The range and suitability of outcome measures used in the assessment of palliative treatment for inoperable malignant bowel obstruction: A systematic review.

BACKGROUND: Malignant bowel obstruction, a complication of certain advanced cancers, causes severe symptoms which profoundly affect quality of life. Clinical management remains complex, and outcome assessment is inconsistent. AIM: To identify outcomes evaluating palliative treatment for inoperable malignant bowel obstruction, as part of a four-phase study developing a core outcome set. DESIGN: The review is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA); PROSPERO (ID: CRD42019150648). Eligible studies included at least one subgroup with obstruction below the ligament of Treitz undergoing palliative treatment for inoperable malignant bowel obstruction. Study quality was not assessed because the review does not evaluate efficacy. DATA SOURCES: Medline, Embase, the Cochrane Database, CINAHL, PSYCinfo Caresearch, Open Grey and BASE were searched for trials and observational studies in October 2021. RESULTS: A total of 4769 studies were screened, 290 full texts retrieved and 80 (13,898 participants) included in a narrative synthesis; 343 outcomes were extracted verbatim and pooled into 90 unique terms across six domains: physiological, nutrition, life impact, resource use, mortality and survival. Prevalent outcomes included adverse events (78% of studies), survival (54%), symptom control (39%) and mortality (31%). Key individual symptoms assessed were vomiting (41% of studies), nausea (34%) and pain (33%); 19% of studies assessed quality of life. CONCLUSIONS: Assessment focuses on survival, complications and overall symptom control. There is a need for definitions of treatment 'success' that are meaningful to patients, a more consistent approach to symptom assessment, and greater consideration of how to measure wellbeing in this population.

Symptom burden and lived experiences of patients, caregivers and healthcare professionals on the management of malignant bowel obstruction: A qualitative systematic review.

BACKGROUND: Malignant bowel obstruction occurs in up to 50% of people with advanced ovarian and 15% of people with gastrointestinal cancers. Evaluation and comparison of interventions to manage symptoms are hampered by inconsistent evaluations of efficacy and lack of agreed core outcomes. The patient perspective is rarely incorporated. AIM: To synthesise the qualitative data regarding patient, caregiver and healthcare professionals' views and experience of malignant bowel obstruction to inform the development of a core outcome set for the evaluation of malignant bowel obstruction. DESIGN: A qualitative systematic review was conducted, with narrative synthesis. The review protocol was registered prospectively (https://www.crd.york.ac.uk/prospero, CRD42020176393). DATA SOURCES: MEDLINE, EMBASE, CINAHL, PsycINFO and Scopus databases were searched for studies published between 2010 and 2021. Reference lists were screened for further relevant publications, and citation tracking was performed. RESULTS: Nine papers were included, reporting on seven studies which described the views and experiences of malignant bowel obstruction through the perspectives of 75 patients, 13 caregivers and 62 healthcare professionals. Themes across the papers included symptom burden, diverse experiences of interventions, impact on patient quality of life, implications and trajectory of malignant bowel obstruction, mixed experience of communication and the importance of realistic goals of care. CONCLUSION: Some of the most devastating sequelae of malignant bowel obstruction, such as pain and psychological distress, are not included routinely in its clinical or research evaluation. These data will contribute to a wider body of work to ensure the patient and caregiver perspective is recognised in the development of a core outcome set.

The relationship between pain, analgesics and survival in patients with advanced cancer; a secondary data analysis of the international European palliative care Cancer symptom study.

PURPOSE: Opioids reduce cancer-related pain but an association with shorter survival is variably reported. AIM: To investigate the relationship between pain, analgesics, cancer and survival within the European Palliative Care Cancer Symptom (EPCCS) study to help inform clinical decision making. METHODS: Secondary analysis of the international prospective, longitudinal EPCCS study which included 1739 adults with advanced, incurable cancer receiving palliative care. In this secondary analysis, for all participants with date of death or last follow up, a multilevel Weibull survival analysis examined whether pain, analgesics, and other relevant variables are associated with time to death. RESULTS: Date of death or last follow-up was available for 1404 patients (mean age 65.7 [SD:12.3];men 50%). Secondary analysis of this group showed the mean survival from baseline was 46.5 (SD:1.5) weeks (95% CI:43.6-49.3). Pain was reported by 76%; 60% were taking opioids, 51% non-opioid analgesics and 24% co-analgesics. Opioid-use was associated with decreased survival in the multivariable model (HR = 1.59 (95% CI:1.38-1.84), p < 0.001). An exploratory subgroup analysis of those with C-reactive protein (CRP) measures (n = 219) indicated higher CRP was associated with poorer survival (p = 0.001). In this model, the strength of relationship between survival and opioid-use weakened (p = 0.029). CONCLUSION: Opioid-use and survival were associated; this relationship weakened in a small sensitivity-testing subgroup analysis adjusting for CRP. Thus, the observed relationship between survival and opioid-use may partly be due to tumour-related inflammation. Larger studies, measuring disease activity, are needed to confirm this finding to more accurately judge the benefits and risks of opioids in advanced progressive disease.

Development of a Core Outcome Set for the research and assessment of inoperable malignant bowel obstruction.

BACKGROUND: Malignant bowel obstruction is experienced by 15% of people with advanced cancer, preventing them from eating and drinking and causing pain, nausea and vomiting. Surgery is not always appropriate. Management options include tube or stent drainage of intestinal contents and symptom control using medication. Published literature describing palliative interventions uses a broad range of outcome measures, few of which are patient-relevant. This hinders evidence synthesis, and fails to consider the perspectives of people undergoing treatment. AIMS: To develop a Core Outcome Set for the assessment of inoperable malignant bowel obstruction with clinician, patient and caregiver involvement, using COMET methodology (Core Outcome Measures in Effectiveness Trials). METHODS: A systematic review of clinical trials and observational studies, a rapid review of the qualitative literature and in-depth patient and clinician interviews were conducted to identify a comprehensive list of outcomes. Outcomes were compared and consolidated by the study Steering Group and Patient and Public Involvement contributors, and presented to an international clinical Expert Panel for review. Outcomes from the finalised list were rated for importance in a three-round international Delphi process: results of two survey rounds were circulated to respondents, and two separate consensus meetings were conducted with clinicians and with patients and caregivers via virtual conferencing, using live polling to reach agreement on a Core Outcome Set. RESULTS: 130 unique outcomes were identified. Following the independent Expert Panel review, 82 outcomes were taken into round 1 of the Delphi survey; 24 outcomes reached criteria for critical importance across all stakeholder groups and none reached criteria for dropping. All outcomes rated critically important were taken forward for re-rating in round 2 and all other outcomes dropped. In round 2, all outcomes were voted critically important by at least one stakeholder group. Round 2 outcomes were presented again at online consensus meetings, categorised as high ranking (n = 9), middle ranking (n = 7) or low ranking (n = 8). Stakeholders reached agreement on 16 core outcomes across four key domains: Symptom control, Life impact, Treatment outcomes, and Communication and patient preferences. CONCLUSION: Use of this Core Outcome Set can help to address current challenges in making sense of the evidence around treatment for inoperable malignant bowel obstruction to date, and underpin a more robust future approach. Clearer communication and an honest understanding between all stakeholders will help to provide a basis for responsible decision-making in this distressing situation in clinical practice.

Cannabinoids for adult cancer-related pain: systematic review and meta-analysis.

OBJECTIVES: There is increased interest in cannabinoids for cancer pain management and legislative changes are in progress in many countries. This study aims to determine the beneficial and adverse effects of cannabis/cannabinoids compared with placebo/other active agents for the treatment of cancer-related pain in adults. METHODS: Systematic review and meta-analysis to identify randomised controlled trials of cannabinoids compared with placebo/other active agents for the treatment of cancer-related pain in adults to determine the effect on pain intensity (primary outcome) and adverse effects, including dropouts. Searches included Embase, MEDLINE, PsycINFO, Web of Science, ClinicalTrials.gov, Cochrane and grey literature. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. RESULTS: We identified 2805 unique records, of which six randomised controlled trials were included in this systematic review (n=1460 participants). Five studies were included in the meta-analysis (1442 participants). All had a low risk of bias. There was no difference between cannabinoids and placebo for the difference in the change in average Numeric Rating Scale pain scores (mean difference -0.21 (-0.48 to 0.07, p=0.14)); this remained when only phase III studies were meta-analysed: mean difference -0.02 (-0.21 to 0.16, p=0.80). Cannabinoids had a higher risk of adverse events when compared with placebo, especially somnolence (OR 2.69 (1.54 to 4.71), p<0.001) and dizziness (OR 1.58 (0.99 to 2.51), p=0.05). No treatment-related deaths were reported. Dropouts and mortality rates were high. CONCLUSIONS: Studies with a low risk of bias showed that for adults with advanced cancer, the addition of cannabinoids to opioids did not reduce cancer pain. TRIAL REGISTRATION NUMBER: CRD42018107662.

Persistent pain in cancer survivors.

PURPOSE OF REVIEW: As people are living longer after a diagnosis and primary treatment for cancer, or indeed living with cancer as a chronic disease, new problems are emerging in this growing population of so-called 'survivors'. Persistent or chronic pain is one of the commonest complaints, arising from the tissue damage caused by the original neoplasm, consequences of surgery and other therapies, and - especially in older people - multimorbidity. This review explores some of the principle causes and mechanisms of this phenomenon and reviews the evidence for their management. RECENT FINDINGS: We review recent findings regarding persistent pain in adults after surgery, chemotherapy (including targeted biological therapies), hormone manipulation and radiation therapy; and osteonecrosis from corticosteroid treatment in children with cancer. Recent research has revealed some of the molecular, genetic, phenotypic and psychological factors that predispose some people to developing more persistent pain after cancer, and their long-term outcomes. SUMMARY: Although persistent pain in cancer patients surviving after primary treatment has been recognized for decades, only recently has research shown how this arises and some possible ways to intervene by prevention and interventions. New holistic models for management of persistent cancer-related pain are needed.

Effect of Opioids and Benzodiazepines on Clinical Outcomes in Patients Receiving Palliative Care: An Exploratory Analysis.

BACKGROUND: Medications for symptom management in palliative care have associated, but poorly understood, harms. Drug-related harms have important clinical implications, may impact on patients' compliance and contribute to symptoms. OBJECTIVE: To explore the longitudinal relationship between oral morphine equivalent daily dose (MEDD) and oral diazepam equivalent daily dose (DEDD) with functional, cognitive, and symptom outcomes in patients receiving palliative care. DESIGN: Secondary longitudinal analysis of cancer decedents (n = 235) was carried out from a palliative care randomized controlled trial with multiple outcome measures. At each time point, MEDD and DEDD were calculated. Multilevel modeling was used to investigate independent associations between MEDD and DEDD, and cognitive and gastrointestinal symptoms, quality of life (QoL), performance status, and survival. SETTING/SUBJECTS: Participants were recruited from a specialist palliative care program in southern Adelaide, were expected to live ≥48 hours, had pain in the previous 3 months, and a baseline Folstein Mini-Mental Status Examination score ≥25. RESULTS: Cognitive and gastrointestinal symptoms, performance status, and QoL worsened over time. In the adjusted multilevel analysis, statistically significant relationships remained between MEDD/DEDD and worsening performance status (p = 0.001), DEDD and gastrointestinal effects (p < 0.001), MEDD and QoL (p < 0.022). CONCLUSIONS: Commonly used palliative medications were associated with deteriorating performance status. The lack of association between MEDD with gastrointestinal or cognitive symptoms underlines that these associations are not inevitable with close attention. This analysis highlights the importance of including other medications as confounders when exploring medication-related harms. An understanding of the risk-benefit balance of medications is needed to maximize net benefits for patients.

Somatostatin Analogues Compared With Placebo and Other Pharmacologic Agents in the Management of Symptoms of Inoperable Malignant Bowel Obstruction: A Systematic Review.

CONTEXT: Somatostatin analogues are commonly used to relieve symptoms in malignant bowel obstruction (MBO) but are more expensive than other antisecretory agents. OBJECTIVES: To evaluate the evidence of effectiveness of somatostatin analogues compared with placebo and/or other pharmacologic agents in relieving vomiting in patients with inoperable MBO. METHODS: MEDLINE, EMBASE, CINAHL, and The Cochrane Controlled Trials Register databases were systematically searched; reference lists of relevant articles were hand searched. Cochrane risk of bias tool was used. RESULTS: The search identified 420 unique studies. Seven randomized controlled trials (RCTs) met the inclusion criteria (six octreotide studies and one lanreotide); 220 people administered somatostatin analogues and 207 placebo or hyoscine butylbromide. Three RCTs compared a somatostatin analogue with placebo and four with hyoscine butylbromide. Two adequately powered multicenter RCTs with a low Cochrane risk of bias reported no significant difference between somatostatin analogues and placebo in their primary end points. Four RCTs with a high/unclear Cochrane risk of bias reported that somatostatin analogues were more effective than hyoscine butylbromide in reducing vomiting. CONCLUSION: There is low-level evidence of benefit with somatostatin analogues in the symptomatic treatment of MBO. However, high-level evidence from trials with low risk of bias found no benefit of somatostatin analogues for their primary outcome. There is debate regarding the clinically relevant study end point for symptom control in MBO and when it should be measured. The role of somatostatin analogues in this clinical situation requires further adequately powered, well-designed trials with agreed clinically important end points and measures.

Classification of neuropathic pain in cancer patients.

PURPOSE OF REVIEW: Neuropathic pain can affect up to 40% in patients with cancer, which could be related to the tumour, treatment or comorbid diseases. Effective assessment to diagnose neuropathic pain is crucial in order to choose the right treatment. RECENT FINDINGS: There is to date no systematic classification system; the Neuropathic Pain Special Interest Group of the International Association for the Study of Pain developed a neuropathic pain grading system intended to be used for both clinical and research purposes, and a recent review describes a step-by-step process for applying the grading system in a clinical setting for cancer pain. SUMMARY: We have combined these recommendations to outline a clinically relevant process to classify neuropathic pain in patients with cancer.

Is regular systemic opioid analgesia associated with shorter survival in adult patients with cancer? A systematic literature review.

Opioids are important in the management of pain in patients with cancer. Clinicians and patients are sometimes concerned about the effect of opioids on survival, which might decrease opioid prescription, compliance, and symptom control. We wanted to determine whether opioid analgesia was associated with shorter survival in adult patients with cancer. We systematically searched for studies that assessed the effect of regular systemic opioid analgesia on survival. We identified 526 unique records, with 20 articles meeting inclusion criteria. Thirteen end-of-life studies, including 11 very low-quality retrospective studies, did not find a consistent association between opioid analgesic treatment and survival; this evidence comes from low-quality studies, so should be interpreted with caution. Seven longer-term studies, including three randomised controlled trials and two prospective studies, were included. Six of these studies indicated that opioids were likely to be associated with a shorter survival. None of these studies were powered to assess the effect of opioids on survival as a primary endpoint. In view of this, no definitive conclusions can be made as to whether opioids affect survival in patients with cancer. These data suggest that while opioid analgesia does not affect survival at the end of life, in the context of longer-term treatment, higher-quality studies, with survival as a primary endpoint, are needed to confirm an independent association between opioid analgesia and shorter survival. An important limitation of research in this field is that the relationship between greater analgesic requirements and shorter survival may be mediated by painful progressive cancer.

Central pain processing in chronic chemotherapy-induced peripheral neuropathy: a functional magnetic resonance imaging study.

Life expectancy in multiple myeloma has significantly increased. However, a high incidence of chemotherapy induced peripheral neuropathy (CIPN) can negatively influence quality of life during this period. This study applied functional magnetic resonance imaging (fMRI) to compare areas associated with central pain processing in patients with multiple myeloma who had chemotherapy induced peripheral neuropathy (MM-CIPN) with those from healthy volunteers (HV). Twenty-four participants (n = 12 MM-CIPN, n = 12 HV) underwent Blood Oxygen Level-Dependent (BOLD) fMRI at 3T whilst noxious heat-pain stimuli were applied to the foot and then thigh. Patients with MM-CIPN demonstrated greater activation during painful stimulation in the precuneus compared to HV (p = 0.014, FWE-corrected). Patients with MM-CIPN exhibited hypo-activation of the right superior frontal gyrus compared to HV (p = 0.031, FWE-corrected). Significant positive correlation existed between the total neuropathy score (reduced version) and activation in the frontal operculum (close to insular cortex) during foot stimulation in patients with MM-CIPN (p = 0.03, FWE-corrected; adjusted R2 = 0.87). Painful stimuli delivered to MM-CIPN patients evoke differential activation of distinct cortical regions, reflecting a unique pattern of central pain processing compared with healthy volunteers. This characteristic activation pattern associated with pain furthers the understanding of the pathophysiology of painful chemotherapy induced peripheral neuropathy. Functional MRI provides a tool for monitoring cerebral changes during anti-cancer and analgesic treatment.