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CHICAGO -- Standard pelvic chemoradiotherapy prior to surgery can be safely omitted in select patients with locally advanced rectal cancer whose tumors respond to neoadjuvant chemotherapy, findings from a large cooperative group trial demonstrated.

Of over 1,100 patients eligible for sphincter-sparing surgery, disease-free survival (DFS) over a median follow-up of 58 months was no different for those randomized to preoperative FOLFOX -- with pelvic radiotherapy held in reserve only for select cases -- and for those assigned to standard chemoradiotherapy (HR 0.92, 90% CI 0.74-1.14, P=0.005 for noninferiority), reported Deborah Schrag, MD, MPH, of Memorial Sloan Kettering Cancer Center in New York City.

"Most intermediate-risk rectal cancer patients can be cured without needing pelvic radiation," Schrag said during a press briefing at the American Society of Clinical Oncology (ASCO) meeting here. "Why is this a big deal? It's a big deal because we have been radiating pelvises to treat this type of rectal cancer for the past 30 years."

At 5 years, DFS rates reached 80.8% in the FOLFOX group and 78.6% in the control group. Furthermore, overall survival and local recurrence rates were no different, according to the findings, which were published simultaneously in the .

Ultimately, only 9.1% of patients in the investigational arm required pelvic chemoradiotherapy prior to surgery; an additional 1.4% received it postoperatively.

Findings from the so-called PROSPECT trial show that physicians can successfully de-escalate treatment in locally advanced rectal cancer while achieving the same high cure rate, with less long-term toxicity and late effects, said Schrag.

"It's not for all patients," she cautioned, noting that the study did not include patients with very large or symptomatic tumors.

Patients were eligible for enrollment if they had clinically staged T2 node-positive, T3 node-negative, or T3 node-positive disease, and if their surgeons considered neoadjuvant pelvic chemoradiotherapy followed by sphincter-sparing surgery the appropriate treatment course.

In the FOLFOX group, patients received six cycles of (fluorouracil, leucovorin, oxaliplatin) followed by restaging with pelvic imaging and rectal endoscopy. If tumor regression was less than 20%, pelvic chemoradiotherapy was given prior to total mesorectal excision. Those unable to complete at least five FOLFOX cycles were given chemoradiotherapy, and it was recommended for those without complete resections (R0) as well.

Along with the DFS findings, no significant differences at 5 years were seen for overall survival or local recurrence rates between the FOLFOX and chemoradiotherapy groups:

• Overall survival: 89.5% vs 90.2%, respectively
• Local recurrence: 1.8% vs 1.6%

The findings are "practice changing" for these patients with locally advanced rectal cancer, said ASCO-designated expert Pamela Kunz, MD, of Yale School of Medicine in New Haven, Connecticut.

"This is really 'less is more,'" she said during the press briefing. "We can spare select patients from receiving radiation without compromising efficacy. This leads to improved quality of life and reduced side effects, including things like early menopause and infertility."

Pelvic Recurrence a 'Cause of Enormous Suffering'

An estimated 48,000 new cases of rectal cancer are diagnosed each year in the U.S., with roughly half locally advanced at the time of diagnosis. The standard curative approach involves 5.5 weeks of daily pelvic radiation (50.4 Gy delivered over 28 fractions) plus "a dollop" of sensitizing fluoropyrimidine-based chemotherapy (capecitabine or fluorouracil), said Schrag.

"The reason radiation is so important is that rectal cancer has a nasty predilection to come back in the pelvis," she said. "Pelvic recurrence in rectal cancer is a cause of enormous suffering, so when it was developed, radiation was a critically important advance."

And it's been a mainstay of treatment since the 1990s. "We achieve great outcomes for our patients, but it's long and it's hard," said Schrag.

The motivation underlying was that although pelvic radiation works, it has real toxicities, she explained. These include impaired bowel, bladder, and sexual function and later risks such as pelvic fractures and secondary malignancies. Radiation can also negatively affect bone marrow function, which can complicate treatment if patients need chemotherapy later on.

Over the years, advancements in chemotherapy, surgical technique, screening, and staging allowed the researchers to test whether using radiation more selectively for people who fail to respond to chemotherapy would be feasible.

Study Details

From June 2012 to December 2018, the PROSPECT (Chemotherapy Alone or Chemotherapy Plus Radiation Therapy in Treating Patients With Locally Advanced Rectal Cancer Undergoing Surgery) trial randomized 1,194 patients with pathologically confirmed rectal adenocarcinoma from 264 centers across North America and Switzerland, with the vast majority of participants from the U.S.

Ultimately, 1,128 started treatment, including 585 in the FOLFOX group and 543 in the chemoradiotherapy group. Participants were stratified by Eastern Cooperative Oncology Group (ECOG) performance status score (0-1 vs 2) -- more than 99% had a score of 0-1.

Patients had a mean age of 57 years, about two-thirds were women, with 85% white, 4% Black, and 4% Asian. Of these, 8.5% were Hispanic.

For clinical tumor staging, a majority had T3 node-positive disease, over a third had T3 node-negative tumors, and under 10% had T2 node-positive tumors. Most of the tumors were in the mid-rectum (median 8 cm from the anal verge).

The primary endpoint was DFS at 5 years (noninferiority), with secondary endpoints including overall survival, local recurrence, surgical endpoints, and safety.

For surgical outcomes, 98.9% of patients in the FOLFOX group had a complete resection (R0) versus 97.1% of those in the control group, with 21.9% and 24.3% achieving a complete pathological response, respectively.

During neoadjuvant therapy, nearly twice the rate of grade ≥3 adverse events were reported in the FOLFOX group (41% vs 22.8%), though the researchers noted that the treatment duration was roughly twice as long with FOLFOX (12 vs 5.5 weeks). Neuropathy was more frequent and severe with FOLFOX, while diarrhea was more frequent and severe with chemoradiotherapy.

Following surgery, adjuvant therapy was administered in 82% of patients in the FOLFOX group and 83% of those in the chemoradiotherapy group. In this case, the FOLFOX arm experienced a lower rate of grade ≥3 adverse events than the chemoradiotherapy group (25.6% vs 32.6%).

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