Experts debate best treatment for metastatic colorectal cancer patients

Metastatic colorectal cancer (mCRC) can be controlled with chemotherapy and targeted drugs for several years, but optimal management strategies—particularly treatment duration and continuity—remain controversial. There is growing consensus that continuation of full-dose chemotherapy until tumor progression is not justified by clinical trial data.

But some researchers and clinicians advocate following induction treatment with chemotherapy-free intervals (“drug holidays”) to mitigate toxicities like peripheral neuropathy, while others advocate de-escalated maintenance therapy with chemotherapy and bevacizumab to avoid interruption in the inhibition signaling within tumor cells’ molecular pathways.

A leading proponent of each view spoke during a June 7 educational panel, “Debating Current Controversies in Medical Management of Metastatic Colorectal Cancer,” at the American Society of Clinical Oncology (ASCO) Annual Meeting 2016.

Dirk Arnold, MD, PhD: Maintenance therapy is best

“Metastatic colorectal cancer is a rather indolent disease in most of our patients, allowing control with mild—or even without—active treatment,” said Dirk Arnold, MD, PhD, director of the department of medical oncology at the Klinik für Tumorbiologie in Freiburg, Germany.  

The disease can be controlled but not cured, he said. “The goal of palliative therapy is to extend a patient’s life and maintain the quality of life for as long as possible, using the least amount of treatment necessary to control the disease.”

De-escalation of chemotherapy for maintenance chemotherapy should be the standard of care, and discontinuing treatment too early runs the risk of harming patients, Arnold argued, citing findings from clinical studies of bevacizumab-based de-escalated maintenance regimens. In one of these studies, for example, Arnold’s group’s AIO 0207 trial—patients were transitioned from a regimen of bevacizumab plus oxaliplatin and fluoropyrimidine, to a de-escalated maintenance regimen of bevacizumab with or without fluoropyrimidine.

“Progression-free survival in all of these trials favors active maintenance,” Arnold reported.

Findings even suggest “a trend” toward improved overall survival, he was quick to note. (His group’s AIO study, for example, found that patients on de-escalated maintenance therapy with fluoropyrimidine plus bevacizumab had a median overall survival time of 21.6 months, compared to 18.1 months among patients who were randomly assigned to receive no therapy—an additional 3.5 months of overall survival.)

There do not appear to be particular patient subgroups driving these findings and maintenance therapy seems to have “broad efficacy,” he said.

Nor does maintenance therapy impair patients’ quality of life, he added.

“Toxicity is not a concern,” he said. “Quality of life was maintained.”

During de-escalated maintenance therapy, patients undergo five months of treatment but in return, they see a median duration of disease control of eight months, “with good quality of life and potentially, overall survival gain,” he concluded.

Next: Treatment holidays

Tim Maughan, MD: Treatment holidays are better

“Treatment holidays are the standard of care,” countered Tim Maughan, MD, MA, MBBS, FRCP, FRCR, of the University of Oxford in England.

Three studies have compared continuous chemotherapy with a chemo-free interval, he noted. None clearly demonstrated a “proven overall survival benefit” for continuous chemotherapy, Maughan said.

Five studies have compared maintenance therapy and drug holidays, and none found convincing, statistically-significant improvements in overall survival among patients on maintenance therapy, he pointed out.

“But adverse events are doubled with maintenance therapy,” Maughan said. That denies patients time free of treatment side-effects.

Patients frequently express relief at a chance to take a break from treatment, he noted.

Maughan pointed to results from a study comparing patients on cetuximab therapy to a drug-free interval as evidence that quality of life is indeed better for patients allowed a chemotherapy-free interval. From fatigue, nausea and vomiting, to appetite, constipation, and diarrhea, drug holidays are associated with reduced symptoms, he reported.

Time free of treatment side-effects, to “live life as normal,” financial considerations, and time away from clinic visits and treatment, all favor intermittent therapy, Maughan concluded—whereas progression-free survival time and time free of cancer symptoms favor maintenance therapy, he acknowledged.

“I’m not saying that chemo-free intervals are right for everyone,” Maughan said. “But they are a viable and evidence-based option for many patients with mCRC.”

“There is no role for continuing full-dose chemotherapy until progression,” he added. “Patients need to be given a balanced account to assess the trade-offs for themselves of maintenance versus chemotherapy-free intervals.”