Quality of life is significantly associated with survival in women with advanced epithelial ovarian cancer: An ancillary data analysis of the NRG Oncology/Gynecologic Oncology Group (GOG-0218) study.

OBJECTIVE: Evaluate association between baseline quality of life (QOL) and changes in QOL measured by FACT-O TOI with progression-free disease (PFS) and overall survival (OS) in advanced epithelial ovarian cancer (EOC). METHODS: Patients enrolled in GOG-0218 with completed FACT-O TOI assessments at baseline and at least one follow-up assessment were eligible. Baseline FACT-O TOI scores were sorted by quartiles (Q1-4) and outcomes compared between Q1 and Q2-4 with log-rank statistic and multivariate Cox regression adjusting for age, stage, post-surgical residual disease size, and performance status (PS). Trends in FACT-O TOI scores from baseline to the latest follow-up assessment were evaluated for impact on intragroup (Q1 or Q2-4) outcome by log-rank analysis. RESULTS: Of 1152 eligible patients, 283 formed Q1 and 869 formed Q2-4. Mean baseline FACT-O TOI scores were 47.5 for Q1 vs. 74.7 for Q2-4 (P<0.001). Q1 compared to Q2-4 had worse median OS (37.5 vs. 45.6months, P=0.001) and worse median PFS (12.5 vs. 13.1months, P=0.096). Q2-4 patients had decreased risks of disease progression (HR 0.974, 95% CI 0.953-0.995, P=0.018), and death (HR 0.963, 95% CI 0.939-0.987, P=0.003) for each five-point increase in baseline FACT-O TOI. Improving versus worsening trends in FACT-O TOI scores were associated with longer median PFS (Q1: 12.7 vs. 8.6months, P=0.001; Q2-4: 16.7 vs. 11.1months, P<0.001) and median OS (Q1: 40.8 vs. 16months, P<0.001; Q2-4: 54.4 vs. 33.6months, P<0.001). CONCLUSIONS: Baseline FACT-O TOI scores were independently prognostic of PFS and OS while improving compared to worsening QOL was associated with significantly better PFS and OS in women with EOC.

Effect of nivolumab on health-related quality of life in patients with treatment-naïve advanced melanoma: results from the phase III CheckMate 066 study.

BACKGROUND: Nivolumab has shown significant survival benefit and a favorable safety profile compared with dacarbazine chemotherapy among treatment-naïve patients with metastatic melanoma in the CheckMate 066 phase III study. Results from the health-related quality of life (HRQoL) analyses from CheckMate 066 are presented. PATIENTS AND METHODS: HRQoL was evaluated at baseline and every 6 weeks while on treatment using the European Organisation for Research and Treatment of Care (EORTC) Core Quality of Life Questionnaire (QLQ-C30) and the EuroQoL Five Dimensions Questionnaire (EQ-5D). Via a multi-step statistical plan, data were analyzed descriptively, cross-sectionally, and longitudinally, adjusting for baseline covariates, in patients having baseline plus ≥1 post-baseline assessment. RESULTS: Baseline-adjusted completion rates for all HRQoL questionnaires across treatment arms were 65% and 70% for dacarbazine and nivolumab, respectively, and remained similar throughout treatment. The mean baseline HRQoL scores were similar for patients treated with nivolumab and dacarbazine. Baseline HRQoL levels with nivolumab were maintained over time. This exploratory analysis showed a between-arm difference in favor of nivolumab on the EQ-5D utility index and clinically meaningful EQ-5D improvements from baseline at several time points for patients receiving nivolumab. Patients treated with nivolumab did not show increased symptom burden as assessed by the EORTC QLQ-C30. No HRQoL change was noted with dacarbazine patients up to week 43, although the high attrition rate after week 13 did not allow any meaningful analyses. Patients receiving nivolumab deteriorated significantly later than those receiving dacarbazine on several EORTC QLQ-C30 scales and the EQ-5D utility index. CONCLUSIONS: In addition to prolonged survival, these exploratory HRQoL results show that nivolumab maintains baseline HRQoL levels to provide long-term quality of survival benefit, compared with dacarbazine in patients with advanced melanoma.

Patient experience in the treatment of metastatic castration-resistant prostate cancer: state of the science.

BACKGROUND: Contemporary therapies for metastatic castration-resistant prostate cancer (mCRPC) have shown survival improvements, which do not account for patient experience and health-related quality of life (HRQoL). METHODS: This literature review included a search of MEDLINE for randomized clinical trials enrolling ⩾50 patients with mCRPC and reporting on patient-reported outcomes (PROs) since 2010. RESULTS: Nineteen of 25 publications describing seven treatment regimens (10 clinical trials and nine associated secondary analyses) met the inclusion criteria and were critically appraised. The most commonly used measures were the Functional Assessment of Cancer Therapy-Prostate (n=5 trials) and Brief Pain Inventory Short Form (n=4 trials) questionnaires. The published data indicated that HRQoL and pain status augmented the clinical efficacy data by providing a better understanding of treatment impact in mCRPC. Abiraterone acetate and prednisone, enzalutamide, radium-223 dichloride and sipuleucel-T offered varying levels of HRQoL benefit and/or pain mitigation versus their respective comparators, whereas three treatments (mitoxantrone, estramustine phosphate and docetaxel, and cabazitaxel) had no meaningful impact on HRQoL or pain. The main limitation of the data were that the PROs utilized were not developed for use in mCRPC patients and hence may not have comprehensively captured symptoms important to this population. CONCLUSIONS: Recently published randomized clinical trials of new agents for mCRPC have captured elements of the patient experience while on treatment. Further research is required to standardize methods for measuring, quantifying and reporting on HRQoL and pain in patients with mCRPC in the clinical practice setting.

Risk stratification, treatment selection, and transplant eligibility in multiple myeloma: a qualitative study of the perspectives and self-reported practices of oncologists.

BACKGROUND: Since the early 2000s, treatment options for multiple myeloma have rapidly expanded, adding significant complexity to the management of this disease. To our knowledge, no systematic qualitative research on clinical decision-making in multiple myeloma has been published. We sought to characterize how physicians view and implement guidelines and incorporate novel approaches into patient care. METHODS: We designed a semi-structured qualitative interview guide informed by literature review and an expert advisory panel. We conducted 60-minute interviews with a diverse sample of oncology physicians in the southeast United States. We used a constant comparative method to code and analyze interview transcripts. The research team and advisory panel discussed and validated emergent themes. RESULTS: Participants were 13 oncologists representing 5 academic and 4 community practices. Academic physicians reported using formal risk-stratification schemas; community physicians typically did not. Physicians also described differences in eligibility criteria for transplantation; community physicians emphasized distance, social support, and psychosocial capacity in making decisions about transplantation referral; the academic physicians reported using more specific clinical criteria. All physicians reported using a maintenance strategy both for post-transplant and for transplant-ineligible patients; however, determining the timing of maintenance therapy initiation and the response were reported as challenging, as was recognition or definition of relapse, especially in terms of when treatment re-initiation is indicated. CONCLUSIONS: Practices reported by both academic and community physicians suggest opportunities for interventions to improve patient care and outcomes through optimal multiple myeloma management and therapy selection. Community physicians in particular might benefit from targeted education interventions about risk stratification, transplant eligibility, and novel therapies.

Best supportive care in clinical trials: review of the inconsistency in control arm design.

BACKGROUND: Best supportive care (BSC) as a control arm in clinical trials is poorly defined. We conducted a review to evaluate clinical trials' concordance with published, consensus-based framework for BSC delivery in trials. METHODS: A consensus-based Delphi panel previously identified four key domains of BSC delivery in trials: multidisciplinary care; supportive care documentation; symptom assessment; and symptom management. We reviewed trials including BSC control arms from 2002 to 2014 to assess concordance to BSC standards and to selected items from the CONSORT 2010 guidelines. RESULTS: Of 408 articles retrieved, we retained 18 after applying exclusion criteria. Overall, trials conformed to the CONSORT guidelines better than the BSC standards (28% vs 16%). One-third of articles offered a detailed description of BSC, 61% reported regular symptom assessment, and 44% reported using validated symptom assessment measures. One-third reported symptom assessment at identical intervals in both arms. None documented evidence-based symptom management. No studies reported educating patients about symptom management or goals of therapy. No studies reported offering access to palliative care specialists. CONCLUSIONS: Reporting of BSC in trials is incomplete, resulting in uncertain internal and external validity. Such studies risk systematically over-estimating the net clinical effect of the comparator arms.

Prescribing for comorbid disease in a palliative population: focus on the use of lipid-lowering medications.

BACKGROUND: The balance of benefit versus burden of ongoing treatments for comorbid disease in palliative populations as death approaches needs careful consideration given their particular susceptibility to adverse drug effects. AIM: To provide descriptive data regarding the medications being prescribed to patients who have a life-limiting illness at the time of referral to a palliative care service in regional Australia, with particular focus on lipid-lowering medications. METHODS: A prospective case note review of 203 patients reporting the number of medications prescribed and, for lipid-lowering medications, the indication and level of prevention sought (primary, secondary, tertiary). Rates were compared by performance status, disease phase and comorbidity burden. RESULTS: Mean number of regular medications prescribed was 7.2, with higher rates observed in those patients with a non-malignant primary diagnosis (rate ratio 1.28, confidence interval (CI) 1.11-1.50) or poorer performance status (rate ratio 1.37, CI 1.11-1.69) and lower rates for those in the terminal phase of disease (rate ratio 0.48, CI 0.30-0.76). Over one fifth of patients were prescribed a lipid-lowering medication, and two fifths of these prescriptions were for primary prevention of cardiovascular disease. Patients in the highest quartile of Charlson Comorbidity Index score were 4.6 (CI 2.06-10.09) times more likely to be prescribed a lipid-lowering medication than those in the lowest quartile. CONCLUSIONS: Polypharmacy is prevalent for this group of patients, placing them at high risk of drug-drug and drug-host interactions. Prescribing may be driven by risk factors and disease guidelines rather than a rational, patient-centred approach.

Cardiopulmonary fitness in patients undergoing hematopoietic SCT: a pilot study.

Hematopoietic cell transplantation (HCT) is a life-saving treatment for patients with high-risk hematological malignancies. Prognostic measures to determine fitness for HCT are needed to inform decision-making and interventions. VO(2peak) is obtained by measuring gas exchange during cycle ergometry and has not been studied as a prognostic factor in HCT. Thirty-two autologous and allogeneic HCT patients underwent VO(2peak) and 6 Minute Walk (6MW) testing before HCT, and provided weekly symptom and health-related quality of life (HRQOL) assessments before HCT and concluding at Day 100. Twenty-nine patients completed pre-HCT testing. Pre-HCT VO(2peak) was positively correlated with pre-HCT 6MW (r=0.65, P<0.001) and negatively correlated with number of chemotherapy regimens and months of chemotherapy. Patients with lower VO(2peak) reported higher symptom burden and inferior HRQOL at baseline and during early post-HCT period. Patients with pre-HCT VO(2peak) <16 mL/kg/min had higher risk of mortality post HCT (entire cohort: hazard ratio (HR) 9.1 (1.75-47.0), P=0.01; allogeneic HCT patients only: HR 6.70 (1.29-34.75), P=0.02) and more hospitalized days before Day 100 (entire cohort: median 33 vs 19, P=0.003; allogeneic HCT patients only: median 33 vs 21, P=0.004). VO(2peak) pre-HCT is feasible and might predict symptom severity, HRQOL and mortality. Additional studies are warranted.

Investment of palliative medicine in bridging the gap with academia: a call to action.

Palliative care and palliative medicine define a relatively new medical discipline that has arisen in response to the need for better approaches to caring for people with advanced life-limiting illnesses. For professional, managerial and cultural reasons, it has evolved largely outside of academic structures. As the discipline has matured, its needs for education, training, intellectual discourse, evidence development and new science have become more apparent. Traditional academia remains sceptical about the role of palliative medicine, and bastions of palliative medicine expertise in universities have been slow to develop. Yet the engagement of the academic sector in palliative medicine has distinct benefits: (1) promoting the exploration of the culture, humanities and science of the discipline; (2) generating evidence to support practice; (3) creating a legion of educators to train a palliative medicine workforce and to inform clinical colleagues of the role of palliative medicine; and (4) providing order and direction to the discipline's development. A roadmap leading to better engagement between palliative medicine and academia is needed. Examples of developments that could help bridge the two domains include: standardisation of terminology and clarification of boundaries of influence; focus on high-quality research that will generate robust evidence to support clinical decision-making; and clear definition of outcomes, with measures that are understandable across medical disciplines.

Does palliative home oxygen improve dyspnoea? A consecutive cohort study.

Palliative oxygen for refractory dyspnoea is frequently prescribed, even when the criteria for long-term home oxygen (based on survival, rather than the symptomatic relief of breathlessness) are not met. Little is known about how palliative home oxygen affects symptomatic breathlessness. A 4-year consecutive cohort from a regional community palliative care service in Western Australia was used to compare baseline breathlessness before oxygen therapy with dyspnoea sub-scales on the symptom assessment scores (SAS; 0-10) 1 and 2 weeks after the introduction of oxygen. Demographic and clinical characteristics of people who responded were included in a multi-variable logistic regression model. Of the study population (n = 5862), 21.1% (n = 1239) were prescribed oxygen of whom 413 had before and after data that could be included in this analysis. The mean breathlessness before home oxygen was 5.3 (SD 2.5; median 5; range 0-10). There were no significant differences overall at 1 or 2 weeks (P = 0.28) nor for any diagnostic sub-groups. One hundred and fifty people (of 413) had more than a 20% improvement in mean dyspnoea scores. In multi-factor analysis, neither the underlying diagnosis causing breathlessness nor the demographic factors predicted responders at 1 week. Oxygen prescribed on the basis of breathlessness alone across a large population predominantly with cancer does not improve breathlessness for the majority of people. Prospective randomised trials in people with cancer and non-cancer are needed to determine whether oxygen can reduce the progression of breathlessness compared to a control arm.

Changes in anticholinergic load from regular prescribed medications in palliative care as death approaches.

Although there is an understandable emphasis on the side effects of individual medications, the cumulative effects of medications have received little attention in palliative care prescribing. Anticholinergic load reflects a cumulative effect of medications that may account for several symptoms and adverse health outcomes frequently encountered in palliative care. A secondary analysis of 304 participants in a randomised controlled trial had their cholinergic load calculated using the Clinician-Rated Anticholinergic Scale (modified version) longitudinally as death approached from medication data collected prospectively by study nurses on each visit. Mean time from referral to death was 107 days, and mean 4.8 visits were conducted in which data were collected. Relationships to key factors were explored. Data showed that anticholinergic load rose as death approached because of increasing use of medications for symptom control. Symptoms significantly associated with increasing anticholinergic load included dry mouth and difficulty concentrating (P < 0.05). There were also significant associations with increasing anticholinergic load and decreasing functional status (Australia-modified Karnofsky Performance Scale; and quality of life (P < 0.05). This study has documented in detail the longitudinal anticholinergic load associated with medications used in a palliative care population between referral and death, demonstrating the biggest contributor to anticholinergic load in a palliative care population is from symptom-specific medications, which increased as death approached.

Preference for place of care and place of death in palliative care: are these different questions?

Place of death is at times suggested as an outcome for palliative care services. This study aimed to describe longitudinal preferences for place of care and place of death over time for patients and their caregivers. Longitudinal paired data of patient/caregiver dyads from a prospective unblinded cluster randomised control trial were used. Patients and caregivers were separately asked by the palliative care nurse their preference at that time for place of care and place of death. Longitudinal changes over time for both questions were mapped; patterns of agreement (patient and caregiver; and preference for place of death when last asked and actual placed of death) were analysed with kappa statistics. Seventy-one patient/caregiver dyads were analysed. In longitudinal preferences, preferences for both the place of care (asked a mean of >6 times) and place of death (asked a mean of >4 times) changed for patients (28% and 30% respectively) and caregivers (31% and 30%, respectively). In agreement between patients and caregivers, agreement between preference of place of care and preferred place of death when asked contemporaneously for patients and caregivers was low [56% (kappa 0.33) and 36% (kappa 0.35) respectively]. In preference versus actual place of death, preferences were met for 37.5% of participants for home death; 62.5% for hospital; 76.9% for hospice and 63.6% for aged care facility. This study suggests that there are two conversations: preference for current place of care and preference for care at the time of death. Place of care is not a euphemism for place of death; and further research is needed to delineate these. Patient and caregiver preferences may not change simultaneously. Implications of any mismatch between actual events and preferences need to be explored.

Oxygen for relief of dyspnoea in mildly- or non-hypoxaemic patients with cancer: a systematic review and meta-analysis.

The aim of this study was to determine the efficacy of palliative oxygen for relief of dyspnoea in cancer patients. MEDLINE and EMBASE were searched for randomised controlled trials, comparing oxygen and medical air in cancer patients not qualifying for home oxygen therapy. Abstracts were reviewed and studies were selected using Cochrane methodology. The included studies provided oxygen at rest or during a 6-min walk. The primary outcome was dyspnoea. Standardised mean differences (SMDs) were used to combine scores. Five studies were identified; one was excluded from meta-analysis due to data presentation. Individual patient data were obtained from the authors of the three of the four remaining studies (one each from England, Australia, and the United States). A total of 134 patients were included in the meta-analysis. Oxygen failed to improve dyspnoea in mildly- or non-hypoxaemic cancer patients (SMD=-0.09, 95% confidence interval -0.22 to 0.04; P=0.16). Results were stable to a sensitivity analysis, excluding studies requiring the use of imputed quantities. In this small meta-analysis, oxygen did not provide symptomatic benefit for cancer patients with refractory dyspnoea, who would not normally qualify for home oxygen therapy. Further study of the use of oxygen in this population is warranted given its widespread use.

Conflict associated with decisions to limit life-sustaining treatment in intensive care units.

OBJECTIVE: To determine the incidence and nature of interpersonal conflicts that arise when patients in the intensive care unit are considered for limitation of life-sustaining treatment. DESIGN: Qualitative analysis of prospectively gathered interviews. SETTING: Six intensive care units at a university medical center. PARTICIPANTS: Four hundred six physicians and nurses who were involved in the care of 102 patients for whom withdrawal or withholding of treatment was considered. MEASUREMENTS: Semistructured interviews addressed disagreements during life-sustaining treatment decision making. Two raters coded transcripts of the audiotaped interviews. MAIN RESULTS: At least 1 health care provider in 78% of the cases described a situation coded as conflict. Conflict occurred between the staff and family members in 48% of the cases, among staff members in 48%, and among family members in 24%. In 63% of the cases, conflict arose over the decision about life-sustaining treatment itself. In 45% of the cases, conflict occurred over other tasks such as communication and pain control. Social issues caused conflict in 19% of the cases. CONCLUSIONS: Conflict is more prevalent in the setting of intensive care decision making than has previously been demonstrated. While conflict over the treatment decision itself is most common, conflict over other issues, including social issues, is also significant. By identifying conflict and by recognizing that the treatment decision may not be the only conflict present, or even the main one, clinicians may address conflict more constructively.

Families looking back: one year after discussion of withdrawal or withholding of life-sustaining support.

OBJECTIVE: To identify critical psychosocial supports and areas of conflict for families of intensive care unit (ICU) patients during decisions to withdraw or withhold life-sustaining treatment. DESIGN: Cross-sectional survey. SETTING: Six intensive care units in a tertiary care academic medical center. PARTICIPANTS: Forty-eight family members, one per case, of patients previously hospitalized in the ICU who had been considered for withdrawal or withholding of life-sustaining treatment. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two raters coded transcripts of audiotaped interviews with family members about their experiences in the ICU and the decision-making process for withdrawing or withholding life-sustaining treatment. Codes identified sources of conflict and personal, institutional, and staff supports on which families relied during the decision-making process. Forty-six percent of respondents perceived conflict during their family member's ICU stay; the vast majority of conflicts were between themselves and the medical staff and involved communication or perceived unprofessional behavior (such as disregarding the primary caregiver in treatment discussions). Sixty-three percent of family members previously had spoken with the patient about his or her end-of-life treatment preferences, which helped to lessen the burden of the treatment decision. Forty-eight percent of family members reported the reassuring presence of clergy, and 27% commented on the need for improved physical space to have family discussion and conferences with physicians. Forty-eight percent of family members singled out their attending physician as the preferred source of information and reassurance. CONCLUSIONS: Many families perceived conflict during end-of-life treatment discussions in the ICU. Conflicts centered on communication and behavior of staff. Families identified pastoral care and prior discussion of treatment preferences as sources of psychosocial support during these discussions. Families sought comfort in the identification and contact of a "doctor-in-charge." ICU policies such as family conference rooms and lenient visitation accommodate families during end-of-life decision-making.