EXPERT ANALYSIS FROM ICACT 2015
PARIS (FRONTLINE MEDICAL NEWS) – Treatment algorithms for metastatic colorectal cancer are “dynamic and fast changing” in order to keep up with the multiple cytotoxic and biologic options that are currently or will soon be available, Dr. Eric Van Cutsem said at an international congress on anticancer treatment.
“We are making progress. If you look at the past 10-15 years you see that the median survival is going up with the introduction of different agents and with the results of different trials,” Dr. Van Cutsem of University Hospitals Leuven, Belgium, said.
It is becoming increasingly clear that mCRC is “not one disease” and that patient and tumor characteristics vary wildly. Multiple molecular alterations have been identified and there are many molecular signaling pathways known to be involved in tumor progression.
Recent work by the SAGE Colorectal Cancer Subtyping Consortium suggest that there are four or five molecular subtypes of mCRC ( Ann. Oncol. 2014;25:iii1-iii9 ). While it is too early to determine if each subtype might require a different therapeutic strategy, it is another step along the path to achieving the goal of personalized medicine in the disease.
“Treatment choice depends on more than efficacy,” Dr. Van Cutsem said. Together with tumor characteristics (clinical presentation, tumor biology, RAS and BRAF mutation status), patient characteristics (age, performance status, prior adjuvant treatment and comorbidities) and their preferences (expectations, toxicities, socioeconomic factors, and quality of life) need to be incorporated into the treatment plan.
In terms of optimizing the use of targeted treatments in mCRC, Dr. Van Cutsem noted that are three antiangiogenic agents currently approved for use in Europe – bevacizumab (Avastin), aflibercept (Zaltrap), and regorafenib (Stivarga) – and two epidermal growth factor receptor inhibitors, cetuximab (Erbitux) and panitumumab (Vectibix). Promising data from the phase III RAISE trial recently presented at ASCO GI mean that another antiangiogenic agent, ramucirumab (Cyramza), could soon be added to this list.
How to best choose between these agents remains an area of active research but data already show that patients’ RAS status can determine if they might respond to anti-epidermal growth factor receptor monoclonal antibody treatment. BRAF analysis remains more experimental but it can be performed alongside RAS testing with limited extra effort and cost.
Dr. Van Cutsem gave highlights of an expert discussion on mCRC held at the 2014 ESMO/World Congress on Gastrointestinal Cancer in Barcelona, where it was agreed that while chemotherapy remains the backbone of first-line treatment, biologics are also indicated as first-line treatment in most patients, unless there are specific contraindications.
As yet, there is no unequivocal evidence that one biologic agent is superior to another as a first-line choice and the decision to use bevacizumab or an anti-EGFR monoclonal antibody will depend on the subsequent strategy if treatment fails, as well as likely toxicities and patient quality of life.
According to current European Society of Medical Oncology guidelines ( Ann. Oncol. 2014;25: iii1–iii9 ) dividing patients into four categories may help direct the therapeutic strategy. Category 0 patients are those with resectable disease and category 1 patients have potentially resectable disease. Category 2 patients have nonresectable tumors with a heavy tumor load and aggressive biology and Category 3 patients are those who are nonresectable, nonaggressive, and asymptomatic disease.
The categories are not perfect, however, and will be refined in the next iteration of the guidelines due out later this year, Dr. Van Cutsem commented. He added that patients do not always need high-intensity treatment; it depends on what is trying to be achieved. For example, treatment may be more intense at the start when the goal may be to try to shrink tumors to allow surgery and less intense when the aim is to provide good disease control with low toxicity.
In potentially resectable patients in which conversion to surgery is the goal, there is uncertainty on the best combination of cytotoxic and biologic agents to use, with different combinations suggested in RAS mutant and RAS wild-type patients.
In RAS mutant patients, for example, doublet chemotherapy plus bevacizumab or FOLFOXIRI with or without bevacizumab may be reasonable choices, whereas in RAS wild-type patients doublet chemotherapy maybe be combined with an anti-EGFR monoclonal antibody. Another front-line option in the future may be ramucirumab added to FOLFIRI but this has yet to be approved and incorporated into the guidelines. Reevaluation of treatment is important so that patients with resectable disease are not overtreated.
Second-line options may include bevacizumab or aflibercept added to chemotherapy, with third- and later lines of treatment including anti-EGFR monoclonal antibodies possibly used alone in RAS wild-type patients or with irinotecan in the case of cetuximab, and regorafenib in patients who are refractory to other therapies.
Another “new kid on the block” yet to be approved and incorporated into the guidelines is TAS-102, an oral fluoropyrimidine. Data from the recent RECOURSE study (Refractory Colorectal Cancer Study) showed an overall survival benefit of the novel drug vs. placebo when added to best supportive care after two or more prior regimens for mCRC ( Ann. Oncol. 2014;25-4: Abstr. LBA13 ).
Dr. Van Cutsem has received research funding from Amgen, Bayer, Boehringer, Lilly, Merck, Merck Serono, Novartis, Roche, and Sanofi.
