the clinician and patient perspective.
Although the two trial arms were well balanced in terms of outcomes, there was a major imbalance in toxicities experienced by patients around the treatment period. Whereas there were worse neuropathy outcomes at 12 months with mFOLFOX6, the toxicities with chemoradiotherapy "tip the scale" in favor of chemotherapy.
Marijnen also pointed out that the definition of "locally advanced" in rectal cancer varies by region, and that in Europe many of the patients in the current trial would be defined as early and intermediate stage, and so would not qualify for neoadjuvant therapy. This has also affected the local recurrence rates compared with other trials, in which they have been much higher, suggesting that in a more unequivocally locally advanced patient population mFOLFOX6 "on its own may not be enough."
She said that the reduction in long-term radiotherapy-related toxicities make the novel regimen a good choice, although the decision should be made with the patient. It may depend on whether the long-term neuropathy associated with chemoradiotherapy may be more relevant for some, such as musicians, while the early toxicities with mFOLFOX6 may be unsupportable for people looking after young families.
Marijnen concluded that that future aims should be to increase the complete response rate above the current 25%, and to ask whether, in the population studied in this trial, neoadjuvant therapy "is needed at all."
Chemoradiation Is Standard Approach
Presenting the findings, Schrag began by noting that approximately half of all new rectal cancer diagnoses have locally advanced disease, which in the US represents 48,000 cases per year.
She explained that the "standard approach" to treatment is 5½ weeks of daily chemoradiation, comprising radiation to the pelvis alongside sensitizing chemotherapy with a fluoropyrimidine, followed by surgery, and then approximately 16 weeks of adjuvant chemotherapy.
"This way, we have achieved very good outcomes," Schrag noted, with the inclusion of radiation in the 1980s a "critically important advance" in slowing rates of recurrence, which is a "cause of enormous suffering."
However, the treatment is "long and hard," and the pelvic radiation causes "real toxicities," she said. These can include impaired bowel, bladder, and sexual function, and an increase in late effects, such as increased risk of pelvic fractures and secondary cancers, as well as infertility and early menopause, and impaired bone marrow function.
This depressed bone marrow function can "become a problem for people going into chemotherapy into the future," while infertility and early menopause are "a big deal because we're seeing increasing diagnosis of rectal cancer in people before the age of 50 years."
Schrag said that, since chemoradiotherapy became the standard of care, there has been "so much progress," with better chemotherapy, better surgical techniques, and more screening, so we're finding more tumors when they are smaller and easier to treat."
The impetus for the PROSPECT trial, Schrag said, was therefore: "Could we use radiotherapy more selectively, and only give it to people who don't respond to chemotherapy rather than giving [it] to everybody?"
The trial enrolled 1128 patients with rectal cancer with clinically staged T2 node-positive, T3 node-negative, or T3 node-positive disease and who were candidates for sphincter-sparing surgery.
They were randomly assigned to receive either a modified chemotherapy regimen (n = 585) or standard chemoradiation (n = 543). The mean age of the patients was 57 years, and 34.5% were female. The majority (85%) were White.
All patients then underwent surgery, with low anterior resection with total mesorectal excision.
The standard chemoradiotherapy consisted of pelvic radiotherapy at 50.4 Gy over 28 fractions alongside sensitizing chemotherapy with either fluorouracil or capecitabine.
The modified chemotherapy regimen consisted of mFOLFOX6, which included modified oxaliplatin with l-leucovorin, and bolus/continuous infusion of 5-fluorouracil.
Patients in the mFOLFOX6 group whose primary tumor decreased in size by at least 20% after the six cycles proceeded straight to surgery, while were rest given the chemoradiotherapy before surgery (9% ended up receiving chemoradiotherapy).
Postoperative adjuvant chemotherapy with six cycles in the mFOLFOX6 group, or eight cycles in the chemoradiotherapy group, was suggested but not mandated.
Schrag told Medscape Medical News that the team chose to use mFOLFOX6 because of their long experience in using it.
FOLFOX first became available in 2002, and randomized controlled trials showed that it was more effective than 5-fluorouracil alone in colon cancer trials.
She explained that locally advanced rectal cancer patients were "never included" in those trials because they were already receiving chemoradiotherapy, but that its use in metastatic rectal cancer, coupled with the data in colon cancer, led them to try it in the current setting.
"It's also quite tolerable, it's given every 2 weeks, and it's familiar to oncologists everywhere," Schrag added.
She noted that it's "not risk-free," with an increased risk of neuropathy, "which is not a great side effect, but we're able to modulate that."
After a median follow-up of 58 months, mFOLFOX6 was found to be noninferior to chemoradiotherapy for disease-free survival (DFS), at a hazard ratio for disease recurrence or death of 0.92 (P = .005 for noninferiority).
Five-year disease-free survival was 80.8% in the mFOLFOX6 group and 78.6% among patients assigned to chemoradiotherapy, while 5-year overall survival was 89.5% vs 90.2%, at a nonsignificant hazard ratio for death of 1.04.
Rates of local recurrence at 5 years were low, at 1.8% with mFOLFOX6 and 1.6% with chemoradiotherapy.
Grade 3 or higher adverse effects were twice as common in the mFOLFOX6 group than among patients who received chemoradiotherapy, at 41% vs 22.8%, although the researchers highlight that the treatment period was also twice as long in the chemotherapy arm.
The most common grade 3 or higher adverse effects in with mFOLFOX6 were neutropenia (20.3%), pain (3.1%), and hypertension (2.9%), while those with chemoradiotherapy were lymphopenia (8.3%), diarrhea (6.4%), and hypertension (1.7%).
In terms of patient reported outcomes, patients receiving mFOLFOX6 reported lower rates of diarrhea and better overall bowel function during the neoadjuvant phase than those given chemoradiotherapy (P < .05 for all).
However, those assigned to chemoradiotherapy experienced lower rates of anxiety, appetite loss, constipation, depression, dysphagia, dyspnea, edema, fatigue, mucositis, nausea, neuropathy, and vomiting during treatment (P < .05 for all).
At 12-month postoperative follow-up, however, those differences had disappeared, and patients originally assigned to mFOLFOX6 had lower rates of fatigue and neuropathy, and better sexual function, than those given chemoradiotherapy (P < .05 for all).
"During the treatment itself, multiple symptoms were worse with chemotherapy, but a year after treatment ended, those symptoms resolved and the pattern flipped so that patients who received radiation exhibited lingering symptoms," said co-investigator Ethan Basch, MD, MSc, chief of medical oncology, and director of the Cancer Outcomes Research Program at University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill.
"Patients ideally will understand the potential impact of treatments on how they feel and function when making choices, so as oncologists we need to talk with our patients about their options and the consequences of those options," he said in a statement.
The study was funded by the National Cancer Institute of the National Institutes of Health.
Schrag reports relationships with Merck (Inst), JAMA, AACR (Inst), and Grail (Inst). Basch reports relationships with AstraZeneca, Navigating Cancer, Resilience Care, SIVAN Innovation, American Society of Clinical Oncology, Centers for Medicare & Medicaid Services, JAMA-Journal of the American Medical Association, National Cancer Institute, Patient-Centered Outcomes Research Institute. Disclosure forms for the study authors can be found here.
Kunz reports relationships with Novartis, Genentech/Roche, Amgen, Crinetics Pharmaceuticals, Natera, HUTCHMED, Isotope Technologies Munich SE. Gralow reports relationships with Genentech/Roche.
American Society of Clinical Oncology 2023 Annual Meeting: Abstract LBA2. Presented June 4, 2023.
N Engl J Med. Published online June 4, 2023. Abstract
J Clin Oncol. Published online June 4, 2023. Abstract
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Cite this: Omitting Radiation in Rectal Cancer: 'Less Is More' - Medscape - Jun 04, 2023.