Colon ca chemo: Sequencing or upfront combinations?

SAN FRANCISCO—The notion of "lines" of therapy for treatment of patients with colorectal cancer appears to be blurred, with the actual sequence of treatment becoming less important than making sure patients have access to all active agents, Axel Grothey, MD, of the Mayo Clinic, said at the Third Annual Oncology Congress. Rather than using either single-agent sequencing or upfront combinations in all patients, he noted, "the goal of therapy, whether curative or palliative, defines the overall strategy and treatment algorithm."

Dr. Grothey cited the FOCUS trial, which brought into question the assumption that in the palliative setting, combination therapy is the only first-line option. In FOCUS (Lancet 370:143-152, 2007), 2,135 patients were randomized to receive single-agent fluorouracil/leucovorin until treatment failure, then irinotecan (Camptosar); single-agent fluorouracil, then combination chemotherapy with either FOLFIRI or FOLFOX; or combination chemotherapy with either FOLFIRI or FOLFOX as first-line treatment.

The results showed that fluorouracil followed by either combination therapy was not inferior to using combination therapy upfront, but that any regimen containing a combination was superior to sequential fluorouracil/irinotecan.

Only 20% received all 3 agents

Dr. Grothey pointed out that overall survival rates in FOCUS were somewhat lower than seen in other similar phase III trials, probably because of the limited use of second- and third-line therapies. Only about 20% of FOCUS patients received all three active agents.

So, in palliative therapy for metastatic colorectal cancer, he said, "the actual sequence of treatment regimens does not matter as much as the ultimate goal, which is to expose all patients to all active agents."

Dr. Grothey is also concerned over the notion of "piling up" therapies, pointing out that combining multiple therapies upfront in unselected patients is not an appropriate treatment strategy.

He pointed to the CAIRO study (Lancet 370:135-142, 2007) in which 820 patients with advanced colorectal cancer were randomized to either sequential treatment with first-line capecitabine (Xeloda), second-line irinotecan, and third-line capecitabine/oxaliplatin (Eloxatin) or combination treatment with capecitabine/irinotecan followed by capecitabine/oxaliplatin.

The CAIRO study, conducted, like the FOCUS trial, before biologic agents were available for colorectal cancer, found no significant difference in median overall or progression-free survival between patients treated upfront with the combination and those treated sequentially.

"We need a middle ground," Dr. Grothey concluded, between one-by-one sequential therapy and high-toxicity upfront combinations. Thus, he thinks it is more appropriate to talk about a continuum of care rather than lines of therapy "because we're going to re-utilize drugs that our patients might have failed on in early lines of therapy," he explained.

Over the next 5 years, Dr. Grothey sees researchers and clinicians focusing more on a tailored approach to therapy that might utilize predictive factors to define the best treatment option for individual patients.