Neoadjuvant, Nonoperative Regimens Being Investigated in Rectal Cancer

Katherine Van Loon, MD, MPH

Investigators conducting the multicenter phase Il/ III PROSPECT trial are comparing the FOLFOX chemotherapy regimen to the standard chemoradiation, followed by surgery and adjuvant therapy in patients with locally advanced rectal cancer to determine whether or not patients can be spared the toxicity of pelvic radiation therapy, explains Katherine Van Loon, MD, MPH. Additionally, the trial will hopefully answer whether or not upfront chemotherapy can reduce the occurrence of distant metastatic disease (NCT01515787).

“It’s a lofty ambition,” says Van Loon, a gastrointestinal cancer specialist at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center.

A second clinical trial in the space, is investigating the use of nonoperative management for patients with locally advanced disease. The phase II study is randomizing patients to either FOLFOX followed by chemoradiation or chemoradiation followed by FOLFOX (NCT02008656).

OncLive^®: What are the updates we have seen in rectal cancer?

Based on the evolution of treatment, what does the future of rectal cancer look like?

Will we ever reach a place where neoadjuvant immunotherapy is used in place of neoadjuvant chemotherapy?

What ongoing clinical trials in this space are you excited about?

Although the trial will examine the sequence of therapy, “The important question that’s being addressed is whether or not patients who show complete pathologic responses can be safely followed with surveillance in a nonoperative approach,” says Van Loon. In an interview during the 2018 OncLive^® State of the Science Summit™ on Gastrointestinal Cancers, Van Loon discussed the emerging use of neoadjuvant therapy and nonoperative approaches for patients with locally advanced rectal cancer.Van Loon: I spoke about the evolving paradigm for the management of locally advanced rectal cancer, the sequence of therapies, and the rise of nonoperative management over the past decade. Also, the National Comprehensive Cancer Network (NCCN) guidelines now include the option of neoadjuvant chemotherapy followed by neoadjuvant chemoradiation and total mesorectal excision for locally advanced disease.My practice has completely changed over the past 5 years with regard to the management of locally advanced rectal cancer. Only over the past year has neoadjuvant chemotherapy been incorporated into NCCN guidelines. At first, I thought about which patients with poor-risk factors, such as T4 and N2 disease, this would be appropriate for. As my practice and my experience have evolved, I have observed that patients tolerate neoadjuvant chemotherapy very well and are highly compliant. Responses are generally very favorable in terms of complete pathologic or response rates. Now, I routinely offer FOLFOX followed by chemoradiation and a concluding total mesorectal excision to my patients. Colorectal cancer (CRC) is among one of the diseases where we have seen a very low signal of response [with immunotherapy], specifically in microsatellite stable (MSS) cancers. Immunotherapy has been approved for treatment of mismatch repair deficient or microsatellite instability-high (MSI-H) cancers and is now being explored in the adjuvant setting for stage III disease. For the large proportion of patients with rectal cancer who are even less likely to have MSI-H tumors, it’s a far reach to think that the disease is going to involve immunotherapy in the immediate future. There are 2 multicenter trials that will inform our management of the disease. The first is the PROSPECT trial, which is randomizing patients to the standard of care, chemoradiation, followed by surgery and adjuvant therapy, to neoadjuvant FOLFOX for 6 cycles. The patients who undergo neoadjuvant FOLFOX then undergo restaging. Those who have a greater than 20% response rate proceed directly to surgery—potentially sparing them from pelvic radiation therapy.

The second trial, OPRAH, is of particular interest as it addresses the use of nonoperative management for patients with locally advanced rectal cancer who desire a nonsurgical approach. The trial randomized patients to 2 sequences of total neoadjuvant therapy. I don’t anticipate a meaningful difference between those 2 arms alone.

I’m interested in whether or not these patients who show complete responses can be safely followed with surveillance. A complete pathologic response would show no evidence of residual tumor at restaging with proctoscopic examination and full radiographic imaging. These patients go into an arm with very close surveillance, specifically repeat proctoscopies, MRIs, and CT scans at very structured intervals. We are watching them very closely with the understanding that they’re at the highest risk for recurrence within 12 to 24 months after completion of therapy.

Will active surveillance have more of a role in this field, as it has in prostate cancer?

Much of the field offers nonoperative management that is not evidence based. It’s also important to think about the disparities in who is receiving nonoperative management. It tends to be the underinsured; it also tends to be African American patients. These are patients who tend to require additional levels of attentiveness in terms of ongoing surveillance. field, as it has in prostate cancer? It’s too soon to tell. The OPRAH trial will inform my answer to that. I don’t think that nonoperative management is something that I’m routinely recommending outside of a clinical trial. For patients who decline to undergo surgery, we require that they are followed with a very structured approach and are actively engaged in their surveillance care. That is true for all of our patients who survive CRC. The difficulty of following both the primary site and regional lymph nodes in rectal cancer at the time of diagnosis and anterior follow-up is an area of great concern.