Role of Early Palliative Care in Advanced Head-and-Neck Cancers Patients.

Head-and-neck cancers (HNCs) are significant in India. Poverty, illiteracy, lack of access to healthcare, and poor treatment infrastructure pose a major challenge in the management of these cancers. The majority of these patients present with advanced stage and are not amenable to curative treatment. The majority have the potential to benefit from palliative care (PC) interventions. Our experience has been that usually the referrals from HNC clinic for PC are at the end-of-life or terminal stage. Unfortunately, in the state of intractable suffering, it is difficult for patients to understand and fully benefit from the role of PC. Developing an effective working relationship and communication between the PC service and referring surgeons or oncologists is a key to foster more timely, appropriate referral, as both patients and clinicians often misunderstand or fail to recognize the role of PC. In preparation for a quality improvement project to improve access to PC for HNC patients at the All India Institute of Medical Sciences, we reviewed the needs, challenges, conceptual models, and potential of early integration of PC in advanced HNC patients.

A randomized open-label study of guideline-driven antiemetic therapy versus single agent antiemetic therapy in patients with advanced cancer and nausea not related to anticancer treatment.

BACKGROUND: Nausea/vomiting (N/V) not related to anti-cancer treatment is common in patients with advanced cancer. The standard approach to management is to define a dominant cause, and treat with an antiemetic selected through pathophysiologic knowledge of emetic pathways. High rates of N/V control have been reported using both etiology-based guideline-driven antiemetic regimens and an empiric approach using single agents in uncontrolled studies. These different approaches had never been formally compared. METHODS: This randomized, prospective, open label, dose-escalating study used readily available antiemetics in accordance with etiology-based guidelines or single agent therapy with haloperidol. Participants had a baseline average nausea score of ≥3/10. Response was defined as a ≥ 2/10 point reduction on a numerical rating scale of average nausea score with a final score < 3/10 at 72 h. RESULTS: Nausea scores and distress from nausea improved over time in the majority of the 185 patients randomized. For those who completed each treatment day, a greater response rate was seen in the guideline arm than the single agent arm at 24 h (49% vs 32%; p = 0.02), but not at 48 or 72 h. Response rates at 72 h in the intention to treat analysis were 49 and 53% respectively, with no significant difference between arms (0·04; 95% CI: -0·11, 0·19; p = 0·59). Over 80% of all participants reported an improved global impression of change. There were few adverse events worse than baseline in either arm. CONCLUSION: An etiology-based, guideline-directed approach to antiemetic therapy may offer more rapid benefit, but is no better than single agent treatment with haloperidol at 72 h. CLINICAL TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ANZCTRN12610000481077 .

Establishment and preliminary outcomes of a palliative care research network.

OBJECTIVE: The difficulties in conducting palliative care research have been widely acknowledged. In order to generate the evidence needed to underpin palliative care provision, collaborative research is considered essential. Prior to formalizing the development of a research network for the state of Victoria, Australia, a preliminary study was undertaken to ascertain interest and recommendations for the design of such a collaboration. METHOD: Three data-collection strategies were used: a cross-sectional questionnaire, interviews, and workshops. The questionnaire was completed by multidisciplinary palliative care specialists from across the state (n = 61); interviews were conducted with senior clinicians and academics (n = 21) followed by two stakeholder workshops (n = 29). The questionnaire was constructed specifically for this study, measuring involvement of and perceptions of palliative care research. RESULTS: Both the interview and the questionnaire data demonstrated strong support for a palliative care research network and aided in establishing a research agenda. The stakeholder workshops assisted with strategies for the formation of the Palliative Care Research Network Victoria (PCRNV) and guided the development of the mission and strategic plan. SIGNIFICANCE OF RESULTS: The research and efforts to date to establish the PCRNV are encouraging and provide optimism for the evolution of palliative care research in Australia. The international implications are highlighted.

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

PURPOSE: Although 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. METHODS: A 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. RESULTS: Participants 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. CONCLUSION: Findings 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.

The Palliative Care-Promoting Access and Improvement of the Cancer Experience (PC-PAICE) Project in India: A Multisite International Quality Improvement Collaborative.

Mentors at seven U.S. and Australian academic institutions initially partnered with seven leading Indian academic palliative care and cancer centers in 2017 to undertake a program combining remote and in-person mentorship, didactic instruction, and project-based learning in quality improvement (QI). From its inception in 2017 to 2020, the Palliative Care-Promoting Accesst and Improvement of the Cancer Experience Program conducted three cohorts for capacity building of 22 Indian palliative care and cancer programs. Indian leadership established a Mumbai QI training hub in 2019 with philanthropic support. In 2020, the project which is now named Enable Quality, Improve Patient care - India (EQuIP-India) focuses on both palliative care and cancer teams. EQuIP-India now leads ongoing Indian national collaboratives and training in QI and is integrated into India's National Cancer Grid. Palliative Care-Promoting Accesst and Improvement of the Cancer Experience demonstrates a feasible model of international collaboration and capacity building in palliative care and cancer QI. It is one of the several networked and blended learning approaches with potential for rapid scaling of evidence-based practices.

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

GOALS OF WORK: Multiple 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'. METHODS: Six 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 RESULTS: Of 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. CONCLUSIONS: These 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.

Clinical and palliative care outcomes for patients of poor performance status treated with antiprogrammed death-1 monoclonal antibodies for advanced melanoma.

BACKGROUND: Antiprogrammed death-1 antibodies (anti-PD1) have response rates of 40% in metastatic melanoma. Patients with poor performance status (PS) were excluded from clinical trials, yet use of anti-PD1 is widespread in clinical practice. Literature regarding clinical and palliative care outcomes in patients with poor PS treated with anti-PD1 is lacking. METHODS: Retrospective review of outcomes for all patients with advanced melanoma treated with anti-PD1 between 2012 and June 2015 at Peter MacCallum Cancer Centre, a tertiary specialist cancer center in Australia. RESULTS: Between 2012 and 2015, 91 patients received anti-PD1: median age 63, 65% males, 77% elevated LDH>1xULN (37/48 patients). Fifty-eight patients had baseline ECOG PS of 0-1 (64%), 24 patients ECOG PS 2-3 (26%) and ECOG PS was not recorded in nine patients (10%). Median overall survival (OS) for the ECOG PS 0-1 group was 19.5 months and 1.8 months for ECOG PS 2-3 (HR 5.5; 95% CI, 9.1-50.3; P = 0.0001). Tumor response was 23/58 (39%) in ECOG PS 0-1, 2/16 (12%) in ECOG PS 2 and 0/8 in ECOG PS 3. Toxicity did not differ between different groups. ECOG PS 2-3 patients were more likely to be treated and hospitalized within the last month of life compared to ECOG PS 0-1 patients, RR 1.75 (95% CI, 1.04-2.56, P = 0.019) and RR 1.73 (95% CI, 1.10-2.16, P = 0.009), respectively. ECOG PS 2-3 patients were more likely to die in an acute hospital RR 2.68 (95% CI, 1.17-6.51, P = 0.016). CONCLUSIONS: Patients with poor baseline PS have a significantly lower OS and reduced response to anti-PD1. Further quality of life and palliative care research is needed.

A randomized, double-blind, crossover trial of the effect of oxygen on dyspnea in patients with advanced cancer.

Dyspnea is a common symptom in palliative care. Despite this, there is uncertainty regarding the role of oxygen to treat the symptom in patients with advanced illness. This randomized, double-blind, crossover trial examined the effect of oxygen versus air on the relief of dyspnea in patients with advanced cancer. Following the blinded administration of air and oxygen via nasal prongs, 51 patients rated dyspnea and indicated preferences for the blinded treatments. On average, patients improved symptomatically with both air and oxygen, and there were no significant differences between the treatments. The subgroup of 17 hypoxic patients overall did not demonstrate a significant difference between air and oxygen, despite having improved oxygen saturations when administered oxygen. Hypoxia was corrected in 13 of 17 patients using the treatment dose of 4 L/min of oxygen. The experience of dyspnea is a complex, multifactorial phenomenon, with oxygen tension not correlating with the subjective experience. The administration of either air or oxygen via nasal prongs on average confers improvement of the symptom.

Pharmacovigilance in hospice/palliative care: net effect of pregabalin for neuropathic pain.

INTRODUCTION: Real-world effectiveness of many medications has been poorly researched, including in hospice/palliative care. Directly extrapolating findings from other clinical settings may not yield robust clinical advice. Pharmacovigilance studies provide an opportunity to understand better the net impact of medications. The study aimed to examine immediate and short-term benefits and harms of pregabalin in routine practice for neuropathic pain in hospice/palliative care. METHODS: A consecutive cohort of 155 patients from 62 centres in 5 countries was started on pregabalin and studied prospectively. Data were collected at three time points: baseline; day 7 (immediate, short-term harms); ad hoc reports of any harms ≤21 days; and day 21 (short-term benefits). RESULTS: Median dose for 155 patients at day 21 was 150 mg/24 h. Benefits were reported by 61 patients (39%), of whom 11 (7%) experienced complete pain resolution. Harms were reported by 51 (35%) patients at or before 7 days, the most frequent of which were somnolence, fatigue, cognitive disturbance and dizziness. 10 patients (6%) ceased pregabalin due to harms, but 82 patients (53%) were being treated at 21 days. In regression modelling, people with worse baseline pain derived more benefit (OR=8.5 (95% CI 2.5 to 28.68). CONCLUSIONS: Pregabalin delivered benefit to many patients, with 4 of 10 experiencing pain reductions by 21 days. Harms, occurring in 1 in 3 patients, may be difficult to detect in clinical practice, as they mostly involve worsening of symptoms prevalent at baseline.

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.

Nebulized versus subcutaneous morphine for patients with cancer dyspnea: a preliminary study.

This study compared the effects of nebulized versus subcutaneous morphine on the intensity of dyspnea in cancer patients. Patients with a resting dyspnea intensity > or =3 on a 0-10 scale (0=no dyspnea, 10=worst possible dyspnea) who received regular oral or parenteral opioids were included. On day 1, patients received either subcutaneous (SC) morphine plus nebulized placebo or nebulized morphine plus SC placebo. On day 2, a crossover was made. Dyspnea intensity, side effects, and blinded preference of treatment were assessed. Eleven patients completed the study. Dyspnea decreased from a median of 5 (range, 3-8) to 3 (range, 0-7) after SC morphine (P=0.025) and from 4 (range, 3-9) to 2 (range, 0-9) after nebulized morphine (P=0.007). There was no significant difference in dyspnea intensity between nebulized and subcutaneous morphine at 60 minutes. Unfortunately, due to limited sample size, there was insufficient power to rule out a significant difference between both routes of administration. Nebulized morphine offered dyspnea relief similar to that of SC morphine. Larger randomized controlled trials in patients with both continuous dyspnea and earlier stages of dyspnea are justified.

Multidisciplinary Prognostication Using the Palliative Prognostic Score in an Australian Cancer Center.

CONTEXT: Accurate prognostication is important in oncology and palliative care. A multidisciplinary approach to prognostication provides a novel approach, but its accuracy and application is poorly researched. In this study, we describe and analyze our experience of multidisciplinary prognostication in palliative care patients with cancer. OBJECTIVES: To assess our accuracy of prognostication using multidisciplinary team prediction of survival (MTPS) alone and within the Palliative Prognostic (PaP) Score. METHODS: This retrospective study included all new patients referred to a palliative care consultation service in a tertiary cancer center between January 2010 and December 2011. Initial assessment data for 421 inpatients and 223 outpatients were analyzed according to inpatient and outpatient groups to evaluate the accuracy of prognostication using MTPS alone and within the PaP score (MTPS-PaP) and their correlation with overall survival. RESULTS: Inpatients with MTPS-PaP group A, B, and C had a median survival of 10.9, 3.4, and 0.7 weeks, respectively, and a 30-day survival probability of 81%, 40%, and 10%, respectively. Outpatients with MTPS-PaP group A and B had a median survival of 17.3 and 5.1 weeks, respectively, and a 30-day survival probability of 94% and 50%, respectively. MTPS overestimated survival by a factor of 1.5 for inpatients and 1.2 for outpatients. The MTPS-PaP score correlated better than MTPS alone with overall survival. CONCLUSION: This study suggests that a multidisciplinary team approach to prognostication within routine clinical practice is possible and may substitute for single clinician prediction of survival within the PaP score without detracting from its accuracy. Multidisciplinary team prognostication can assist treating teams to recognize and articulate prognosis, facilitate treatment decisions, and plan end-of-life care appropriately. PaP was less useful in the outpatient setting, given the longer survival interval of the outpatient palliative care patient group.

Pharmacovigilance in hospice/palliative care: net effect of gabapentin for neuropathic pain.

OBJECTIVE: Hospice/palliative care patients may differ from better studied populations, and data from other populations cannot necessarily be extrapolated into hospice/palliative care clinical practice. Pharmacovigilance studies provide opportunities to understand the harms and benefits of medications in routine practice. Gabapentin, a γ-amino butyric acid analogue antiepileptic drug, is commonly prescribed for neuropathic pain in hospice/palliative care. Most of the evidence however relates to non-malignant, chronic pain syndromes (diabetic neuropathy, postherpetic neuralgia, central pain syndromes, fibromyalgia). The aim of this study was to quantify the immediate and short-term clinical benefits and harms of gabapentin in routine hospice/palliative care practice. DESIGN: Multisite, prospective, consecutive cohort. POPULATION: 127 patients, 114 of whom had cancer, who started gabapentin for neuropathic pain as part of routine clinical care. SETTINGS: 42 centres from seven countries. Data were collected at three time points-at baseline, at day 7 (and at any time; immediate and short-term harms) and at day 21 (clinical benefits). RESULTS: At day 21, the average dose of gabapentin for those still using it (n=68) was 653 mg/24 h (range 0-1800 mg) and 54 (42%) reported benefits, of whom 7 (6%) experienced complete pain resolution. Harms were reported in 39/127 (30%) patients at day 7, the most frequent of which were cognitive disturbance, somnolence, nausea and dizziness. Ten patients had their medication ceased due to harms. The presence of significant comorbidities, higher dose and increasing age increased the likelihood of harm. CONCLUSIONS: Overall, 42% of people experienced benefit at a level that resulted in continued use at 21 days.

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.

Acceptability of early integration of palliative care in patients with incurable lung cancer.

BACKGROUND: Lung cancer remains the leading cause of cancer death, and it is known many affected will have significant palliative care needs. Evidence suggests that early involvement of palliative care can translate into improvements in quality of care, quality of life, and survival. However, routine early integration is yet to be embraced as standard of care for the majority of patients, and it is unclear what lung cancer clinicians continue to perceive as the barriers to this model of care. METHODS: We performed a qualitative exploration of lung cancer clinicians' perceptions, focusing on current experiences of engaging with palliative care, perceptions of palliative care for patients with lung cancer, and views of barriers and benefits of referring to palliative care. RESULTS: Focus group and targeted interviews were conducted with 28 clinicians, with four key emergent themes: 1) Competence/skill--with referrers needing to be confident in the quality and capability of palliative care provision; 2) Care Coordination--the need to ensure integrated care, with defined lines of responsibility and clear team communication; 3) Ease of referral--the need for ready access to a palliative care provider in the lung cancer clinic; and 4) Perceptions--concerns about loss of hope and fears of negative patient reaction. CONCLUSIONS: Early and routine involvement of palliative care in patients with incurable lung cancer is acceptable to the majority of treating clinicians. To facilitate early integration of palliative care, palliative care providers need to become front-line team members who provide a high-quality service. Lung cancer clinicians need further education as to the role and benefits of early palliative care, and how best to introduce this.

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.

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.