Influence from genetic variability on opioid use for cancer pain: a European genetic association study of 2294 cancer pain patients.

Cancer pain patients need variable opioid doses. Preclinical and clinical studies suggest that opioid efficacy is related to genetic variability. However, the studies have small samples, findings are not replicated, and several candidate genes have not been studied. Therefore, a study of genetic variability with opioid doses in a large population using a confirmatory validation population was warranted. We recruited 2294 adult European patients using a World Health Organization (WHO) step III opioid and analyzed single nucleotide polymorphisms (SNPs) in genes with a putative influence on opioid mechanisms. The patients' mean age was 62.5 years, and the average pain intensity was 3.5. The patients' primary opioids were morphine (n=830), oxycodone (n=446), fentanyl (n=699), or other opioids (n=234). Pain intensity, time on opioids, age, gender, performance status, and bone or CNS metastases predicted opioid dose and were included as covariates. The patients were randomly divided into 1 development sample and 1 validation sample. None of 112 SNPs in the 25 candidate genes OPRM1, OPRD1, OPRK1, ARRB2, GNAZ, HINT1, Stat6, ABCB1, COMT, HRH1, ADRA2A, MC1R, TACR1, GCH1, DRD2, DRD3, HTR3A, HTR3B, HTR2A, HTR3C, HTR3D, HTR3E, HTR1, or CNR1 showed significant associations with opioid dose in both the development and the validation analyzes. These findings do not support the use of pharmacogenetic analyses for the assessed SNPs to guide opioid treatment. The study also demonstrates the importance of validating findings obtained in genetic association studies to avoid reporting spurious associations as valid findings. To elicit knowledge about new genes that influence pain and the need for opioids, strategies other than the candidate gene approach is needed.

Palliative sedation therapy does not hasten death: results from a prospective multicenter study.

BACKGROUND: Palliative sedation therapy (PST) is indicated for and used to control refractory symptoms in cancer patients undergoing palliative care. We aimed to evaluate whether PST has a detrimental effect on survival in terminally ill patients. METHODS: This multicenter, observational, prospective, nonrandomized population-based study evaluated overall survival in two cohorts of hospice patients, one submitted to palliative sedation (A) and the other managed as per routine hospice practice (B). Cohorts were matched for age class, gender, reason for hospice admission, and Karnofsky performance status. RESULTS: Of the 518 patients enrolled, 267 formed cohort A and 251 cohort B. In total, 25.1% of patients admitted to the participating hospices received PST. Mean and median duration of sedation was 4 (standard deviation 6.0) and 2 days (range 0-43), respectively. Median survival of arm A was 12 days [90% confidence interval (CI) 10-14], while that of arm B was 9 days (90% CI 8-10) (log rank = 0.95, P = 0.330) (unadjusted hazard ratio = 0.92, 90% CI 0.80-1.06). CONCLUSION: PST does not shorten life when used to relieve refractory symptoms and does not need the doctrine of double effect to justify its use from an ethical point of view.

The MERITO Study: a multicentre trial of the analgesic effect and tolerability of normal-release oral morphine during 'titration phase' in patients with cancer pain.

Adequate and rapid pain control is one of the main goals of cancer pain treatment. The objective of this study was to assess the effect and tolerability of oral normal-release morphine during the initial phase of treatment in patients with moderate-to-severe cancer pain. Consecutive patients naïve to strong opioids received normal-release morphine 5 or 10 mg every 4 h during the titration phase (first 5 days), depending on previous analgesic therapy. Pain intensity was assessed using an 11-point Numerical Rating Scale (0-10), and data were recorded in a patient-compiled diary. The primary endpoint was the proportion of time with pain control (a reduction of at least 50% with respect to the baseline pain score) during the titration phase. A total of 159 consecutive patients (102 men; mean age 65 years) with cancer-related pain were enrolled. Pain control was observed for 75% (95% CI 70-80) of the follow-up period in the intent-to-treat population. Overall, 50% and 75% of patients achieved pain control within 8 and 24 h after starting normal-release morphine therapy respectively. The mean pain score was 7.63 points at baseline, and decreased to 2.43 and 1.67 points (both P<0.001) at days 3 and 5 respectively. The most commonly reported adverse events were somnolence (24% of patients), constipation (22%), vomiting (13%), nausea (10%) and confusion (7%). Normal-release morphine results in rapid and satisfactory pain control, and is well tolerated, during the strong-opioid titration phase in patients with moderate-to-severe cancer pain.

Describing oscillations of high energy neutrinos in matter precisely.

We present a formalism for precise description of oscillation phenomena in matter at high energies or high densities, V > Delta m(2)/2E, where V is the matter-induced potential of neutrinos. The accuracy of the approximation is determined by the quantity, where is the mixing angle in matter and is a typical change of the potential over the oscillation length (). We derive simple and physically transparent formulas for the oscillation probabilities, which are valid for arbitrary matter density profiles. They can be applied to oscillations of high-energy accelerator, atmospheric, and cosmic neutrinos in the matter of the Earth, substantially simplifying numerical calculations and providing an insight into the physics of neutrino oscillations in matter. The effect of parametric enhancement of the oscillations of high-energy neutrinos is considered.

Palliative care in advanced cancer.

Palliative care represents a new field among clinical approaches to patients with advanced or terminal cancer. The modern concept of palliative care can be considered in several ways: 1) the relationship between palliative care and primary treatments of cancer (surgery, radiotherapy or chemotherapy); 2) the treatment of symptoms and the relationship between symptom control and quality of life; 3) end-of-life care. With regard to the relationship between palliative care and primary cancer treatments, it is common opinion that a continuity of care is needed from diagnosis to the terminal phase of the disease, and oncology departments could represent the ideal dimension in which to fulfil this requirement. In a continuity-of-care setting, symptom control becomes vitally important to improve quality of life of the patient throughout all the stages of the disease. Moreover, support for the patient and his/her family during the terminal phase of the disease is one of the most important dimensions of palliative care. In addition, assistance provided during the last hours of life and support for the family after the patient's death represent the so-called global assistance, which is distinctive of palliative care.

Breakthrough pain characteristics and syndromes in patients with cancer pain. An international survey.

Breakthrough pain (BKP) is a transitory flare of pain that occurs on a background of relatively well controlled baseline pain. Previous surveys have found that BKP is highly prevalent among patients with cancer pain and predicts more severe pain, pain-related distress and functional impairment, and relatively poor quality of life. An international group of investigators assembled by a task force of the International Association for the Study of Pain (IASP) evaluated the prevalence and characteristics of BKP as part of a prospective, cross-sectional survey of cancer pain. Fifty-eight clinicians in 24 countries evaluated a total of 1095 patients with cancer pain using patient-rated items from the Brief Pain Inventory (BPI) and observer-rated measures. The observer-rated information included demographic and tumor-related data, the occurrence of BKP, and responses on checklists of pain syndromes and pathophysiologies. The clinicians reported BKP in 64.8% of patients. Physicians from English-speaking countries were significantly more likely to report BKP than other physicians. BKP was associated with higher pain scores and functional interference on the BPI. Multivariate analysis showed an independent association of BKP with the presence of more than one pain, a vertebral pain syndrome, pain due to plexopathy, and English-speaking country. These data confirm the high prevalence of BKP, its association with more severe pain and functional impairment, and its relationship to specific cancer pain syndromes. Further studies are needed to characterize subtypes of BKP. The uneven distribution of BKP reporting across pain specialists from different countries suggests that more standardized methods for diagnosing BKP are needed.

Palliative medicine and medical oncology.

Traditionally, medical oncology and palliative care have been considered two distinct and separate disciplines, both as regards treatment objectives and delivery times. Palliative care in terminal stages, aimed exclusively at evaluating and improving quality of life, followed antitumor therapies, which concentrated solely on quantitative results (cure, prolongation of life, tumoral mass shrinkage). Over the years, more modern concepts have developed on the subject. Medical oncology, dealing with the skills and strategic co-ordination of oncologic interventions from primary prevention to terminal phases, should also include assessment and treatment of patients' subjective needs. Anticancer therapies should be evaluated in terms of both the quantitative and qualititative impact on patients' lives. Hence, the traditional view of palliative care has to be modified: it constitutes a philosophical and methodological approach to be adopted from the early phases of illness. It is not the evident cultural necessity of integrating medical oncology with palliative medicine that may be a matter of argument, but rather the organizational models needed to put this combined care into practice: should continuous care be guaranteed by a single figure, the medical oncologist, or rather by an interdisciplinary providers' team, including full-time doctors well-equipped for palliative care? In this paper the needs of cancer patients and the part that a complete oncologist should play to deal with such difficult and far-reaching problems are firstly described. Then, as mild provocation, data and critical considerations on the ever increasing needs of palliative care, the present shortcomings in quality of life and pain assessment and management by medical oncologists, and the uncertain efficacy of interventional programmes to change clinical practice are described. Finally, a model of therapeutic continuity is presented. which in our view is realistic and feasible: an Oncologic Programme as the unifying process, and the Comprehensive Cancer Centre, or the Oncologic Department, the delivering structure.

High-dose progestins for the treatment of cancer anorexia-cachexia syndrome: a systematic review of randomised clinical trials.

BACKGROUND: The aim of the present study was to summarise evidence from scientific studies on cancer anorexia-cachexia syndrome in order to assess and highlight the efficacy of high-dose progestins (megestrol acetate and medroxyprogesterone acetate) compared with placebo in patients with hormone-independent tumors. MATERIALS AND METHODS: A systematic review of published randomised clinical trials was carried out by an extensive electronic and hand search through databases, relevant journals and books, congress, proceedings, reference lists, without any language or year of publication restriction. The research was conducted by two independent operators who collected the data in a form specifically designed for this review. Among the several possible outcomes, appetite and body weight were chosen. RESULTS: Fifteen randomised clinical trials (more than 2000 patients) were retrieved for the review. There was a statistically significant advantage for high-dose progestins as regards improved appetite: pooled odds ratio (OR) = 4.23, 95% confidence interval (CI): 2.53-7.04. Although the effect of high-dose progestins on body weight was less impressive, statistical significance was also reached for this outcome: pooled OR = 2.66, 95% CI: 1.80-3.92. Treatment morbidity was very low, due to the brief period of the treatment in most of the studies. CONCLUSIONS: The effects of high-dose progestins on appetite and body weight were clearly demonstrated. However, further studies are undoubtedly warranted to investigate other aspects of progestin activity, especially as regards dosage, duration and timing with best therapeutic index.

Assessing delirium in cancer patients: the Italian versions of the Delirium Rating Scale and the Memorial Delirium Assessment Scale.

To validate the Italian versions of the Delirium Rating Scale (DRS) and the Memorial Delirium Assessment Scale (MDAS), 105 cancer patients consecutively referred for neurological or psychiatric consultation for mental status change were evaluated using the Confusion Assessment Method (CAM), the DRS, the MDAS, and the Mini-Mental State Examination (MMSE). According to the CAM criteria and clinical examination, 66 patients were delirious, and 39 received diagnoses other than delirium. The DRS and the MDAS scores significantly distinguished delirious from non-delirious patients. The MDAS and the DRS were mutually correlated. When using the proposed cut-off scores for the two scales, the MDAS had higher specificity (94%) but lower sensitivity (68%) than the DRS (sensitivity = 95%, specificity = 61% for DRS cut-off 10; sensitivity = 80%, specificity = 76%, DRS cut-off 12). The MMSE showed high sensitivity (96%) and very low specificity (38%). Exploratory factor analysis of the DRS and the MDAS suggested a three-factor and two-factor structure, respectively. Both instruments in their Italian version proved to be useful for the assessment of delirium among cancer patients. Further research is needed to examine the use of the DRS and the MDAS in other clinical contexts.

Survival, quality of life and breast cancer.

In recent years, evaluating quality of life (QoL) has become increasingly important as an additional measured outcome in cancer clinical trials, in particular in the field of breast cancer. This paper, after a general introduction to the present debate on the methodological issues involved in QoL evaluation, reviews results and open questions regarding the use of this measure in surgical, adjuvant and metastatic studies.

The specialist palliative care team in Forlì, Italy.

A specialist palliative care team (SPCT) for the care of terminal cancer patients was established at Forli in 1986. Over the years, its staff and the patients cared for have been increasing in numbers up to the present levels of importance. For 12 years the service was supplied by a private institution, Istituto Oncologico Romagnolo (IOR). The National Health Service (NHS) has since stepped in and is now supplying home care directly, leaving the IOR with a cultural, supporting, role and with the promotion of volunteer recruitment. The care provided by the specialist group active in the patients' homes is integrated into the primary care provided by the family doctors. A plan is being realized to establish a palliative care unit (PCU) within the city hospital. The group has also been engaged in research for many years, giving special attention both to prognostic factors in very advanced cancer patients and to the organization and evaluation of the service costs. Moreover, two training courses in palliative care are organized biennially, one for all health workers in the region and one for volunteers co-operating with the medical teams.

Impact of delirium on the short term prognosis of advanced cancer patients. Italian Multicenter Study Group on Palliative Care.

BACKGROUND: The objective of this study was to evaluate the impact of delirium on the survival of advanced cancer patients also assessed with a validated prognostic score (the palliative prognostic [PaP] score). METHODS: The study population was a prospective multicenter consecutive case series of advanced cancer patients for whom chemotherapy was no longer considered viable and who were referred to palliative care programs. Clinical and biologic prognostic factors included in the PaP score were assessed at study entry. The Confusion Assessment Method criteria were applied to screen patients presenting with delirium. Survival times were measured from time of enrollment and death taken as an outcome. Survival curves were traced with the Kaplan-Meier method and comparison were based on log rank tests. RESULTS: Delirium was found in 109 cases among 393 consecutive patients (27.7%). The diagnosis of delirium was independently associated with male gender, central nervous system metastases, lower performance status, worse clinical prediction of survival, and progestational treatment. The survival curve of patients with delirium was significantly different from the nondelirious patients curve (log rank, 31.6, P < 0.0001). The median survival time was 21 days (95% confidence interval [CI], 16-27) for the delirious patients and 39 days (95% CI 33-49) for the others. Multivariate analysis showed that the diagnosis of delirium and PaP score were independently associated with prognosis. CONCLUSIONS: The diagnosis of delirium significantly worsens life expectancy prognosticated with the PaP score. By using the PaP score together with the assessment of cognitive status, physicians can correctly predict patients 30-day survival in greater than 70% of cases.

A new palliative prognostic score: a first step for the staging of terminally ill cancer patients. Italian Multicenter and Study Group on Palliative Care.

In recent years, extensive research has been performed to identify prognostic factors that predict survival in terminally ill cancer patients. This study describes the construction of a simple prognostic score based on factors identified in a prospective multicenter study of 519 patients with a median survival of 32 days. An exponential multiple regression model was adopted to evaluate the joint effect of some clinico-biological variables on survival. From an initial model containing 36 variables, a final parsimonious model was obtained by means of a backward selection procedure. The Palliative Prognostic Score (PaP Score) is based on the final model and includes the following variables: Clinical Prediction of Survival (CPS), Karnofsky Performance Status (KPS), anorexia, dyspnea, total white blood count (WBC) and lymphocyte percentage. A numerical score was given to each variable, based on the relative weight of the independent prognostic significance shown by each single category in the multivariate analysis. The sum of the single scores gives the overall PaP Score for each patient and was used to subdivide the study population into three groups, each with a different probability of survival at 30 days: (1) group A: probability of survival at 30 days > 70%, with patient score < or = 5.5; (2) group B: probability of survival at 30 days 30-70%, with patient score 5.6-11.0; and (3) group C: probability of survival at 30 days < 30%, with patient score > 11.0. Using this method, 178/519 (34.3%) patients were classified in risk group A, 205 (39.5%) patients were in risk group B, and 136 (26.2%) patients were in risk group C. The patients classified in the three risk groups had a very different survival experience (logrank = 294.8, P < 0.001), with a median survival of 64 days for group A, 32 days for group B, and 11 days for group C. The PaP Score based on simple clinical and biohumoral variables proved to be statistically significant in a multivariate analysis. The score is valid in this population (training set). An independent validation on another patient series (testing set) is required and is the object of a companion paper.

Successful validation of the palliative prognostic score in terminally ill cancer patients. Italian Multicenter Study Group on Palliative Care.

The aim of this work was to validate a previously constructed prognostic score for terminally ill cancer patients in order to determine its value in clinical practice. The Palliative Prognostic Score (PaP Score) was tested on a population of 451 evaluable patients consecutively entered in the hospice programs of 14 Italian Palliative Care Centers. The score subdivided patients into three specific risk classes based on the following six predictive factors of death: dyspnea, anorexia, Karnofsky Performance Status (KPS), Clinical Prediction of Survival (CPS), total white blood count (WBC), and lymphocyte percentage. The performance of the PaP Score index in the training and testing sets was evaluated by comparing mortality rates in the 3 prognostic risk categories. The score was able to subdivide the validation-independent case series into three risk groups. Median survival was 76 days in group A (with a 86.6% probability of 30-day survival), 32 days in group B (with a 51.6% probability of 30-day survival), and 14 days in group C (with a 16.9% probability of 30-day survival). Survival medians were remarkably similar to those of the training set (64 days in group A, 32 days in group B, and 11 days in group C). In the complex process of staging terminally ill patients, the PaP Score is a simple instrument which permits a more accurate quantification of expected survival. It has been validated on an independent case series and is thus suitable for use in clinical practice.

Evaluation of cost of home therapy for patients with terminal diseases.

Palliative care and palliative medicine embrace the philosophy and the body of knowledge regarding the correct treatment of patients with terminal disease. Palliative treatments can be delivered intramurally (eg, in a hospice or palliative care unit) or at home (home care hospice). The optimal delivery pattern consists of the co-utilization of both care settings, to allow patients who need palliative, supportive, and terminal care to benefit from each setting. In obtaining the available resources, health service costs in Western countries have lately become exorbitant. Home care hospice is a system capable of defeating the challenge on two fronts: to meet the patients' needs and to fulfill this task through economically advantageous practices. Home care hospice is undoubtedly more cost-effective than conventional or generic home care, conventional care (hospitalization), and inpatient hospice care. Its advantage is more evident in the last 3 months of life, due to shorter hospitalization and nonutilization of high-technology interventions and high-cost drugs. The development of a range of palliative care programs integrating primary territorial care and specialized palliative services can constitute the ideal synthesis to respond to patients' needs in a threefold manner: firstly, the patient's right to qualified palliative and terminal care; secondly, the requirements of health services, and lastly, cost containment through a correct and tailored use of available resources.

Gastric cancer: epidemiologic and biological aspects.

Although temporal trends and regional-racial variations in gastric cancer incidence have led to the formulation of different hypotheses, no definite association has been seen between this disease and any behavioural or genetic determinant. In fact, several aetiological factors have been associated with risk of gastric cancer, but not without controversy. Various studies have suggested that genetic factors might be of importance in the pathogenesis of gastric tumours. In fact, stomach carcinoma occurs more frequently among close relatives of affected individuals than in the general population and some of the most common pre-cancerous lesions seem to be genetically determined. In the light of this circumstantial evidence, we decided to investigate the role of various genetic alterations in gastric cancer in order to study their relationship with aetiopathogenesis and disease progression and their value as indicators of risk and prognosis. Our main areas of interest were: i. c-Ha-ras locus polymorphism; ii, truncated c-myc gene variant; iii. loss of heterozygosity, iv. p53 gene mutations; v. oncogene amplification; vi. oncogene amplification proliferative activity and their relation to prognosis in gastric cancer.

Evaluation of the cost of home care for terminally ill cancer patients.

The aim of this work was to carry out a cost evaluation of the home care programme for terminally ill cancer patients run by the Istituto Oncologico Romagnolo (I.O.R.) in the areas of Forlì, Cesena, Ravenna and Rimini (Romagna, Italy). To determine effective home care direct costs, we first selected 1 week of care as an observation unit. We then proceeded to assess the medical and nursing care units together with the clinical protocols administered for each patient. The Karnofsky Performance Status (KPS) was also assessed weekly. In this way, we calculated care costs for each patient and for each week as the sum of medical costs, nursing costs, treatment costs and other costs. A consecutive series of 574 patients were involved in the study from 1 April 1994 to 31 March 1995. A total of 5164 patient-weeks of care was provided, with an average cost per week of 177.6 Ecu. This weekly cost increased in the last 100 days of life (week -15 = 179.5 Ecu; week -8 = 188.3 Ecu; week -2 = 221.0 Ecu; P < 0.001). When single components were analysed in relation to total cost (treatment protocols, physician and nursing care) the increased global cost was found to be mainly attributable to the intensification in nursing care (21.8% of costs in week -15 vs 27.3% of costs in week -2). Examination of the relation between the cost of 1 week of care and KPS values clearly shows that healthcare costs increased as KPS decreased (from 152.2 Ecu with KPS > or = 60 to 292.6 Ecu with KPS < or = 20; P < 0.001). Home care costs were also seen to vary with some clinical characteristics and symptoms present when patients entered the study: asthenia, anorexia, nausea/vomiting, bedsores. Given the good results of home care for cancer patients in terms of quality of life, this method of cost accounting for home-care providers can help to monitor the rising cost of assistance and confirm the cost effectiveness of this type of care.

Serum levels of tumour necrosis factor alpha and other cytokines do not correlate with weight loss and anorexia in cancer patients.

Cancer anorexia-cachexia syndrome (CACS), which is characterized by progressive weight loss (WL) and anorexia (A), is present in 50% of advanced cancer patients and in 80% of terminally ill cancer patients. One of the most controversial aspects of CACS is its oetiopathogenesis; experimental studies have identified certain cytokines [Tumour necrosis factor alpha (TNF-alpha), interleukin 1 (IL-1), interleukin 6 (IL-6), and gamma interferon (gamma-IFN)] as possible co-factors in the onset of the syndrome. The aim of our study was to investigate the correlation between serum levels of circulating cytokines and severity of CACS. The following series of parameters was identified in 61 patients with advanced and terminal cancer: stage of disease; Karnofsky performance status (KPS) and clinical symptoms; biohumoral, anthropometric and immunological situation; level of circulating cytokines. All these parameters were evaluated for a possible link with WL/A. Our data do not show any significant correlation between circulating cytokines and WL/A. A direct correlation was identified between WL/A and nausea (P = 0.03 and P < 0.001, respectively) whereas inverse correlations were observed for both factors as regards arm circumference (P < 0.001 for both), wrist circumference (P < 0.001 for both), KPS (P < 0.001 and P = 0.003, respectively) and creatinine (P = 0.005 and P = 0.03, respectively). Other biochemical factors, such as haemoglobin, haematocrit, glycaemia, prealbumin, sodium and chlorine were also correlated with at least one of two clinical parameters in question. Unexpected results were seen in the increases in CD20 and CD4 and in the CD4/CD8 ratio. Serum levels of these cytokines do not, therefore, appear to be critical in the onset of CACS. On the contrary, our findings confirmed the clinico-laboratory picture that is characteristic of CACS. If we consider the possibility that CACS is provoked by an aspecific response of the host's defence mechanisms against prolonged neoplastic attack, the increase in CD4 (helper lymphocytes) could be linked to the persistent response.