Sequential and combination chemotherapy equally effective in treating advanced colorectal cancer

Many patients with incurable advanced colorectal cancer could be offered a more gentle treatment strategy starting with a single chemotherapy drug, as an alternative to current standard initial combination chemotherapy, without compromising their survival.

They believe their results challenge conventional clinical practice in this area; however, an accompanying Comment says that evidence supports the continuing use of initial combination chemotherapy.

Colorectal cancer causes over half a million deaths every year worldwide. This death toll could fall with advances in prevention, screening and treatment – but there are many patients in which controlling the cancer sufficiently to delay death and reduce symptoms is the only realistic therapeutic goal.

In the first Article, Professor Matt Seymour, University of Leeds and the Gastrointestinal Research Unit, Cookridge Hospital, Leeds, UK and colleagues at the UK National Cancer Research Institute discuss the results of the Medical Research Council FOCUS Trial. This trial is the largest randomised clinical trial ever conducted in the treatment of advanced colorectal cancer, and involved 2135 patients divided into three groups. The first group received single-drug treatment with fluorouracil for as long as it controlled their disease, followed by single-drug treatment irinotecan. The second group received fluorouracil followed by combination treatment (fluorouracil plus irinotecan or oxaliplatin), while the third group received combination chemotherapy from the outset.

The researchers found that patients in the first group had the shortest survival, but the second and third groups had similar overall survival. Toxic effects were lowest during the single-treatment fluorouracil, and quality of life scores were similar throughout all the treatment regimens.

The authors conclude: “This large randomised trial has produced a surprising result which challenges accepted standard treatment approaches in advanced colorectal cancer therapy.” For the larger number of patients with more extensive metastases who will not be cured, they add: “FOCUS offers an important choice, informed by the knowledge that a decision to opt for staged treatment approach, starting with less toxic therapy and keeping active agents in reserve, entails minimal, if any, compromise in survival.”

In the second Article, Professor Cornelis Punt, Department of Medical Oncology, Radboud University Nijmegen Medical Centre, The Netherlands, and colleagues report the results of the CAIRO trial. In this study, 820 patients were randomly assigned to receive either sequential treatment with capecitabine, irinotecan and oxaliplatin; or combination treatment of capecitabine plus irinotecan followed by capecitabine plus oxaliplatin. They found that median overall survival rates were similar in the two groups. Previous studies have shown at least similar efficacy and a favourable toxicity profile for capecitabine when compared with fluorouracil.

The authors conclude: “Our results show that, for patients with advanced colorectal cancer, combination treatment with all effective cytotoxic drugs was no better than their sequential use. Progression-free survival over all subsequent treatment lines was not significantly different between the study groups. Additionally, sequential treatment was associated with less toxicity during first-line treatment than was combination therapy.”

“Chemotherapy remains the backbone of systemic treatment in this disease, and our results indicate that sequential treatment remains a valid treatment option for these patients.”

In the accompanying Comment, Dr Hans-Joachim Schmoll, Martin-Luther University, Halle, and Dr Daniel Sergeant, Mayo Clinic, Rochester, Minnesota, USA, say: “Clinically validated prognostic and predictive factors, such as genomic tests, are needed to define in which patients more intensive therapy is worthwhile, and ideally, which specific treatment should be used.

“Until then, to maximise potential benefit for each patient, an approach based on prognosis and disease presentation with initial combination chemotherapy for most patients, reserving single-agent fluorouracil for a subgroup with less aggressive or never-resectable disease, should be the standard of care for first-line treatment of metastatic colorectal cancer.

"FOCUS and CAIRO support the use of first-line single agent fluorouracil for the latter subgroup of patients and therefore provide an ethical basis for investigating novel drugs in combination with single-agent fluoropyrimidines in future trials, to further develop the treatment armamentarium for patients with colorectal cancer."