Odette Spruyt

Methadone Versus Morphine As a First-Line Strong Opioid for Cancer Pain: A Randomized, Double-Blind Study

PURPOSE To compare the effectiveness and side effects of methadone and morphine as first-line treatment with opioids for cancer pain. PATIENTS AND METHODS Patients in international palliative care clinics with pain requiring initiation of strong opioids were randomly assigned to receive methadone (7.5 mg orally every 12 hours and 5 mg every 4 hours as needed) or morphine (15 mg sustained release every 12 hours and 5 mg every 4 hours as needed). The study duration was 4 weeks. RESULTS A total of 103 patients were randomly assigned to treatment (49 in the methadone group and 54 in the morphine group). The groups had similar baseline scores for pain, sedation, nausea, confusion, and constipation. Patients receiving methadone had more opioid-related drop-outs (11 of 49; 22%) than those receiving morphine (three of 54; 6%; P =.019). The opioid escalation index at days 14 and 28 was similar between the two groups. More than three fourths of patients in each group reported a 20% or more reduction in pain intensity by day 8. The proportion of patients with a 20% or more improvement in pain at 4 weeks in the methadone group was 0.49 (95% CI, 0.34 to 0.64) and was similar in the morphine group (0.56; 95% CI, 0.41 to 0.70). The rates of patient-reported global benefit were nearly identical to the pain response rates and did not differ between the treatment groups. CONCLUSION Methadone did not produce superior analgesic efficiency or overall tolerability at 4 weeks compared with morphine as a first-line strong opioid for the treatment of cancer pain.

Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Toxicity of Subcutaneous Ketamine in the Management of Cancer Pain

PURPOSE The anesthetic ketamine is widely used for pain related to cancer, but the evidence to support its use in this setting is weak. This study aimed to determine whether ketamine is more effective than placebo when used in conjunction with opioids and standard adjuvant therapy in the management of chronic uncontrolled cancer pain. Ketamine would be considered of net benefit if it provided clinically relevant improvement in pain with limited breakthrough analgesia and acceptable toxicity. PATIENTS AND METHODS In this multisite, dose-escalation, double-blind, randomized, placebo-controlled phase III trial, ketamine or placebo was delivered subcutaneously over 3 to 5 days. RESULTS In all, 185 participants were included in the primary analysis. There was no significant difference between the proportion of positive outcomes (0.04; 95% CI, -0.10 to 0.18; P = .55) in the placebo and intervention arms (response rates, 27% [25 of 92] and 31% [29 of 93]). Pain type (nociceptive v neuropathic) was not a predictor of response. There was almost twice the incidence of adverse events worse than baseline in the ketamine group after day 1 (incidence rate ratio, 1.95; 95% CI, 1.46 to 2.61; P < .001) and throughout the study. Those receiving ketamine were more likely to experience a more severe grade of adverse event per day (odds ratio, 1.09; 95% CI, 1.00 to 1.18; P = .039). The number of patients needed to treat for one additional patient to have a positive outcome from ketamine was 25 (95% CI, six to ∞). The number needed to harm, because of toxicity-related withdrawal, was six (95% CI, four to 13). CONCLUSION Ketamine does not have net clinical benefit when used as an adjunct to opioids and standard coanalgesics in cancer pain.

An international multicentre validation study of a pain classification system for cancer patients.

PURPOSE The studys primary objective was to assess predictive validity of the Edmonton Classification System for Cancer Pain (ECS-CP) in a diverse international sample of advanced cancer patients. We hypothesised that patients with problematic pain syndromes would require more time to achieve stable pain control, more complicated analgesic regimens and higher opioid doses than patients with less complex pain syndromes. METHODS Patients with advanced cancer (n=1100) were recruited from 11 palliative care sites in Canada, USA, Ireland, Israel, Australia and New Zealand (100 per site). Palliative care specialists completed the ECS-CP for each patient. Daily patient pain ratings, number of breakthrough pain doses, types of pain adjuvants and opioid consumption were recorded until study end-point (i.e. stable pain control, discharge and death). RESULTS A pain syndrome was present in 944/1100 (86%). In univariate analysis, younger age, neuropathic pain, incident pain, psychological distress, addictive behaviour and initial pain intensity were significantly associated with more days to achieve stable pain control. In multivariate analysis, younger age, neuropathic pain, incident pain, psychological distress and pain intensity were independently associated with days to achieve stable pain control. Patients with neuropathic pain, incident pain, psychological distress or higher pain intensity required more adjuvants and higher final opioid doses; those with addictive behaviour required only higher final opioid doses. Cognitive deficit was associated with fewer days to stable pain control, lower final opioid doses and fewer pain adjuvants. CONCLUSION The replication of previous findings suggests that the ECS-CP can predict pain complexity in a range of practice settings and countries.

Planning phase III multi-site clinical trials in palliative care: the role of consecutive cohort audits to identify potential participant populations

Goals of workMultiple sites enable more successful completion of adequately powered phase III studies in palliative care. Audits of the frequency and distribution of the symptoms of interest can better inform research planning by determining realistic recruitment goals for each site. The proposed studies are to improve the evidence-base for registration and subsidy applications for frequently encountered symptoms where current pharmacological interventions are being used ‘off-licence’.MethodsSix services participated in a standardised, retrospective, consecutive cohort audit of five symptoms of their inpatient populations to inform the design of double blind randomised controlled phase III studies to which each site would recruit simultaneously. The audit covered all deaths in a 3-month period for people who were referred to a specialist palliative care service who had at least one inpatient admission between referral and death, regardless of when the person was referred to the service. The audits were based around inclusion and exclusion criteria for the proposed studies.Main resultsOf the 468 people whose medical records were reviewed, potential study participant rates varied by symptom having accounted for general and specific inclusion and exclusion criteria: pain 17.7%; delirium 5.8%; anorexia 5.1%; bowel obstruction 2.8% and cholestatic itch 0%. For those people with a symptom of interest, it was noted at the beginning of the inpatient admission more than half the time. Of all inpatients, fewer than one third would be eligible to participate in at least one study.ConclusionsThese data provide a baseline estimate of potential people to approach about clinical trials in supportive care but do not account for clinician ‘gate-keeping’, lack of interest in participating nor withdrawal from the study once initiated. The data are retrospective and therefore, limited by clinical documentation. The audit directly informed an increase in the number of participating sites.

Understanding how cancer patients actualise, relinquish, and reject advance care planning: implications for practice

PurposeAlthough advance care planning (ACP) is recognised as integral to quality cancer care, it remains poorly integrated in many settings. Given cancer patients’ unpredictable disease trajectories and equivocal treatment options, a disease-specific ACP model may be necessary. This study examines how Australian cancer patients consider ACP. Responses will inform the development of an Australian Cancer Centre’s ACP programme.MethodsA constructivist research approach with grounded theory design was applied. Eighteen adults from lung and gastro-intestinal tumour streams participated. Participants first described their initial understanding of ACP, received ACP information, and finally completed a semi-structured interview assisted by the vignette technique. Qualitative inter-rater reliability was integrated.ResultsParticipants initially had scant knowledge of ACP. On obtaining further information, their responses indicated that: For cancer patients, ACP is an individualised, dynamic, and shared process characterised by myriad variations in choices to actualise, relinquish, and/or reject its individual components (medical enduring power of attorney, statement of choices, refusal of treatment certificate, and advanced directive). Actualisation of each component involves considering, possibly conversing about, planning, and communicating a decision, usually iteratively. Reactions can change over time and are informed by values, memories, personalities, health perceptions, appreciation of prognoses, and trust or doubts in their substitute decision makers.ConclusionFindings endorse the value of routinely, though sensitively, discussing ACP with cancer patients at various time points across their disease trajectory. Nonetheless, ACP may also be relinquished or rejected and ongoing offers for ACP in some patients may be offensive to their value system.

Placebo and Nocebo Effects in Randomized Controlled Trials: The Implications for Research and Practice

Placebo and nocebo effects are known to contribute significantly to the response to symptom control, including analgesia. Clinical trial methodologies using placebo controls are designed to identify the magnitude of these effects in the research context. An adequately powered, randomized, double-blind, placebo-controlled trial of ketamine in cancer pain has recently been reported, which demonstrated no net clinical benefit for ketamine over and above that of placebo. Rates of placebo and nocebo responses were high. The setting of a clinical trial provides an opportunity to quantify the nonpharmacologic aspects of patient responses to analgesia, raising important clinical and ethical issues for practice. The findings of the ketamine study are analyzed in the context of a methodological discussion of placebo and nocebo effects, what is known about the biological and psychological bases for each of these, and their implications for a clinical trial design in the palliative care setting. Along with reviewing the use of ketamine after this negative trial, clinicians need to remain aware of the strength and significance of both placebo and nocebo responses in their own practices and the biopsychosocial complexity of why and how patients actually respond to pain management strategies. The results of this study strongly reinforce the importance of the therapeutic relationship and the context of care.

Palliative Care and Hematological Malignancies: Increased Referrals at a Comprehensive Cancer Centre

BACKGROUND Current evidence indicates that patients with hematological malignancies are less likely to receive input from specialist palliative care services compared to those with solid tumors. AIM We aimed to analyze data for referrals to our palliative care service, in order to assess trends in the number and proportion of referrals received from hematology, and changes in the characteristics of these referrals. DESIGN Prospective information was collected for all referrals to the Department of Pain and Palliative Care (DPPC) over a four-year period. This included inpatient/outpatient status, diagnosis, symptoms, and goals of the referring clinician; and information linked to hospital inpatient data to obtain date and location of death. SETTINGS/PARTICIPANTS All hematology referrals were from January 2007 to December 2010. RESULTS Hematology referrals constituted 11.6% of all referrals received during the study period. Outpatient referrals increased significantly with each year, as did the proportion of patients referred for symptom control. The median time from referral to death was 34 days, with poorest survival seen in acute leukemia and inpatients. Overall, 54% of inpatient hematology deaths had consultation from the DPPC, with these patients less likely to die in the intensive care unit. CONCLUSIONS Over recent years, collaboration between hematology and palliative care has resulted in increased referral numbers, with potentially positive results for patients.

Patient reporting and doctor recognition of dyspnoea in a comprehensive cancer centre

The aim of this study was to examine different aspects of dyspnoea in an Australian acute cancer care population, specifically prevalence, recognition, reporting, symptom control methods and prognostic significance. Patients and treating hospital medical officer were concurrently asked to evaluate the experience of dyspnoea. The prevalence of dyspnoea was 33%, with discrepancies observed between patient and doctor reporting of the presence of dyspnoea (P = 0.021), as well as its intensity and distress. Symptomatic methods for the relief of cancer‐related dyspnoea are underused, particularly opioids. The medical underestimation of dyspnoea is consistent with previous studies and potentially detracts from effective management of this symptom.

A community-based model of rapid autopsy in end-stage cancer patients

To the Editor: Systematic genomic studies, including the Cancer Genome Atlas (TCGA)1 and the International Cancer Genome Consortium (ICGC)2, have provided an unprecedented catalog of driver mutations in human cancer. However, these studies use mainly primary, pre-treatment tumor material obtained at surgery with curative intent. There is an urgent need to identify and characterize resistance mechanisms to understand how cancers can evade even the best medical efforts and kill patients; therefore, access to end-stage disease is important. Solid cancers show considerable spatial3, temporal4,5 and genomic heterogeneity at diagnosis. Selective pressure and mutagenic impact of treatment6 drives intra-patient evolution of cancer cell populations4,7. Understanding acquired resistance requires access to paired preand post-treatment samples4,7; however, curative surgery is typically confined to patients with locoregional disease, and opportunities for tumor sampling in advanced disseminated disease are limited. Here, we describe Cancer Tissue Collection After Death (CASCADE), an autopsy program that overcomes logistical challenges to enable collection of samples at end stage for research in melanoma and breast, ovarian and prostate cancers. For the CASCADE study, we aimed to recruit cancer patients close to the end of life, including those outside the minority of patients who die in hospitals. To preserve tissue integrity, autopsies must commence within a few hours of death, requiring access to around-the-clock services. Intervention in the emotionally charged end-of-life environment must be managed in an ethical manner and to a high standard. Finally, we aimed for the study to be highly cost-effective. We believe our approach to meeting these challenges is applicable to researchers in other large urban centers. Here we summarize the main steps in CASCADE’s operating protocol and our experiences from the initial 3 years and 30 autopsies performed (Fig. 1). Information about institutional review board approvals (including a detailed patient informationand-consent form), the autopsy procedure and certain laboratory processes is given in Supplementary Methods and Supplementary Figure 1. Recruitment of participants was led by the clinicians. Such discussions require careful consideration, in timing and in language, and were initiated only if there was a perception that tissue donation would be acceptable to the patients and their families. Factors suggesting acceptability include the emotional stability of the participant and family members and their clarity about and acceptance of the terminal nature of the disease. On occasion, participants prompted discussion by asking about organ or body donation. Consent discussions typically involved oncologists and/or palliative care physicians employed at recruiting hospitals who had established a care relationship with the participant and their family during the patient’s cancer journey. Frequently, the study was introduced at one meeting and discussed over several subsequent clinic visits, allowing patients and their families time to consider participation. We view the involvement of family members in the consent process as essential to support the participant and facilitate decisionmaking. Involvement of family members also ensures that they are fully aware of the autopsy process and helps to clarify funeral arrangements for the study team. After obtaining consent, study investigators collated clinical information, including that related to past and current treatment and diagnostic procedures such as imaging, on an ongoing basis. Between September 2012 and August 2015, 40 patients were approached, and 37 (92.5%) expressed interest in participating. Of those 32 patients (80%) consented; the other 5 had rapid clinical deterioration precluding

A randomised, double-blind, placebo-controlled study to assess the safety and efficacy of methoxyflurane for procedural pain of a bone marrow biopsy.

Context Pain during bone marrow biopsy (BMB) under local anaesthesia (LA) is reported in 70% of patients, of whom 35% rate the pain as severe. Pain is experienced during both the biopsy and the marrow aspiration. Many medical centres use conscious sedation involving benzodiazepines and/or opioids administered orally or intravenously for BMB analgesia. Methoxyflurane (MEOF) is self-administered by a handheld device (the Penthrox inhaler), which is licensed in Australia for the relief of pain associated with short surgical procedures. Objectives To evaluate the efficacy and safety of MEOF analgesia in patients with cancer undergoing BMB. Methods Patients received LA plus either MEOF or placebo. The primary endpoint was worst pain intensity measured with the Numerical Rating Scale. Anxiety was assessed with the State Trait Anxiety Inventory (STAI-Y-1). Patients, operators and the research nurse rated global medication performance using a 5-point Likert scale. Results Forty-nine of the 50 patients randomised to MEOF and 48 of the 50 patients randomised to placebo effectively received the allocated intervention. Mean±SD worst pain overall was 4.90±2.07 in MEOF group and 6.0±2.24 in placebo group (p=0.011). Worst pain during the aspiration was 3.3±2.0 in MEOF group and 5.0±2.4 in placebo group (p<0.001). 49% of patients treated with MEOF rated the medication as very good or excellent compared with 16.5% of the patients treated with placebo (p=0.005). 20.4% of patients treated with MEOF had an adverse event (AE) compared with 4.2% in the placebo arm (p=0.028). All AEs were grade 1. Conclusions MEOF was safe and performed better than placebo for analgesia in BMB procedures.