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Background Radiationtherapy (RT) provide pain reduction in about 60% of patients with painful bone metastases. Studies have identified demographic and clinical characteristics to predict RT response, but no model is clinical useful. Tumor characteristics and inflammation can influence cancer induced bone pain, but the association with RT response are not studied. We test if tumor characteristics and the inflammation marker CRP improve prediction of RT response. Methods We included adult patients receiving RT for painful bone metastases in a multicenter, multinational longitudinal observational study. The primary endpoint was analgesic response within 8 weeks after RT defined according to current guidelines. Seventeen independent potential predictor variables assessed at baseline included patient demographics, RT administration, pain characteristics and treatment, cancer diagnosis, tumor characteristics, depression and inflammation (CRP). Multivariate logistic regression analysis with multiple imputation of missing data were applied to identify predictors of RT response. Results are reported as odds ratios (OR) and 95% confidence intervals (CI). Results 565 eligible patients were enrolled, 424 patients (75%) had complete data on the variables of interest and multiple imputation allowed the final regression models to be carried out on 513 patients (91%). 232 patients (41%, CI 37%-45%) responded to RT. Higher Karnofsky performance status (OR 1.45, CI 1.21-1.73), breast cancer (OR 2.61, CI 1.20-5.69) and prostate cancer (OR 2.64, CI 1.24-5.63) (compared to GI cancer), presence of soft tissue expansion (OR 1.78, CI 1.13-2.81) and higher maximum pain intensity at the radiated site (OR 1.1, CI 1.00-1.21) were significant predictors of positive RT response, while the use of steroids was a negative predictor (OR 0.62, CI 0.42-0.93). The discriminative ability of the model was moderate, with C-statistics 0.70. Conclusions This study supports previous findings that higher performance status, cancer diagnosis and higher baseline pain intensity predict analgesic RT response. The study presents new data showing that presence of soft tissue expansion predicts RT response and that CRP is not significantly associated with analgesic RT response. Clinical trial identification NCT02107664 (Date of registration April 8, 2014). Legal entity responsible for the study Pal Klepstad. Funding The European Palliative Care Research Centre (PRC). Disclosure All authors have declared no conflicts of interest.

Context Few studies have addressed the impact of previous opioid exposure on the effect of opioids for the treatment of severe cancer pain episodes. Objectives We aimed to test whether previous exposure to higher opioid doses was associated with a reduced analgesic effect of fentanyl sublingual tablets (FST) and subcutaneous morphine (SCM) and whether it had an influence on their relative effect. Methods This is a secondary analysis of a placebo-controlled randomized trial comparing 100 μg FST with 5 mg SCM for the acute treatment of severe cancer pain episodes. The effect of previous opioid exposure (oral morphine equivalent daily dose from 20 to 120 mg) on pain intensity difference (PID) and side effects at 30 and 60 minutes after administration (PID 0–30 minutes, PID 0–60 minutes, and adverse events 30–60 minutes) and on re-medication for inefficacy, was studied by multivariable linear and logistic regression models and statistical tests for interaction. Results A total of 114 patients were enrolled. Results indicate modest and nonstatistically significant effect of previous opioid exposure on all the outcomes examined (P = 0.11, P = 0.35, P = 0.07, and P = 0.52, respectively, for PID 0–30 minutes, re-medication, PID 0–60 minutes, and adverse events 30–60 minutes). Nonstatistically significant tests for interaction for all models indicated a lack of impact of previous opioid exposure on the difference in the analgesic effect between treatments. Conclusion In this study, we could not demonstrate an effect of previous opioid exposure, from 20 to 120 mg oral morphine equivalent daily dose, on the absolute and relative efficacy and tolerability of 100 μg FST and 5 mg SCM for severe cancer pain episodes.

Context Cancer pain can appear with spikes of higher intensity. Breakthrough cancer pain (BTCP) is the most common term for the transient exacerbations of pain, but the ability of the nomenclature to capture relevant pain variations and give treatment guidance is questionable. Objectives To reach consensus on definitions, terminology, and subclassification of transient cancer pain exacerbations. Methods The most frequent authors on BTCP literature were identified using the same search strategy as in a systematic review and invited to participate in a two-round Delphi survey. Topics with a low degree of consensus on BTCP classification were refined into 20 statements. The participants rated their degree of agreement with the statements on a numeric rating scale (0–10). Consensus was defined as a median numeric rating scale score of ≥7 and an interquartile range of ≤3. Results Fifty-two authors had published three or more articles on BTCP over the past 10 years. Twenty-seven responded in the first round and 24 in the second round. Consensus was reached for 13 of 20 statements. Transient cancer pain exacerbations can occur without background pain, when background pain is uncontrolled, and regardless of opioid treatment. There exist cancer pain exacerbations other than BTCP, and the phenomenon could be named “episodic pain.” Patient-reported treatment satisfaction is important with respect to assessment. Subclassification according to pain pathophysiology can provide treatment guidance. Conclusion Significant transient cancer pain exacerbations include more than just BTCP. Patient input and pain classification are important factors for tailoring treatment. This is the authors' accepted and refereed manuscript to the article.

Few studies regarding palliative sedation (PS) have been carried out in home care (HC) setting. A comparison of PS rate and practices between hospice (HS) and HC is also lacking.Comparing HC and HS settings for PS rate, patient clinical characteristics before and during PS, decision-making process, and clinical aspects of PS.About 38 HC/HS services in Italy participated in a multicenter observational longitudinal study. Consecutive adult cancer patients followed till death during a four-month period and undergoing PS were eligible. Symptom control and level of consciousness were registered every eight hours to death.About 4276 patients were screened, 2894 followed till death, and 531 (18%) underwent PS. PS rate was 15% in HC and 21% in HS (P 0.001). Principal refractory symptoms were delirium (54%) and dyspnea (45%), respectively, more common in HC (P 0.001) and HS (P = 0.03). Informed consent was not obtained in 72% of patients but achieved by 96% of families. Midazolam was the most used drug (94% HS vs. 75% HC; P 0.001) mainly by continuous infusion (74% HC vs. 89% HS; P 0.001). PS duration was less than 48 hours in 67% of patients. Hydration during PS was less frequent in HC (27% vs. 49%; P 0.001). In the eight hours before death, consciousness level was unrousable to mild physical stimulation in 81% and symptom control complete in 89% of cases.Our results show feasibility of PS in HC and HS and suggest setting differences in rates, indications, and practice of PS, possibly related to patients' selection or care organization.

The End-of-Life Preferences Interview (ELPI) was developed with the purpose of supporting physicians in communicating with advanced cancer patients.This study aimed to evaluate ELPI feasibility and compare home care/hospice (HC-H) vs. outpatient (OU) care settings.Twenty-eight physicians were trained in the use of the ELPI and were asked to apply the new instrument in their daily clinical practice for two months. ELPI feasibility was evaluated through three indices: the percentage of eligible patients, the percentage of patients to whom the ELPI was proposed, and the percentage of completed interviews.The 23 physicians participating in the data collection screened 633 patients, and 156 of them (25%, 95% confidence interval 21%-28%) were judged to be eligible. Eligibility in HC-H was lower than that in the OU setting (18% vs. 46%; P0.0001), whereas the differences were reduced when looking at patients to whom the ELPI was proposed (12% vs. 20%; P=0.017) and who completed the ELPI (8% vs. 18%; P0.001). The percentage of eligible patients refusing the interview was very low in the entire sample (1.9%).Results indicate that discussing end-of-life preferences in an earlier disease phase, such as in the OU setting, could be preferable but that its accomplishment in this setting may be more difficult, mainly as a result of organizational reasons. This observation could indicate that the system is not yet ready to offer patients such an opportunity and although communication on these sensitive issues cannot be reduced to a procedure, the ELPI can become a useful tool to help physicians in accomplishing this difficult task.

To describe how patients die in hospital, 370 patients (age >18 years; in hospital for>24 hours) who died on the general wards of 40 Italian hospitals were assessed. Differences between patients whose death was expected and patients whose death was unexpected were evaluated. Data on treatments and care in proximity of death were collected after interviewing the nurse responsible for the patient within 72 hours of the patient's death, and from clinical and nursing records. For 58% of patients, death was highly expected. Symptom control was inadequate for the most severely ill patients: 75% experienced at least one "severe" symptom (42% pain and 45% dyspnea). Nurses tended to judge patients' global care as "good" or "very good" (76%), in spite of the persistence of symptoms and the scant use of analgesics. Despite some encouraging signs of sensitivity to end-of-life problems, acute inpatient institutions in Italy still deal inadequately with the needs of dying persons.

Accurate pain assessment is considered essential for effective management of cancer pain. The aim of this study was to evaluate the compliance of hospitalized patients with chronic cancer pain, referred to an inpatient palliative care consultation service, with self-assessment of pain intensity by means of a daily pain form. The form was distributed daily by the pain consult nurse and required three daily pain intensity measurements on 0 to 10 numerical scales, separately for pain at rest and pain on movement. Of 174 consecutive patients, 106 (61%) participated in the study and were followed up for a median of 10.6 days (range 1-32 days). Compliance was defined as the number of assessment forms completed over the number of evaluation days available for each patient. Mean compliance was 58%. The main reasons for not completing the form were related to subjective psychological variables (44%), physical distress (26%), and absence of pain (16%). Lack of understanding of the method was reported as the main reason for non-compliance by only 1% of patients.

In the last few years, palliative care for advanced and terminal cancer patients has undergone considerable evolution. We determined the characteristics of patients admitted to the 4-bed Palliative Care Unit (PCU) of the National Cancer Institute (NCI) of Milan in 1987, 1993 and 2000 to evaluate how our diagnostic and therapeutic approaches have changed over the years. We reviewed the charts of every patient admitted to the PCU in 1987, 1993, and the first ten months of 2000. We recorded demographic data; the primary tumor sites; the main reason for admission; the types of therapies administered (oncologic, analgesic, surgical, neurosurgical analgesic procedures, and supportive therapy); the type and number of cardiological, radiological and endoscopic examinations, as well as specialist consultations; the duration of stay and eventual death on the Unit. There were no significant differences regarding gender, age, primary tumor site and death in hospital of the patients admitted during these years. The time spent in hospital increased over time (P = 0.006). A significant increase was observed in the percentage of patients admitted for supportive therapy (P

This study describes the characteristics of a representative sample of terminally ill cancer patients at admission to Italian palliative care programs, the rate and reasons for discontinuation of care, and survival after enrollment. All Italian palliative care units (PCUs) specifically committed to palliative care were asked to consecutively register all new patients (n = 3901) between January and June, 1995. Fifty-eight of the 62 PCUs contacted by the Steering Committee completed the study. A random sample of 589 evaluable patients was prospectively selected from the 2667 eligible patients. Patients were mostly referred by a general practitioner (31.2%) or a specialist (42.1%). Most patients (84.7%) were followed until death. Seventy-seven discontinued care because of hospital admission (6.6%), change of residence (3.9%), refusal (1.7%), or improvement (0.8%). Median survival was 37.9 days; 14.3% of the patients died within 7 days, and 15.3% lived longer than 180 days. A statistically significant association between survival and gender, cancer type, setting of the first visit, and type of unit was observed. In Italy, as in other countries with different health systems, referral of cancer patients to palliative care tends to occur late in the course of the disease. This study suggests that the process of enrollment and the duration of patients' survival in palliative care, when studied in large unselected populations, can provide important information relevant to the care of terminally ill patients.

A multicenter study involving six palliative care units in Italy was carried out on 159 terminal cancer patients seen at home or in hospital. The physician or the nurse completed independently from the patient the Therapy Impact Questionnaire (TIQ), a questionnaire devised for quality-of-life evaluation in terminal cancer patients. The patient's assessment was used as the valid reference measurement to compare with the health-care workers' evaluation to assess the validity of the latter. The results showed that percentages of agreement were higher for physical than for psychological and cognitive symptoms, and that there was a greater agreement on the absence rather than on the presence of a problem. None of the characteristics of the patient nor of the proxy showed any statistically significant relationship with the two disagreement indexes. The results suggest that caution is needed in the use of health-care workers as alternative sources of information regarding patients' quality of life.

Context Oxycodone and morphine are recommended as first-choice opioids for moderate/severe cancer pain, but evidence about their relative tolerability has significant methodological limitations. Objectives This study was mainly aimed at comparing the risk of developing adverse events (AEs) with controlled-release oral morphine vs. oxycodone; secondary aims were comparing their analgesic efficacy and testing heterogeneity in tolerability across different age and renal function subgroups. Methods An open-label multicenter RCT (EudraCT number: 2006-003151-21) was carried out in patients with moderate/severe cancer pain. At baseline, 7 and 14 days, patients scored on 0–10 rating scales (0–10 numerical rating scale) the intensity of pain and of a list of common opioid side effects. The primary end point was the percentage of patients reporting an AE (a worsening ≥ 2 points on any of the listed side effects); tolerability by subgroups and average follow-up pain intensity were compared through regression models. Results One hundred eighty-seven patients were enrolled (47% of originally planned). Intention to treat (ITT) analysis (N = 185, morphine 94, oxycodone 91) did not show any difference in the risk of developing AEs (risk difference −0.6%, 95% CI −11.0% to 9.9%) nor in analgesia (0–10 numerical rating scale pain intensity difference −0.28, 95% CI −0.83 to 0.27). No evidence of heterogeneity of tolerability across age and renal function patient subgroups emerged. Conclusion This trial failed to show any difference in tolerability and analgesic efficacy of morphine and oxycodone as first-line treatment for moderate/severe cancer pain but results interpretation is difficult due to lack of power, potential bias from open-label design, and concerns about assay sensitivity. These data, however, can significantly contribute to future meta-analyses comparing WHO Step-III opioids and are relevant in designing future randomized studies.

The capability to make decisions about one's own dying and death is commonly considered a necessary component of a good death, but difficulties in communicating about imminent death have been documented. This paper attempts to describe the process of constructing an instrument to elicit individual preferences concerning dying, while respecting the patient's awareness, and to verify its applicability in a palliative care setting. The development of the End-of-Life Preferences Interview (ELPI) was performed through (a) a literature search aimed at identifying relevant issues; (b) examination by a panel of experts in the field of palliative care of the items generated; and (c) pretesting of feasibility on all eligible consecutive patients referred to three centers of palliative care during a two-month period. The final version of the ELPI consisted of two parts: The first level explores preferences about issues regarding the caregiving process, and the second level focuses on preparation for death. Each of the two parts is introduced by key questions aimed at allowing the patient to decide whether and when to stop exploring such sensitive matters. Among the 49 eligible patients (41%), the interview was proposed to only 13 of them (27%), and only one of them refused. The reasons for such a low compliance of physicians in proposing the ELPI were evaluated by a semi-structured interview and are herein discussed. The use of the ELPI in clinical practice can favor the passage to a greater consideration of the self-determination of the patient at the end of life, with due consideration of his or her cultural and emotional needs.

In the last few years, palliative care for advanced and terminal cancer patients has undergone considerable evolution. We determined the characteristics of patients admitted to the 4-bed Palliative Care Unit (PCU) of the National Cancer Institute (NCI) of Milan in 1987, 1993 and 2000 to evaluate how our diagnostic and therapeutic approaches have changed over the years. We reviewed the charts of every patient admitted to the PCU in 1987, 1993, and the first ten months of 2000. We recorded demographic data; the primary tumor sites; the main reason for admission; the types of therapies administered (oncologic, analgesic, surgical, neurosurgical analgesic procedures, and supportive therapy); the type and number of cardiological, radiological and endoscopic examinations, as well as specialist consultations; the duration of stay and eventual death on the Unit. There were no significant differences regarding gender, age, primary tumor site and death in hospital of the patients admitted during these years. The time spent in hospital increased over time (P = 0.006). A significant increase was observed in the percentage of patients admitted for supportive therapy (P0.001) and investigation concerning the stage of the disease (P0.001). There was a significant decrease in admission for invasive analgesic procedures (P0.001), as well as for pain diagnosis and/or uncontrolled pain. Uncontrolled pain remained the most frequent reason for admission. Over the years, during hospitalization, 7% to 12% of the patients underwent radiotherapy,1% to 9% had computerized tomography, and 4% to 8% had palliative surgery. More than 50% of the patients received intravenous hydration; a few patients received hypodermoclysis in 1987. Over time, there was a significant increase in "as needed" administration of nonsteroidal anti-inflammatory drugs and a significant reduction in their regular administration (from 24% in 1987 and 1993 to 3% in 2000) (P0.001). The use of codeine, tramadol and methadone increased (P0.001), whereas the use of oral morphine, buprenorphine and oxycodone decreased in 2000 (P0.001). There was a reduction in the use of antidepressants (no significant constant trend) and a significant increase in the use of anticonvulsants, laxatives and pamidronate (P0.001). Regularly administered hypnotics decreased in 1993 and increased in 2000 (P0.001). Over these years, no significant differences were found in the routes of opioid administration, in route switching and in the mean maximum oral opioid dose (ranging from 108 to 126 mg/day). The percentage of patients undergoing percutaneous cordotomy significantly decreased in 1993 and 2000 (P0.001). Over time, there was an increase in requests for specialist consultations, which was significant for neurological, cardiological and oncological consults (P0.001). Although the characteristics of the patients admitted to the PCU did not change over these years, there have been significant modifications in our therapeutic approaches, above all in the use of supportive therapy, adjuvant drugs, opioids and neurosurgical invasive procedures. Moreover, a major collaborative interaction with other specialists of the NCI took place with the aim to tailor treatment for each single patient.