An international, open-label, randomised trial comparing a two-step approach versus the standard three-step approach of the WHO analgesic ladder in patients with cancer.

BACKGROUND: Worldwide, cancer pain management follows the World Health Organization (WHO) three-step analgesic ladder. Using weak opioids (e.g. codeine) at step 2 is debatable with low-dose strong opioids being potentially better, particularly in low- and middle-income countries where weak opioids are expensive. We wanted to assess the efficiency, safety and cost of omitting step 2 of the WHO ladder. PATIENTS AND METHODS: We carried out an international, open-label, randomised (1 : 1) parallel group trial. Eligible patients had cancer, pain ≥4/10 on a 0-10 numerical rating scale, required at least step 1 (paracetamol) of the WHO ladder and were randomised to the control arm (weak opioid, step 2 of the WHO ladder) or the experimental arm (strong opioid, step 3). Primary outcome was time to stable pain control (3 consecutive days with pain ≤3). Secondary outcomes included distress, opioid-related side-effects and costs. The primary outcome analysis was by intention to treat and the follow-up was for 20 days. RESULTS: One hundred and fifty-three patients were randomised (76 control, 77 experimental). There was no statistically significant difference in time to stable pain control between the arms, P = 0.667 (log-rank test). The adjusted hazard ratio for the control arm was 1.03 (95% confidence interval 0.72-1.49). In the control arm, 38 patients (53%) needed to change to a strong opioid due to ineffective analgesia. The median time to change was day 6 (interquartile range 4-11). Compared to the control arm, patients in the experimental arm had less nausea (P = 0.009) and costs were less. CONCLUSION: This trial provides some evidence that the two-step approach is an alternative option for cancer pain management.

Elderly gynaecological cancer patients at risk for poor end of life care: a population-based study from the Swedish Register of Palliative Care.

Introduction: Poorer end-of-life (EOL) care for elderly cancer patients has been reported. We assessed the impact of age on 13 indicators for the quality of EOL care as well as adherence to 6 national quality indicators in gynaecological cancer patients.Methods: Age-dependent differences in 13 palliative care quality indicators were studied in gynaecological cancer patients registered in the population-based Swedish Register of Palliative Care. Association between the patient's age and each quality indicator was analyzed by logistic regression, adjusted for place of death where appropriate. Adherence to six national quality indicators determined by the Swedish National Board of Health and Welfare was estimated in all patients.Results: We included 3940 patients with the following age distribution: 1.6% were 18-39 years of age, 12.3% 40-59 years, 37.2% 60-74 years, 28.9% 75-84 years and 20% were ≥85 years. Age-dependent differences in implementation rate were present for some of the 13 quality indicators. Compared to elderly cancer patients, younger patients were more likely to be cared for by a specialized palliative care service, more often informed about imminent death as well as assessed for pain. For most national quality indicators, the goal level was not met. Only for the 'on demand prescription for pain', the goal level was reached.Conclusions: EOL care did not meet national quality indicators in this population-based data from Sweden, in particular in the elderly population. Elderly gynaecological cancer patients are at high risk of poorer EOL care without the involvement of specialized palliative care services. Palliative care services need to be implemented across all institutions of EOL care to ensure good and equal care.

Which factors can aid clinicians to identify a risk of pain during the following month in patients with bone metastases? A longitudinal analyses.

PURPOSE: Explore clinical factors associated with higher pain intensity and future pain in patients with bone metastases to identify patients who can benefit from closer follow-up or pain-modifying interventions. METHODS: This is a secondary analysis of 606 patients with bone metastases included in a multicenter longitudinal study. The dependent variables were "average pain" and "worst pain" in the last 24 h (0-10 NRS). Twenty independent variables with potential association to pain intensity were selected based on previous literature. Cross-sectional analyses were performed with multiple linear regression to explore factors associated with pain intensity at baseline. Longitudinal data were analyzed with a generalized equation models to explore current factors associated with pain intensity at the next visit in 1 month. RESULTS: Current pain intensity (p < 0.001), sleep disturbances (p 0.01 and 0.006), drowsiness (p 0.003 and 0.033) and male gender (p 0.045 and 0.001) were associated with higher average and worst pain intensity in 1 month. In addition, breakthrough pain was related to higher worst pain intensity (p 0.003) in 1 month. The same variables were also associated with higher average pain intensity at baseline. CONCLUSION: Higher current pain intensity, sleep disturbances, drowsiness, male gender, and breakthrough pain are factors associated with higher pain intensity in patients with bone metastases at the next follow-up in 1 month. These factors should be assessed in clinical practice and may aid clinicians in identifying patients that can benefit from closer follow-up or interventions to prevent lack of future pain control. TRIAL REGISTRATION IN CLINICALTRIALS.GOV : NCT01362816.

European Society for Medical Oncology (ESMO) position paper on supportive and palliative care.

Oncology has come a long way in addressing patients' quality of life, together with developing surgical, radio-oncological and medical anticancer therapies. However, the multiple and varying needs of patients are still not being met adequately as part of routine cancer care. Supportive and palliative care interventions should be integrated, dynamic, personalised and based on best evidence. They should start at the time of diagnosis and continue through to end-of-life or survivorship. ESMO is committed to excellence in all aspects of oncological care during the continuum of the cancer experience. Following the 2003 ESMO stand on supportive and palliative care (Cherny N, Catane R, Kosmidis P. ESMO takes a stand on supportive and palliative care. Ann Oncol 2003; 14(9): 1335-1337), this position paper highlights the evolving and growing gap between the needs of cancer patients and the actual provision of care. The concept of patient-centred cancer care is presented along with key requisites and areas for further work.

The effect of real-time electronic monitoring of patient-reported symptoms and clinical syndromes in outpatient workflow of medical oncologists: E-MOSAIC, a multicenter cluster-randomized phase III study (SAKK 95/06).

BACKGROUND: Patients with advanced, incurable cancer receiving anticancer treatment often experience multidimensional symptoms. We hypothesize that real-time monitoring of both symptoms and clinical syndromes will improve symptom management by oncologists and patient outcomes. PATIENTS AND METHODS: In this prospective multicenter cluster-randomized phase-III trial, patients with incurable, symptomatic, solid tumors, who received new outpatient chemotherapy with palliative intention, were eligible. Immediately before the weekly oncologists' visit, patients completed the palm-based E-MOSAIC assessment (Edmonton-Symptom-Assessment-Scale, ≤3 additional symptoms, estimated nutritional intake, body weight change, Karnofsky Performance Status, medications for pain, fatigue, nutrition). A cumulative, longitudinal monitoring sheet (LoMoS) was printed immediately. Eligible experienced oncologists were defined as one cluster each and randomized to receive the immediate print-out LoMoS (intervention) or not (control). Primary analysis limited to patients having uninterrupted (>4/6 visits with same oncologist) patient-oncologist sequences was a mixed model for the difference in patients global quality of life (G-QoL; items 29/30 of EORTC-QlQ-c30) between baseline (BL) and week 6. Intention-to-treat (ITT) analysis included all eligible patients. RESULTS: In 8 centers, 82 oncologists treated 264 patients (median 66 years; overall survival intervention 6.3, control 5.4 months) with various tumors. The between-arm difference in G-QoL of 102 uninterrupted patients (intervention: 55; control: 47) was 6.8 (P = 0.11) in favor of the intervention; in a sensitivity analysis (oncologists treating ≥2 patients; 50, 39), it was 9.0 (P = 0.07). ITT analysis revealed improvement in symptoms (difference last study visit-BL: intervention -5.4 versus control 2.1, P = 0.003) and favored the intervention for communication and coping. More patients with high symptom load received immediate symptom management (chart review, nurse-patient interview) by oncologists getting the LoMoS. CONCLUSION: Monitoring of patient symptoms, clinical syndromes and their management clearly reduced patients' symptoms, but not QoL. Our results encourage the implementation of real-time monitoring in the routine workflow of oncologist with a computer solution.

Are strong opioids equally effective and safe in the treatment of chronic cancer pain? A multicenter randomized phase IV 'real life' trial on the variability of response to opioids.

BACKGROUND: Guidelines tend to consider morphine and morphine-like opioids comparable and interchangeable in the treatment of chronic cancer pain, but individual responses can vary. This study compared the analgesic efficacy, changes of therapy and safety profile over time of four strong opioids given for cancer pain. PATIENT AND METHODS: In this four-arm multicenter, randomized, comparative, of superiority, phase IV trial, oncological patients with moderate to severe pain requiring WHO step III opioids were randomly assigned to receive oral morphine or oxycodone or transdermal fentanyl or buprenorphine for 28 days. At each visit, pain intensity, modifications of therapy and adverse drug reactions (ADRs) were recorded. The primary efficacy end point was the proportion of nonresponders, meaning patients with worse or unchanged average pain intensity (API) between the first and last visit, measured on a 0-10 numerical rating scale. (NCT01809106). RESULTS: Forty-four centers participated in the trial and recruited 520 patients. Worst pain intensity and API decreased over 4 weeks with no significant differences between drugs. Nonresponders ranged from 11.5% (morphine) to 14.4% (buprenorphine). Appreciable changes were made in the treatment schedules over time. Each group required increases in the daily dose, from 32.7% (morphine) to 121.2% (transdermal fentanyl). Patients requiring adjuvant analgesics ranged from 68.9% (morphine) to 81.6% (oxycodone), switches varied from 22.1% (morphine) to 12% (oxycodone), discontinuation of treatment from 27% ( morphine) to 14.5% (fentanyl). ADRs were similar except for effects on the nervous system, which significantly prevailed with morphine. CONCLUSION: The main findings were the similarity in pain control, response rates and main adverse reactions among opioids. Changes in therapy schedules were notable over time. A considerable proportion of patients were nonresponders or poor responders. CLINICAL TRIAL REGISTRATION: NCT01809106 (https://clinicaltrials.gov/ct2/show/NCT01809106?term=cerp&rank=2).

Who experiences higher and increasing breathlessness in advanced cancer? The longitudinal EPCCS Study.

PURPOSE: Breathlessness is a major cause of suffering in advanced cancer. We aimed to determine the symptom trajectory in people with advanced cancer and to identify those at increased risk of experiencing higher or increasing breathlessness over time in advanced cancer. PATIENTS AND METHODS: This was an analysis of the multinational, prospective, longitudinal European Palliative Care Cancer Symptom (EPCCS) study. We included adults with confirmed incurable cancer enrolled in palliative care, with prospective monthly assessments for up to 6 months, withdrawal or death, whichever came first. Symptom severity (0-10 numerical rating scales) was analyzed using multivariate random coefficients regression. RESULTS: A total of 1689 patients (50 % women; mean age 65.7 ± [standard deviation; SD] 12.4 years) were included. Main diagnoses were digestive (31 %), lung (20 %), and breast (17 %) cancers. During a median follow-up of 62 (interquartile range, 0 to 133) days, 65 % were breathless at some point and 36 % of all patients reported moderate/severe breathlessness. The group mean (1.6 points; SD, 2.4) was unchanged over time, but the severity varied markedly between patients and over time. Independent predictors for worse breathlessness were COPD, lung cancer, living alone, lung metastases, anxiety, pain, depression, and lower performance status. Predictors of worsening breathlessness over time were low performance status (p = 0.039) and moderate to severe pain (p = 0.012). CONCLUSION: In the largest longitudinal clinical study to date in advanced cancer alone, breathlessness was frequent and associated with factors including respiratory disease, other concurrent unpleasant symptoms, and impaired performance status. Increase in severity over time was predicted by performance status and pain.

The rare Arg181Cys mutation in the µ opioid receptor can abolish opioid responses.

BACKGROUND: Genetic variability contributes to variable clinical response to opioids. This study emerged from the observation of three Norwegian patients who showed no or extraordinary poor response to very high doses of opioids. We suspected a genetic defect and applied a 'most likely candidate gene' approach to investigate this possibility. METHODS: DNA sequencing was used to search for mutations in coding regions of the OPRM1 gene, encoding the µ opioid receptor (hMOR), in one patient. The remaining two patients, and two cohorts comprising 2158 European cancer pain patients and 600 Norwegian healthy volunteers, respectively, were genotyped using a custom-made TaqMan SNP allelic discrimination assay. RESULTS: DNA sequencing disclosed a homozygous, inactivating Arg181Cys mutation in hMOR in the patient who showed no effects from opioids. The two patients with poor effect from very high doses of opioids were both heterozygous for the mutation. Six heterozygous patients identified among the European cancer patients all used high doses of opioids and/or reported inferior effect on their pain. About one in every 100 Norwegians is heterozygous for the mutation. CONCLUSIONS: The Arg181Cys mutation occurs at clinically relevant frequencies and produces a signaling dead hMOR which may abolish or significantly reduce opioid effects in affected individuals. Anesthesiologists and practitioners in pain medicine should be aware of this mutation as a possible explanation for inefficiency of opioids and consider genotyping in relevant cases. Individuals homozygous for the mutation may need a highly personalized approach to pain therapy.

Indicators of integration of oncology and palliative care programs: an international consensus.

BACKGROUND: Recently, the concept of integrating oncology and palliative care has gained wide professional and scientific support; however, a global consensus on what constitutes integration is unavailable. We conducted a Delphi Survey to develop a consensus list of indicators on integration of specialty palliative care and oncology programs for advanced cancer patients in hospitals with ≥100 beds. METHODS: International experts on integration rated a list of indicators on integration over three iterative rounds under five categories: clinical structure, processes, outcomes, education, and research. Consensus was defined a priori by an agreement of ≥70%. Major criteria (i.e. most relevant and important indicators) were subsequently identified. RESULTS: Among 47 experts surveyed, 46 (98%), 45 (96%), and 45 (96%) responded over the three rounds. Nineteen (40%) were female, 24 (51%) were from North America, and 14 (30%) were from Europe. Sixteen (34%), 7 (15%), and 25 (53%) practiced palliative care, oncology, and both specialties, respectively. After three rounds of deliberation, the panelists reached consensus on 13 major and 30 minor indicators. Major indicators included two related to structure (consensus 95%-98%), four on processes (88%-98%), three on outcomes (88%-91%), and four on education (93%-100%). The major indicators were considered to be clearly stated (9.8/10), objective (9.4/10), amenable to accurate coding (9.5/10), and applicable to their own countries (9.4/10). CONCLUSIONS: Our international experts reached broad consensus on a list of indicators of integration, which may be used to identify centers with a high level of integration, and facilitate benchmarking, quality improvement, and research.

Renal function and symptoms/adverse effects in opioid-treated patients with cancer.

BACKGROUND: Renal impairment and the risk of toxicity caused by accumulation of opioids and/or active metabolites is an under-investigated issue. This study aimed at analysing if symptoms/adverse effects in opioid-treated patients with cancer were associated with renal function. METHODS: Cross-sectional multicentre study (European Pharmacogenetic Opioid Study, 2005-2008), in which 1147 adult patients treated exclusively with only one of the most frequently reported opioids (morphine/oxycodone/fentanyl) for at least 3 days were analysed. Fatigue, nausea/vomiting, pain, loss of appetite, constipation and cognitive dysfunction were assessed (EORTC QLQ-C30). Glomerular filtration rate (GFR) was estimated using Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI Creatinine) equations. RESULTS: Mild to severe low GFR was observed among 40-54% of patients. CG equation showed that patients with mild and moderate/severe low GFR on morphine treatment had higher odds of having severe constipation (P < 0.01) than patients with normal GFR. In addition, patients with moderate/severe low GFR on morphine treatment were more likely to have loss of appetite (P = 0.04). No other significant associations were found. CONCLUSION: Only severe constipation and loss of appetite were associated with low GFR in patients treated with morphine. Oxycodone and fentanyl, in relation to the symptoms studied, seem to be safe as used and titrated in routine cancer pain care.

Early recognition of malnutrition and cachexia in the cancer patient: a position paper of a European School of Oncology Task Force.

BACKGROUND: Weight loss and cachexia are common, reduce tolerance of cancer treatment and the likelihood of response, and independently predict poor outcome. METHODS: A group of experts met under the auspices of the European School of Oncology to review the literature and-on the basis of the limited evidence at present-make recommendations for malnutrition and cachexia management and future research. CONCLUSIONS: Our focus should move from end-stage wasting to supporting patients' nutritional and functional state throughout the increasingly complex and prolonged course of anti-cancer treatment. When inadequate nutrient intake predominates (malnutrition), this can be managed by conventional nutritional support. In the presence of systemic inflammation/altered metabolism (cachexia), a multi-modal approach including novel therapeutic agents is required. For all patients, oncologists should consider three supportive care issues: ensuring sufficient energy and protein intake, maintaining physical activity to maintain muscle mass and (if present) reducing systemic inflammation. The results of phase II/III trials based on novel drug targets (e.g. cytokines, ghrelin receptor, androgen receptor, myostatin) are expected in the next 2 years. If effective therapies emerge, early detection of malnutrition and cachexia will be increasingly important in the hope that timely intervention can improve both patient-centered and oncology outcomes.

Validation of the Consensus-Definition for Cancer Cachexia and evaluation of a classification model--a study based on data from an international multicentre project (EPCRC-CSA).

BACKGROUND: Weight loss limits cancer therapy, quality of life and survival. Common diagnostic criteria and a framework for a classification system for cancer cachexia were recently agreed upon by international consensus. Specific assessment domains (stores, intake, catabolism and function) were proposed. The aim of this study is to validate this diagnostic criteria (two groups: model 1) and examine a four-group (model 2) classification system regarding these domains as well as survival. PATIENTS AND METHODS: Data from an international patient sample with advanced cancer (N = 1070) were analysed. In model 1, the diagnostic criteria for cancer cachexia [weight loss/body mass index (BMI)] were used. Model 2 classified patients into four groups 0-III, according to weight loss/BMI as a framework for cachexia stages. The cachexia domains, survival and sociodemographic/medical variables were compared across models. RESULTS: Eight hundred and sixty-one patients were included. Model 1 consisted of 399 cachectic and 462 non-cachectic patients. Cachectic patients had significantly higher levels of inflammation, lower nutritional intake and performance status and shorter survival. In model 2, differences were not consistent; appetite loss did not differ between group III and IV, and performance status not between group 0 and I. Survival was shorter in group II and III compared with other groups. By adding other cachexia domains to the model, survival differences were demonstrated. CONCLUSION: The diagnostic criteria based on weight loss and BMI distinguish between cachectic and non-cachectic patients concerning all domains (intake, catabolism and function) and is associated with survival. In order to guide cachexia treatment a four-group classification model needs additional domains to discriminate between cachexia stages.

Feasibility and acceptance of electronic monitoring of symptoms and syndromes using a handheld computer in patients with advanced cancer in daily oncology practice.

PURPOSE: We investigated the feasibility and acceptance of electronic monitoring of symptoms and syndromes in oncological outpatient clinics using a PALM (handheld computer). METHODS: The assessment of a combination of symptoms and clinical benefit parameters grouped in four pairs was tested in a pilot phase in advanced cancer patients. Based on these experiences, the software E-MOSAIC was developed, consisting of patient-reported symptoms and nutritional intake and objective assessments (weight, weight loss, performance status and medication for pain, fatigue, and cachexia). E-MOSAIC was then tested in four Swiss oncology centers. In order to compare the methods, patients completed the E-MOSAIC as a paper and a PALM version. Preferences of version and completion times were collected. Assessments were compared using Wilcoxon signed-rank tests , and the test-retest reliability was evaluated. RESULTS: The pilot phase was completed by 22 patients. Most patients and physicians perceived the assessment as useful. Sixty-two patients participated in the feasibility study. Twelve patients reported problems (understanding, optical, tactile), and five patients could not complete the assessment. The median time to complete the PALM-based assessment was 3 min. Forty-nine percent of patients preferred the PALM, 23 % preferred a paper version, and 28 % of patients had no preference. Paper vs. PALM revealed no significant differences in symptoms, but in nutritional intake (p = 0.013). Test-retest (1 h, n = 20) reliability was satisfactory (r = 073-98). CONCLUSION: Electronic symptom and clinical benefit monitoring is feasible in oncology outpatient clinics and perceived as useful by patients, oncology nurses, and oncologists. E-MOSAIC is tested in a prospective randomized trial.

Genetic clustering of European cancer patients indicates that opioid-mediated pain relief is independent of ancestry.

The European Pharmacogenetic Opioid Study (EPOS) of a large series of European cancer patients treated with opioids was carried out to assess the influence of genetics on cancer pain relief. As response to opioid therapy was associated with the patients' country of origin, we tested whether population stratification might represent a confounding factor in the analysis of genetic control of response to opioid therapy. From the whole EPOS series representing 2294 patients' genotypes for 379 single-nucleotide polymorphisms (SNPs), we extracted 117 autosomal SNPs with minor allele frequency>0.28 to obtain highly informative genetic markers, and analyzed the SNPs in 1724 individuals showing <20% missing genotypes. Use of the AWclust program to detect clusters of genetically related individuals in the EPOS series showed that the 117-SNP panel distinguished four main European subgroups statistically associated with ethnicity, but not with country of origin or with the pain relief phenotype. Subethnic European groups of genetically related individuals exist that can be correctly identified using an ∼100-SNP panel. Such genetic clustering may control for admixture in association studies and may allow discrimination between genetic and environmental effects on phenotypes showing association with country of origin, as in the case of pain relief.

Low-dose transdermal buprenorphine - long-term use and co-medication with other potentially addictive drugs.

INTRODUCTION: Recently, low-dose transdermal buprenorphine (LD-TD-BUP) was introduced for treatment of patients with chronic non-malignant pain. The primary aim of this study was to determine the proportion of patients who were prescribed LD-TD-BUP for non-malignant pain who became long-term users. The secondary aim was to determine the proportion of patients who co-medicated with other opioids or benzodiazepines during treatment with LD-TD-BUP. METHODS: Data were drawn from the Norwegian Prescription Database that covers all prescriptions dispensed at pharmacies to the entire Norwegian population (4.7 million inhabitants). The study population consisted of all patients who were dispensed at least one prescription of LD-TD-BUP from its introduction in November 2005 to 31 December 2008. Patients who were dispensed more than 24 patches (≥ 6 months) were defined as long-term users. Reimbursement codes were used to stratify patients as having cancer pain or non-malignant pain. RESULTS: Among new users of LD-TD-BUP for non-malignant pain (n = 13,451), only 22% became long-term users, while 44% were only dispensed one prescription. Among long-term users who were opioid naive when LD-TD-BUP was initiated, 43% co-medicated with other opioids or benzodiazepines, compared with 82% of those who previously had used opioids. CONCLUSION: Three years after introduction, 0.4% of the Norwegian population had been dispensed LD-TD-BUP. Only one-fifth had become long-term users. Those who used opioids before the first dispension of LD-TD-BUP co-medicated with other potentially addictive drugs to a much higher degree compared with those who were opioid naive.

ESMO Designated Centres of Integrated Oncology and Palliative Care (ESMO DCs): education, research and programme development survey.

BACKGROUND: The European Society for Medical Oncology (ESMO) Designated Centres (DCs) of Integrated Oncology and Palliative Care is an incentive programme established in 2003 aiming to improve the integration of oncology and palliative care services provided by oncologists and oncology centres worldwide. Currently, the ESMO DCs programme has over 250 centres accredited from 54 countries worldwide, in all six world regions. MATERIALS AND METHODS: To evaluate how ESMO can support centres to improve programme development, education and research and vice versa what each single centre can do to improve in these areas, we developed a survey which was shared with all active centres. Two hundred and seven ESMO DCs representing 44 countries were invited to participate. We used content analysis to identify response categories using a stepwise approach. After reviewing and coding all responses to each question separately, they were placed into categories, counted and labelled. RESULTS: Of the 207 centres that were invited to participate, 146 centres started the survey, representing 43 countries. Five overarching topics were identified. They included (i) joint events and educational activities; (ii) sharing of materials and defining common standards; (iii) sharing of experiences, scientific knowledge and expertise; (iv) research collaboration; and (v) ESMO support. Respondents were willing to support the ESMO DC community group in all topics and were also asking ESMO to support their centres in these issues in the future. CONCLUSION: The study showed that the ESMO DCs are willing to provide support to improve education, research and programme development. They are also eager to contribute and collaborate amongst each other, but also request ESMO to offer advice and help to improve these issues in the DCs. In the future, facilitation of joint research projects and development of arenas to share experiences, educational and programme developments, and other resources are to be explored and could be offered to the DCs worldwide.

Health-related quality of life in patients with advanced melanoma treated with ipilimumab: prognostic implications and changes during treatment.

BACKGROUND: We have previously reported that the safety and efficacy of ipilimumab in real-world patients with metastatic melanoma were comparable to clinical trials. Few studies have explored health-related quality of life (HRQL) in real-world populations receiving checkpoint inhibitors. This study reports HRQL in real-world patients receiving ipilimumab and assesses the prognostic value of patient-reported outcome measures. PATIENTS AND METHODS: Ipi4 (NCT02068196) was a prospective, multicentre, interventional phase IV trial. Real-world patients (N = 151) with metastatic melanoma were treated with ipilimumab 3 mg/kg intravenously as labelled. HRQL was assessed by the European Organisation of Research and Treatment of Cancer Quality of Life Questionnaire at baseline and after 10-12 weeks. RESULTS: The European Organisation of Research and Treatment of Cancer Quality of Life Questionnaire was completed by 93% (141/151 patients) at baseline, and by 82% at 10-12 weeks. Poor performance status and elevated C-reactive protein (CRP) were associated with worse baseline HRQL. Clinically relevant and statistically significant deteriorations in HRQL from baseline to weeks 10-12 were reported (P <0.05). Baseline physical functioning [hazard ratio (HR) 1.96, P = 0.016], role functioning (HR 2.15, P <0.001), fatigue (HR 1.60, P = 0.030), and appetite loss (HR 1.76, P = 0.012) were associated with poorer overall survival independent of performance status, lactate dehydrogenase (LDH), and CRP. We further developed a prognostic model, combining HRQL outcomes with performance status, LDH, and CRP. This model identified three groups with large and statistically significant differences in survival. CONCLUSIONS: Systemic inflammation is associated with impaired HRQL. During treatment with ipilimumab, HRQL deteriorated significantly. Combining HRQL outcomes with objective risk factors provided additional prognostic information that may aid clinical decision making.

Is there a genetic cause for cancer cachexia? - a clinical validation study in 1797 patients.

BACKGROUND: Cachexia has major impact on cancer patients' morbidity and mortality. Future development of cachexia treatment needs methods for early identification of patients at risk. The aim of the study was to validate nine single-nucleotide polymorphisms (SNPs) previously associated with cachexia, and to explore 182 other candidate SNPs with the potential to be involved in the pathophysiology. METHOD: A total of 1797 cancer patients, classified as either having severe cachexia, mild cachexia or no cachexia, were genotyped. RESULTS: After allowing for multiple testing, there was no statistically significant association between any of the SNPs analysed and the cachexia groups. However, consistent with prior reports, two SNPs from the acylpeptide hydrolase (APEH) gene showed suggestive statistical significance (P=0.02; OR, 0.78). CONCLUSION: This study failed to detect any significant association between any of the SNPs analysed and cachexia; although two SNPs from the APEH gene had a trend towards significance. The APEH gene encodes the enzyme APEH, postulated to be important in the endpoint of the ubiquitin system and thus the breakdown of proteins into free amino acids. In cachexia, there is an extensive breakdown of muscle proteins and an increase in the production of acute phase proteins in the liver.