Cancer is the second most common cause of death in Australia, and the incidence is likely to increase with an ageing population. A prevalent condition associated with cancer and/or its treatment is fatigue with negative consequences on patients and carers quality of life and function.
Evidence for the use of psychostimulants in managing fatigue in cancer is still largely based on non-randomized studies or small studies and in patients with a range of cancer severity (eg [24
]). In trials, there are mixed results, with one prophylactic placebo-controlled trial of methylphenidate in people undergoing radiotherapy for brain tumors showing no effect in preventing fatigue [27
]. Another phase III trial of methylphenidate in patients receiving chemotherapy also found no effect on cancer-related fatigue or QOL, except after a subset analysis for those with more severe fatigue and/or advanced disease [28
]. In contrast, Lower et al. in their placebo controlled trial in cancer patients undergoing chemotherapy found a significant improvement in fatigue symptoms [29
]. A recent systematic review concluded that preliminary evidence provides partial evidence for the use of psychostimulants to treat cancer-related fatigue [26
]. Given the uncertainty around the benefit of psychostimulants in the management of fatigue in patients with advanced cancer, and the high prevalence of this problem and its negative impact on QOL of many patients and their families/carers, it is imperative that further evidence is obtained from well-designed studies [26
Due to the challenges in recruiting patients with advanced disease into trials, we propose an alternative approach to RCTs while providing high-level evidence on treatment effects. Aggregated SPTs, due to their cross-over design, reduce the required sample size while controlling for confounding.
The main limitation of SPTs in the palliative care population is the possibility of disease progression causing differences between arms of a test cycle. This problem is addressed in the methodology. SPTs are appropriate where (a) the condition remains relatively stable during follow-up period (to the extent that changes observed within replicate pairs cannot be attributed to disease progression) (b) the medication does not alter the pathophysiology of the condition; (c) the medication has a short half-life; and (d) there is validated measurement of effect [9
]. In palliative care, single crossover trials have been published [30
], but there are few multiple crossover formal SPTs [31
]. MPH meets the criteria for utilising an n-of-1 trial method in advanced cancer as (a) the cancer fatigue should remain stable as a short period of follow-up, (b) there is no residual impact on the target symptom once excreted, (c) it has a short half-life and (d) validated measures are used.
SPTs offer two advantages not currently available in palliative care. The first is that the individual patient receives the strongest evidence possible about the effectiveness of the test treatment against the comparator for them. Treatment can be tailored to the individual to allow treatment recommendations. The second is that a series of such individual trials of a given treatment can yield an estimate of the population effect comparable to a RCT, but requiring substantially less numbers of participants to gather that evidence, which in a difficult to recruit population is an important design strength.
This study is the first study to employ aggregated, multiple n-of-1 s in palliative care research, and will not only assess the effectiveness of methylphenidate on fatigue reduction, but will also evaluate the methodological and analytical approaches to conducting SPTs in this population. SPTs require evidence on the proof of concept, and establishment of their place as a practical and reliable research approach in the palliative care population. The availability of this information will influence research policy and change clinical practice by improving availability of high quality evidence in drug studies in difficult to recruit and/or follow patient populations.