Preoperative FOLFOX Is Noninferior to Preoperative Chemoradiation in Locally Advanced Rectal Cancer

Neoadjuvant treatment with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) proved to be as effective as pelvic chemoradiation with fewer adverse effects in patients with locally advanced rectal cancer who were eligible for sphincter-sparing surgery, according to data from the phase 2/3 PROSPECT trial (NCT01515787) presented in a press briefing during the 2023 ASCO Annual Meeting and The New England Journal of Medicine.^1,2

Patients who received the intervention (n = 585) experienced a 5-year disease-free survival (DFS) rate of 80.8% (95% CI, 77.9%-83.7%) compared with 78.6% (95% CI, 75.4%-81.8%) in those who received the standard approach (n = 543), meeting the study’s prespecified noninferiority criteria (HR, 0.92; 90.2% CI, 0.74-1.14; P = .005 for noninferiority).

The 5-year estimated overall survival (OS) rates were 89.5% (95% CI, 87.0%-92.2%) and 90.2% (95% CI, 87.6%-92.9%), respectively (HR, 1.04; 95% CI, 0.74-1.44). Moreover, 98.2% (95% CI, 97.1%-99.4%) of those in the FOLFOX arm were free of local recurrence at this time point vs 98.4% (95% CI, 97.3%-99.6%) of those in the standard arm (HR, 1.18; 95% CI, 0.44-3.16). 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 neoadjuvant pelvic chemoradiation because restaging demonstrated a clinical response of less than 20% or they did not tolerate at least 5 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,” 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 previously untreated, pathologically confirmed, locally advanced rectal cancer who had been staged as T2 node-positive (cT2N+), T3 node-negative (cT3N-), or T3 node-positive (cT3N+) 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 for 6 cycles every 2 weeks 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 (R0), postoperative chemoradiation was recommended. Adjuvant chemotherapy with an additional 6 cycles of FOLFOX was suggested, but not required.

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 R0 resection, pathologic complete response (pCR), toxicity, and quality-of-life (QOL) measures.

The mean age across the FOLFOX and chemoradiation arms was 57 years, and most patients were male (63.1% vs 68.1%), White (84.1% vs 86.0%), and not Hispanic (88.2% vs 87.5%). The majority of patients were from the United States (89.6% vs 90.1%) and the remainder were from Canada or Switzerland. The tumor location from the anal verge was 8 cm. In the investigative arm, 11%, 39%, and 50% of patients, respectively, had cT2N+, cT3N-, and cT3N+ clinical stage at baseline; in the control arms, these rates were 7%, 37%, and 56%, respectively.

Additional data showed that 98.9% of patients in the FOLFOX arm had R0 vs 97.1% of those in the chemoradiation arm. Moreover, the low anterior resection rates were 97.6% and 98.0%, respectively. The pCR observed in the investigative arm was 21.9% compared with 24.3% in the control arm. Lastly, the percentages of positive radial margin (≤1 mm) in the FOLFOX and chemoradiation arms were 1.2% and 1.5%, respectively.

Regarding postoperative treatment, 74.9% of those in the FOLFOX arm and 77.9% of those in the chemoradiation arm received adjuvant chemotherapy; 79.5% and 66.4% of patients, respectively, received adjuvant FOLFOX for a median of 6 cycles and 8 cycles, respectively. In the chemoradiation arm, an additional 60 patients received post-operative capecitabine and oxaliplatin.

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 (interquartile range [IQR,] 32.9-39.3) and 37.0 weeks (IQR, 34.0-40.4), respectively.

Neoadjuvant grade 3 or higher AEs were observed in 41% of those in the FOLFOX arm vs 23% of those in the chemoradiation arm; adjuvant grade 3 or higher AEs were reported in 25% and 39% of patients, respectively. Schrag noted that during neoadjuvant treatment, more diarrhea was reported in the chemoradiation group, and more neuropathy was observed in the FOLFOX group. During adjuvant treatment, more diarrhea and neuropathy were observed in the chemoradiation group vs the FOLFOX group.

“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.”

Patient-reported serious AEs reported at 12 months in the FOLFOX and chemoradiation arms included anxiety (3% vs 2%), loss of appetite (1% vs 1%), constipation (3% vs 4%), depression (2% vs 3%), diarrhea (2% vs 4%), dysphagia (1% vs 0%), edema (1% vs 1%), fatigue (3% vs 7%), nausea (1% vs 0%), and neuropathy (3% vs 8%), pain (5% vs 4%).

For the QOL assessments, Schrag and colleagues evaluated overall health-related QOL, 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, 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.”

References

1. 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; abstr LBA2).
2. Schrag D, Shi Q, Weiser MR, et al. Preoperative treatment of locally advanced rectal cancer. N Engl J Med. Published June 4, 2023. doi:10.1056/NEJMoa2303269