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Patients can prepare for end of life and their forthcoming death to enhance the quality of dying.We aimed to longitudinally evaluate the never-before-examined associations of cancer patients' death-preparedness states by conjoint cognitive prognostic awareness and emotional preparedness for death with psychological distress, quality of life (QOL), and end-of-life care received.In this cohort study, we simultaneously evaluated associations of four previously identified death-preparedness states (no-death-preparedness, cognitive-death-preparedness-only, emotional-death-preparedness-only, and sufficient-death-preparedness states) with anxiety symptoms, depressive symptoms, and QOL over 383 cancer patients' last six months and end-of-life care received in the last month using multivariate hierarchical linear modeling and logistic regression modeling, respectively. Minimal clinically important differences (MCIDs) have been established for anxiety- (1.3-1.8) and depressive- (1.5-1.7) symptom subscales (0-21 Likert scales).Patients in the no-death-preparedness and cognitive-death-preparedness-only states reported increases in anxiety symptoms and depressive symptoms that exceed the MCIDs, and a decline in QOL from those in the sufficient-death-preparedness state. Patients in the emotional-death-preparedness-only state were more (OR [95% CI]=2.38 [1.14, 4.97]) and less (OR [95% CI]=0.38 [0.15, 0.94]) likely to receive chemotherapy/immunotherapy and hospice care, respectively, than those in the sufficient-death-preparedness state. Death-preparedness states were not associated with life-sustaining treatments received in the last month.Conjoint cognitive and emotional preparedness for death is associated with cancer patients' lower psychological distress, better QOL, reduced anti-cancer therapy, and increased hospice-care utilization. Facilitating accurate prognostic awareness and emotional preparedness for death is justified when consistent with patient circumstances and preferences.

Background/Objective Preparing family caregivers, cognitively, emotionally, and behaviorally, for their relative's death is an actionable component of high-quality end-of-life care. We aimed to examine the never-before-examined associations of conjoint cognitive prognostic awareness and emotional preparedness for death with caregiving outcomes and end-of-life care received by cancer patients. Design/Setting/Participants/Main measures For this longitudinal study, associations of death-preparedness states (no-death-preparedness, cognitive-death-preparedness-only, emotional-death-preparedness-only, and sufficient-death-preparedness states) with subjective caregiving burden, depressive symptoms, and quality of life (QOL) and patients’ end-of-life care (chemotherapy and/or immunotherapy, cardiopulmonary resuscitation, intensive care unit care, intubation, mechanical ventilation support, vasopressors, nasogastric tube feeding, and hospice care) were evaluated using multivariate hierarchical linear and logistic regression modeling, respectively, for 377 caregivers in cancer patients’ last 6 months and 1 month, respectively. Key results Caregivers in the cognitive-death-preparedness-only state experienced a higher level of subjective caregiving burden than those in the sufficient-death-preparedness state. Caregivers in the no-death-preparedness and cognitive-death-preparedness-only states reported significantly more depressive symptoms and worse QOL than those in the sufficient-death-preparedness state. Cancer patients with caregivers in the sufficient-death-preparedness state were less likely to receive chemotherapy and/or immunotherapy, intubation, mechanical ventilation, and nasogastric tube feeding than patients with caregivers in other death-preparedness states. However, patients’ receipt of hospice care was not associated with their caregivers’ death-preparedness states. Conclusion Family caregivers’ death-preparedness states were associated with caregiving outcomes and their relative's end-of-life care. Cultivating caregivers’ accurate prognostic awareness and improving their emotional preparedness for their relative's death may facilitate more favorable end-of-life-caregiving outcomes and may limit potentially nonbeneficial end-of-life care.

Summary Background Dual blockade of PD-L1 and VEGF has enhanced anticancer immunity through multiple mechanisms and augmented antitumour activity in multiple malignancies. We aimed to assess the efficacy and safety of atezolizumab (anti-PD-L1) alone and combined with bevacizumab (anti-VEGF) in patients with unresectable hepatocellular carcinoma. Methods GO30140 is an open-label, multicentre, multiarm, phase 1b study that enrolled patients at 26 academic centres and community oncology practices in seven countries worldwide. The study included five cohorts, and the two hepatocellular carcinoma cohorts, groups A and F, are described here. Inclusion criteria for these two groups included age 18 years and older; histologically, cytologically, or clinically (per American Association for the Study of Liver Diseases criteria) confirmed unresectable hepatocellular carcinoma that was not amenable to curative treatment; no previous systemic treatment; and Eastern Cooperative Oncology Group performance status of 0 or 1. In group A, all patients received atezolizumab (1200 mg) and bevacizumab (15 mg/kg) intravenously every 3 weeks. In group F, patients were randomly assigned (1:1) to receive intravenous atezolizumab (1200 mg) plus intravenous bevacizumab (15 mg/kg) every 3 weeks or atezolizumab alone by interactive voice-web response system using permuted block randomisation (block size of two) and stratification factors of geographical region; macrovascular invasion, extrahepatic spread, or both; and baseline α-fetoprotein concentration. Primary endpoints were confirmed objective response rate in all patients who received the combination treatment for group A and progression-free survival in the intention-to-treat population in group F, both assessed by an independent review facility according to Response Evaluation Criteria in Solid Tumors version 1.1. In both groups, safety was assessed in all patients who received at least one dose of any study treatment. This study is registered with ClinicalTrials.gov , NCT02715531 , and is closed to enrolment. Findings In group A, 104 patients were enrolled between July 20, 2016, and July 31, 2018, and received atezolizumab plus bevacizumab. With a median follow-up of 12·4 months (IQR 8·0–16·2), 37 (36%; 95% CI 26–46) of 104 patients had a confirmed objective response. The most common grade 3–4 treatment-related adverse events were hypertension (13 [13%]) and proteinuria (seven [7%]). Treatment-related serious adverse events occurred in 25 (24%) patients and treatment-related deaths in three (3%) patients (abnormal hepatic function, hepatic cirrhosis, and pneumonitis). In group F, 119 patients were enrolled and randomly assigned (60 to atezolizumab plus bevacizumab; 59 to atezolizumab monotherapy) between May 18, 2018, and March 7, 2019. With a median follow-up of 6·6 months (IQR 5·5–8·5) for the atezolizumab plus bevacizumab group and 6·7 months (4·2–8·2) for the atezolizumab monotherapy group, median progression-free survival was 5·6 months (95% CI 3·6–7·4) versus 3·4 months (1·9–5·2; hazard ratio 0·55; 80% CI 0·40–0·74; p=0·011). The most common grade 3–4 treatment-related adverse events in group F were hypertension (in three [5%] patients in the atezolizumab plus bevacizumab group; none in the atezolizumab monotherapy group) and proteinuria (in two [3%] patients in the atezolizumab plus bevacizumab group; none in the atezolizumab monotherapy group). Treatment-related serious adverse events occurred in seven (12%) patients in the atezolizumab plus bevacizumab group and two (3%) patients in the atezolizumab monotherapy group. There were no treatment-related deaths. Interpretation Our study shows longer progression-free survival with a combination of atezolizumab plus bevacizumab than with atezolizumab alone in patients with unresectable hepatocellular carcinoma not previously treated with systemic therapy. Therefore, atezolizumab plus bevacizumab might become a promising treatment option for these patients. This combination is being compared with standard-of-care sorafenib in a phase 3 trial. Funding F Hoffmann-La Roche/Genentech.

Context Family caregivers constitute a critical component of the end-of-life care system with considerable cost to themselves. However, the joint association of terminally ill cancer patients' symptom distress and functional impairment with caregivers' subjective caregiving burden, quality of life (QOL), and depressive symptoms remains unknown. Objectives/Methods We used multivariate hierarchical linear modeling to simultaneously evaluate associations between five distinct patterns of conjoint symptom distress and functional impairment (symptom-functional states) and subjective caregiving burden, QOL, and depressive symptoms in a convenience sample of 215 family caregiver–patient dyads. Data were collected every 2 to 4 weeks over patients' last 6 months. Results Caregivers of patients in the worst symptom-functional states (States 3–5) reported worse subjective caregiving burden and depressive symptoms than those in the best two states, but the three outcomes did not differ between caregivers of patients in State 3 and States 4–5. Caregivers of patients in State 5 endured worse subjective caregiving burden and QOL than those in State 4. Caregivers of patients in State 4 suffered worse subjective caregiving burden and depressive symptoms but comparable QOL to those in State 2. Conclusion Patients' five distinct, conjoint symptom-functional states were significantly and differentially associated with their caregivers' worse subjective caregiving burden, QOL, and depressive symptoms while caring for patients over their last 6 months.

Summary: Background: Determining the survival outcome for gastric cancer patients with metastases to more than 15 regional lymph nodes is difficult. This study aims to develop a lymph node metastatic ratio (LNR)-based prognostic model to predict the survival outcome after D2 surgery in such patient groups. Methods: Our study retrospectively enrolled 139 gastric cancer patients with metastases to more than 15 regional lymph nodes who underwent D2 surgery between 2007 and 2014. Clinicopathologic variables to predict overall survival (OS) using multivariate Cox regression were selected to create a prognostic model. Results: The prognostic model for predicting OS was developed based on five independent factors, namely, T-classification (T2 or T3 vs. T4), LNR (

Summary Background Patients with advanced gastric or gastro-oesophageal junction cancer that progresses on chemotherapy have poor outcomes. We compared pembrolizumab with paclitaxel in patients with advanced gastric or gastro-oesophageal junction cancer that progressed on first-line chemotherapy with a platinum and fluoropyrimidine. Methods This randomised, open-label, phase 3 study was done at 148 medical centres in 30 countries. Eligible patients were randomised (1:1) in blocks of four per stratum with an interactive voice-response and integrated web-response system to receive either pembrolizumab 200 mg every 3 weeks for up to 2 years or standard-dose paclitaxel. Primary endpoints were overall survival and progression-free survival in patients with a programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or higher. Safety was assessed in all patients, irrespective of CPS. The significance threshold for overall survival was p=0·0135 (one-sided). This trial is registered at ClinicalTrials.gov, number NCT02370498. Findings Between June 4, 2015, and July 26, 2016, 592 patients were enrolled. Of the 395 patients who had a PD-L1 CPS of 1 or higher, 196 patients were assigned to receive pembrolizumab and 199 patients were assigned to receive paclitaxel. As of Oct 26, 2017, 326 patients in the population with CPS of 1 or higher had died (151 [77%] of 196 patients in the pembrolizumab group and 175 [88%] of 199 patients in the paclitaxel group). Median overall survival was 9·1 months (95% CI 6·2–10·7) with pembrolizumab and 8·3 months (7·6–9·0) with paclitaxel (hazard ratio [HR] 0·82, 95% CI 0·66–1·03; one-sided p=0·0421). Median progression-free survival was 1·5 months (95% CI 1·4–2·0) with pembrolizumab and 4·1 months (3·1–4·2) with paclitaxel (HR 1·27, 95% CI 1·03–1·57). In the total population, grade 3–5 treatment-related adverse events occurred in 42 (14%) of the 294 patients treated with pembrolizumab and 96 (35%) of the 276 patients treated with paclitaxel. Interpretation Pembrolizumab did not significantly improve overall survival compared with paclitaxel as second-line therapy for advanced gastric or gastro-oesophageal junction cancer with PD-L1 CPS of 1 or higher. Pembrolizumab had a better safety profile than paclitaxel. Additional trials of pembrolizumab in gastric and gastro-oesophageal cancer are ongoing. Funding Merck Sharp & Dohme, a subsidiary of Merck & Co.

Background/purpose: To investigate the diagnostic accuracy of 68Ga-DOTATOC and 18F-FDG PET/CT to identify the primary foci in Taiwanese patients with clinically suspected neuroendocrine tumors (NET) and NET of unknown primary site. Methods: Patients with clinically suspected NET and NET of unknown primary site were eligible. All participants underwent a conventional workup (including CT, MR, endoscopic ultrasound), 68Ga-DOTATOC, and 18F-FDG PET/CT. The results of pathology and findings on clinical follow-up served as the gold standard. Results: Among the 36 patients included in the study, we were able to identify the primary tumor in 17 participants (47.2%). The overall sensitivity values of 68Ga-DOTATOC, 18F-FDG, and conventional workup were 88%, 41%, and 53%, respectively, whereas the specificities were 100%, 100%, 68%, respectively. The areas under curve of 68Ga-DOTATOC, 18F-FDG, and conventional workup were 0.941, 0.706, and 0.607, respectively. 68Ga-DOTATOC was more sensitive than 18F-FDG and more specific than conventional workup. Treatment changes as a result of 68Ga-DOTATOC PET/CT findings occurred in 12 (33.3%) of the 36 study participants. Conclusion: Our data confirm the usefulness of 68Ga-DOTATOC in the identification of NET. In addition, treatment modifications as a result of 68Ga-DOTATOC PET/CT findings were evident in approximately one third of NET patients. Keywords: 68Ga-DOTATOC, 18F-FDG, Neuroendocrine tumors, PET/CT

AIM: Sunitinib has shown benefit in patients with imatinib (IM)–resistant gastrointestinal stromal tumor (GIST). However, its advantages are somewhat diminished because of associated toxicities. Herein, we clarify the efficacy and safety of fractioned dose regimen of sunitinib by a pharmacokinetic and efficacy study. MATERIALS AND METHODS: Between 2001 and March 2013, a total of 214 patients with metastatic GIST was treated at Chang Gung Memorial Hospital. Among them, 55 (11.6%) patients who received sunitinib were investigated. One group of patients was administered with standard dose of once-daily sunitinib (standard dose group) and the other group was administered with standard total daily dose of sunitinib in fractioned doses (fractioned dose group). RESULTS: Thirty-two male and 23 female patients with a median age of 55 years received sunitinib. The median duration of sunitinib administration was 9.2 months. The clinical benefit was 65.2%. The mean peak blood level of sunitinib in patients with fractioned doses was significantly lower than that in those with once-daily dose (83.4 vs 50.1 ng/ml, P = .01). The rates of adverse effects of hand-foot syndrome, mucositis, and yellow skin were significantly decreased by fractioned doses of sunitinib. However, the progression-free and overall survival did not differ between patients with different treatment regimens. CONCLUSION: The fractioned dose regimen of sunitinib appears to be a safe and effective treatment for patients with IM-resistant/intolerant GISTs. Significantly decreased toxicity of this regimen could be explained by significantly lower peak sunitinib blood level. However, the treatment efficacy is not reduced by this regimen.

Context Emotional preparedness for death is a distinct but related concept to prognostic awareness (PA). Both allow patients to prepare psychologically and interpersonally for death, but they have primarily been examined in cross-sectional studies. Objectives To 1) explore the courses of change in good emotional preparedness for death and accurate PA and 2) evaluate their associations with severe anxiety symptoms, severe depressive symptoms, and quality of life in cancer patients' last year. Methods For this prospective, longitudinal study, we consecutively recruited 277 terminally ill cancer patients. Aims 1 and 2 were examined by univariate and multivariate generalized estimating equation analyses, respectively. Results The prevalence of good emotional preparedness for death was 54.43%–65.85% in the last year, with a significant decrease only 91–180 vs. 181–365 days before death (odds ratio [95% CI] = 0.67 [0.47, 0.97]). Good emotional preparedness for death was associated with a lower likelihood of severe anxiety symptoms (adjusted odds ratio [95% CI] = 0.47 [0.27, 0.79]) and severe depressive symptoms (0.61 [0.39, 0.95]), but not with quality of life (β [95% CI] = 0.49 [−2.13, 3.11]). However, accurate PA improved substantially (55.12%–70.73%) as death approached and accurate PA was positively associated with severe depressive symptoms (2.63 [1.63, 4.25]). Conclusion Good emotional preparedness for death and accurate PA remained largely stable and improved substantially, respectively, in cancer patients' last year. Both measures were significantly associated with psychological distress. Health care professionals should not only cultivate accurate PA but also promote cancer patients' emotional preparedness for death, which may improve their psychological well-being.

Context High-quality end-of-life (EOL) care depends on thoroughly assessing terminally ill patients' preferences for EOL care and tailoring care to individual needs. Studies on predictors of EOL-care preferences were primarily cross-sectional and assessed preferences for multiple life-sustaining treatments (LSTs), making clinical applications difficult. Objective/Methods We examined factors predisposing cancer patients (N = 303) to specific LST-preference states (life-sustaining preferring, comfort preferring, uncertain, and nutrition preferring) derived from six LSTs (cardiopulmonary resuscitation, intensive care unit care, chest compression, intubation with mechanical ventilation, intravenous nutrition, and tube feeding) in patients' last six months by multilevel multinomial logistic regression. Results Participants with accurate prognostic awareness and physician-patient EOL-care discussions were less likely to be in life-sustaining-preferring, uncertain, and nutrition-preferring states than in the comfort-preferring state. Better quality of life (QOL) and more depressive symptoms predisposed participants to be less likely to be in the uncertain than in the comfort-preferring state. Membership in the nutrition-preferring rather than the comfort-preferring state was significantly higher for participants in the state of moderate symptom distress with severe functional impairment than in the state of mild symptom distress with high functioning. Conclusion Accurate prognostic awareness, physician-patient EOL-care discussions, QOL, depressive symptoms, and symptom-functional states predisposed terminally ill cancer patients to distinct LST-preference states. Clinicians should cultivate patients' accurate prognostic awareness and facilitate EOL-care discussions to foster realistic expectations of LST efficacy at EOL. Clinicians should enhance patients' QOL to reduce uncertainty in EOL-care decision making and provide adequate psychological support to those with more depressive symptoms who prefer comfort care only.

Purpose To evaluate the therapeutic efficacy of 3-month triplet induction chemotherapy (ICT) followed by concomitant chemoradiotherapy (CCRT) in patients with locally advanced pancreatic cancer (LAPC). Patients and Methods Chemonaive patients with measurable, histologically confirmed LAPC were eligible. The ICT consisted of biweekly gemcitabine (800 mg/m 2 ) infusion at a fixed dose rate (10 mg/m 2 /min), followed by 85 mg/m 2 oxaliplatin and 48-h infusion of 5-fluorouracil/leucovorin (3000/150 mg/m 2 ) for 6 cycles. Patients without disease progression 4 weeks after ICT would receive weekly 400 mg/m 2 gemcitabine and 5040 cGy radiation in 28 fractions. After CCRT, patients were subjected for surgical intervention and/or maintenance chemotherapy until progression or intolerable toxicity. Results Between December 2004 and August 2008, 50 patients were enrolled. The best responses after ICT were partial response (PR) in 9, stable disease in 26, and progressive disease or not evaluable in 15. Among the former 35 patients, 2 had disease progression before CCRT, and 3 declined to have CCRT. Of the 30 patients receiving CCRT, an additional 4 and 1 patient(s) achieved PR at the end of CCRT and during maintenance chemotherapy, respectively. On intent-to-treat analysis, the overall best response was PR in 14 patients and stable disease in 21. The overall response rate and disease control rate were 28% (95% confidence interval [CI], 16.2–42.5%) and 70% (95% CI, 44.4–99.2%), respectively. The median time to progression and overall survival of the intent-to-treat population was 9.3 (95% CI, 5.8–12.8) months and 14.5 (95% CI, 11.9–17.1) months, respectively. One- and two-year survival rates were 68% (95% CI, 55.1–80.9%) and 20.6% (95% CI, 8.7–32.5%), respectively. Neutropenia was the most common Grade 3–4 toxicity of both ICT and CCRT, with a frequency of 28% and 26.7%, respectively. Significant sensory neuropathy occurred in 9 patients (18%). Conclusion Three months of triplet ICT followed by gemcitabine-based CCRT is feasible, moderately active, and associated with encouraging survival in patients with LAPC.

Use of the hospital ICU is rising rapidly for end-of-life care. The purpose of this population-based study was to determine the prevalence of ICU care in the last month of life of patients with cancer and the associations between ICU care and patient demographics, disease characteristics, physician specialty, hospital characteristics, and availability of health-care resources at the hospital and regional levels in Taiwan.This retrospective cohort study used administrative data for 204,850 cancer decedents from 2001 to 2006.Rates of hospital ICU care in the last month of life did not change significantly from 2001 to 2006 (11.27%-12.71%). ICU use in the last month of life was more likely for single male patients aged65 years who had hematologic malignancies or esophageal cancer and more comorbidities or a nononcologist as primary-care physician. Patients with cancer were one-third less likely to use ICU care in their last month of life if they received care in a private hospital than if they were cared for in a public hospital. Patient propensity to receive ICU care in the last month of life was positively associated with increasing quartile of total hospital beds in their primary hospital's region.Slightly more than one-tenth of Taiwanese patients with cancer received ICU care in their last month of life. ICU use was strongly influenced by receiving care in hospitals and regions with abundant health-care resources. Resources should be devoted to ensure that ICU care at the end of life best meets patients' individual needs and interests.

Context/Objective The extent to which patients' preferences for end-of-life (EOL) care are honored may be distorted if preferences are measured long before death, a common approach of existing research. We examined the concordance between cancer patients' states of life-sustaining treatments (LSTs) received in their last month and LST preference states assessed longitudinally over their last six months. Methods We examined states of preferred and received LSTs (cardiopulmonary resuscitation, intensive care unit care, chest compression, intubation with mechanical ventilation, intravenous nutrition, and nasogastric tube feeding) in 271 cancer patients' last six months by a transition model with hidden Markov modeling (HMM). The extent of concordance was measured by a percentage and a kappa value. Results HMM identified four LST preference states: life-sustaining preferring, comfort preferring, uncertain, and nutrition preferring. HMM identified four LST states received in patients' last month: generally received LSTs, LSTs uniformly withheld, selectively received LSTs, and received intravenous nutrition only. LSTs received concurred poorly with patients' preferences estimated right before death (39.5% and kappa value: 0.06 [95% CI: −0.02, 0.13]). Patients in the life-sustaining–preferring, uncertain, and nutrition-preferring states primarily received no LSTs, and patients in three of four states received intravenous nutrition against their preferences. Concordance was strongest for comfort-preferring patients. Conclusions Concordance was poor between patients' preferred and received LST states. Interventions are needed to clarify patients' EOL care goals and to facilitate their understanding about LST's ineffectiveness in prolonging life at EOL. Such interventions might increase patients' comfort preference and ensure concordance between their preferred and received EOL care.

Context It is important to determine the etiology of fever in cancer patients. Such patients often undergo extensive laboratory and radiographic investigations and prolonged anti-infective therapy that are time- and resource- consuming, risk drug toxicity, and postpone systemic chemotherapy. Objectives To investigate neoplastic fever (NF) patterns from vital sign flow sheets. Methods Between September 1997 and February 2009, data on 150 consecutive hospitalized patients with advanced or metastatic solid tumors documented to have NF were retrospectively collected. Sixty patients with sepsis were used as a comparison group. Results All patients with NF demonstrated intermittent fever patterns. Peak body temperature was 39.0±0.6°C (38.0–40.8°C). Baseline pulse rates in 139 (93%) patients showed no increase except during febrile periods. The remaining 11 (7%) patients had transiently elevated baseline pulse rates at the time of cessation of postchemotherapy dexamethasone. Once-daily fever spike patterns occurred in 108 (72%) patients. Fever spikes were most commonly found at 9 am (42%) and 5 pm (37%). Twice-daily fever spike patterns were noted in the 42 (28%) remaining patients. In the comparison group, baseline pulse rate elevated in all patients during febrile periods and 20 (33%) showed intermittent fever patterns. Conclusion We conclude that the NF pattern is characterized by intermittent fever without an obvious increase in baseline pulse rate except during febrile periods. Knowing NF patterns from vital sign flow sheets can help identify NF and other possible causes of fever in oncology patients.

Context Evidence for the association of hospice exposure with lower health care expenditures at end of life (EOL) remains inconclusive and neglects EOL care being concentrated in patients' last few months. Objective The association between hospice exposure and health care expenditures in cancer patients' last one, three, six, and 12 months was evaluated. Methods In this population-based, retrospective cohort study, Taiwanese cancer decedents in 2001–2010 (N = 195,228) were matched 1:1, with proportions of matched hospice users reaching 87.8%, by a hospice-utilization propensity score. For each matched pair, exposure to hospice (time from hospice enrollment to death) was matched to equivalent periods for hospice nonusers before death. Hospice-care associations with health care expenditures were evaluated by hospice use/exposure interactions with multilevel linear regression modeling using generalized estimating equations. Results The unadjusted main effect showed lower total mean health care expenditures for hospice users than for hospice nonusers only in the last one and three months (rate ratio [95% CI]: 0.86 [0.81, 0.90] and 0.93 [0.89, 0.96], respectively). However, after accounting for exposure time, hospice care was significantly associated with lower health care expenditures at exposures of ≤30, ≤60, and ≤180 days for health care expenditures measured in the last one and three months, six months, and 12 months, respectively. Savings for patients with lengthy hospice stays were neutralized or even disappeared. Conclusion Hospice care was associated with lower health care expenditures when it could actively intervene in EOL care. Hospice philosophy should be applied not only shortly before death but also throughout the dying trajectory to achieve maximum cost savings.

Dexamethasone is likely to play a role in the etiology of hiccups in patients receiving cisplatin-based regimens. Two hundred seventy-seven patients received three doses of ondansetron 8mg intravenously (IV) at 4hour intervals plus dexamethasone 20mg IV from the start of chemotherapy, followed by dexamethasone 5mg IV every 12hours, until chemotherapy was complete. Hiccups were observed in 114 (41.2%) patients, of whom 97.4% were men. Nausea and vomiting showed inverse correlations with hiccups (P < 0.0001 and P = 0.001, respectively). In 73 patients who experienced hiccups but lacked nausea/vomiting (H+N/V-), we discontinued dexamethasone in subsequent cycles. Sixty-six patients (90.4%) ceased hiccuping, but complete protection rates of nausea and vomiting decreased to 63% and 74%, respectively. For patients who experienced both hiccups and nausea/vomiting, the onset of nausea/vomiting usually was delayed to Day 3 or 4 and began after the cessation of hiccups. We conclude that cisplatin-related hiccups are predominant in males, dexamethasone-induced, and associated with protection against nausea/vomiting.

We determined the maximum tolerated dose (MTD) and then further evaluated the response rate and safety profile of gemcitabine (Gem) plus doxorubicin (Dox) in chemonaïve patients with advanced hepatocellular carcinoma (HCC).Dose escalation was tested over four dose levels in each 21-day cycle: level 1 (Gem 1000 mg/m(2) on days 1 and 8, Dox 30 mg/m(2) on day 1), level 2 (Gem/Dox 1250/30), level 3 (Gem/Dox 1250/45) and level 4 (Gem/Dox 1250/60). The MTD was further evaluated in phase II.Patients' characteristics were: 47 men, three women; median age 53 years (range 28-70); Zubrod performance status (PS) scores 0-1 (74%), PS 2 (26%); Okuda stage I (24%) and stage II (76%). Fifteen patients were enrolled in phase I: level 1 (n = 3), level 2 (n = 6), level 3 (n = 6), level 4 (n = 0). Level 2 was identified as the MTD. Dose-limiting toxicities included esophageal bleeding, grade 4 neutropenia and neutropenic fever. Of the 34 patients evaluable for response in phase II (of 35 total), there were four (11.8%) partial responses (95% CI, 0.8% to 22.8%) and six (17.6%) minor responses; nine (26.5%) had stable disease and 15 (44.1%) progressed. Sixteen per cent of patients had a decline ofor=50% in alpha-fetoprotein levels after treatment. Median survival and progression-free survival were 4.6 months (range 0.3-19.2) and 2.5 months (range 0.2-7.8), respectively, for 35 patients. Grade 3/4 hematological toxicities included anemia (45.7%), neutropenia (51.4%), thrombocytopenia (25.7%); febrile neutropenia (11.8%) and non-hematological toxicities were mild to moderate.Gemcitabine plus doxorubicin produces modest activity and moderate toxicity in this cohort of Chinese patients with advanced HCC.

Context/Objective Temporal changes have not been examined in patient-caregiver agreement on life-sustaining treatment (LST) preferences at end of life (EOL). We explored the extent of and changes in patient-caregiver agreement on LST-preference patterns for two independent cohorts of Taiwanese cancer patient-family caregiver dyads recruited a decade apart. Methods We surveyed preferences for cardiopulmonary resuscitation, intensive care unit care, cardiac massage, intubation with mechanical ventilation, intravenous nutritional support, tube feeding, and dialysis among 1049 and 1901 dyads in 2003–2004 and 2011–2012, respectively. LST-preference patterns were examined by multi-group latent class analysis. Extent of patient-caregiver agreement on LST-preference patterns was determined by percentage agreement and kappa coefficients. Results For both patients and family caregivers, we identified seven distinct LST-preference classes. Patient-caregiver agreement on LST-preference patterns was poor to fair across both study cohorts, indicated by 24.4%–43.5% agreement and kappa values of 0.06 (95% CI: 0.04, 0.09) to 0.27 (0.23, 0.30), and declined significantly over time. Agreement on LST-preference patterns was most likely when both patients and caregivers uniformly rejected LSTs. When patients disagreed with caregivers on LST-preference patterns, discrepancies were most likely when patients totally rejected LSTs but caregivers uniformly preferred LSTs or preferred nutritional support but rejected other treatments. Conclusion Patients and family caregivers had poor-to-fair agreement on LST-preference patterns, and agreement declined significantly over a decade. Encouraging an open dialogue between patients and their family caregivers about desired EOL care would facilitate patient-caregiver agreement on LST-preference patterns, thus honoring terminally ill cancer patients' wishes when they cannot make EOL-care decisions.

Context The stability of life-sustaining treatment (LST) preferences at end of life (EOL) has been established. However, few studies have assessed preferences more than two times. Furthermore, associations of LST preferences with modifiable variables of accurate prognostic awareness, physician-patient EOL care discussions, and depressive symptoms have been investigated in cross-sectional studies only. Objectives To explore longitudinal changes in LST preferences and their associations with accurate prognostic awareness, physician-patient EOL care discussions, and depressive symptoms in terminally ill cancer patients' last year. Methods LST preferences (cardiopulmonary resuscitation, intensive care unit [ICU] care, intubation, and mechanical ventilation) were measured approximately every two weeks. Changes in LST preferences and their associations with independent variables were examined by hierarchical generalized linear modeling with logistic regression. Results Participants ( n = 249) predominantly rejected cardiopulmonary resuscitation, ICU care, intubation, and mechanical ventilation at EOL without significant changes as death approached. Patients with inaccurate prognostic awareness were significantly more likely than those with accurate understanding to prefer ICU care, intubation, and mechanical ventilation than to reject these LSTs. Patients with more severe depressive symptoms were less likely to prefer ICU care and to be undecided about wanting ICU care and mechanical ventilation than to reject such LSTs. LST preferences were not associated with physician-patient EOL care discussions, which were rare in our sample. Conclusion LST preferences are stable in cancer patients' last year. Facilitating accurate prognostic awareness and providing adequate psychological support may counteract the increasing trend for aggressive EOL care and minimize emotional distress during EOL care decisions.

2twice daily days 1–14 q3w) for 8 cycles or surgery alone. The primary endpoint was 3-year disease-free survival. The clinical cut-off date for the prospectively planned final 5-year efficacy analysis was 22 November 2012. Results: At data cut-off, 103 (20%) patients in the XELOX group and 141 (27%) patients in the surgery alone group had died. This represented a 34% reduction in the risk of death with XELOX versus surgery alone (hazard ratio 0.66, 95% CI 0.51–0.85; p = 0.0015 by stratified Cox regression analysis). The 5-year overall survival rate was 78% in the XELOX group and 69% in the surgery alone group (p = 0.0029, log-rank test unstratified). 76 (15%) patients in the XELOX group and 135 (26%) patients in the surgery alone group received subsequent, non-protocol-specified anticancer therapies after progression of disease. In the analysis of disease-free survival, 139 (26.7%) patients in the XELOX group and 203 (39.4%) patients in the surgery alone group had relapsed, developed a new gastric cancer or died. This represented a 42% reduction in the risk of an event with XELOX versus surgery alone (hazard ratio 0.58, 95% CI 0.47– 0.72; p < 0.0001 by stratified Cox regression analysis). The 5-year disease-free survival rate was 68% in the XELOX group and 53% in the surgery alone group (p < 0.0001, log-rank test unstratified). Conclusion: The final analysis of the CLASSIC trial, after a median follow-up of 5 years, supports the findings from the primary analysis performed 2 years earlier. Adjuvant XELOX after curative D2 gastrectomy improves overall survival compared with surgery alone and should be considered as a standard treatment option for patients with operable gastric cancer.

Background: This prospective phase II clinical trial evaluated the efficacy and toxicity of cisplatin, oral tegafur-uracil, leucovorin, and mitomycin C in patients with recurrent or metastatic nasopharyngeal carcinoma. Methods: Patients with histologically proven non-keratinizing or undifferentiated nasopharyngeal carcinoma were prospectively enrolled from April 2002 to June 2005. Cisplatin 50 mg/m 2 on day 1, 22 and mitomycin C 6 mg/m 2 on day 1 were administered. Oral tegafur-uracil 300 mg/m 2 /day and oral leucovorin 60 mg/day were given on day 1-14 and day 22-35, respectively. Each cycle was repeated every 6 weeks. Primary and secondary endpoints are response rate and toxic profiles with survivals, respectively. Results: Twenty-two patients with the median age of 47 (35-69) years were enrolled in the study. Sixteen (72.7%) patients had undifferentiated nasopharyngeal carcinoma. The regimen was well-tolerated by all patients with the exception of one patient (4.6%) who experienced grade IV anorexia, and two patients (9.1%) who had grade IV vomiting. There was no treatment-related death. The overall response rate was 59.1%, including 3 (13.6%) complete remissions. The median duration of response was 15.9 months, the median time to tumor progression was 10.0 months, and the median overall survival was 16.0 months. Conclusion: This outpatient chemotherapy regimen is acceptably effective and toxic among patients with recurrent or metastatic nasopharyngeal carcinoma.

Introduction The molecular chaperone HSP90 plays a pivotal role in the folding and maturation of proteins implicated in the tumorigenesis of gastric cancers. Gastric cancer-relevant HSP90 client proteins include HER2, AKT, and thymidylate synthase. AUY922 is a novel non-geldanamycin HSP90 inhibitor that degrades these client proteins, and exhibits potent preclinical activity against gastric cancer cell lines and xenograft models (IC50 2-40 nM). This open-label Phase II study compared AUY922 with either docetaxel or irinotecan in patients with advanced gastric cancer, who had progressed after one line of chemotherapy. Methods AUY922 (once-weekly, 70 mg/m2), docetaxel (three-weekly, 75 mg/m2), or irinotecan (three-weekly, 350 mg/m2) were administered intravenously in adult patients with radiologically confirmed gastric or gastro-esophageal junction adenocarcinoma (WHO PS ≤1), who had progressed following 1 prior line of chemotherapy. The primary endpoint was progression-free survival. Secondary endpoints were overall survival, objective response rate, safety (adverse events [AEs] and cardiac safety) and tolerability. Results 65 patients (mean age 56.5 years; 74% male; 51% WHO PS 1) were assigned for treatment with AUY922 (33 patients), or comparator chemotherapy (32 patients; docetaxel [25 patients], or irinotecan [7 patients]). All patients had received at least 1 prior antineoplastic regimen. In the AUY922 arm, median duration of exposure was 6 weeks (range 1-41 weeks); the most frequent study drug-related AEs of any grade were diarrhea (46%), nausea (36%), photopsia (21%), blurred vision (18%), and decreased appetite (18%). Most drug-related AEs in the AUY922 arm were Grade 1/2; Grade 3/4 AEs that were suspected to be study drug-related were rare (all Conclusion AUY922 had an acceptable safety profile, which was different than that observed with docetaxel or irinotecan chemotherapy. There were fewer drug-related Grade 3/4 toxicities with AUY922 compared with the comparators, and hematologic AEs and SAEs, in particular Grade 3/4 neutropenia and neutropenic sepsis, were significantly more common with docetaxel and irinotecan. Grade 1/2 eye disorders were more common in the AUY922 treatment group, but no Grade 3 events were observed, and visual AEs were reversible with treatment interruption, dose reduction, or discontinuation. Efficacy data will be presented at a later date.

Background: A gemcitabine-cisplatin combination is a standard treatment option for patients with advanced biliary tract carcinoma (BTC). We assessed the efficacy and safety of this regimen at Chang Gung Memorial Hospital. Methods: Between April 2009 and December 2010, 30 chemotherapy-naοve patients (13 men and 17 women; median age: 61.5 years) with advanced BTC were retrospectively analyzed. Treatment consisted of gemcitabine (Gemmis®; TTY, Taipei, Taiwan) 1000 mg/m2, followed by cisplatin 30 mg/m2 on days 1 and 8 every 3 weeks. Tumor response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria every 2-3 cycles. The toxicity was assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3. Results: At the end of July, 2011, 27 patients were evaluated using the RECIST criteria. According to the intent to treat analysis of response, 5 patients (16.7%) had a partial response, 10 patients (33.3%) had stable disease and 12 patients (40.0%) had progressive disease. The median time to progression (TTP) and median overall survival (OS) of the 30 patients were 4.8 months and 13.4 months, respectively. The patients with biliary obstruction requiring drainage before treatment had a significantly shorter OS than those without biliary obstruction (p = 0.02) even though the TTP showed no statistically significant difference (p = 0.69) between groups. The major grade III/IV adverse events in the 30 patients included infection (n = 8, 26.7%), anemia (n = 5, 16.7%), neutropenia (n = 4, 13.3%), and elevated alanine aminotransferase (n = 2, 6.7%). There were no treatment-related deaths. Conclusions: Gemcitabine plus cisplatin is a feasible chemotherapy regimen with manageable toxicity in patients with advanced BTC. Maintaining good biliary drainage is essential for these patients.