Pharmacological prevention and treatment of opioid-induced constipation in cancer patients: A systematic review and meta-analysis.

BACKGROUND: Cancer-related pain often requires opioid treatment with opioid-induced constipation (OIC) as its most frequent gastrointestinal side-effect. Both for prevention and treatment of OIC osmotic (e.g. polyethylene glycol) and stimulant (e.g. bisacodyl) laxatives are widely used. Newer drugs such as the peripherally acting µ-opioid receptor antagonists (PAMORAs) and naloxone in a fixed combination with oxycodone have become available for the management of OIC. This systematic review and meta-analysis aims to give an overview of the scientific evidence on pharmacological strategies for the prevention and treatment of OIC in cancer patients. METHODS: A systematic search in PubMed, Embase, Web of Science and the Cochrane Library was completed from inception up to 22 October 2022. Randomized and non-randomized studies were systematically selected. Bowel function and adverse drug events were assessed. RESULTS: Twenty trials (prevention: five RCTs and three cohort studies; treatment: ten RCTs and two comparative cohort studies) were included in the review. Regarding the prevention of OIC, three RCTs compared laxatives with other laxatives, finding no clear differences in effectivity of the laxatives used. One cohort study showed a significant benefit of magnesium oxide compared with no laxative. One RCT found a significant benefit for the PAMORA naldemedine compared with magnesium oxide. Preventive use of oxycodone/naloxone did not show a significant difference in two out of three other studies compared to oxycodone or fentanyl. A meta-analysis was not possible. Regarding the treatment of OIC, two RCTs compared laxatives, of which one RCT found that polyethylene glycol was significantly more effective than sennosides. Seven studies compared an opioid antagonist (naloxone, methylnaltrexone or naldemedine) with placebo and three studies compared different dosages of opioid antagonists. These studies with opioid antagonists were used for the meta-analysis. Oxycodone/naloxone showed a significant improvement in Bowel Function Index compared to oxycodone with laxatives (MD -13.68; 95 % CI -18.38 to -8.98; I2 = 58 %). Adverse drug event rates were similar amongst both groups, except for nausea in favour of oxycodone/naloxone (RR 0.51; 95 % CI 0.31-0.83; I2 = 0 %). Naldemedine (NAL) and methylnaltrexone (MNTX) demonstrated significantly higher response rates compared to placebo (NAL: RR 2.07, 95 % CI 1.64-2.61, I2 = 0 %; MNTX: RR 3.83, 95 % CI 2.81-5.22, I2 = 0 %). With regard to adverse events, abdominal pain was more present in treatment with methylnaltrexone and diarrhea was significantly more present in treatment with naldemedine. Different dosages of methylnaltrexone were not significantly different with regard to both efficacy and adverse drug event rates. CONCLUSIONS: Magnesium oxide and naldemedine are most likely effective for prevention of OIC in cancer patients. Naloxone in a fixed combination with oxycodone, naldemedine and methylnaltrexone effectively treat OIC in cancer patients with acceptable adverse events. However, their effect has not been compared to standard (osmotic and stimulant) laxatives. More studies comparing standard laxatives with each other and with opioid antagonists are necessary before recommendations for clinical practice can be made.

Magnesium hydroxide versus macrogol/electrolytes in the prevention of opioid-induced constipation in incurable cancer patients: study protocol for an open-label, randomized controlled trial (the OMAMA study).

BACKGROUND: Opioid-induced constipation (OIC) is a common symptom in cancer patients treated with opioids with a prevalence of up to 59%. International guidelines recommend standard laxatives such as macrogol/electrolytes and magnesium hydroxide to prevent OIC, although evidence from randomized controlled trials is largely lacking. The aim of our study is to compare magnesium hydroxide with macrogol /electrolytes in the prevention of OIC in patients with incurable cancer and to compare side-effects, tolerability and cost-effectiveness. METHODS: Our study is an open-label, randomized, multicenter study to examine if magnesium hydroxide is non-inferior to macrogol/electrolytes in the prevention of OIC. In total, 330 patients with incurable cancer, starting with opioids for pain management, will be randomized to treatment with either macrogol/electrolytes or magnesium hydroxide. The primary outcome measure is the proportion of patients with a score of < 30 on the Bowel Function Index (BFI), measured on day 14. The Rome IV criteria for constipation, side effects of and satisfaction with laxatives, pain scores, quality of life (using the EQ-5D-5L), daily use of laxatives and escape medication, and cost-effectiveness will also be assessed. DISCUSSION: In this study we aim to examine if magnesium hydroxide is non-inferior to macrogol/electrolytes in the prevention of OIC. The outcome of our study will contribute to prevention of OIC and scientific evidence of guidelines on (opioid-induced) constipation. TRIAL REGISTRATION: This trial is registered at clinicaltrials.gov: NCT05216328 and in the Dutch trial register: NTR80508. EudraCT number 2022-000408-36.

Long-term cardiovascular health in adult cancer survivors.

The number of cancer survivors has tremendously increased over the past decades as a result of aging of the population and improvements in early cancer detection and treatment. Ongoing successes in cancer treatment are expected to result in a further increase in the number of long-term survivors. However, cancer treatment can have detrimental cardiovascular side-effects that impact morbidity and mortality, reducing quality of life in cancer survivors. The spectrum of radiotherapy- and chemotherapy-induced cardiovascular disease is broad, varying from subclinical valvular dysfunction to overt congestive heart failure, and such effects may not be apparent for more than twenty years after the initial cancer treatment. Awareness of these long-term side-effects is of crucial value in the management of these patients, in order to reduce the impact of cardiovascular morbidity and mortality. This review provides a comprehensive overview of the long-term cardiovascular complications of cancer treatments (radiotherapy and chemotherapy) in adult cancer survivors.

Impact of integration of clinical and outpatient units on cancer patient satisfaction.

OBJECTIVE: There is an ongoing drive to measure and improve quality of care. Donabedians' quality framework with structure, process and outcome domains provides a useful hold to examine quality of care. The aim of this study was to address the effect of an intervention in hospital structure (integration of three units into one) with the purpose of improving processes (increase meeting, cooperation and communication between professionals and patients) and its effect on the outcome (cancer patient satisfaction). DESIGN: Pre-test-post-test. SETTING: University Medical Center Utrecht, The Netherlands, Department of Medical Oncology. PARTICIPANTS: Cancer patients (n = 174, n = 97). INTERVENTIONS: Physical integration by bringing separately located units (outpatient clinic, day-care clinic, clinical ward) together in one wing of the hospital and adjustments in communication and coordination structures. MAIN OUTCOME MEASURE: Patient satisfaction questionnaire. RESULTS: Satisfaction with care improved for six scales (27%) after integration. Effect sizes (ESs) ranged from 0.36 to 0.80, indicating a small to moderate effect. The most important improvement was found at the day-care clinic on aspects like 'the degree in which the nurses were informed about a patients situation', 'privacy', 'interior design', 'quality of hospital equipment', 'sanitary supplies' and 'waiting periods'. With regard to continuity and coordination of care, satisfaction increased for five items (28% of items concerning continuity and coordination of care). ESs ranged from 0.42 to 0.75. CONCLUSIONS: Integration of three oncology units into one unit had a positive impact on care delivery processes and resulted in improved patient satisfaction concerning care and treatment.

Medical oncology patients' preferences with regard to health care: development of a patient-driven questionnaire.

BACKGROUND: To improve quality of care for cancer patients, it is important to have an insight on the patient's view on health care and on their specific wishes, needs and preferences, without restriction and without influence of researchers and health care providers. The aim of this study was to develop a questionnaire assessing medical oncology patients' preferences for health care based on their own input. PATIENTS AND METHODS: Items were generated using 10 focus group interviews with 51 cancer patients. A preliminary questionnaire was handed out to 681 patients of seven Dutch departments of medical oncology. Explorative factor analysis was carried out on the 386 returned questionnaires (response 57%). RESULTS: Focus group interviews resulted in a preliminary questionnaire containing 136 items. Explorative factor analysis resulted in a definitive questionnaire containing 123 items (21 scales and eight single items). Patients rated expertise, safety, performance and attitude of physicians and nurses as the most important issues in cancer care. CONCLUSION: This questionnaire may be used to assess preferences of cancer patients and to come to a tailored approach of health care that meets patients' wishes and needs.

[The role of consultation in palliative sedation in the central region of the Netherlands]. / De rol van consultatie bij palliatieve sedatie in de regio Midden-Nederland.

OBJECTIVE: To gain insight into the role of consultation in palliative sedation. DESIGN: Retrospective analysis. METHOD: All consultation records of the Palliation Team Midden Nederland (PTMN) from 1 November 2005 to 31 October 2006 were analysed. If palliative sedation was mentioned in the record, the following variables were listed: character of the consultation, data of the questioner, patient data, consultation question, indication for palliative sedation, and character of the advice given. RESULTS: Palliative sedation was a topic in 206 of the 659 consultation records investigated (31%). Intractable delirium, pain, exhaustion, dyspnoea and nausea or vomiting were the most important grounds for palliative sedation. In 47 of the 113 consultations (41%) about starting palliative sedation a negative advice was given, and this was nearly always because there were no intractable somatic symptoms. Existential problems played an important role in 14 of these 113 consultations (12%). In 25 consultations (22%) euthanasia versus palliative sedation was considered explicitly. For these cases there was hardly ever an indication for sedation. CONCLUSION: Palliative sedation was an important reason for consulting the PTMN. The high percentage of negative advice indicates that consultation about palliative sedation has an added value. It gives the questioner the opportunity to check whether all options for treatment have been tried. The question as to whether existential problems are an indication for palliative sedation should be discussed between medical professionals as well as publicly. Palliative sedation rarely is an alternative for euthanasia.

Safety and pharmacology of paclitaxel in patients with impaired liver function: a population pharmacokinetic-pharmacodynamic study.

AIMS: To assess quantitatively the safety and pharmacology of paclitaxel in patients with moderate to severe hepatic impairment. METHODS: Solid tumour patients were enrolled into five liver function cohorts as defined by liver transaminase and total bilirubin concentrations. Paclitaxel was administered as a 3-h intravenous infusion at doses ranging from 110 to 175 mg m(-2), depending on liver impairment. Covariate and semimechanistic pharmacokinetic-pharmacodynamic (PK-PD) population modelling was used to describe the impact of liver impairment on the pharmacology and safety of paclitaxel. RESULTS: Thirty-five patients were included in the study, and PK data were assessed for 59 treatment courses. Most patients had advanced breast cancer (n = 22). Objective responses to paclitaxel were seen in four patients (11%). Patients in higher categories of liver impairment had a significantly lower paclitaxel elimination capacity (R2 = -0.38, P = 0.05), and total bilirubin was a significant covariate to predict decreased elimination capacity with population modelling (P = 0.002). Total bilirubin was also a significant predictor of increased haematological toxicity within the integrated population PK-PD model (P < 10(-4)). Data simulations were used to calculate safe initial paclitaxel doses, which were lower than the administered doses for liver impairment cohorts III-V. CONCLUSIONS: Total bilirubin is a good predictor of paclitaxel elimination capacity and of individual susceptibility to paclitaxel-related myelosuppression in cancer patients with moderate to severe liver impairment. The proposed, adapted paclitaxel doses need validation in prospective trials.

Are anxiety and depressed mood related to physical symptom burden? A study in hospitalized advanced cancer patients.

BACKGROUND: Anxiety and depressed mood are common symptoms in hospitalized advanced cancer patients. It is often presumed that anxiety and depression affect the occurrence and experience of physical symptoms. PURPOSE: To analyse the relation between anxiety, depressed mood and the presence and intensity of physical symptoms. PATIENTS AND METHODS: Anxiety and depressed mood were assessed in a hospitalized advanced cancer population (n = 79) primarily by the Hospital Anxiety and Depression Scale (HADS), and also by a single-item question ;Are you anxious and/or depressed?' and by the Edmonton Symptom Assessment System (ESAS). Physical symptoms were assessed by a semi-structured interview and by the ESAS. RESULTS: Thirty-four percent of the patients reported anxiety, 56% depressed mood and 29% both, as assessed by the HADS. The correlations between HADS, the single-item question and the ESAS were low. No association was found between anxiety or depressed mood and the presence of physical symptoms. Patients who were anxious or depressed had higher ESAS scores for insomnia and drowsiness; scores for pain, anorexia, asthenia, nausea and dyspnea were independent of anxiety and/or depressed mood. CONCLUSION: The relationship between anxiety, depressed mood and the presence and intensity of physical symptoms in hospitalized advanced cancer patients is very limited.

Telephone consultation in palliative care for cancer patients: 5 years of experience in The Netherlands.

GOALS OF WORK: To analyze cancer patient-related consultations of a telephone helpdesk (TH) for palliative care over a period of 5 years in the region of Utrecht, The Netherlands. MATERIALS AND METHODS: A descriptive analysis was performed of consultations over a period of 5 years (2001-2006). The discipline and location of requesting professionals, patient characteristics, reasons for calling, symptoms, palliative care problems and needs for support were registered. MAIN RESULTS: A total of 1,794 consultations were analyzed. There was an increasing number of consultations during the study period. Of the patients, 51% were male and their median age was 65 years (range 0-104). Eighty-four percent were treated at home by their general practitioner. Two thirds of the patients had a life expectancy <4 weeks. Most questions referred to pain (49%), delirium (20%), nausea and vomiting (16%) and dyspnea (12%). The median number of symptoms was 1 (0-6). Of the questions, 54% were related to pharmacological problems, 19% to psychological problems and 21% to the organization of care. Of the requesting professionals, 17% asked for support for themselves. Of the consultations, 14% were related to end-of-life issues: palliative sedation (11%) and euthanasia (3%). CONCLUSION: After more than 5 years, the 24-h telephone consultation service fulfills a need for general practitioners dealing with daily dilemmas in palliative care treatment for cancer patients at home during the last period of their life.

The use of differential item functioning analyses to identify cultural differences in responses to the EORTC QLQ-C30.

INTRODUCTION: The European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 is a widely used health-related quality of life instrument. The main aim of this study is to investigate whether there are international differences in response to the questionnaire that can be explained by cultural factors. METHODS: Analyses involved a database of 106 separate studies including data from over 28,000 respondents. Differential item functioning (DIF) analyses using logistic regression were conducted for each item of the EORTC QLQ-C30 with respect to cultural/geographic group. Results were qualitatively compared with previously reported DIF analyses by translation to explore whether the source of the DIF was more likely to be linguistic or cultural in nature. RESULTS: Although most response patterns were similar, there were a number of international differences in how the questionnaire was answered. The largest variations were found in the results for Eastern Europe and East Asia. Results for the UK, the US and Australia tended to be similar. Many of the European results followed patterns that were more clearly explained when grouped by translation than when grouped by geographical region. DISCUSSION: Our results suggest that, in general, the EORTC QLQ-C30 is suitable for use in a wide variety of countries and settings. Some response variations that have the potential to affect the results of international studies were identified, but it was not always clear whether the source of the variation was primarily linguistic or cultural.

Comparing translations of the EORTC QLQ-C30 using differential item functioning analyses.

The European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 is one of the most widely used quality of life instruments for cancer patients. The aim of this study was to assess whether there were linguistic differences in the way an international sample answered the EORTC QLQ-C30 questionnaire. Thirteen translations of the EORTC QLQ-C30, representing 22 countries, were investigated using a database of 27,891 respondents, incorporating 103 separate studies. Differential item functioning (DIF) analyses were conducted using logistic regression to identify items which, after controlling for subscale, were answered differently by language of administration. Both uniform and non-uniform DIF were assessed. Although most languages showed similar results to English, at least one instance of statistically significant DIF was identified for each translation, and a few of these differences were large. In some cases, the patterns were supported by the results of qualitative interviews with bilingual people. Although, overall, there appeared to be good linguistic equivalence for most of the EORTC QLQ-C30 items, several scales showed strongly discrepant results for some translations. Some of these effects are large enough to impact on the results of clinical trials. Based on our experience in this study, we suggest that validation of translations of health-related quality of life instruments should include exploration of DIF.

[Palliative sedation]. / Palliatieve sedatie.

Palliative sedation is the intentional lowering of the level of consciousness ofa patient in the last phase of life by means of the administration of sedatives. The objective of palliative sedation is to relieve severe physical or psychological suffering that is otherwise untreatable. Sedation is used in 12% of all patients dying in the Netherlands. Refractory delirium, dyspnoea or pain are the most common indications. If deep palliative sedation is used, the estimated life expectancy should be a few days to at most one week. Midazolam is used most often for continuous sedation, usually by subcutaneous infusion; if the response is insufficient, a combination of midazolam with levomepromazine or phenobarbital or monotreatment with propofol may be used. If continuous infusion is not desired or feasible, intermittent administration of midazolam, diazepam, lorazepam or chlorpromazine may be considered. Provided that it is used under the right circumstances, palliative sedation does not shorten life.

Quality of life after pelvic exenteration.

OBJECTIVES: Pelvic exenteration, for gynecological and urological cancer, is an extensive and mutilating procedure. The 5-year survival rate is fairly good (40-60%), but little is known about the long-term quality of life. METHODS: In this retrospective cohort study, the quality of life was assessed using the EORTC QLQ-C30 (version 3.0) and the EORTC QLQ-OV28 questionnaires. RESULTS: Healthy females and those who underwent pelvic exenteration for a gynecological or urological malignancy reported comparable levels of emotional functioning and general quality of life. More physical, sexual, and social problems were, however, noted after exenteration. Younger patients and patients who underwent total pelvic exenteration had the most difficulty in adapting to daily life, disease, and treatment. They also had a worse body image, and the influence of the operation on their sex life was greater compared to other patient groups of this study. CONCLUSION: Despite the immense effect of pelvic exenteration on physical, sexual, and social functioning, women who underwent this procedure reported similar levels of emotional functioning and general quality of life compared to healthy women. Adaptation and the mechanism of response shift presumably play an important role.

The content and amount of information given by medical oncologists when telling patients with advanced cancer what their treatment options are. palliative chemotherapy and watchful-waiting.

This study aimed to determine the content and the amount of information given by medical oncologists when proposing palliative chemotherapy and whether this information given is influenced by patient or physician background characteristics. In a prospective study, 95 patients with incurable cancer were interviewed before they consulted their medical oncologist. Their first consultation was audiotaped, and their eventual decision scored. A coding scheme comprised six categories of information given during the consultation. Medical oncologists mentioned or explained the disease course (53%), symptoms (35%) and prognosis (39%). Most patients were told about the absence of cure (84%). Watchful-waiting was mentioned to only half of the patients, either in one sentence (23%) or explained more extensively (27%). Multilevel analysis revealed that the patients' age, patient's marital status, and consulting in an academic hospital explained 38% of the amount of information given. Most of the physicians' attention is spent on the 'active' treatment option. Older patients, married patients and patients in academic hospitals receive more information.

Palliative chemotherapy or best supportive care? A prospective study explaining patients' treatment preference and choice.

In palliative cancer treatment, the choice between palliative chemotherapy and best supportive care may be difficult. In the decision-making process, giving information as well as patients' values and preferences become important issues. Patients, however, may have a treatment preference before they even meet their medical oncologist. An insight into the patient's decision-making process can support clinicians having to inform their patients. Patients (n=207) with metastatic cancer, aged 18 years or older, able to speak Dutch, for whom palliative chemotherapy was a treatment option, were eligible for the study. We assessed the following before they consulted their medical oncologist: (1) socio-demographic characteristics, (2) disease-related variables, (3) quality-of-life indices, (4) attitudes and (5) preferences for treatment, information and participation in decision-making. The actual treatment decision, assessed after it had been made, was the main study outcome. Of 207 eligible patients, 140 patients (68%) participated in the study. At baseline, 68% preferred to undergo chemotherapy rather than wait watchfully. Eventually, 78% chose chemotherapy. Treatment preference (odds ratio (OR)=10.3, confidence interval (CI) 2.8-38.0) and a deferring style of decision-making (OR=4.9, CI 1.4-17.2) best predicted the actual treatment choice. Treatment preference (total explained variance=38.2%) was predicted, in turn, by patients' striving for length of life (29.5%), less striving for quality of life (6.1%) and experienced control over the cause of disease (2.6%). Patients' actual treatment choice was most strongly predicted by their preconsultation treatment preference. Since treatment preference is positively explained by striving for length of life, and negatively by striving for quality of life, it is questionable whether the purpose of palliative treatment is made clear. This, paradoxically, emphasises the need for further attention to the process of information giving and shared decision-making.

A prospective quality of life study in patients with locally advanced prostate cancer, treated with radiotherapy with or without regional or interstitial hyperthermia.

INTRODUCTION: The aim of this prospective study was to describe quality of life (QoL) in patients with locally advanced prostate carcinoma treated with conventional radiotherapy and to evaluate the influence of adding regional or interstitial hyperthermia. MATERIALS AND METHODS: All patients were irradiated using a CT-planned conventional three field technique, administering 70 Gy to prostate and vesicles. In two different phase I studies, hyperthermia was added to the radiotherapy. Twelve patients were treated with one interstitial hyperthermia treatment, lasting 60 min. Fourteen patients have been treated with five regional hyperthermia treatments, lasting 75 min each. In both hyperthermia studies, the body, bladder and rectum temperatures remained below safety limits. Patients treated with radiotherapy alone (n = 58) or combined with regional (n = 8) or interstitial hyperthermia (n = 12) completed the European Organization for Research and Treatment of Cancer (EORTC) core questionnaire (C30 + 3), the EORTC prostate cancer module (PR25) and the Rand 36 health survey before treatment and 1 and 6 months after completion of treatment. Analysis of Variance (ANOVA) for repeated measurements has been performed to describe the data. RESULTS: All patient groups were comparable concerning patient characteristics. No significant interaction or difference in QoL has been noticed between the two hyperthermia patient groups and the patient group without hyperthermia. Therefore, all groups were analysed together (n = 78) to detect QoL changes in time. A deterioration of QoL has been measured from baseline to 1 month after treatment. Fatigue, pain, urinary symptoms, bowel symptoms and financial difficulties increased significantly. Social, physical and role functioning worsened significantly. No differences in QoL were measured 6 months after treatment compared to the baseline measurement, except for a decrease in sexual activity. CONCLUSIONS: After radiotherapy with or without hyperthermia only a temporary deterioration of QoL occurs, concerning social, psychological and disease related symptoms. Additional hyperthermia does not seem to decrease QoL.

Palliative chemotherapy or watchful waiting? A vignettes study among oncologists.

PURPOSE: To determine the preferences of oncologists for palliative chemotherapy or watchful waiting and the factors considered important to that preference. METHODS: Sixteen vignettes (paper case descriptions), varying on eight patient and treatment characteristics, were designed to assess the oncologists' preferences. Their strength of preference was rated on a 7-point scale. An orthogonal main effects design provided a subset of all possible combinations of the characteristics, allowing estimations of the relative weights of the presented characteristics. A written questionnaire was sent to a random sample of oncologists (N = 1,235). RESULTS: The response rate was 67%, and 697 questionnaires were available for analysis. Eighty-one percent of the respondents were male. The mean age was 46 years. We found considerable variation among the oncologists. No major associations between physician characteristics and preferences were found. Of the patient and treatment characteristics affecting treatment preference, age was the strongest predictor, followed by the patient's wish to be treated and the expected survival gain. Other patient and treatment characteristics had a limited effect on preferences, except for psychologic distress, which had no independent impact. CONCLUSION: Patients will encounter different decisions depending on their oncologists' preferences and their own personal background. Therefore, to ensure adequate information for decision-making processes, decision aids are proposed.