Presurgical FOLFOX/Chemo as Effective as Chemoradiation in Rectal Cancer

Patients with locally advanced rectal cancer who underwent treatment with fluorouracil, leucovorin and oxaliplatin — a combination referred to as FOLFOX — before sphincter-sparing surgery had similar outcomes and fewer side effects compared with those treated with pelvic chemoradiation before surgery, according to recent trial results.

Data from the phase 2/3 PROSPECT trial were presented during the 2023 ASCO Annual Meeting and published in The New England Journal of Medicine.

Patients who received the intervention (585 patients) experienced a five-year disease-free survival rate (the length of time after primary treatment that a patient survives without signs or symptoms of cancer) of 80.8% compared with 78.6% in those who received the standard approach (543 patients), meeting the study’s prespecified noninferiority criteria. In other words, researchers determined that results from treatment with FOLXFOX were not worse than those obtained with the standard approach.

The five-year estimated overall survival rates (the percentage of patients who are still alive during a certain period of time after treatment) were 89.5% and 90.2%, respectively. Moreover, 98.2% of those in the FOLFOX arm were free of local recurrence (when cancer is in the same location or somewhere close by in the body) at this time point versus 98.4% of those in the standard arm. No meaningful difference in these areas was observed between the arms.

Notably, only 9% of patients who were assigned to the investigative arm ended up needing to receive neoadjuvant pelvic chemoradiation because restaging demonstrated a clinical response of less than 20% or they did not tolerate at least five cycles of FOLFOX.

“We think that we can successfully de-escalate treatment of rectal cancer and achieve the same high cure rates (and) keep patients disease free, with less long-term toxicity and effects,” Dr. Deb Schrag, lead author of the study, said in a presentation of the data. Schrag is also the chair of the Department of Medicine and the George J. Bosl Chair at Memorial Sloan Kettering Cancer Center, in New York, New York.

Globally, there are approximately 800,000 new rectal cancer diagnoses expected, and about half of them have locally advanced rectal cancer, according to Schrag. About 48,000 cases are expected in the United States alone.

The standard approach for these patients, which has been used for the past 30 years, is a 5.5-week course of daily pelvic chemoradiation with concurrent chemotherapy, followed by an approximate eight-week recovery, subsequent surgery, an approximate six-week recovery and adjuvant chemotherapy with FOLFOX or capecitabine and oxaliplatin for about 16 weeks.

“The reason radiation is so important is that rectal cancer has a nasty predilection to come back in the pelvis,” Schrag explained. “Pelvic recurrence of rectal cancer is a cause of enormous suffering, so when it was developed, radiation was a critically important advance. It was first introduced in the 1980s, it became a quality measure in the 1990s and has remained a mainstay of treatment ever since.”

She added that although pelvic chemoradiation is effective, it comes with “real toxicities.” Long-term toxicities from this approach include impaired bowel, bladder and sexual function, as well as increased risk of pelvic fracture and second cancer. Pelvic chemoradiation can also result in impaired marrow reserve, infertility and premature menopause, “which is a big deal because we are seeing increasing diagnoses of rectal cancer in people before the age of 50 years,” Schrag noted.

Over the past two decades, significant progress has been made in the paradigm, with effective chemotherapy regimens like FOLFOX, stronger surgical techniques and improved screening, with tumors being found when they are smaller in size and easier to treat. Imaging techniques have also improved with the use of pelvic MRI.

PROSPECT enrolled patients with previously untreated, locally advanced rectal cancer who had been staged as T2 node-positive, T3 node-negative or T3 node-positive for whom chemoradiation was indicated. All patients needed to be candidates to undergo sphincter-sparing surgery. “(The study) did not include patients with very large or symptomatic tumors,” Schrag noted.

Study participants were randomly assigned to the standard approach or the intervention. Those in the intervention arm first received modified FOLFOX and then were restaged with pelvic imaging and rectal endoscopy. If they responded to treatment in that they experienced a tumor reduction of at least 20%, they went on to surgery. Those who had tumor reduction of less than 20% were given pelvic chemoradiation. If patients did not have a complete resection, postoperative chemoradiation was recommended. Adjuvant chemotherapy with an additional cycles of FOLFOX was suggested but not required.

In addition to disease-free survival serving as the primary focus of the trial, local recurrence and overall survival represented other areas of interest. Researchers also focused on complete resection, pathologic complete response, toxicity and quality-of-life measures.

Additional data showed that 98.9% of patients in the FOLFOX arm had complete resection versus 97.1% of those in the chemoradiation arm.

Regarding postoperative treatment, 74.9% of those in the FOLFOX arm and 77.9% of those in the chemoradiation arm received adjuvant chemotherapy.

A total of 10.4% of those in the FOLFOX arm received chemoradiation; 9.1% received it prior to surgery and 1.4% received it post procedure. The median duration from randomization to last dose of postoperative therapy was 35.6 weeks and 37 weeks, respectively.

Patient-reported serious side effects reported at 12 months in the FOLFOX and chemoradiation arms included anxiety (3% versus 2%), loss of appetite (1% versus 1%), constipation (3% versus 4%), depression (2% versus 3%), diarrhea (2% versus 4%), difficulty swallowing (1% versus 0%), swelling (1% versus 1%), fatigue (3% versus 7%), nausea (1% versus 0%), neuropathy (3% versus 8%) and pain (5% versus 4%).

For the quality-of-life assessments, Schrag and colleagues evaluated overall health-related quality-of-life, bowel function, male sexual function and female sexual function. No significant difference was observed between the group, although bowel function and sexual function favored the FOLFOX group.

Following the presentation, Dr. Pamela L. Kunz, spoke to the significance of the study’s findings for the paradigm. “What’s important here is that radiation can be safely omitted in many patients with locally advanced rectal cancer. This is really less is more,” she said. “This study shows that we can spare select patients from receiving radiation without compromising efficacy. This leads to improved (quality-of-life), and it reduced side effects including things like early menopause and infertility. This trial is 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.”

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