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Neoadjuvant, Nonoperative Regimens Being Investigated in Rectal Cancer

Caroline Seymour
Published: Tuesday, Apr 10, 2018

Dr Katherine Van Loon
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).

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.

OncLive®: What are the updates we have seen in 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.

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

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. 

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

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. 

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

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.


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