Breakthrough pain in patients with multiple myeloma: a secondary analysis of IOPS MS study.

OBJECTIVE: The aim of this study was to characterize breakthrough pain (BTcP) in patients with multiple myeloma (MM). PATIENTS AND METHODS: This was a secondary analysis of a large multicenter study of patients with BTcP. Background pain intensity and opioid doses were recorded. The BTcP characteristics, including the number of BTcP episodes, intensity, onset, duration, predictability, and interference with daily activities were recorded. Opioids prescribed for BTcP, time to achieve a meaningful pain relief after taking a medication, adverse effects, and patients' satisfaction were assessed. RESULTS: Fifty-four patients with MM were examined. In comparison with other tumors, in patients with MM BTcP was more predictable (p=0.04), with the predominant trigger being the physical activity (p<0.001). Other BTcP characteristics, pattern of opioids used for background pain and BTcP, satisfaction and adverse effects did not differ. CONCLUSIONS: Patients with MM have their own peculiarities. Given the peculiar involvement of the skeleton, BTcP was highly predictable and triggered by movement.

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.

Epithelioid hemangioendothelioma, an ultra-rare cancer: a consensus paper from the community of experts.

Epithelioid hemangioendothelioma (EHE) is an ultra-rare, translocated, vascular sarcoma. EHE clinical behavior is variable, ranging from that of a low-grade malignancy to that of a high-grade sarcoma and it is marked by a high propensity for systemic involvement. No active systemic agents are currently approved specifically for EHE, which is typically refractory to the antitumor drugs used in sarcomas. The degree of uncertainty in selecting the most appropriate therapy for EHE patients and the lack of guidelines on the clinical management of the disease make the adoption of new treatments inconsistent across the world, resulting in suboptimal outcomes for many EHE patients. To address the shortcoming, a global consensus meeting was organized in December 2020 under the umbrella of the European Society for Medical Oncology (ESMO) involving >80 experts from several disciplines from Europe, North America and Asia, together with a patient representative from the EHE Group, a global, disease-specific patient advocacy group, and Sarcoma Patient EuroNet (SPAEN). The meeting was aimed at defining, by consensus, evidence-based best practices for the optimal approach to primary and metastatic EHE. The consensus achieved during that meeting is the subject of the present publication.

Clinical prognostic factors in advanced epithelioid haemangioendothelioma: a retrospective case series analysis within the Italian Rare Cancers Network.

BACKGROUND: This multicentric, retrospective study conducted within the Italian Rare Cancer Network describes clinical features and explores their possible prognostic relevance in patients with advanced epithelioid haemangioendothelioma (EHE) started on surveillance. PATIENTS AND METHODS: We collected data on adult patients with molecularly confirmed, advanced EHE consecutively referred at five sarcoma reference centres between January 2010 and June 2018, with no evidence of progressive disease (PD) and started on surveillance. Overall survival (OS) and progression-free survival (PFS) univariable and multivariable Cox analyses were performed. In the latter, due to the low number of cases and events, penalized likelihood was applied, and variable selection was performed using a random forest model. RESULTS: Sixty-seven patients were included. With a median follow-up of 50.2 months, 51 (76%) patients developed PD and 16 (24%) remained stable. PD at treatment start did not meet RECIST version 1.1 in 15/51 (29%) patients. The 3-year PFS and OS were 25.4% and 71.1%, respectively, in the whole population. Tumour-related pain (TRP) was the most common baseline symptom (32.8%), followed by temperature (20.9%), fatigue (17.9%), and weight loss (16.4%). Baseline TRP (P = 0.0002), development of TRP during follow-up (P = 0.005), baseline temperature (P = 0.002), and development of fatigue during follow-up (P = 0.007) were associated with a significantly worst PFS. An association between baseline TRP (P < 0.0001), development of TRP during follow-up (P = 0.0009), evidence of baseline serosal effusion (P = 0.121), and OS was recorded. CONCLUSION: Because of the poor outcome observed in EHE patients presenting with serosal effusion, TRP, temperature, or serosal effusion, upfront treatment in this subgroup could be considered.

Characteristics of the case mix, organisation and delivery in cancer palliative care: a challenge for good-quality research.

OBJECTIVES: Palliative care (PC) services and patients differ across countries. Data on PC delivery paired with medical and self-reported data are seldom reported. Aims were to describe (1) PC organisation and services in participating centres and (2) characteristics of patients in PC programmes. METHODS: This was an international prospective multicentre study with a single web-based survey on PC organisation, services and academics and patients' self-reported symptoms collected at baseline and monthly thereafter, with concurrent registrations of medical data by healthcare providers. Participants were patients ≥18 enrolled in a PC programme. RESULTS: 30 centres in 12 countries participated; 24 hospitals, 4 hospices, 1 nursing home, 1 home-care service. 22 centres (73%) had PC in-house teams and inpatient and outpatient services. 20 centres (67%) had integral chemotherapy/radiotherapy services, and most (28/30) had access to general medical or oncology inpatient units. Physicians or nurses were present 24 hours/7 days in 50% and 60% of centres, respectively. 50 centres (50%) had professorships, and 12 centres (40%) had full-time/part-time research staff. Data were available on 1698 patients: 50% females; median age 66 (range 21-97); median Karnofsky score 70 (10-100); 1409 patients (83%) had metastatic/disseminated disease; tiredness and pain in the past 24 hours were most prominent. During follow-up, 1060 patients (62%) died; 450 (44%) <3 months from inclusion and 701 (68%) within 6 months. ANOVA and χ2 tests showed that hospice/nursing home patients were significantly older, had poorer performance status and had shorter survival compared with hospital-patients (p<.0.001). CONCLUSIONS: There is a wide variation in PC services and patients across Europe. Detailed characterisation is the first step in improving PC services and research. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT01362816.

Best practices for the management of local-regional recurrent chordoma: a position paper by the Chordoma Global Consensus Group.

Chordomas are rare, malignant bone tumors of the skull-base and axial skeleton. Until recently, there was no consensus among experts regarding appropriate clinical management of chordoma, resulting in inconsistent care and suboptimal outcomes for many patients. To address this shortcoming, the European Society of Medical Oncology (ESMO) and the Chordoma Foundation, the global chordoma patient advocacy group, convened a multi-disciplinary group of chordoma specialists to define by consensus evidence-based best practices for the optimal approach to chordoma. In January 2015, the first recommendations of this group were published, covering the management of primary and metastatic chordomas. Additional evidence and further discussion were needed to develop recommendations about the management of local-regional failures. Thus, ESMO and CF convened a second consensus group meeting in November 2015 to address the treatment of locally relapsed chordoma. This meeting involved over 60 specialists from Europe, the United States and Japan with expertise in treatment of patients with chordoma. The consensus achieved during that meeting is the subject of the present publication and complements the recommendations of the first position paper.

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).

A consensus review on the development of palliative care for patients with chronic and progressive neurological disease.

BACKGROUND AND PURPOSE: The European Association of Palliative Care Taskforce, in collaboration with the Scientific Panel on Palliative Care in Neurology of the European Federation of Neurological Societies (now the European Academy of Neurology), aimed to undertake a review of the literature to establish an evidence-based consensus for palliative and end of life care for patients with progressive neurological disease, and their families. METHODS: A search of the literature yielded 942 articles on this area. These were reviewed by two investigators to determine the main areas and the subsections. A draft list of papers supporting the evidence for each area was circulated to the other authors in an iterative process leading to the agreed recommendations. RESULTS: Overall there is limited evidence to support the recommendations but there is increasing evidence that palliative care and a multidisciplinary approach to care do lead to improved symptoms (Level B) and quality of life of patients and their families (Level C). The main areas in which consensus was found and recommendations could be made are in the early integration of palliative care (Level C), involvement of the wider multidisciplinary team (Level B), communication with patients and families including advance care planning (Level C), symptom management (Level B), end of life care (Level C), carer support and training (Level C), and education for all professionals involved in the care of these patients and families (Good Practice Point). CONCLUSIONS: The care of patients with progressive neurological disease and their families continues to improve and develop. There is a pressing need for increased collaboration between neurology and palliative care.

Long-term morbidity after multivisceral resection for retroperitoneal sarcoma.

BACKGROUND: More than 60 per cent of patients treated surgically for primary retroperitoneal sarcoma survive for at least 5 years. Extended surgical resection has been proposed for primary disease, but long-term morbidity data are lacking. A cross-sectional study was conducted to assess the long-term morbidity of patients undergoing surgery for retroperitoneal sarcoma. METHODS: Patients operated on between January 2002 and December 2011 were eligible for the study. Long-term morbidity was evaluated based on a semistructured clinical interview. Lower limb function was assessed by means of the Lower Extremity Functional Scale (LEFS), a self-report questionnaire with a total score ranging from 0 (low functioning) to 80 (high functioning). Pain was investigated by means of the Brief Pain Inventory--Short Form, with pain intensity scores reported on a scale from 0 (no pain) to 10 (worst pain). RESULTS: Some 243 patients underwent surgery, and 101 of 160 patients who were alive at the time of the investigation responded to the study invitation letter. Finally, 95 patients were enrolled in the study. Sensory impairment of the limbs was reported in 72 patients (76 per cent). The median LEFS score was 60 (i.q.r. 43-73). Mean scores for the pain intensity items varied from 1.23 to 2.68. In multivariable analysis, there was no difference in median levels of creatinine at survey between patients who did or did not undergo nephrectomy (difference between median values 13 (95 per cent c.i. -4 to 30) µmol/l; P = 0.170). CONCLUSION: Severe chronic pain and lower limb motor impairment after multivisceral resection for retroperitoneal sarcomas are rare. Long-term renal function is not significantly impaired when nephrectomy is performed.

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.

Careful monitoring of the use of sedative drugs at the end of life: the role of Epidemiology. The ITAELD study.

BACKGROUND: Sedative drugs are often used at the end of life for different clinical indications, and sometimes sedation is not interrupted until the patient dies. The aim of this study was to estimate the prevalence of patients who died while deeply sedated in Italy in 2007. METHODS: Cross-sectional survey which asked physicians about the last death that occurred among their assisted patients during the last year, and about their attitudes towards end-of-life decisions. All general practitioners (N=5,710) and a random sample of hospital physicians (N=8,950) from 14 Italian provinces were invited to participate. RESULTS: The response rate was 20%. Among 1855 reported deaths, 1466 (79.2%) were classified by physicians as expected or non-sudden; 18.2% of these expected or non-sudden deaths occurred while the patient was deeply sedated. GPs were the least likely to report deep sedation, whereas anesthetists were the most likely. In 8% of cases, sedation occurred along with an abrupt increase in the dosage of opioids during the last day of life, reaching a dosage considered higher than necessary by the doctor. No association with positive attitudes of the physician towards physician assisted death was found, whereas reporting sedation was associated with a positive attitude towards respecting the choice of relatives to forgo life-sustaining treatment in the case of an incompetent patient. CONCLUSION: Our study confirms the high prevalence of patients in Italy who die while being deeply sedated and shows that different practices may converge under the same label. Careful descriptive language is needed.

Selective axillary dissection after axillary reverse mapping to prevent breast-cancer-related lymphoedema.

BACKGROUND: It has recently been reported that, using axillary reverse mapping (ARM), the lymphatics from the arm can be spared to reduce the incidence of breast-cancer-related lymphoedema (BCRL). The aim of this study was to assess the feasibility of selective axillary dissection (SAD) after using ARM and partially preserving arm drainage, and to assess the occurrence of BCRL. METHODS: Using a radioisotope and lymphoscintigraphy, ARM was performed in 60 patients scheduled for SAD, who were subsequently divided for the purpose of comparing the BCRL rates into: group A, comprising 45 patients who successfully underwent SAD with a residual lymphatic hot spot; and group B with 15 whose hot nodes were removed as is normally the case during complete axillary lymph node dissection (ALND). RESULTS: SAD was feasible in 75% of the 60 patients. SAD was completed successfully in 19 of the first 30 patients, and in 26 of the second 30 patients (p = 0.072). The median follow-up was 16 months (6-36), during which 9 patients developed a BCRL, 4 in group A (9%) and 5 in group B (33%); p = 0.035. None of the patients had nodal relapses during the follow-up. CONCLUSIONS: Using a radioisotope enables an effective and safe SAD in a large proportion of patients. There was evidence of a trend to suggest a learning curve. The rate of BCRL after SAD was less than one third of the rate recorded after ALND, a result that should encourage the development of the former technique.

Trends in opioid analgesics sales to community pharmacies and hospitals in Italy (2000-2010).

BACKGROUND: Opioid consumption data in Italy have been widely studied. However, only aggregate data can be found in the published literature, and differences are expected by distribution setting (community pharmacies and hospitals). The aim of our paper is to analyse opioids sales trends in Italy in the decade 2000-2010, in an effort to explore such differences. METHODS: Quarterly sales data of opioid medicinal products sold by wholesalers to both community pharmacies (retail) and to hospitals (non-retail) during the time period 2000-2010 were supplied by IMS Italy. Data were standardized using the Defined Daily Doses per day per 1000 inhabitants (DDDd/1000). RESULTS: Opioid sales have steadily increased during the time period considered going from 1.04 DDDd/1000 in 2000 to 4.9 in 2010 (+292%). Nonetheless relevant differences can be found both by distribution setting and drug type. In particular retail sales have increased by 286 % for WHO Step II opioids and by 575% for WHO Step III drugs, while non-retail sales have increased by 48% and 263%, respectively. In 2010, fentanyl and buprenorphine transdermal patches and oxycodone are more widely prescribed than morphine, in the retail setting, with fentanyl at large in the first position. In hospitals morphine and fentanyl almost equally share the 75% of the market. CONCLUSION: Data suggest that morphine is no more the opioid of first choice for severe pain in Italy, at least for outpatients. This is contradicting most international guidelines available in the 2000-2010 decade.

How to evaluate the effect of pain treatments in cancer patients: results from a longitudinal outcomes and endpoint Italian cohort study.

BACKGROUND: Dealing with cancer pain implies assessing the intensity and other attributes of pain and identifying appropriate outcomes and endpoints to evaluate the effect of treatments. METHODS: In the context of an observational longitudinal prospective study, 1461 painful cancer patients were evaluated at baseline and weekly over 4 weeks. Four pain intensity (PI) measures (worst, average, least and right now: WP, AP, LP, and PRN), pain relief and patients' satisfaction with pain treatments were recorded. Starting from these data, we extrapolated the full responder (FR) subjects, whose PI decreased by ≥2 points, or by ≥30%, or who obtained a final score of ≤5 points, according to criteria previously suggested by literature. The receiver operating characteristics (ROC) curve analysis was used to estimate the predictive accuracy. RESULTS: All the PI measures decreased from the initial to final visit: the reduction was 1.9 as WP, 1.3, 0.8 and 1.2 as AP, LP and PRN, respectively. The proportion of FR differed from 47.8% to 88.3% depending on PI measures and the criterion adopted. ROC analysis showed an acceptable accuracy of all endpoints and confirmed the cut-offs recommended by the literature. The best criterion corresponded to a PI absolute value of ≤4 points when measured as AP. CONCLUSIONS: All measures applied seem able to profile the evolution of pain, with some differences. This implies the need of an appropriate choice of outcomes and endpoints according to the goal and objective of the intervention under evaluation.

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.

Artificial nutrition and hydration in the last week of life in cancer patients. A systematic literature review of practices and effects.

BACKGROUND: The benefits and burdens of artificial nutrition (AN) and artificial hydration (AH) in end-of-life care are unclear. We carried out a literature review on the use of AN and AH in the last days of life of cancer patients. MATERIALS AND METHODS: We systematically searched for papers in PubMed, CINAHL, PsycInfo and EMBASE. All English papers published between January 1998 and July 2009 that contained data on frequencies or effects of AN or AH in cancer patients in the last days of life were included. RESULTS: Reported percentages of patients receiving AN or AH in the last week of life varied from 3% to 53% and from 12% to 88%, respectively. Five studies reported on the effects of AH: two found positive effects (less chronic nausea, less physical dehydration signs), two found negative effects (more ascites, more intestinal drainage) and four found also no effects on terminal delirium, thirst, chronic nausea and fluid overload. No study reported on the sole effect of AN. CONCLUSIONS: Providing AN or AH to cancer patients who are in the last week of life is a frequent practice. The effects on comfort, symptoms and length of survival seem limited. Further research will contribute to better understanding of this important topic in end-of-life care.

Content development for EUROPEAN GUIDELINES on the use of opioids for cancer pain: a systematic review and Expert Consensus Study.

Workpackage 3.1 (WP 3.1), within the European Palliative Research Collaborative (EPCRC), was aimed at critically revising and updating the European Association for Palliative Care recommendations on cancer pain management. The aim of this paper is to report the results of the first phase in the revision process which consists of a literature review and an expert consensus about the contents to be considered relevant in the development of the new guidelines. A systematic literature search was carried out from 2001 to 2008 through various databases including Medline, Cinahl, Cochrane Database of Systematic Reviews, Embase and Google. Through this process, guideline quality was evaluated, content was compared with EAPC recommendations and a first set of key-points was developed. A modified two-round Delphi method was applied to choose the most relevant topics for future systematic literature reviews. Fourteen guidelines on cancer pain management, published or updated after 2000, were retrieved. A comparison of these guidelines with the EAPC recommendations led to the formulation of 37 key-points, which were submitted to a panel of experts through a Delphi method. Through the responses given by the experts (25 after the first round and 19 after the second) and after a revision by the WP 3.1 local and steering committees, a final list of 22 topics was generated to answer all identified key-points. Each of these topics will be the object of systematic literature reviews. The final version of the "Evidence-based guidelines for the use of opioid analgesics in the treatment of cancer pain: the EAPC recommendations" will be based on the results of the 22 systematic literature reviews.