Timing of Palliative Care Referral Before and After Evidence from Trials Supporting Early Palliative Care.

BACKGROUND: Evidence from randomized controlled trials has demonstrated benefits in quality of life outcomes from early palliative care concurrent with standard oncology care in patients with advanced cancer. We hypothesized that there would be earlier referral to outpatient palliative care at a comprehensive cancer center following this evidence. MATERIALS AND METHODS: Administrative databases were reviewed for two cohorts of patients: the pre-evidence cohort was seen in outpatient palliative care between June and November 2006, and the post-evidence cohort was seen between June and November 2015. Timing of referral was categorized, according to time from referral to death, as early (>12 months), intermediate (>6 months to 12 months), and late (≤6 months from referral to death). Univariable and multivariable ordinal logistic regression analyses were used to determine demographic and medical factors associated with timing of referral. RESULTS: Late referrals decreased from 68.8% pre-evidence to 44.8% post-evidence; early referrals increased from 13.4% to 31.1% (p < .0001). The median time from palliative care referral to death increased from 3.5 to 7.0 months (p < .0001); time from diagnosis to referral was also reduced (p < .05). On multivariable regression analysis, earlier referral to palliative care was associated with post-evidence group (p < .0001), adjusting for shorter time since diagnosis (p < .0001), referral for pain and symptom management (p = .002), and patient sex (p = .04). Late referrals were reduced to <50% in the breast, gynecological, genitourinary, lung, and gastrointestinal tumor sites. CONCLUSIONS: Following robust evidence from trials supporting early palliative care for patients with advanced cancer, patients were referred substantially earlier to outpatient palliative care. IMPLICATIONS FOR PRACTICE: Following published evidence demonstrating the benefit of early referral to palliative care for patients with advanced cancer, there was a substantial increase in early referrals to outpatient palliative care at a comprehensive cancer center. The increase in early referrals occurred mainly in tumor sites that have been included in trials of early palliative care. These results indicate that oncologists' referral practices can change if positive consequences of earlier referral are demonstrated. Future research should focus on demonstrating benefits of early palliative care for tumor sites that have tended to be omitted from early palliative care trials.

Systemic Anti-Cancer Therapy Use in Palliative Care Outpatients With Advanced Cancer.

PURPOSE: To evaluate factors associated with continuation of systemic anti-cancer therapy (SACT) after palliative care consultation, and SACT administration in the last 30 days of life, in outpatients with cancer referred to palliative care. Timing of referral was of particular interest. METHODS: Patient, disease, and treatment-related factors associated with SACT before and after palliative care, and in the last 30 days of life, were identified using 3-level multinomial logistic regression. Referral to palliative care was categorized by time from death as early (>12 months), intermediate (6-12 months), and late (≤6 months). RESULTS: Of the 337 patients, 240 (71.2%) received SACT for advanced cancer; of these, 126 (52.5%) received SACT only prior to palliative care while 114 (47.5%) also received SACT afterward. Only 35/337 (10.4%) received SACT in the last 30 days of life. On multivariable analysis, factors associated with continuing SACT after palliative care consultation were a cancer diagnosis for <1 year (OR 3.09, p = 0.01), breast primary (OR 11.88, p = 0.0008), and early (OR 28.8, p < 0.001) or intermediate (OR 6.67, p < 0.001) referral timing. No factors were significantly associated with receiving SACT in the last 30 days versus earlier, but the median time from palliative care referral to death in those receiving SACT in the last 30 days versus stopping SACT earlier was 1.78 versus 4.27 months. CONCLUSION: Patients who received SACT following palliative care consultation were more likely to be referred early; however, patients receiving SACT in their last 30 days tended to be referred late.

Optimal sequencing of enzalutamide and abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase 2, crossover trial.

BACKGROUND: Abiraterone acetate plus prednisone and enzalutamide are both used for the treatment of metastatic castration-resistant prostate cancer. We aimed to determine the best sequence in which to use both drugs, as well as their second-line efficacy. METHODS: In this multicentre, randomised, open-label, phase 2, crossover trial done in six cancer centres in British Columbia, Canada, we recruited patients aged 18 years or older with newly-diagnosed metastatic castration-resistant prostate cancer without neuroendocrine differentiation and Eastern Cooperative Oncology Group performance status 2 or less. Patients were randomly assigned (1:1) using a computer-generated random number table to receive either abiraterone acetate 1000 mg orally once daily plus prednisone 5 mg orally twice daily until PSA progression followed by crossover to enzalutamide 160 mg orally once daily (group A), or the opposite sequence (group B). Treatment was not masked to investigators or participants. Primary endpoints were time to second PSA progression and PSA response (≥30% decline from baseline) on second-line therapy, analysed by intention-to-treat in all randomly assigned patients and in patients who crossed over, respectively. The trial is registered with ClinicalTrials.gov, NCT02125357. FINDINGS: Between Oct 21, 2014, and Dec 13, 2016, 202 patients were enrolled and randomly assigned to either group A (n=101) or group B (n=101). At the time of data cutoff, 73 (72%) patients in group A and 75 (74%) patients in group B had crossed over. Time to second PSA progression was longer in group A than in group B (median 19·3 months [95% CI 16·0-30·5] vs 15·2 months [95% CI 11·9-19·8] months; hazard ratio 0·66, 95% CI 0·45-0·97, p=0·036), at a median follow-up of 22·8 months (IQR 10·3-33·4). PSA responses to second-line therapy were seen in 26 (36%) of 73 patients for enzalutamide and three (4%) of 75 for abiraterone (χ2 p<0·0001). The most common grade 3-4 adverse events throughout the trial were hypertension (27 [27%] of 101 patients in group A vs 18 [18%] of 101 patients in group B) and fatigue (six [10%] vs four [4%]). Serious adverse events were reported in 15 (15%) of 101 patients in group A and 20 (20%) of 101 patients in group B. There were no treatment-related deaths. INTERPRETATION: Enzalutamide showed activity as a second-line novel androgen receptor pathway inhibitor, whereas abiraterone acetate did not, leading to a longer time to second PSA progression for the sequence of abiraterone followed by enzalutamide than with the opposite treatment sequence. Our data suggest that using a sequencing strategy of abiraterone acetate followed by enzalutamide provides the greatest clinical benefit. FUNDING: Canadian Cancer Society Research Institute, Prostate Cancer Canada, Movember Foundation, Prostate Cancer Foundation, Terry Fox New Frontiers Program, BC Cancer Foundation, Jane and Aatos Erkko Foundation, Janssen, and Astellas.

Factors Associated with Early Referral to Palliative Care in Outpatients with Advanced Cancer.

BACKGROUND: Although timely palliative care is recommended for patients with advanced cancer, referrals to palliative care services are often late. OBJECTIVES: To identify factors associated with early referral to an oncology palliative care clinic and to describe symptom severity according to timing of referral. DESIGN: We conducted a retrospective review of 337 patients with advanced cancer referred to outpatient palliative care at a comprehensive cancer center. We gathered data related to patient demographics, diagnosis, and referral. Timing of referral was categorized as early (>12 months before death), intermediate (6-12 months before death), or late (<6 months before death). Ordinal logistic regression was used to determine factors related to referral timing, and the Kruskal-Wallis test to determine symptom severity in each referral timing category. RESULTS: Of the 337 patients, 232 (69%) referrals were late, 60 (18%) intermediate, and 45 (13%) early. On multivariable analysis, earlier referral was associated with earlier primary cancer diagnosis (p = 0.004), and referral for pain and symptom management (p = 0.001). Patients who were referred late had worse overall Edmonton Symptom Assessment System distress scores, as well as worse tiredness, nausea, drowsiness, appetite, and wellbeing (all p ≤ 0.001). Severity of pain, shortness of breath, anxiety, and depression did not differ based on time of referral. CONCLUSIONS: A longer disease course and referral for symptom management were associated with earlier referral, whereas overall symptom burden was higher for late referrals. Further research is required on combining symptom screening with timely referral to improve symptom management in advanced cancer.

Quality of life and mental health in caregivers of outpatients with advanced cancer.

OBJECTIVE: This study evaluates the quality of life (QOL) and mental health (MH) of caregivers of patients with advanced cancer who are receiving ambulatory oncology care and associations with patient, caregiver and care-related characteristics. METHODS: Patients with advanced gastrointestinal, genitourinary, breast, lung or gynaecologic cancer, and their caregivers, were recruited from 24 medical oncology clinics for a cluster-randomized trial of early palliative care. Caregivers completed the Caregiver QOL--Cancer scale and the Medical Outcomes Study Short Form, version 2, and a questionnaire including care-related factors such as hours/day providing care and change in work situation. Patients completed a demographic questionnaire and measures of their QOL and symptom severity. Associations of these factors with caregiver QOL and MH were examined using linear regression analyses. RESULTS: Of the 191 caregivers, 84% were spouses/partners, 90% cohabited with the patient, half were working and 25% had a change in work situation since the patient's diagnosis. On multiple regression analysis, better caregiver QOL was associated with better caregiver MH and patient physical well-being and with not providing care for other dependents. Worse caregiver MH was associated with female caregiver sex, worse patient emotional well-being, more hours spent caregiving and change in the caregiver's work situation. CONCLUSIONS: Caregivers of ambulatory patients with advanced cancer may have compromised QOL and MH associated with worse patient physical and emotional well-being and with simultaneously caring for others and working outside the home. Early palliative care interventions directed at patient symptoms and caregiver support may improve QOL in this population.

Trastuzumab mediated cardiotoxicity in the setting of adjuvant chemotherapy for breast cancer: a retrospective study.

Background The incidence and management of trastuzumab-mediated cardiotoxicity outside of clinical trials has not been well described. Objective and methods The aim of the study was to retrospectively evaluate the incidence of cardiac dysfunction, characterize its natural history, and identify the degree of reversibility using cardiac MRI, in a population of HER-2 positive breast cancer patients receiving trastuzumab in the adjuvant setting. Results Out of 152 patients (mean age 52 +/- 10 years), 36 (24%) developed trastuzumab mediated cardiomyopathy, the majority asymptomatic. Factors that predicted the development of trastuzumab mediated cardiac dysfunction were a pre-existing history of hypertension, smoking history, and a family history of coronary artery disease. Within 3 months of treatment with trastuzumab, there was a difference in LVEF between the normal cohort and those patients who developed LV systolic dysfunction (61 +/- 5% vs. 51 +/- 8%, P < 0.01). During the 6-month-followup, 34/36 patients demonstrated subepicardial linear delayed enhancement of the lateral wall of the left ventricle on cardiac MRI, suggesting trastuzumab induced myocarditis. Conclusion Approximately 1 in 4 women may develop LV systolic dysfunction after treatment with adjuvant trastuzumab, necessitating careful patient selection and close serial monitoring using noninvasive cardiac imaging.