Clinicians Highlight the Changing Treatment Landscape for Colon and Rectal Cancers

At the National Comprehensive Cancer Network (NCCN) 23rd Annual Conference, held March 22-24 in Orlando, Florida, Christopher G. Willett, MD, of Duke Cancer Institute; Axel Grothey, MD, of Mayo Clinic Cancer Center; and Alan P. Venook, MD, of University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, presented updates to NCCN’s guidelines for the treatment of colon and rectal cancers.

Willett discussed emerging approaches to treatment of rectal cancer, including the difference between the European-preferred short-course radiation treatment for rectal cancer versus the US-preferred long-course chemoradiation. The European short course, which uses a 25-gray (Gy) dose and immediate surgery, is associated with a lower cost, excellent compliance, and possibly less acute toxicity. The US treatment method, which uses a 50.4-Gy dose plus chemotherapy and delayed surgery, is associated with improved pathological response, more tumor regression, sphincter preservation, and potentially improved later effects.

Willett pointed to the TROG trial,¹ in which patients were randomized to receive either a short course of radiation and resection within 1 week (plus adjuvant chemotherapy for 6 cycles), or a long course of radiation and resection within 4 to 6 weeks (followed by adjuvant chemotherapy for 4 cycles). Three-year recurrence rates between the 2 groups were not statistically different, and there were no differences in rates of distant recurrence, relapse-free survival, or overall survival. Thus, a quality-of-life measure can be key to assessing the relative merits of the 2 treatment options.

Willett also discussed the potential for nonoperative treatment of rectal cancer after radiation and chemotherapy.

“There is now interest in the groups of patients with rectal cancer who have what appear to be a complete clinical response,” he said, and in what treatments may be appropriate for this group. Willett noted that the NCCN guidelines now hold that patients who achieve a complete clinical response with no evidence of residual disease (on digital examination, MRI, and endoscopic evaluation) may be able to adopt a watch-and-wait approach to treatment. In the nonoperative approach, rectal preservation rates are higher, and survival rates are about the same, compared to an operative approach.

Yet, he cautioned, “although we are trying to select our patients well, there are some limitations” in to imaging. “If one is to adopt this type of strategy, it has to be in the setting of a team” of multidisciplinary physicians.

In a presentation that also focused on improving the quality of life for patients, Grothy discussed the possibility of reducing the number of cycles of oxaliplatin-based adjuvant therapy for patients with stage III colon cancer versus the current standard of care.

Oxaliplatin is associated with cumulative dose-dependent neurotoxicity, which can be debilitating in the short and long term. “Most of my patients that I see who have gone through 12 cycles of [folinic acid, fluorouracil, and oxaliplatin, FOLFOX] have longer lasting neuropathies,” said Grothy, which have a negative impact on quality of life. A shorter duration of treatment without a loss of efficacy would be beneficial to patients and the healthcare system as a whole, he said.

Grothy discussed his work on the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) collaboration, an as-yet unpublished study from 6 randomized phase 3 trials in 12 countries, in 12,834 patients with stage III disease, which investigated a shorter (3-month) course of FOLFOX or capecitabine and oxaliplatin (CAPEOX) versus a longer (6-month) course.

For patients treated with 3 months of CAPEOX, especially in a low-risk population, disease-free survival (DFS) was noninferior to a longer course of treatment. For patients treated with FOLFOX, 6 months added an extra benefit in terms of DFS. Shorter courses were associated with a reduction in neurotoxicity, even at 5 years of follow up. These findings, said Grothy, provide a framework for discussing risks and benefits with patients in developing individualized approaches to treatment.

Taking the stage after Grothy, Venook recalled a time when the NCCN guidelines for treating colon cancer were just 4 pages long. “I don’t think we envisioned that these guidelines would take on the life that they have,” he said.

One of the newest additions to those guidelines is a recommendation that suspected or proven metastatic synchronous adenocarcinoma be assessed for biomarkers for RAS and BRAF tumor gene status, as well as mismatch repair gene or microsatellite instability status. “We believe that these test should be run up front,” said Venook.

In the choice of therapy, Venook said, “one thing I think is underutilized is [the] result from the TRIBE study.” The study, said Venook, shows that FOLFOXIRI (FOLFOX and irinotecan) plus bevacizumab is superior to folinic acid, fluorouracil, and irinotecan (FOLFIRI) plus bevacizumab. “Where we think we have to take a stand…we tend to lean toward FOLFOXIRI and drop to oxaliplatin as we go along."

On the use of biologics, Venook’s own research² has shown no difference in outcomes between cetuximab plus chemotherapy or bevacizumab plus chemotherapy, but patients with left-sided disease responded best to cetuximab and lived 15 months longer than those with right-sided disease, though it is not clear why the differences in sidedness exist.

Looking to the future of treatment, Venook says that he is eagerly awaiting details on studies of regorafenib dosing and on trifluridine and tipiracil plus bevacizumab, as well as study results on microsatellite-stable metastatic colorectal cancer treated with atezolizumab plus cobimetinib, as well as BRAF mutant metastatic colorectal cancer treated with encorafenib plus cetuximab, with or without binimetinib.

References

1. Ngan SY, Burmeister B, Fisher RJ, et al. Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-Tasman Radiation Oncology Group trial 01.04. J Clin Oncol. 2012;30(31) :3827-33. doi: 10.1200/JCO.2012.42.9597.

2. Venook AP, Niedzwiecki D, Lenz HJ, et al. Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer: a randomized clinical trial. JAMA. 2017;317(23):2392-2401. doi: 10.1001/jama.2017.7105.