Deb Schrag, MD, MPH, discusses the rationale for exploring the use of selective preoperative chemoradiation in patients with locally advanced rectal cancer, the safety and efficacy findings from the PROSPECT trial, and the importance of reviewing patient-reported outcomes during clinical trials.
Similar efficacy and safety outcomes generated by neoadjuvant fluorouracil, leucovorin, and oxaliplatin (FOLFOX) plus selective chemoradiation compared with chemoradiation indicated the selective use of chemoradiation is a feasible treatment strategy for patients with locally advanced rectal cancer, according to Deb Schrag, MD, MPH.
Data from the phase 2/3 PROSPECT trial (NCT01515787) presented at the 2023 ASCO Annual Meeting showed that patients who were treated with chemotherapy alone (n = 585) experienced a 5-year disease-free survival (DFS) rate of 80.8% (95% CI, 77.9%-83.7%) vs 78.6% (95% CI, 75.4%-81.8%) in patients treated with chemotherapy and pelvic chemoradiation (n = 543), meeting the trial’s primary end point (HR, 0.92; 95% CI, 0.74-1.14; P = .005).1,2
Patients in the intervention arm receiving FOLFOX and selective chemoradiation experienced 5-year local recurrence–free survival and overall survival (OS) rates of 98.2% and 89.5%, respectively. Those rates were 98.4% and 90.2%, respectively, in the control arm.
“We can tailor radiation and use it selectively, rather than reflexively, for patients [with locally advanced rectal cancer]. Patients with mid-rectal tumors that are clinical T3 and node positive or node negative can be spared long-term AEs from radiation with chemotherapy alone, and then only be given radiation if they do not achieve a good clinical response,” said Schrag, the 2023 Giants of Cancer Care inductee in Prevention/Genetics. “I believe that this has established a new standard of care. A chemotherapy-only approach is a viable, efficacious, and safe treatment option for curing rectal cancer.”
In an interview with OncLive®, Schrag, a gastrointestinal oncologist, chair of the Department of Medicine, and George J. Bosl Chair at Memorial Sloan Kettering Cancer Center, in New York, New York, described the rationale for exploring the use of selective chemoradiation in patients with locally advanced rectal cancer, detailed the safety and efficacy findings from PROSPECT, and explained the importance of reviewing patient-reported outcomes (PROs) during clinical trials.
Schrag: For many years, the way we've treated locally advanced rectal cancer [has been] with pelvic chemoradiation. We do that because rectal cancer has a nasty tendency to come back and recur locally in the pelvis; we call this local recurrence. It's a terrible outcome that causes a lot of suffering. It was common in the 1970s and 1980s. We learned through clinical trials that local recurrence could essentially be eliminated to very rare [instances] if we used pelvic radiation.
Pelvic radiation became the standard in approximately 1990, and it's been the standard ever since. Since 2004, we've given it preoperatively, and we've reduced pelvic recurrence. However, pelvic radiation has some pretty significant adverse effects [AEs], both short term in the acute setting, but most importantly, in the long-term setting.
We launched PROSPECT because we thought that given that we now have other tools—including better surgical technique, better imaging with pelvic MRI, and better chemotherapy with FOLFOX—we thought that we may back off on radiation and use it more selectively.
PROSPECT was for patients with locally advanced rectal cancer who surgeons decided were eligible for a sphincter-sparing operation from the get-go. There were a couple of important exclusions. This [study] did not include patients with very large T4 tumors, [such as] the type that are attached to the pelvic side. We know those [patients] need radiation, so they were excluded. We also excluded patients who had very low tumors because those [patients] would not be amenable to a sphincter-sparing operation.
We also focused specifically on those patients where the surgeon [determined prior to operation] that this patient will need preoperative treatment. Patients were included based on having specific clinical stages, [including] T3/node positive, T3/node negative, and T2/node positive. These are the most common stages of rectal cancer that we see, so [the study] pertained to many patients.
The trial was set up as a non-inferiority study, and it met its non-inferiority end points. We had good long-term follow-up with a median of 58 months. We were able to report out the primary end point of DFS, [and secondary end points of] OS and local recurrence rate.
In the intervention group, at 5 years, 80.8% of patients were alive and disease free. In the control group, [the 5-year DFS] was 78.6%. However, the primary statistical hypothesis, which was a non-inferiority hypothesis, was easily met. That was true in the population of patients who initiated treatment per protocol, as well as in the entire group of patients who were randomly assigned. This is a mature trial, and there was no difference in OS.
Importantly, for rectal cancer, since the reason we give the radiation is local recurrence, we had local recurrence data, and local recurrence rates were [less than] 2% in both groups, essentially nearly identical.
Regarding safety, the AEs of both chemoradiation and FOLFOX are well known. We did have toxicity both reported by clinicians and, importantly, by patients. We saw more toxicity in the FOLFOX group in the neoadjuvant setting. Then it flipped. In the post-operative setting, we saw more toxicity in the chemoradiation group. This was a wash of acute treatment toxicity.
We have more work to do with PROSPECT. We will be looking in a lot more detail at the surgical end points. We will look at the group of patients who are microsatellite instability–high. We will look at radiation oncology, and we will look very carefully at the MRI findings. We have a pelvic MRI library from nearly 1200 patients.
Importantly, we're looking forward to the molecular correlatives that are underway to try to identify the molecular signatures that correspond to exquisite chemotherapy responsiveness and exquisite radiation responsiveness. Ideally, if we could identify, based on the molecular features, which patients’ tumors are destined to respond particularly well to 1 modality or the other, we could make strategic treatment recommendations.
There is a landmark feature about PROSPECT that I’d like to emphasize. We included the PROs version of the Common Terminology Criteria for Adverse Events [CTCAE]. Patients reported their symptoms during the duration of the trial electronically or digitally. The vast majority of patients were able to successfully report their symptoms. We got very high response rates and we proved it's feasible.
This is setting a new standard for how we measure toxicity in the context of clinical trials, cutting out a lot of the game of telephone that happens when [data] go from patient to clinician to research staff to the study database. [Rather], we’re getting the information directly from patients. Patients know what their own symptoms are, and I am proud that we did that in this study.
The tool that we used—PRO-CTCAE—the questions themselves are in public domain and they're maintained by the National Cancer Institute. [The questions] are in multiple languages, so there shouldn't be barriers to access. We've also worked to develop a mechanism whereby the PRO-CTCAE system is integrated into EPIC, which is the dominant electronic health record system, so that this is easily, quickly, and inexpensively available, and can be integrated into other trials. PRO-CTCAE has now been integrated into hundreds of ongoing clinical trials, but PROSPECT was really the landmark, initial trial.