Rohan Vora

Pilot Study To Determine the Optimal Dose of Methylphenidate for an n-of-1 Trial for Fatigue in Patients with Cancer

PURPOSE In advanced cancer, the prevalence of fatigue is high and can be related to treatment or disease. Methylphenidate hydrochloride (MPH) is a central nervous system stimulant that has been used to palliate fatigue. There is no standard dose for MPH when used for this indication; recommended doses range from 5–20 + mg/d. METHOD To identify a dose to test formally in a subsequent n-of-1 trial of fatigue, we recruited patients with advanced cancer and a fatigue score of 4 or more on a 10-point scale. Following a 3-day baseline assessment, each patient titrated MPH at doses ranging from 5 mg/d to 15 mg twice daily at 3-day intervals. In a daily diary, patients recorded measures of fatigue, depression, toxicity, and symptom control. RESULTS Ten patients provided consent, 9 completed 8 days and 5 received maximum dose at day 15. Three patients were unwilling to increase the dose to maximum levels as they were satisfied with the response at a lower dose. Across all patients, there was a pattern of rapidly improving fatigue and depression scores to day 9 (5 mg twice daily), with minimal improvement thereafter. CONCLUSION The results indicate a dose of 5 mg twice daily for the definitive study. There was little correlation between performance status and maximum tolerated dose. No patient withdrew because of toxicity.

Using aggregated single patient (N-of-1) trials to determine the effectiveness of psychostimulants to reduce fatigue in advanced cancer patients: a rationale and protocol

BackgroundIt is estimated that 29% of deaths in Australia are caused by malignant disease each year and can be expected to increase with population ageing. In advanced cancer, the prevalence of fatigue is high at 70–90%, and can be related to the disease and/or the treatment. The negative impact of fatigue on function (physical, mental, social and spiritual) and quality of life is substantial for many palliative patients as well as their families/carers.Method/designThis paper describes the design of single patient trials (n-of-1 s or SPTs) of a psychostimulant, methylphenidate hydrochloride (MPH) (5 mg bd), compared to placebo as a treatment for fatigue, with a population estimate of the benefit by the aggregation of multiple SPTs. Forty patients who have advanced cancer will be enrolled through specialist palliative care services in Australia. Patients will complete up to 3 cycles of treatment. Each cycle is 6 days long and has 3 days treatment and 3 days placebo. The order of treatment and placebo is randomly allocated for each cycle. The primary outcome is a reduction in fatigue severity as measured by the Functional Assessment of Cancer Therapy-fatigue subscale (FACIT-F). Secondary outcomes include adverse events, quality of life, additional fatigue assessments, depression and Australian Karnovsky Performance Scale.DiscussionThis study will provide high-level evidence using a novel methodological approach about the effectiveness of psychostimulants for cancer-related fatigue. If effective, the findings will guide clinical practice in reducing this prevalent condition to improve function and quality of life.Trial registrationAustralian New Zealand Clinical Trials Registry ACTRN12609000794202

Do pilocarpine drops help dry mouth in palliative care patients: a protocol for an aggregated series of n-of-1 trials

BackgroundIt is estimated that 39,000 Australians die from malignant disease yearly. Of these, 60% to 88% of advanced cancer patients suffer xerostomia, the subjective feeling of mouth dryness. Xerostomia has significant physical, social and psychological consequences which compromise function and quality of life. Pilocarpine is one treatment for xerostomia. Most studies have shown some variation in individual response to pilocarpine, in terms of dose used, and timing and extent of response.We will determine a population estimate of the efficacy of pilocarpine drops (6 mg) three times daily compared to placebo in relieving dry mouth in palliative care (PC) patients. A secondary aim is to assess individual patients’ response to pilocarpine and provide reports detailing individual response to patients and their treating clinician.Methods/DesignAggregated n-of-1 trials (3 cycle, double blind, placebo-controlled crossover trials using standardized measures of effect). Individual trials will identify which patients respond to the medication. To produce a population estimate of a treatment effect, the results of all cycles will be aggregated.DiscussionManaging dry mouth with treatment supported by the best possible evidence will improve functional status of patients, and improve quality of life for patients and carers. Using n-of-1 trials will accelerate the rate of accumulation of high-grade evidence to support clinical therapies used in PC.Trial registrationAustralia and New Zealand Clinical Trial Registry Number: 12610000840088.

A good death down under

In 1983, Mills and colleagues undertook an observational study of patients dying in a hospital in Scotland. 1 They describe disturbing scenes of neglect and poor care of patients dying on busy medical wards. This is an old study and although most readers today would balk at these descriptions, it is likely that many of us can recall tip-toeing past the closed curtains of a patient about to die in the belief that there was ‘nothing more to be done’ and that the patient was best left alone. With the recent emphasis on clinical governance, patient centred care and patient choice, coupled with an increase in the number of complaints about issues related to death in hospitals in the UK, much has been written about the quality of death and dying. This was highlighted by the publication of a special supplement of the British Medical Journal dedicated to research into improving care of the dying patient. 2

Single-patient multiple crossover studies to determine the effectiveness of paracetamol in relieving pain suffered by patients with advanced cancer taking regular opioids: A pilot study.

What is already known about the topic? Paracetamol is a useful adjunct when used in combination with “weak opioids” for chronic pain in palliative care patients with advanced cancer; however, it is not certain that there is continuing benefit when used in conjunction with “strong” opioids. What this paper adds? N-of-1 trials allowed individual treatment decisions to be made for each participant: there was no added benefit for any of the participants, although no conclusion about the added benefit of paracetamol above regular opioids was possible for the group, due to insufficient numbers recruited. Implications for practice, theory, or policy Paracetamol may not provide added benefit above regular opioids; this should be assessed on a case-by-case basis to justify the extra tablet load.

The Value of Expert Opinion in Guiding Policy Development To Support Better Care of the Dying in Australasia: A Response to the Letter by Chan and Webster

Dear Editor: Australia New Zealand Society of Palliative Medicine (ANZSPM) Clinical Indicators Working Group is committed to the development of a Clinical Indicator (CI) for the care of the dying. As part of the development of such a CI, a Care-of-theDying Pathway (CODp) workshop was convened at the 2010 ANZSPM Conference. This brought together clinical leaders from Australia and New Zealand in Palliative Medicine to specifically examine the evidence for and relevance of pathway use for supporting terminal care. Scoping of prevalence of pathway use indicated that throughout all states of Australia and throughout New Zealand CODp development and implementation was widespread. The majority of CODps were modified versions of the Liverpool Care Pathway. There is recognition that a CODp is based on previously identified gaps in care and evidence of poor quality care. We wish to emphasize that the CODp guides appropriate and proactive diagnosis of dying, rational deprescribing and relevant prescribing, removes the burden of unnecessary clinical interventions that may be construed as futile treatment, and prompts communication with patient and family. The pathway is supported by evidence-based symptom control. Palliative medicine specialists, through their unique multiple experiences as engaged clinicians, recognise dying and do not view death as a failure, unlike much of the rest of medicine. This aspect is an important component of any CODp. Such recognition and acceptance allows for truthful, realistic and timely endof-life discussions with patients and their caregivers or families. Chan and Webster understand the pathway as a single clinical intervention, rather than a framework that guides the clinician. The danger of applying a reductionist approach, thereby subjecting a quality framework of care for a population of patients (terminal phase) to the rigors of pure randomized control clinical trial research, reduces the individual care of a dying person to ‘a one size fits all’ approach. No two ‘‘pathways’’ look the same on scrutiny, just as no two patients make the same ‘‘journey into the night.’’ As such the argument in the letter by Chan and Webster raises issues profound around the best research methodology to use for investigating the impact of complex multidisciplinary care plans, and the impact of health system changes brought about by care pathways for improving the care of the dying. The limitations of randomized controlled trials as a research methodology are made more obvious when we try to use them to investigate questions around: quality of care provision, health systems design changes, and their impact on evidence. Currently there is debate raging within the Cochrane Collaboration itself with the development of the qualitative methods research group and the effective practice and organization of care subgroups. There was unanimous agreement at the aforementioned ANZSPM workshop that there was no evidence of harm with the use of a pathway. If the CODp was a prescribed medication (thus applying a ‘‘one size fits all’’-reductionist approach) the number needed to harm (NNH) would imply low level of risk to the prescriber. Importantly the ANZSPM Clinical Indicators Working Group was able to determine that there was consensus through expert opinion that the use of a CODp provides current best practice care of the dying. The ANZSPM Clinical Indicators Working Group are progressing the development of the care of the dying CI. We in the Antipodes are grateful that compassionate and rational care can be afforded to the dying.

Testing pilocarpine drops for dry mouth in advanced cancer using n-of-1 trials: A feasibility study:

Background: Dry mouth is a common and troublesome symptom in palliative care. Pilocarpine is a cholinergic agent that promotes salivation. Aim: This study aimed to test the feasibility of using n-of-1 trials to test pilocarpine drops compared to placebo, for patients of palliative care units with advanced cancer, who experienced dry mouth. Design: This was an N-of-1 study, in which each participant was offered three cycles of pilocarpine drops 4% (6 mg tds) (3 days) and placebo drops (3 days) in random order. Setting/participants: Participants were patients of specialist palliative care services with advanced cancer assessed as having a dry mouth, defined as having a score of ⩾3 on an 11-point self-rated xerostomia numerical rating scale, from any cause. Patients self-completed a diary using validated symptom and quality-of-life scores. The randomisation order was unmasked at the end of each person’s trial by a clinician independent of the trial to allow a treatment decisions for individual patients to be made. Results: Nine patients completed at least 1 cycle; 33 cycles of data were completed in total, comprising 438 doses of pilocarpine. Four patients completed the trial: two responded and two did not. Most withdrawals related to deteriorating condition, unacceptable toxicity, non-compliance with study procedures or withdrawal of consent. Many issues contributed to slow recruitment and high withdrawal rate. Conclusion: The formulation of pilocarpine drops proved unacceptable to most participants. More work is required to determine an appropriate formulation, dose and method of delivery and then a retest of pilocarpine drops for this symptom.