FOLFOX Demonstrates Comparable Efficacy to Chemoradiation for Neoadjuvant Treatment of Locally Advanced Rectal Cancer


Preoperative FOLFOX demonstrated noninferior efficacy outcomes vs preoperative chemoradiation in locally advanced rectal cancer.

Neoadjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) elicited a 5-year disease-free survival (DFS) rate of 80.8% in patients with locally advanced rectal cancer compared with standard pelvic chemoradiation (78.6%), demonstrating noninferiority for those who were eligible for sphincter-sparing surgery, according to data from the phase 2/3 PROSPECT trial (NCT01515787).

The findings, which were presented in a press briefing during the 2023 ASCO Annual Meeting, also showed that patients who received the intervention (n = 585) experienced fewer adverse effects than those who received the standard approach (n = 543).

Moreover, 98.2% of those in the FOLFOX arm were reported to be free of local recurrence at this time point vs 98.4% of those in the standard arm. The 5-year overall survival rates were 89.5% and 90.2%, respectively. No meaningful difference in these secondary end points was observed between the arms.

Notably, only 9% of patients who were assigned to the investigative arm ended up needing to receive pelvic chemoradiation.

“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,” Deb Schrag, MD, FASCO, MPH, lead author of the study, and a 2023 Giant of Cancer Care® winner in Prevention/Genetics, 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 at 5040 cGy with concurrent chemotherapy comprised of 5-fluorouracil or capecitabine, followed by an approximate 8-week recovery, subsequent surgery with total mesorectal excision, an approximate 6-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 2 decades, significant progress has been made in the paradigm, with effective chemotherapy regimens like FOLFOX, stronger surgical techniques like total mesorectal excision, 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.

“So, we asked the question: Could we use radiation more selectively and only give it to people who do not respond to chemotherapy rather than giving the radiation to everyone as part of the standard?” Schrag said. “This is a theme of, can we de-escalate or de-intensify therapy?”

PROSPECT enrolled patients with 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 FOLFOX for 6 cycles and then were restaged. If they responded to treatment, they went on to surgery, but if they did not, they were given pelvic chemoradiation. Adjuvant chemotherapy could be given postoperatively at physician’s discretion.

In addition to DFS serving as the primary end point, local recurrence and OS represented key secondary end points. Other end points of interest included complete surgical resection, complete pathologic response, toxicity, and quality-of-life (QOL) measures.

“We spent a lot of time evaluating toxicity, and what I’m proudest of is that we measured toxicity based on what the patients told us,” Schrag said. “I won’t belabor that but that was really a paradigm shift in how we conducted the trial.”

Following the presentation, Pamela L. Kunz, MD, 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 QOL, 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.”


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 (TME) for treatment of locally advanced rectal cancer (LARC) (Alliance N1048). J Clin Oncol. 2023;41(suppl 17):LBA2.

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