Ciombor Cites Challenges in Optimizing Care for Locally Advanced Rectal Cancer

Determining the appropriate sequencing for chemotherapy and radiation in patients with locally advanced rectal cancer is important and may depend on whether the goal of therapy is nonoperative management, according to Kristen K. Ciombor, MD, MSCI.

The optimal duration and intensity of radiation treatment continues to be an area of active debate, and the question of whether chemotherapy should be intensified up front or with radiosensitizers are all questions that beg for further exploration, Ciombor added.

“We tend to do more of the total neoadjuvant therapy [TNT] approach now at our institution, where chemotherapy is being done as the first [treatment], at least preoperatively,” Ciombor said. “Many patients that we see tend to have very bulky disease, [with] either T4 lesions or lots of nodes. We feel that those patients have a high risk for distant metastasis; therefore, we like to start chemotherapy first. Chemoradiation is certainly still key, and surgery is still important, however, we try to do most of the chemotherapy and chemoradiation up front.”

In an interview with OncLive® during an Institutional Perspective in Cancer webinar on Gastrointestinal Cancers, Ciombor, an assistant professor of medicine at Vanderbilt-Ingram Cancer Center, discussed several important trials conducted in patients with locally advanced rectal cancer, remaining challenges that need to be addressed, and ongoing efforts that are gaining ground.

OncLive®: How do you approach sequencing therapies for patients with locally advanced rectal cancer? What factors do you consider?

Ciombor: This is definitely an area that has changed a lot over the past few years. How we used to sequence therapy for patients with locally advanced rectal cancer was fairly standard. We gave chemoradiation followed by total mesorectal excision [TME], which was then followed by adjuvant chemotherapy.

With the [launch] of multiple trials and the data that have come out of them, we now have a variety of [approaches that we use]. It is a tough space, because we're trying to [individualize treatment] for each individual person [based on] what [approach] makes the most sense and what has the best [supportive] data. Some of the recent studies that came out of ASCO last year really helped to quantify and clarify exactly what types of treatments are needed [for these patients].

In some cases, we’ll start off with radiation. Based on the OPRA data, it seems like that sequencing might make a lot of sense for patients who are seeking a nonoperative management approach.

Could you expand on the approach used in the phase 2 OPRA trial (NCT02008656)?

OPRA was a really interesting trial that was done at Memorial Sloan Kettering Cancer Center; [it included] patients who had stage II or III distal rectal tumors. Patients were randomized to either consolidation chemotherapy or induction chemotherapy. The difference was really the sequence. All patients received [4 months of] either 5-fluorouracil, leucovorin, and oxaliplatin [FOLFOX] or capecitabine and oxaliplatin [CapeOX] before or after [fluorouracil- or capecitabine-based chemoradiotherapy]. However, whether patients started or finished that component with chemotherapy set them apart.

All patients went on to restaging after completion of those 2 modalities. If they did not have a clinical complete response [CR], they went on to TME as usual. If they did have a clinical CR, they could go on the watch-and-wait protocol. In terms of overall results, the primary end point was 3-year disease-free survival [DFS]. The study was not powered to compare the 2 arms, but really to compare each arm with the historical control.

This was technically a negative study because the 3-year DFS in either of those arms did not beat the historical controls. What was really interesting, however, is that a definite difference in TME-free survival [was observed] in the patients who received the consolidation chemotherapy; these patients started with radiation and then ultimately finished with chemotherapy followed by restaging. More than half of those patients are potentially eligible for the watch-and-wait protocol after that, as opposed to a lower percentage who had started with chemotherapy and received radiation last.

The phase 3 RAPIDO trial (NCT01558921) examined another sequencing approach, with different durations of radiation. What sets this research apart from other efforts?

That was a very interesting study. The design [evaluated] short-course radiation followed by chemotherapy with CapeOX or FOLFOX for 18 weeks. What was different about that study, in comparison with some others, is that [it enrolled] very high-risk patients. Based on magnetic resonance imaging, they had to have either T4 disease, N2 disease, enlarged lateral nodes, vascular invasion, or positive mesorectal fascia. Many of those patients met more than 1 of those criteria. These were patients who were quite high risk for recurrence or metastasis.

How did this regimen perform in this patient population?

Patients randomized to the experimental arm [received] short-course radiation, followed by chemotherapy, followed by [TME]. Those in the control arm, where they received standard chemoradiation, followed by TME, [and potentially] adjuvant chemotherapy, [if stipulated by hospital policy]. All patients had a very high likelihood of going to surgery and having an R0 resection, which was nice to see. Interestingly, we also saw almost a doubling of pathologic CR (pCR) in the experimental arm vs the control.

The primary end point of the trial was 3-year disease-related treatment failure, and that was statistically significantly better in the experimental arm. We also saw that distant metastases were less commonly seen in the experimental arm. We have to follow that end point for locoregional failure out for a longer period of time; however, at least at 3 years, no statistically significant [difference was observed] between arms. [Investigators did observe a] slight trend toward an increased rate of locoregional [progression] in the experimental arm. Even though these were very high-risk patients, overall survival was very good; it was not different between the arms, and it was almost 90% in this entire group at 3 years.

The NRG-GI002 study evaluated the addition of a radiosensitizer to TNT in this population. What was learned from this research?

With the NRG-GI002 study, or the TNT trial, the most recent arm was presented at the 2021 Gastrointestinal Cancers Symposium. However, at the 2019 ASCO Annual Meeting, [data from] the first experimental arm [of the trial were presented]. Essentially, [investigators enrolled] patients who had very high-risk disease. Patients had to have either distal abdominoperineal resection–requiring rectal tumors, bulky disease, or N2 disease.

[Patients] randomized to the control arm, which was the TNT approach, [received] FOLFOX times 8, followed by chemoradiation with capecitabine, followed by surgery. Then at different time points, depending on which experimental arm was open, the initial experimental arm was actually a combination in the radiation components. In addition to capecitabine, some patients also got veliparib [ABT-888], a PARP inhibitor. Everything else was the same as the control arm.

That was a negative study in the sense that it did not improve the primary end point, which was the neoadjuvant rectal [NAR] score. We found that adding veliparib did not improve patient outcomes. The next arm, which was recently presented, [included] the addition of pembrolizumab [Keytruda] to capecitabine and radiation. Unfortunately, we found that this [approach] did not improve the NAR score either. Although these [approaches both] had very good preclinical rationale, it just didn't pan out in terms of actual results. [Still], they were very important arms to complete. That study is being redesigned right now in light of all of the other recent data in the space.

PRODIGE 23 (NCT01804790) also evaluated TNT, this time with modified FOLFIRINOX, but yielded more favorable results. What should be taken away from this work?

PRODIGE 23 was a slightly different study in that it really looked at intensification of chemotherapy and the neoadjuvant component of the treatment. Patients with all types of locally advanced rectal cancer were randomized to what we consider to be the historical control of chemoradiation, TME, and adjuvant FOLFOX given for 6 months, vs what they called the TNT arm, where patients received modified FOLFIRINOX for 3 months, followed by chemoradiation, TME, and then completing 6 months of perioperative chemotherapy with 3 months of FOLFOX or capecitabine.

A definite improvement, or an increase, in pCR [was observed] by the time of surgery. Toxicities weren't significantly different [between the arms], and definitely not worse in the TNT group; this was surprising, but definitely welcome. We saw that DFS at 3 years was better for the TNT group, as well as metastasis-free survival. All those end points were really important. We do need to continue the follow-up in that trial, but [we're] definitely seeing different ways to manage patients with locally advanced rectal cancer, and a lot of room to potentially move this field forward.

What ongoing efforts are you excited about?

We have many options when it comes to [patients with] locally advanced rectal cancer. We really need to continue studying these patients, and perhaps look at biomarker selection, as well, as there may be different ways to treat these patients that we previously have not really considered. [These approaches] may lead to more nonoperative management for patients who otherwise would lose their rectum. There may be ways in which we can improve patient outcomes, which clearly is always our goal.

Even beyond the studies that I discussed, there may be opportunities to personalize therapy, as well. One example of this is through ECOG. A study that is launching this spring will look at the microsatellite instability–high population. Instead of doing chemotherapy or chemoradiation, we are [keeping in mind that] immunotherapy works very well in these patients with metastatic disease. Thus, we are looking at neoadjuvant nivolumab [Opdivo] and ipilimumab [Yervoy] plus short-course radiation. We're really looking to that trial in that subset of patients to improve outcomes. Every patient is different. It requires multidisciplinary care and moving the field forward with our research [to help] patients do better in the long run.