PROSPECT Trial Confirms Feasibility of De-escalation of Neoadjuvant Chemoradiation in Locally Advanced Rectal Cancer

With the increasing use of triplet and quadruplet chemotherapy regimens in the neoadjuvant setting for patients with rectal cancer, it is vital to confirm the benefit of these approaches and assess whether standard intensified treatment is necessary for all patients eligible for surgical resection, according to Michael Cecchini, MD.

At the 2023 ASCO Annual Meeting, long-term findings from the phase 2/3 PROSPECT trial (NCT01515787) demonstrated that the use of neoadjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) with selective chemoradiation prior to sphincter-sparing surgery was non-inferior to preoperative pelvic chemoradiation for patients with T2 node-positive, T3 node-negative, or T3 node-positive rectal cancer.¹

The 5-year disease-free survival (DFS) rate in patients treated with chemotherapy alone (n = 585) was 80.8% (95% CI, 77.9%-83.7%) vs 78.6% (95% CI, 75.4%-81.8%) for those treated with chemotherapy and pelvic chemoradiation (n = 543). Moreover, 5-year local recurrence–free survival and overall survival (OS) rates for patients receiving FOLFOX and selective chemoradiation were 98.2% and 89.5%, respectively. For those given the standard regimen, these rates were 98.4% and 90.2%, respectively.

“At the end of the day, [PROSPECT] shows us that for patients [who] have mid-to-high rectal cancer that's low-risk [in whom] we feel that induction FOLFOX is the right step, radiation can safely be omitted,” said Cecchini, a medical oncologist at Yale Medicine, assistant professor of medicine in the Department of Medical Oncology, and co-director of the Colorectal Program at Yale School of Medicine’s Center for Gastrointestinal (GI) Cancers, in New Haven, Connecticut.

In an interview with OncLive^®, Cecchini expanded on key updates in GI cancer from the 2023 ASCO Annual Meeting, including the clinical significance of findings from the PROSPECT and phase 3 PRODIGE 23 (NCT01804790) trials of perioperative chemotherapy vs selective standard chemoradiation. He also spotlighted ongoing trials for patients with colorectal cancer (CRC).

OncLive: Could you detail key findings from PROSPECT? What was the clinical significance of these data?

Cecchini: There were a lot of big, new updates for GI oncology and oncology in general, but we [have to talk about] PROSPECT. That was the biggest trial and the biggest practice-changing evidence that I was anticipating.

PROSPECT was one of the trials presented in the plenary session. It was a non-inferiority study done by the [Alliance for Clinical Trials in Oncology] with [1128] patients enrolled. The study compared induction [neoadjuvant] chemotherapy vs chemoradiotherapy for rectal cancer. In the induction chemotherapy group, there was an evaluation to see if patients responded and whether we could omit chemoradiation, which is the typical standard of care. The idea was [to see] if we could de-escalate our current therapies for low-risk, mid-to-high rectal cancer.These [patients had] T2, T3, and no more than N1 rectal cancer. It was a long effort [involving] about a decade of enrollment.At the end of the day, [it focused on] quality of life and if we could [use] less intensive treatment for our patients.

PROSPECT showed that there was no compromise in efficacy [when de-escalating therapy], and we can omit radiation comfortably for these [patients with] low-risk, mid-to-high rectal cancers. [Although these are] very exciting findings, the field of rectal cancer has also changed dramatically over the last 10 years. Now we're using total neoadjuvant therapy in the majority of patients, and there are some patients that are getting "watch and wait" [approaches]. This does [present] a challenge [regarding] how to fully incorporate these results into our clinical practice.

What were the implications of findings from PRODIGE 23?²

Another rectal cancer study that was exciting was the PRODIGE 23 trial, which was presented at the oral abstract session for colorectal cancer. That trial was evaluating mFOLFIRINOX [leucovorin, fluorouracil, irinotecan, and oxaliplatin] as perioperative therapy for [patients with locally advanced] rectal cancer compared with the more classical chemoradiation and surgery, followed by adjuvant FOLFOX. In that study, patients [in the experimental arm] received neoadjuvant mFOLFIRINOX for 3 months in 6 cycles, underwent surgery, and then got adjuvant mFOLFOX6. For the first time, we saw the long-term results from that study. This study has been presented before, but we [have now] showed that there was an [overall] survival [OS] benefit with this approach.

The big question has always been: are we increasing OS with these neoadjuvant strategies for rectal cancer? Now we've shown that 5- and 7-year OS are clearly improved with neoadjuvant mFOLFIRINOX. That becomes a new option for our patients that we can safely say also prolongs OS.

How might the findings from PROSPECT and PRODIGE 23 be applicable to current practice?

For a young, fit patient with rectal cancer who is in need of total neoadjuvant therapy, I can comfortably say mFOLFIRINOX is perhaps going to be more [often] be my choice because of the OS benefit shown in the PRODIGE 23 study. That will change my practice for patients with higher-risk rectal cancer. However, not all my patients can tolerate mFOLFIRINOX, so [these findings] are not going to apply to everybody.

PROSPECT is practice-changing for patients who have mid-to-high rectal cancer. Induction FOLFOX [could] spare them toxicity, and if they have a radiographic response, I will comfortably omit radiation for these [patients]. Frankly, this is already a discussion we have in tumor boards Do these patients with high rectal cancer need radiation? Now we can be a bit more comfortable saying no.

PROSPECT was a very big deal beyond its results. It showed how important the cooperative groups are. It also showed tremendous rigor by the investigators and commitment from the patients to participate in a study like that to get those important results. [This study] was a decade in the making, and we need to recognize the efforts of all those involved.

Could you spotlight 1 or 2 key trials in CRC that are coming down the pike?

CRC is a very broad area with, unfortunately, a high number of patients who are diagnosed every year. We have some big studies running that are going to answer some very important questions [regarding] what we do with circulating tumor DNA [ctDNA], which is a very hot topic. [These trials] are going to help define [ctDNA’s] predictive power for certain adjuvant strategies. We know ctDNA has highly prognostic predictability for relapse, but we don't know how predictive it is for benefit from adjuvant therapy.

[The phase 2/3] COBRA study [NCT04068103] is going to look at [ctDNA] in [patients with] low-risk, stage IIA CRC, and the [phase 2/3] CIRCULATE-US study [NCT05174169] is going to look at de-escalation or escalation [of therapy] in patients with stage III CRC, depending on their ctDNA status. Those are important studies that I'm looking forward to over the next few years.

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):LBA2. doi:10.1200/JCO.2023.41.17_suppl.LBA2
2. Conroy T, Etienne P-L, Rio E, et al. Total neoadjuvant therapy with mFOLFIRINOX versus preoperative chemoradiation in patients with locally advanced rectal cancer: 7-year results of PRODIGE 23 phase III trial, a UNICANCER GI trial. J Clin Oncol. 2023;41(suppl 17):LBA3504. doi:10.1200/JCO.2023.41.17_suppl.LBA3504