Survival Prediction of Patients Who Were Terminally Ill Using the EORTC QLQ-C15-PAL Scores and Laboratory Test Values.

Background: Prognostics for patients with cancer is especially important for the supportive care of those who are terminally ill. We previously found that symptom scores as patient-reported outcomes (PROs)-such as dyspnea and fatigue scores-some biochemical parameters, the palliative performance scale (PPS) scores, and symptom clusters were useful prognostic factors; however, the predictability of a prognosis based on these factors remains unclear. Objective: To identify appropriate three-week survival predictive factor(s), in terms of performance, in patients who were terminally ill. Design: We collected symptom scores as PROs using the Japanese version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 15 Palliative Care (EORTC QLQ-C15-PAL). Setting/Subjects: We used data from terminally ill patients with cancer who were hospitalized at the palliative care unit of the Higashisumiyoshi-Morimoto Hospital (Osaka, Japan) from June 2018 to December 2019 (n = 130), as well as additional data obtained from the same clinical study from January to March 2020 (n = 31). Measurements: To evaluate predictive performance, indices such as sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy were calculated. Results: We found that the presence of a symptom cluster showed high sensitivity but low specificity and that a higher PPS value (>30) showed high specificity but low sensitivity, suggesting that these factors could provide relevant information for survival prognosis (less than or equal to three weeks). Conclusion: Symptom clusters obtained from patients is important for effective supportive care of those who are terminally ill.

A Retrospective Cohort Study of Multiple Immune-Related Adverse Events and Clinical Outcomes Among Patients With Cancer Receiving Immune Checkpoint Inhibitors.

BACKGROUND AND OBJECTIVES: Immune checkpoint inhibitors (ICIs) are effective in various types of cancer and cause immune-related adverse events (irAEs). The occurrence of irAEs is associated with improved survival outcome. We investigated the association between the occurrence of irAEs and overall survival (OS) and progression free survival (PFS), and the risk factors for the development of irAEs, in patients with non-small-cell lung cancer (NSCLC), gastric cancer (GC) and melanoma (MM) treated with ICIs. METHODS: This was a retrospective observational cohort study, and the data were taken from inpatients in a hospital. OS and PFS were compared among patients with different numbers of irAEs. Log-rank test and Cox regression and logistic regression analysis were applied, and details of irAEs characteristics were summarized. RESULTS: We obtained data from 200 patients. The major tumor types were NSCLC, GC, and MM. Median OS and PFS in all patients were 9.3 and 3.5 months, respectively. Patients without irAEs tended to have shorter OS or PFS compared with those with a single irAE or multi-system irAEs. Covariate analysis suggested that age (≥75 years), albumin (≥3.5 g/dL) and smoking history were significant for increased occurrence of irAEs. Pneumonitis and thyroiditis tended to occur frequently in patients with NSCLC and MM. The irAE grade was ≤2 in 67.3% of all irAEs, and days of irAEs onset varied. CONCLUSION: We observed patients with irAEs tended to have better OS or PFS in patients with various types of cancers treated with ICIs. We suggest that ICIs should be used appropriately by continuously monitoring the irAEs.

The Occurrence of Encephalitis Due to Immune Checkpoint Inhibitors: A Pharmacovigilance Study.

PURPOSE: Immune checkpoint inhibitors (ICIs) are associated with peculiar adverse events related to the mechanism of action. Less than 1% of patients treated with ICIs develop autoimmune encephalitis. The aim of this study was to compare the frequency of encephalitis development due to ICIs with encephalitis due to other drugs using the Japanese Adverse Drug Event Report (JADER) database and Bayesian confidence propagation neural networks for signal detection. METHODS: Data from the JADER database from April 2004 to December 2020 were downloaded via the Pharmaceuticals and Medical Devices Agency (PMDA) website. The Information Component (IC) values were calculated as an index of signal detection based on the Bayesian method. RESULTS: The lower bound of the 95% credible interval (CI) of the IC values for atezolizumab and pembrolizumab were greater than 0 in most of the periods. Thus, encephalitis occurred more frequently for atezolizumab and pembrolizumab than for other drugs. For nivolumab and ipilimumab, a significant signal was detected only for recent data. In contrast, the lower bounds of the 95% CIs for avelumab and durvalumab were smaller than 0 in most of the periods because encephalitis was seldom reported for avelumab and durvalumab. CONCLUSIONS: We showed that encephalitis occurs more frequently for atezolizumab, pembrolizumab, nivolumab, and ipilimumab compared with the frequency for other drugs. The time of onset varied widely, and patients should be monitored for more than 1 year after the last administration of ICIs.

Symptom clusters and their influence on prognosis using EORTC QLQ-C15-PAL scores in terminally ill patients with cancer.

PURPOSE: The aims of the present study were to investigate the symptom clusters in terminally ill patients with cancer using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 15 Palliative Care (EORTC QLQ-C15-PAL), and to examine whether these symptom clusters influenced prognosis. METHODS: We analyzed data from 130 cancer patients hospitalized in the palliative care unit from June 2018 to December 2019 in an observational study. Principal component analysis was used to detect symptom clusters using the scored date of 14 items in the QLQ-C15-PAL, except for overall QOL, at the time of hospitalization. The influence of the existence of these symptom clusters and Palliative Performance Scale (PPS) on survival was analyzed by Cox proportional hazards regression analysis, and survival curves were compared between the groups with or without existing corresponding symptom clusters using the log-rank test. RESULTS: The following symptom clusters were identified: cluster 1 (pain, insomnia, emotional functioning), cluster 2 (dyspnea, appetite loss, fatigue, and nausea), and cluster 3 (physical functioning). Cronbach's alpha values for the symptom clusters ranged from 0.72 to 0.82. An increased risk of death was significantly associated with the existence of cluster 2 and poor PPS (log-rank test, p = 0.016 and p < 0.001, respectively). CONCLUSION: In terminally ill patients with cancer, three symptom clusters were detected based on QLQ-C15-PAL scores. Poor PPS and the presence of symptom cluster that includes dyspnea, appetite loss, fatigue, and nausea indicated poor prognosis.

Relationship between Pain Scores and EORTC QLQ-C15-PAL Scores in Outpatients with Cancer Pain Receiving Opioid Therapy.

Cancer pain is one of the most frequent and distressing symptoms associated with cancer and has a serious impact on the QOL of patients. However, inadequate pain treatment has also been reported in outpatients with cancer pain. The aims of this study were (1) to evaluate the relationship between pain intensity using the Numerical Rating Scale (NRS) and QOL scores using the Japanese version of the European Organization for Research and Treatment of Cancer (QOL Questionnaire Core 15 for Palliative Care (QLQ-C15-PAL)), and (2) to investigate their association with various pain patterns, especially with baseline and breakthrough pain. Forty outpatients who were receiving opioid therapy and obtained informed consent participated. We collected a total of 222 pharmacist consultations during the study period. Global QOL scores and pain scores (PA) in the QLQ-C15-PAL (PA score, 0-100) at the first visit were significantly correlated with worst pain intensity. In addition, the scores for the worst pain were significantly correlated with not only physical functioning scores but also with emotional functioning scores. The correlations between the worst pain NRS and PA scores were positive. Specifically, patients tended to report large variability of NRS scores when the PA score was less than 40 and also when they exhibited pain patterns with "baseline and breakthrough cancer pain in the same day" or "baseline pain throughout the day." Reducing the worst pain NRS and relieving breakthrough pain appear to be important measures to improve the QOL of outpatients receiving opioid therapy for cancer pain.

The role of EORTC QLQ-C15-PAL scores and inflammatory biomarkers in predicting survival in terminally ill patients with cancer.

BACKGROUND: The clinical use of patient-reported outcomes as compared to inflammatory biomarkers for predicting cancer survival remains a challenge in palliative care settings. We evaluated the role of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 15 Palliative scores (EORTC QLQ-C15-PAL) and the inflammatory biomarkers C-reactive protein (CRP), albumin (Alb), and neutrophil-lymphocyte ratio (NLR) for survival prediction in patients with advanced cancer. METHODS: This was an observational study in terminally ill patients with cancer hospitalized in a palliative care unit between June 2018 and December 2019. Patients' data collected at the time of hospitalization were analyzed. Cox regression was performed to examine significant factors influencing survival. A receiver operating characteristic (ROC) analysis was performed to estimate cut-off values for predicting survival within 3 weeks, and a log-rank test was performed to compare survival curves between groups divided by the cut-off values. RESULTS: Totally, 130 patients participated in the study. Cox regression suggested that the QLQ-C15-PAL dyspnea and fatigue scores and levels of CRP, Alb, and NLR were significantly associated with survival time, and cut-off values were 66.67, 66.67, 3.0 mg/dL, 2.5 g/dL, and 8.2, respectively. The areas under ROC curves of these variables were 0.6-0.7. There were statistically significant differences in the survival curves between groups categorized using each of these cut-off values (p < .05 for all cases). CONCLUSION: Our findings suggest that the assessment of not only objective indicators for the systemic inflammatory response but also patient-reported outcomes using EORTC QLQ-C15-PAL is beneficial for the prediction of short-term survival in terminally ill patients with cancer.

Cost-effectiveness Analysis of Atezolizumab Plus Nab-Paclitaxel for Advanced PD-L1 Positive Triple-Negative Breast Cancer in Japan.

BACKGROUND AND OBJECTIVES: Atezolizumab is an anti-programmed death ligand 1 (PD-L1) antibody that shows good safety and efficacy for patients with PD-L1-positive triple-negative breast cancer (TNBC). The cost of atezolizumab therapy is expensive, and its economic burden is an important problem. In this study, we evaluated the cost effectiveness of atezolizumab plus nab-paclitaxel therapy (AnP) compared with nab-paclitaxel monotherapy (nP) for PD-L1-positive TNBC under Japanese medical conditions and environments using a Markov model. METHODS: The medical information was collected from data published by the IMpassion130 trial. A Markov model was established to simulate the number of patients in each disease state after AnP or nP therapy during each time period. As indices for cost effectiveness, total cost, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICER) were calculated. Probabilistic sensitivity analysis (PSA) was used to assess the uncertainty of the model using 10,000 Monte Carlo simulations with difference parameters. RESULTS: The QALYs for AnP treatment were longer than for nP treatment (1.12 vs 0.82 QALYs), but the total cost of AnP treatment was more expensive than that of nP treatment (¥11,070,143 vs ¥2,056,164). The ICER values comparing AnP treatment with nP treatment were ¥30,208,143/QALY. The ICER/QALY was more expensive than the willingness-to-pay (WTP) of ¥15,000,000 per QALY. To achieve a 50% cost-effective probability with a WTP threshold, the price of the atezolizumab should be reduced by 55.1%. CONCLUSIONS: AnP was not cost effective compared to nP for PD-L1-positive inoperable TNBC under the Japanese condition.

Comparison of Patient Self-Reported Quality of Life and Health Care Professional-Assessed Symptoms in Terminally ill Patients With Cancer.

BACKGROUND: Few studies evaluated whether health care professionals accurately assess several symptoms for patients with cancer in palliative care units. We determined the agreement level for several symptoms related to quality of life (QOL) between patient-reported QOL assessment and health care professional-assessed symptoms based on the Support Team Assessment Schedule (STAS). METHOD: An observational study was performed with terminally ill patients with cancer hospitalized in the palliative care unit between June 2018 and December 2019. Patients and health care professionals independently assessed 7 symptoms at the time of hospitalization and after 1 week. Patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C15-PAL). In examining the proportions of exact agreement, "exact agreement" referred to the pairs of the scores (QLQ-C15-PAL vs STAS) being (1 vs 0), (2 vs 1), (3 vs 2 or 3), or (4 vs 4). The relationships of physical functioning between QLQ-C15-PAL and Palliative Performance Scale (PPS) were examined. RESULTS: Of 130 patients, approximately 60% had PPS scores from 40 to 60. The highest mean score on QLQ-C15-PAL was for fatigue (63.8). The exact agreement on symptoms between patients and health care professionals ranged from 15.4% (fatigue) to 57.7% (nausea and vomiting). The mean of the transformed QLQ-C15-PAL and proportions of exact agreement were negatively correlated (R 2 = 0.949, P < .05). The physical function scores in QLQ-C15-PAL for each PPS group showed no differences. CONCLUSION: We expect patient-reported outcomes including QLQ-C15-PAL to be added to health care professionals' assessment of serious symptoms such as fatigue in terminally ill patients with cancer.

Factors Associated With Efficacy and Nivolumab-Related Interstitial Pneumonia in Non-Small Cell Lung Cancer: A Retrospective Survey.

BACKGROUND AND OBJECTIVES: Immune-checitors have been established as a novel standard treatment for non-small cell lung cancer (NSCLC). The aim of this study was to identify factors associated with efficacy and nivolumab-related interstitial pneumonia in NSCLC by evaluating clinical data at the initiation of and during treatment. METHODS: We retrospectively reviewed the medical records of patients who underwent treatment with nivolumab between October 2015 and December 2017. Using pretreatment patient data, we investigated factors associated with overall survival (OS) and the onset of nivolumab-related pneumonitis. We investigated serum biochemistry during treatment to identify the determinants associated with progressive disease (PD) and the onset of nivolumab-related pneumonitis. RESULTS: A total of 94 patients were included. Eleven patients continued treatment, and 54 patients were diagnosed with progressive disease. Nivolumab-related pneumonitis occurred in 15 patients. A pretreatment Eastern Cooperative Oncology Group Performance Status (ECOG PS) = 0 was linked to significantly longer OS than ECOG PS = 1 (median: 20.1 vs. 6.5 months, respectively; p < 0.001). There was a higher incidence of nivolumab-related pneumonitis in patients with a history of interstitial pneumonia than in those without it (p = 0.008). During treatment, the level of albumin gradually decreased prior to PD and onset of nivolumab-related pneumonitis. CONCLUSION: These results suggest that the pretreatment ECOG PS is the determining factor that is associated with OS, whereas history of interstitial pneumonia is the factor associated with nivolumab-related pneumonitis. A decrease in albumin during treatment may be associated with both PD and nivolumab-related pneumonitis.

Effect of Continuous Pharmacist Interventions on Pain Control and Side Effect Management in Outpatients with Cancer Receiving Opioid Treatments.

For improving the QOL of patients diagnosed with cancer, early palliative care is recommended, aiming to minimize pain and opioid-induced side effects. Herein, we evaluated the effect of continuous interventions for pain management and opioid-induced side effects in outpatients with cancer. Pharmacists continuously performed interventions on patients on their hospital visits, starting from the first visit for opioid introduction to intervention via telephone. We recorded their pain patterns and intensities, use of rescue doses, and types and degrees of side effects during these interventions. The physicians were suggested appropriate recommendations for increased doses or alternative opioids when the pharmacists considered the analgesic dose should be titrated. During the study period, palliative care pharmacists conducted 105 interviews for 27 patients (male: 19 and female: 8) with cancer pain. Pain intensities significantly decreased after the pharmacists' continuous intervention, including those from telephone interviews, with their appropriate recommendations and increased opioid doses. Side effects such as nausea and constipation increased or remained unaffected even after the intervention, likely due to the increased opioid doses. Approximately 90% of recommendations for pain control were accepted by the physicians and helped to control the pain intensities. Before starting physician consultations, pharmacists informed the patients that adequate pain control and side effect management were achievable through regular interviews, wherein patient symptoms were monitored and patients received detailed explanations of pharmaceutical care and courteous and continuous counseling.

Evaluation of thromboembolic events in cancer patients receiving bevacizumab according to the Japanese Adverse Drug Event Report database.

Purpose We aimed to examine the risk factors, time of onset, incidence rates, and outcomes of thromboembolic events induced by bevacizumab in patients with cancer using the Japanese Adverse Drug Event Report (JADER) database of the Pharmaceuticals and Medical Devices Agency. Methods Adverse event data recorded in the JADER database between January 2004 and January 2015 were used. After screening the data using the generic drug name bevacizumab, patient data were classified into two groups by age and five groups by cancer type. The histories of disorders were also categorized. Arterial thromboembolic event and venous thromboembolic event were classified as "favorable" or "unfavorable" outcomes. Results In total, 6076 patients were reported to have developed adverse events during the sample period, of which 233 and 453 developed arterial thromboembolic event and venous thromboembolic event, respectively. Logistic analysis suggested that the presence of cancer was a significant risk factor for both arterial thromboembolic event and venous thromboembolic event. Age (≥70 years), histories of either hypertension or diabetes mellitus were also risk factors for arterial thromboembolic event. Median cumulative times of onset for arterial thromboembolic event and venous thromboembolic event were 60 and 80 days, respectively, and were not significantly different by the log-rank test. By the chi-square test, the rate of unfavorable outcomes was found to be higher after developing arterial thromboembolic event than after venous thromboembolic event. Conclusion Thromboembolism is a leading cause of mortality in patients with cancer. Patients should be monitored for the symptoms of thromboembolic events right from the initial stages of bevacizumab treatment.

Prediction of Apparent Oral Clearance of Small-Molecule Inhibitors in Pediatric Patients.

The purpose of this study was to build regression models for the prediction of apparent oral clearance (CL/F) for small-molecule inhibitors in the pediatric population using data obtained from adults. Two approaches were taken; a simple allometric regression model which considers no interdrug or interindividual variability and an allometric regression model with mixed-effects modeling where some variability parameters are included in the model. Average CL/F values were obtained for 15 drugs at various dosages from 31 literatures (a total of 139 data sets) conducted in adults and for 15 drugs from 26 literatures (62 data sets) conducted in children. Data were randomly separated into the "modeling" or "validation" data set, and the 2 allometric regression models were applied to the modeling data set. The predictive ability of the models was examined by comparing the observed and model-predicted CL/F in children using the validation data set. The percentage root mean square error was 17.2% and 26.3% in the simple allometric regression model and the allometric regression model with mixed-effects modeling, respectively. The predictive ability of the 2 models seems acceptable, suggesting that they could be useful for predicting the CL/F of new small-molecule inhibitors and for determining adequate doses in clinical pharmacotherapy for children.

Investigation of Optimal Time for Starting Betamethasone Using Fatigue Scores and Prognostic Nutritional Index in Terminally Ill Patients With Cancer-Related Fatigue.

BACKGROUND: Corticosteroids are frequently used to treat cancer-related fatigue (CRF), but it is yet to be established as standard care, and few reports have defined the appropriate time to start treatment. OBJECTIVES: We investigated the optimal time for starting betamethasone and evaluated the clinical validity of using the prognostic nutritional index (PNI) for this purpose. METHODS: Data were retrospectively collected for patients with terminal cancer receiving betamethasone for palliative care. Fatigue strength was evaluated by the daily occurrence of fatigue, using proportion of adequate fatigue, AF(%), defined as the average of the daily score for all treatment days, AF(%)all, the initial 5 days, AF(%)initi5, or the last 5 days, AF(%)last5. We examined (1) the relationship between survival time and adequate fatigue for CRF and (2) the correlation between survival time and PNI (based on serum albumin and lymphocytes). RESULTS: Data from 24 patients were included. The AF(%)all was approximately 50% at 42 days before death and gradually decreased as the survival time shortened ( R2 =.41, P <.001). There was a clear positive correlation between AF(%)all and AF(%)initi5 ( R2 =.84, P <.001). At 42 days before death, PNI was approximately 30 and significantly correlated with the survival time ( R2 = .873, P <.001). CONCLUSION: The adequate fatigue appears to be dependent on survival time, and PNI might be useful for identifying patients that will benefit from betamethasone use. It is hoped that these results will contribute to individualized pharmacotherapy of terminally ill patients with CRF.

Indication of Adequate Transdermal Fentanyl Dose in Opioid Switching From Oral Oxycodone in Patients With Cancer.

OBJECTIVE: The present study aimed to examine affecting factors for conversion ratio and to predict adequate fentanyl dose for patients with cancer pain in opioid switching from oral oxycodone. METHODS: Patient characteristics, biochemical parameters, daily oxycodone dose, and reasons for opioid switching were retrospectively collected. The effect of variables on the conversion ratio was analyzed by multiple regression analysis. RESULTS: Regression analysis for the data from 122 patients suggested that the typical conversion ratio was 95:1; however, this ratio was significantly reduced in patients taking a daily oral morphine-equivalent dose of <45 mg/d and in patients with poor pain control to 52:1 and 64:1, respectively. CONCLUSION: We should carefully and rapidly control pain in opioid switching based on the adequate dose indicated in this study.