These data support a paradigm shift in the treatment of locally advanced rectal cancer.
Radiation with sensitizing fluoropyrimidine (5FUCRT) has been a standard curative-intent treatment for locally advanced rectal cancer (LARC) for the past 30 years, explained Deborah Schrag, MD, FASCO, MPH, chair of the Department of Medicine and George J. Bosl chair at Memorial Sloan Kettering Cancer Center, during a press conference at the American Society of Clinical Oncology 2023 Annual Meeting. Radiation has been used to improve disease-free survival (DFS) for patients with LARC by decreasing pelvic recurrence; however, there is significant potential for short- and long-term toxicity as a result.
To investigate opportunities to address intermediate risk for patients with LARC with less resulting toxicity, investigators conducted the randomized phase 3 PROSPECT trial (NCT01515787) to compare folinic acid (leucovorin), fluorouracil (5FU; Fluoroplex, McKesson), and oxaliplatin (Eloxatin, Pfizer; FOLFOX) chemotherapy with selective use of 5FUCRT in the intervention arm to 5FUCRT in the control arm for neoadjuvant treatment prior to total mesorectal excision (TME) for LARC.
“A key take-home from this trial is [we learned] most intermediate risk patients with LARC can be cured without needing pelvic radiation,” Schrag said. “This is a big deal because we’ve been radiating pelvises to treat this type of rectal cancer for the past 30 years.”
Globally, there are approximately 800,000 new rectal cancer diagnoses expected in 2023, according to Schrag. Further, approximately half of these diagnoses will be LARC.
“Our standard approach is a 5-and-a-half-week course of daily pelvic radiation with a dollop of chemotherapy given at the same time,” Schrag said. “This is the way we have achieved very strong outcomes for treating rectal cancer [over the past several decades].”
Additionally, Schrag noted that the reason radiation is so important for the treatment of rectal cancer is because this disease has a high rate of recurrence.
“Rectal cancer has a nasty predilection to come back in the pelvis,” Schrag said. “Pelvic recurrence of rectal cancer is the cause of enormous suffering [among patients], so when it was developed, radiation was a critically important advancement.”
Pelvic radiation for rectal cancer was first introduced in the 1980s and became a quality measure in the 1990s, according to Schrag. This practice has also become a mainstay for the treatment of rectal cancer ever since.
“The motivation underlying our study is that, although this treatment for LARC works well, pelvic radiation has real toxicities,” Schrag said. “It impairs bowel, bladder, and sexual function, and it has increased risk of late-effects, such as pelvic fractures and second cancers, and it can impair the function of the bone marrow, which can become a problem if people need chemotherapy in the future.”
Pelvic radiation can also cause infertility and premature menopause, according to Schrag.
“That’s a big deal because we’ve been seeing increased rates of rectal cancer in people before the age of 50,” Schrag said. “So we asked the question: Could we use radiation more selectively, and only give it for people who don’t respond to chemotherapy rather than giving the radiation to everyone as a part of the standard?”
Schrag noted that in this way, the trial investigated a deintensification of the current standard of care for patients with LARC rather than a new drug.
“Another key point about this trial is that it is research that is publicly sponsored by the National Cancer Institute Cooperative Groups,” Schrag said during the press conference. “This [research was conducted through] a partnership with patients and academic community cancer centers across the United States, [as well as] in Canada and Switzerland.”
During the trial, investigators enrolled eligible patients with cT2N+, cT3N-, cT3N+ rectal cancers that were deemed appropriate for neoadjuvant therapy prior to low anterior resection with TME. However, patients with distal, T4 tumors, threatened radial margins or more than 4 enlarged lymph nodes were ineligible.
Patients were randomized 1:1 from June 2012 to December 2018 without blinding. In total, 1194 patients were randomized, and 1128 patients had initiated protocol assigned treatment. The median age of patients enrolled was 57 years; 34.5% of study participants were women and 61.9% had clinically positive nodes. In the intervention group, 53 of 585 patients (9%) received pre-operative 5FUCRT.
In the control group, patients were given 5FUCRT with 5040 cGy over 5.5 weeks with either capecitabine or 5FU. In the intervention group, patients had 6 cycles of mFOLFOX6 followed by restaging. Schrag noted that if tumor regression was greater than 20%, then TME was performed without radiation; however, if less than 20%, then 5FUCRT was given before TME.
The primary endpoint of the trial was DFS, which investigators defined as the time from randomization to any cancer recurrence or death, analyzed in the per protocol population. During the trial, DFS was analyzed after 227 events and median follow-up of 58 months.
One interim analysis was conducted, with noninferiority (NI) of the intervention claimed if the upper limit of the 2-sided 90.2% confidence interval of the DFS hazard ratio did not exceed 1.29 (NI margin). Further, secondary endpoints included overall survival (OS), local recurrence-free survival, R0 resection, pathologic complete response, and toxicity.
“At the end of 5 years, 80.8% of patients were alive without recurrence of their rectal cancer in the intervention arm, which is the selective chemo with selective radiation arm, with 78.6% patients alive in the usual standard of care arm,” Schrag said. “Local recurrence rates were very low and overall survival was similar. So the study met it’s prespecified hypothesis that there were no meaningful differences between the 2 treatment approaches with respect to other outcomes.”
In this way, the study results demonstrated FOLFOX chemotherapy with selective use of 5FUCRT is non-inferior to 5FUCRT for neoadjuvant treatment of LARC prior to low anterior resection with TME. This demonstrates that patients and physicians have available alternative strategies for management of LARC other than radiation as a part of standard of care.
Additionally, Schrag noted that an important additional data point observed in the study was that only 9% of patients in the intervention arm ended up needing the radiation.
“We also 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, and I won’t belabor that, but that was really a paradigm shift in how we conducted this trial,” Schrag said. “We think that we can successfully de-escalate treatment of rectal cancer and achieve the same high cure rates while keeping patients disease free with less long-term toxicity and effects.”
Schrag D. 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). Presented at: 2023 ASCO Annual Meeting in Chicago, IL at press conference on June 3, 2023. Accessed June 3, 2023. https://meetings.asco.org/2023-asco-annual-meeting/15047