Controlling Progression in Patients With Metastatic Colorectal Cancer

Randall F. Holcombe, MD

The prognosis for patients with colorectal cancer has benefited greatly from the advent of advances in chemotherapy and new agents, with nearly threefourths of stage I patients surviving for at least 5 years after diagnosis, according to the American Cancer Society. However, the median survival of patients with metastatic colorectal cancer is about 2 years, and while that number represents a gradual improvement observed over the last couple of decades, new therapies are being designed to keep the upward trends in survival moving forward. At the 2012 Chemotherapy Foundation Symposium, Randall F. Holcombe, MD, professor of Medicine, Hematology and Oncology, at the Mount Sinai Hospital in New York City, discussed how new agents are being used to control the progression of the disease.

Earlier this year, the FDA approved two drugs to treat metastatic colorectal cancer: aflibercept and regorafenib. Through different mechanisms of action, both drugs are able to control progression. Of the two drugs, Holcombe said he believes that regorafenib will have more of an impact in terms of extending survival. Results of the phase III CORRECT trial showed that regorafenib improved median overall survival (OS) by 1.4 months when compared with a placebo in patients whose disease progressed after prior therapy (J Clin Oncol. 2012;30[suppl; abstr 3502]).

“This is a therapy that’s going to be useful for many patients because we have lots of patients who exhaust the other available therapies and still have a reasonably good performance status and are still interested in receiving therapy to try and help prolong survival,” Holcombe said.

Holcombe said that initially bevacizumab had also seemed to be a promising agent for the treatment of metastatic colorectal cancer. In a nonrandomized study published in 2008, an improvement in OS of 11.9 months was observed in patients receiving bevacizumab following progression on a bevacizumabcontaining first-line regimen (J Clin Oncol. 2008;26[33] :5326-5334). Those results led to a randomized study that was presented at the 2012 ASCO Annual Meeting. The results of the second trial were not as positive, with second-line bevacizumab following progression only resulting in a survival benefit of approximately 1.5 months (J Clin Oncol. 2012;30[suppl; abstr CRA3503]).

“This really speaks to the importance of doing well-designed, controlled, randomized studies to evaluate agents in this disease,” Holcombe said. “There clearly is some advantage to utilizing bevacizumab in second line, but it’s fairly modest. It doesn’t provide that huge benefit that we initially hoped it would.”

Holcombe said that other drugs are in development, such as the VEGF-R inhibitor ramicirumumab and the Wnt pathway inhibitor anti-frizzled-7 antibody, are potentially promising therapies based on their molecular targets. Additionally, the incremental benefits of all of these therapies can add up substantially, and Holcombe said that it is important to verify the clinical efficacy of these agents and how they should be used in tandem with one another.

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Dr. Randall Holcombe on Regorafenib for Colorectal Cancer

“Many patients end up getting multiple different types of medications, and some of the new medications that have recently been approved I think will add to the armamentarium that we currently have and hopefully lengthen survival for patients with metastatic disease,” Holcombe said. “As other agents become available, we’ll have to do studies to see what the best sequence is for patients and what really helps to prolong survival.”

Holcombe also noted that even with new agents, there is still a role for chemotherapy in controlling progression in patients with metastatic colorectal cancer. He referred to the results of the OPTIMOX2 study, which were presented at the 2007 ASCO Annual Meeting (J Clin Oncol. 2007;25[suppl; abstr 4013]). That trial demonstrated a 5.7-month improvement in overall OS when LV5FU (5-fluorouracil/folinic acid) was given as maintenance therapy between doses of FOLFOX7 (oxaliplatin, leucovorin, and 5-fluorouracil) chemotherapy instead of a chemotherapy-free interval between doses.