A study published Online First by The Lancet shows that by reducing dosing appropriately, it is possible for elderly patients—the group most affected by colorectal cancer (also known as bowel cancer)—to take part in randomised controlled clinical trials. The Article is by Professor Matt Seymour, St James's University Hospital, Leeds, UK, and colleagues at the National Cancer Research Institute Colorectal Clinical Studies Group. The study was funded by Cancer Research UK and the UK Medical Research Council.
Advanced colorectal cancer is the second most common cause of death from cancer in developed countries, after lung cancer. Over the past two decades, treatment for the condition has progressed significantly, with advances in drug therapy and surgery leading to longer survival. Large randomised clinical trials have been central to the progress, by developing new treatments and providing evidence for their effectiveness.
However, for some patients there is a problem with the trials evidence. Although colorectal cancer sometimes affects young people, it is predominantly a disease of the elderly with 60% of deaths occurring in patients older than 75 years and 42% in the those older than 80 years. And with advancing age more patients are frail or have other medical conditions to contend with as well as cancer. Consequently, fewer elderly patients have entered trials - in fact the average age of participants in most trials is at least 10 years lower than in the community at large - and those that do are usually the fittest for their age group. So when doctors treat frail elderly patients they must extrapolate from evidence from younger and fitter patients in trials.
The FOCUS2 trial reported in this Article is the first large-scale randomised trial to have directly investigated chemotherapy in frail and elderly patients with advanced colorectal cancer who would not normally have participated in research. To do this, the researchers used a comprehensive health assessment to measure all aspects of their patients' fitness, and used reduced-dose chemotherapy schedules to minimise the risk of harmful side-effects.
61 UK centres took part in the trial, which involved 459 patients of average age 74 years, a quarter of whom were over 78 years. The patients were randomly assigned to receive chemotherapy as either an intravenous infusion (fluorouracil) or a tablet (capecitabine), and were also randomly assigned to have that treatment alone or combined with another drug, oxaliplatin. The treatments started at 80% of standard doses, but could be increased to full standard doses after 6 weeks if well tolerated. The researchers then measured the "overall treatment utility", a new way of assessing cancer therapy that combines both conventional measures - cancer shrinkage and survival time - and the patients' own assessment of how worthwhile treatment has been and its impact on their quality of life.
Overall, FOCUS2 showed that patients are most likely to benefit from chemotherapy if they are more active, have less widespread cancer and have fewer symptoms, regardless of their age. Using conventional measurements, oxaliplatin produced less benefit in FOCUS2 than is seen in younger fitter patients, but it still significantly improved the "overall treatment utility". However, contrary to expectations, the use of tablet chemotherapy instead of intravenous infusion produced more side-effects and did not have any clear benefits.
The authors claim that their results have started to identify objective ways of assessing patients before starting chemotherapy to help predict whether or not it will be of benefit to them. They say: "To develop a working predictive model will need cross-validation with other studies, but this approach offers the potential to better inform oncologists' discussions with patients."
They conclude: "We encourage investigators to continue to design trials using appropriate low-toxicity treatments and patient-centred assessment to expand the evidence base in this important specialty."
Professor Matthew T Seymour, St James's University Hospital, Leeds, UK. T) +44 (0) 113 343 0391 E) m.seymour@ncrn.org.uk
Journal
The Lancet