Do we need different trials for the elderly?

One of the bugbears of clinical trials is that they are usually conducted in younger patients. This is especially relevant in CLL where the median age of presentation is 70. The question has been asked as to whether we should have specific trials for older patients and would they give different answers to the trials that we have now.

There has been an attempt to answer these questions published in today's Lancet, not in CLL but in colorectal cancer in which I have more than a passing interest.

Colorectal cancer is the most common tumour worldwide and the second leading cause of cancer death in European countries and the USA, with about 800 000 new cases yearly. Although most clinical trials have not specifically excluded older or frail patients, as long as they have been suitable for the investigated treatment, there is always a strong selection process for patients who will be entered into clinical trials, especially if more toxic or somewhat innovative treatments are investigated. The median age at disease onset ranges between about 65–70 years and at death 72–77 years. 60% of deaths occur in patients older than 75 years and about 40% in those older than 80 years. The median age of a typical trial population for advanced disease is 60–65 years, with a maximum age mostly of 75 years. Retrospective analysis of randomised trials has shown that elderly patients have more or less the same response to chemotherapy as do younger patients.

The MRC FOCUS2 trial is the first randomised trial specifically tailored for this group of patients—elderly, frail, or both—in advanced colorectal cancer, thus representing a major part of the typical population of patients in routine practice. They compared single-agent fluorouracil with an upfront FOLFOX-type combination for overall and progression-free survival, and compared (in a factorial design) the value of the oral fluorouracil prodrug capecitabine with intravenous fluorouracil/levofolinate infusion.

The study showed that the upfront combination with oxaliplatin achieved a significantly increased response rate and made a limited, but not statistically significant, contribution to progression-free survival; overall survival was not improved. However, there was clear evidence of an overall benefit by addition of oxaliplatin defined by a composite index (overall treatment utility [OTU]) which had been developed and which was able to define the overall clinical utility depending on simple clinical variables that represent the biology of the disease and the patients' general characteristics, as well as the subjective opinion of the doctor and patient regarding the real value of the chosen treatment.

This trial supports what has been derived as “standard” from retrospective subgroup analyses of the older population of patients from previous trials, and the clinical experience which led to the definition of a treatment selection according to the treatment aim, the clinical disease characteristics, and co morbidity. Commonly, these patients are considered only for single-agent fluorouracil. FOCUS2 supports the addition of a new measure, OTU, to the selection process, and furthermore supports the use of upfront fluorouracil/oxaliplatin combination in this patient population—but in reduced doses and without capecitabine. Probably the other relevant result of FOCUS2 was that most patients do well with an a-priori dose reduction of fluorouracil or capecitabine and oxaliplatin, with a dose increase only if toxicity allowed (only 30% of the patients), indicating that an initial 20% dose reduction could be the standard of care for these patients.

As an aside I should say that after a few treatments that I found too toxic, they reduced my doses by 20%.

This trial needs confirmation. In addition, it does not represent the typical treatment scenario in most European countries. For example, in Europe many oncologists give fluorouracil/bevacizumab as first-line treatment, or at least as second-line treatment, and try at least to use oxaliplatin and irinotecan and (if the tumour is KRAS wild-type) cetuximab/panitumumab as salvage treatment, even in this population of patients with relatively poor outlook. This relative lack of use of salvage treatment, beyond the generally poorer prognosis in this elderly and frail population, might have relevantly contributed to the short overall survival of only 10–12 months in FOCUS2, rather than just the fact that the patients selected for inclusion were elderly, frail or both.

What this trial does is to emphasize that it is the biology of the disease that determines response and the robustness of the patient that determines whether he or she can survive the treatment. It is not a different disease in the elderly, but co-morbidities will affect the way the drugs are handled and regimes may need to be tailor-made for the elderly and infirm. For example we know that people with impaired renal function need a smaller dose of fludarabine for the same effect.