Prophylactic Fentanyl Sublingual Spray for Episodic Exertional Dyspnea in Cancer Patients: A Pilot Double-Blind Randomized Controlled Trial.

CONTEXT: The optimal dose of fentanyl sublingual spray (FSS) for exertional dyspnea has not been determined. OBJECTIVES: We examined the effect of two doses of prophylactic FSS on exertional dyspnea. METHODS: In this parallel, dose-finding, double-blind randomized clinical trial, opioid-tolerant cancer patients completed a shuttle walk test at baseline. Patients completed a second shuttle walk test 10 minutes after a single dose of FSS equivalent to either 35%-45% (high dose) or 15%-25% (low dose) of the total daily opioid dose. The primary outcome was change in modified dyspnea Borg scale (0-10) between the first and second shuttle walk tests. Secondary outcomes included adverse events as well as changes in walk distance, vital signs, and neurocognitive function. RESULTS: Thirty of the 50 enrolled patients completed the study. High-dose FSS (n = 13) resulted in significantly lower dyspnea (mean change -1.42; 95% CI -2.37, -0.48; P = 0.007) and greater walk distance (mean change 44 m; P = 0.001) compared to baseline. Low-dose FSS (n = 17) resulted in a nonsignificant reduction in dyspnea (mean change -0.47; 95% CI -1.26, 0.32; P = 0.24) and significant increase in walk distance (mean change 24 m; P = 0.01) compared to baseline. Global evaluation showed high-dose group was more likely to report at least somewhat better improvement (64% vs. 24%; P = 0.06). No significant adverse events or detriment to vital signs or neurocognitive function was detected. CONCLUSION: Prophylactic FSS was well tolerated and demonstrated a dose-response relationship in improving both dyspnea and walk distance. High-dose FSS should be tested in confirmatory trials.

Pattern and Predictors of Outpatient Palliative Care Referral Among Thoracic Medical Oncologists.

BACKGROUND: There is significant variation in access to palliative care. We examined the pattern of outpatient palliative care referral among thoracic medical oncologists and identified oncologist characteristics associated with greater referral. MATERIALS AND METHODS: We retrieved data on all patients who died of advanced thoracic malignancies at our institution between January 1, 2007, and December 31, 2012. Using median as a cutoff, we defined two groups (high-referring and low-referring oncologists) based on their frequency of referral. We examined various oncologist- and patient-related characteristics associated with outpatient referral. RESULTS: Of 1,642 decedents, 444 (27%) had an outpatient palliative care referral. The median proportion of referral among 26 thoracic oncologists was 30% (range 9%-45%; median proportion of high-referring 37% vs. low-referring 24% when divided into two groups at median). High-referring oncologists were significantly younger (age 45 vs. 56) than low-referring oncologists; they were also significantly more likely to refer patients earlier (median interval between oncology consultation and palliative care consultation 90 days vs. 170 days) and to refer those without metastatic disease (7% vs. 2%). In multivariable mixed-effect logistic regression, younger oncologists (odds ratio [OR] = 0.97 per year increase, 95% confidence interval [CI] 0.95-0.995), younger patients (OR = 0.98 per year increase, 95% CI 0.97-0.99), and nonmetastatic disease status (OR = 0.48, 95% CI 0.29-0.78) were significantly associated with outpatient palliative care referral. CONCLUSION: The pattern of referral to outpatient palliative care varied widely among thoracic oncologists. Younger oncologists were not only referring a higher proportion of patients, but also referring patients earlier in the disease trajectory. IMPLICATIONS FOR PRACTICE: This retrospective cohort study found that younger thoracic medical oncologists were significantly more likely to refer patients to outpatient palliative care and to do so earlier in the disease trajectory compared with older oncologists, even after adjusting for other known predictors such as patient demographics. The findings highlight the role of education to standardize palliative care access and imply that outpatient palliative care referral is likely to continue to increase with a shifting oncology workforce.

Effect of Prophylactic Fentanyl Buccal Tablet on Episodic Exertional Dyspnea: A Pilot Double-Blind Randomized Controlled Trial.

CONTEXT: Episodic dyspnea is one of the most common, debilitating, and difficult-to-treat symptoms. OBJECTIVE: We conducted a pilot study to examine the effect of prophylactic fentanyl buccal tablet (FBT) on exercise-induced dyspnea. METHODS: In this parallel, double-blind randomized placebo-controlled trial, opioid-tolerant patients were asked to complete a six-minute walk test (6MWT) at baseline and then a second 6MWT 30 minutes after a single dose of FBT (equivalent to 20-50% of their total opioid dose) or matching placebo. We compared dyspnea Numeric Rating Scale (NRS, 0-10, primary outcome), walk distance, vital signs, neurocognitive function, and adverse events between the two 6MWTs. RESULTS: Among 22 patients enrolled, 20 (91%) completed the study. FBT was associated with a significant within-arm reduction in dyspnea NRS between 0 and six minutes (mean change -2.4, 95% CI -3.5, -1.3) and respiratory rate (mean change -2.6, 95% CI -4.7, -0.4). Placebo was also associated with a nonstatistically significant decrease in dyspnea (mean change -1.1). Between-arm comparison of dyspnea scores in the second 6MWT favored FBT, albeit not statistically significant (estimate -0.25, P = 0.068). Global impression revealed more patients in the FBT group than placebo group reporting their dyspnea was at least "somewhat better" in the second 6MWT (4 of 9 vs. 0 of 11, P = 0.03). The other secondary outcomes did not differ significantly between arms. CONCLUSIONS: This study supports that prophylactic FBT was associated with a reduction of exertional dyspnea and was well tolerated. Our findings support the need for larger trials to confirm the therapeutic potential of rapid-onset opioids.

Comparison of four brief depression screening instruments in ovarian cancer patients: Diagnostic accuracy using traditional versus alternative cutpoints.

OBJECTIVES: We compared the diagnostic accuracy of 4 depression screening scales, using traditional and alternative scoring methods, to the gold standard Structured Clinical Interview-DSM IV major depressive episode (MDE) in ovarian cancer patients on active treatment. METHODS: At the beginning of a new chemotherapy regimen, ovarian cancer patients completed the following surveys on the same day: the Center for Epidemiological Studies Depression Scale (CES-D), the Beck Depression Inventory Fast-Screen for Primary Care (BDI-FastScreen), the Patient Health Questionnaire-9 (PHQ-9), and a 1-item screener ("Are you depressed?"). Each instrument's sensitivity, specificity, positive predictive value (PPV) and negative predictive value were calculated with respect to major depression. To control for antidepressant use, the analyses were re-run for a subsample of patients who were not on antidepressants. RESULTS: One hundred fifty-three ovarian cancer patients were enrolled into the study. Only fourteen participants met SCID criteria for current MDE (9%). When evaluating all patients regardless of whether they were already being treated with antidepressants, the two-phase scoring approach with an alternate cutpoint of 6 on the PHQ-9 had the best positive predictive value (PPV=32%). Using a traditional cutpoint of 16 on the CES-D resulted in the lowest PPV (5%); using a more stringent cutpoint of 22 resulted in a slightly improved but still poor PPV, 7%. CONCLUSIONS: Screening with a two-phase PHQ-9 proved best overall, and its accuracy was improved when used with patients who were not already being treated with antidepressants.

Impact of Prophylactic Fentanyl Pectin Nasal Spray on Exercise-Induced Episodic Dyspnea in Cancer Patients: A Double-Blind, Randomized Controlled Trial.

CONTEXT: Episodic breathlessness is common and debilitating in cancer patients. OBJECTIVES: In this pilot study, we examined the effect of prophylactic fentanyl pectin nasal spray (FPNS) on exercise-induced dyspnea, physiologic function, and adverse events. METHODS: In this parallel, double-blind randomized placebo-controlled trial, opioid-tolerant patients performed three six-minute walk tests (6MWTs) to induce dyspnea. They were randomized to receive either FPNS (15%-25% of total daily opioid dose each time) or placebo 20 minutes before the second and third 6MWTs. We compared dyspnea Numeric Rating Scale (NRS, 0-10, primary outcome), walk distance, vital signs, neurocognitive function, and adverse events between the first and second 6MWTs (T2-T1) and between the first and third 6MWTs (T3-T1). RESULTS: Twenty-four patients enrolled, with 96% completion. FPNS was associated with significant within-arm reduction in dyspnea NRS at rest (T2-T1: -0.9 [95% CI -1.7, -0.1]; T3-T1: -1.3 [95% CI -2.0, -0.5]) and at the end of a 6MWT (T2-T1: -2.0 [95% CI -3.5, -0.6]; T3-T1: -2.3 [95% CI -4.0, -0.7]), and longer walk distance (T2-T1 +23.8 m [95% CI +1.3, +46.2 m]; T3-T1: +23.3 m [95% CI -1.7, +48.2]). In the placebo arm, we observed no significant change in walk distance nor dyspnea NRS at rest, but significant reduction in dyspnea NRS at six minutes (T2-T1: -1.7 [95% CI -3.3, -0.1]; T3-T1: -2.5 [95% CI -4.2, -0.9]). Vital signs, neurocognitive function, and adverse effects did not differ significantly. CONCLUSION: FPNS was safe, reduced dyspnea at rest, and increased walk distance in before-after comparison. The placebo effect was substantial, which needs to be factored in future study designs. TRIAL REGISTRATION: ClinicalTrials.govNCT01832402.

Dexamethasone for Dyspnea in Cancer Patients: A Pilot Double-Blind, Randomized, Controlled Trial.

CONTEXT: Dexamethasone is often used to treat dyspnea in cancer patients, but evidence is lacking. OBJECTIVES: We determined the feasibility of conducting a randomized trial of dexamethasone in cancer patients and estimated the efficacy of dexamethasone in the treatment of dyspnea. METHODS: In this double-blind, randomized, controlled trial, patients with dyspnea ≥4 were randomized to receive either dexamethasone 8 mg twice daily × four days then 4 mg twice daily × three days or placebo for seven days, followed by an open-label phase for seven days. We documented the changes in dyspnea (0-10 numeric rating scale), spirometry measures, quality of life, and toxicities. RESULTS: A total of 41 patients were randomized and 35 (85%) completed the blinded phase. Dexamethasone was associated with a significant reduction in dyspnea numeric rating scale of -1.9 (95% CI -3.3 to -0.5, P = 0.01) by Day 4 and -1.8 (95% CI -3.2 to -0.3, P = 0.02) by Day 7. In contrast, placebo was associated with a reduction of -0.7 (95% CI -2.1 to 0.6, P = 0.38) by Day 4 and -1.3 (95% CI -2.4 to -0.2, P = 0.03) by Day 7. The between-arm difference was not statistically significant. Drowsiness improved with dexamethasone. Dexamethasone was well tolerated with no significant toxicities. CONCLUSION: A double-blind, randomized, controlled trial of dexamethasone was feasible with a low attrition rate. Our preliminary data suggest that dexamethasone may be associated with rapid improvement in dyspnea and was well tolerated. Further studies are needed to confirm our findings. TRIAL REGISTRATION: ClinicalTrials.govNCT01670097.

Clinical signs of impending death in cancer patients.

BACKGROUND: The physical signs of impending death have not been well characterized in cancer patients. A better understanding of these signs may improve the ability of clinicians to diagnose impending death. We examined the frequency and onset of 10 bedside physical signs and their diagnostic performance for impending death. METHODS: We systematically documented 10 physical signs every 12 hours from admission to death or discharge in 357 consecutive patients with advanced cancer admitted to two acute palliative care units. We examined the frequency and median onset of each sign from death backward and calculated their likelihood ratios (LRs) associated with death within 3 days. RESULTS: In total, 203 of 357 patients (52 of 151 in the U.S., 151 of 206 in Brazil) died. Decreased level of consciousness, Palliative Performance Scale ≤20%, and dysphagia of liquids appeared at high frequency and >3 days before death and had low specificity (<90%) and positive LR (<5) for impending death. In contrast, apnea periods, Cheyne-Stokes breathing, death rattle, peripheral cyanosis, pulselessness of radial artery, respiration with mandibular movement, and decreased urine output occurred mostly in the last 3 days of life and at lower frequency. Five of these signs had high specificity (>95%) and positive LRs for death within 3 days, including pulselessness of radial artery (positive LR: 15.6; 95% confidence interval [CI]: 13.7-17.4), respiration with mandibular movement (positive LR: 10; 95% CI: 9.1-10.9), decreased urine output (positive LR: 15.2; 95% CI: 13.4-17.1), Cheyne-Stokes breathing (positive LR: 12.4; 95% CI: 10.8-13.9), and death rattle (positive LR: 9; 95% CI: 8.1-9.8). CONCLUSION: We identified highly specific physical signs associated with death within 3 days among cancer patients.

Adherence to preventive exercises and self-reported swallowing outcomes in post-radiation head and neck cancer patients.

BACKGROUND: To reduce the risk of long-term swallowing complications after radiation, swallowing exercises may be helpful. Both the rate of adherence to swallowing exercises and its impact on future swallowing function are unknown. METHODS: In all, 109 patients with oropharyngeal cancer beginning radiation were tracked for 2 years to determine adherence to swallowing exercises. Participants completed the MD Anderson Dysphagia Inventory (MDADI) 1-2 years after treatment, to assess self-reported swallowing function. Adherence, demographics, tumor, and treatment variables were multivariably regressed onto the MDADI physical subscale score. RESULTS: In accord with speech pathologist documentation, 13% of the participants were fully adherent and 32% were partially adherent. Adherence was associated with the Physical MDADI Subscale score in the multivariate model (p = .01). CONCLUSIONS: The majority of patients with head and neck cancer are nonadherent to swallowing exercise regimens and may benefit from supportive care strategies to optimize their adherence.

Development and cross-validation of the in-hospital mortality prediction in advanced cancer patients score: a preliminary study.

PURPOSE: Acute palliative care units (APCUs) provide intensive symptom support and transition of care for advanced cancer patients. Better understanding of the predictors of in-hospital mortality is needed to facilitate program planning and patient care. In this prospective study, we identified predictors of APCU mortality, and developed a four-item In-hospital Mortality Prediction in Advanced Cancer Patients (IMPACT) predictive model. METHODS: Between April and July 2010, we documented baseline demographics, the Edmonton Symptom Assessment Scale (ESAS), 80 clinical signs including known prognostic factors, and 26 acute complications on admission in consecutive APCU patients. Multivariate logistic regression analysis was used to identify factors for inclusion in a nomogram, which was cross-validated with bootstrap analysis. RESULTS: Among 151 consecutive patients, the median age was 58, 13 (9%) had hematologic malignancies, and 52 (34%) died in the hospital. In multivariate analysis, factors associated with in-hospital mortality were advanced education (odds ration [OR]=11.8, p=0.002), hematologic malignancies (OR=8.6, p=0.02), delirium (OR=4.3, p=0.02), and high ESAS global distress score (OR=20.8, p=0.01). In a nomogram based on these four factors, total scores of 6, 10, 14, 17, and 21 corresponded to a risk of death of 10%, 25%, 50%, 75%, and 90%, respectively. The model has 92% sensitivity and 88% specificity for predicting patients at low/high risk of dying in the hospital, and a receiver-operator characteristic curve concordance index of 83%. CONCLUSIONS: Higher education was associated with increased utilization of the interdisciplinary palliative care unit until at the end of life. Patients with higher symptom burden, delirium, and hematologic malignancies were also more likely to require APCU care until death.

Association between patient-reported symptoms and nurses' clinical impressions in cancer patients admitted to an acute palliative care unit.

BACKGROUND: Clinicians typically rely on their own or the nurses' clinical impression (NI) of symptoms rather than patient self-reports. It is unclear whether these means of assessment yield similar results. OBJECTIVE: To prospectively compare patient-reported symptoms on a modified Edmonton Symptom Assessment System (ESAS) with NI scores. METHODS: Consecutive patients with advanced cancer admitted to our acute palliative care unit between April and July 2010 were studied. We collected the results of the ESAS on the day of admission (D1) to the unit and 2 days later (D3). We also collected the NI of each patient's physical and psychological distress on D1 and D3. RESULTS: One hundred eighteen patients completed the ESAS on D1 and 116 on D3. On D1 there was no significant association between NI score and ESAS assessment except for dyspnea, which was weakly correlated with NI score for physical distress (r=0.22, p=0.02). The median ESAS physical and psychosocial scores were 31 and 12 in patients with NI of low or no physical distress, versus 34 (p=0.07) and 15 (p=0.18) in patients with NI of moderate or severe distress, respectively. On D3, we found a significant association between ESAS and NI only for pain (r=0.32, p<0.001) and anxiety (r=0.30, p=0.001). Sensitivity and specificity of the NIs for ESAS scores were low on both days. CONCLUSION: The clinical impression of highly trained palliative care nurses showed poor association with patient-reported symptom intensity. Validated symptom assessment tools are needed for bedside clinical assessment.

The accuracy of probabilistic versus temporal clinician prediction of survival for patients with advanced cancer: a preliminary report.

Clinicians have limited accuracy in the prediction of patient survival. We assessed the accuracy of probabilistic clinician prediction of survival (CPS) and temporal CPS for advanced cancer patients admitted to our acute palliative care unit, and identified factors associated with CPS accuracy. Eight physicians and 20 nurses provided their estimation of survival on admission by (a) the temporal approach, "What is the approximate survival for this patient (in days)?" and (b) the probabilistic approach, "What is the approximate probability that this patient will be alive (0%-100%)?" for ≥24 hours, 48 hours, 1 week, 2 weeks, 1 month, 3 months, and 6 months. We also collected patient and clinician demographics. Among 151 patients, the median age was 58 years, 95 (63%) were female, and 138 (81%) had solid tumors. The median overall survival time was 12 days. The median temporal CPS was 14 days for physicians and 20 days for nurses. Physicians were more accurate than nurses. A higher accuracy of temporal physician CPS was associated with older patient age. Probabilistic CPS was significantly more accurate than temporal CPS for both physicians and nurses, although this analysis was limited by the different criteria for determining accuracy. With the probabilistic approach, nurses were significantly more accurate at predicting survival at 24 hours and 48 hours, whereas physicians were significantly more accurate at predicting survival at 6 months. The probabilistic approach was associated with high accuracy and has practical implications.

Associations with worry about dying and hopelessness in ambulatory ovarian cancer patients.

OBJECTIVE: Women with ovarian cancer face a poor prognosis, with prolonged periods of treatment but relatively high levels of physical functioning. Their thoughts and feelings regarding the prospect of dying are complex and have not been adequately studied. Various demographic, medical and psychosocial factors were examined to determine their independent associations with fear of dying and hopelessness in a cross-sectional design. METHOD: Two hundred fifty-four ovarian cancer patients were assessed at the beginning of a new chemotherapy regimen. Separate logistic regressions were performed for worry about dying and loss of hope. For each analysis, psychosocial variables were entered after the demographic and medical variables to determine whether the psychosocial variables had an independent association with the respective outcome. RESULTS: Fifty-five percent of the sample acknowledged fear of dying, and 31.6% acknowledged loss of hope in the fight against their illness. Being younger (p = .001), being of non-Hispanic White ethnicity (p = .026), and having poorer physical well-being (p = .000) were significantly associated with worry about dying after controlling for all other variables in the model. Regarding loss of hope, depressive symptoms (p = .002), lack of social support/well-being (p = .001), and number of treatments (p = .04) were significant. SIGNIFICANCE OF RESULTS: This is one of the largest studies to examine end-of-life concerns in a sample of advanced cancer patients. Our results underscore the importance of demographic and psychosocial variables in the examination of ovarian cancer patients' end-of-life concerns. Their fears and concerns should be openly acknowledged, even when the clinical focus is still on curative treatment.