Enhanced antitumor effect of binimetinib in combination with capecitabine for biliary tract cancer patients with mutations in the RAS/RAF/MEK/ERK pathway: phase Ib study.

BACKGROUND: A phase Ib study of binimetinib and capecitabine for gemcitabine-pretreated biliary tract cancer (BTC) patients was conducted. METHODS: Binimetinib and capecitabine were dosed twice daily on days 1-14, in 3-week cycles. In the dose-escalation (DE) part, three dose levels (DL) were tested (DL1: binimetinib/capecitabine, 15 mg/1000 mg/m2; DL2: 30 mg/1000 mg/m2; DL3: 30 mg/1250 mg/m2). RESULTS: In the DE part, nine patients were recruited and no dose-limiting toxicity was noted. Therefore, the recommended phase 2 dose was determined as DL3. In the expansion part, 25 patients were enrolled. In total, 34 patients, 25 (73.5%) and 9 patients (26.5%) were second-line and third-line settings, respectively. The 3-month progression-free survival (PFS) rate was 64.0%, and the median PFS and overall survival (OS) were 4.1 and 7.8 months. The objective response rate and disease control rate were 20.6% and 76.5%. In total, 68.4% of stable diseases were durable (> 12 weeks). Furthermore, patients with RAS/RAF/MEK/ERK pathway mutations (38.5%) showed significantly better tumour response (p = 0.028), PFS (5.4 vs. 3.5 months, p = 0.010) and OS (10.8 vs. 5.9 months, p = 0.160) than wild type. Most of the adverse events were grade 1/2 and manageable. CONCLUSIONS: A combination of binimetinib and capecitabine shows acceptable tolerability and promising antitumor efficacy for gemcitabine-pretreated BTC, especially in patients with RAS/RAF/MEK/ERK pathway mutations. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT02773459).

Early palliative care and quality of life of advanced cancer patients-a multicenter randomized clinical trial.

BACKGROUND: To compare quality of life (QoL) of patients receiving early palliative care (EPC) vs. standard oncologic care (SOC). METHODS: Pragmatic, multicenter, randomized trial at five University and Community Hospital Cancer Centers in Northern Italy. Advanced non-small cell lung, gastric, pancreatic and biliary tract cancer patients diagnosed within the previous 8 weeks. In the EPC arm, visits were performed systematically by a dedicated physician/nurse palliative care (PC) team, who assessed physical and psychosocial symptoms, and enacted the necessary services. In the SOC arm, PC visits were only carried out if requested. The primary outcome was the difference in the change of QoL [Functional Assessment of Cancer Therapy-General measure (FACT-G)] from baseline to 12 weeks in the two groups. RESULTS: From November 2014 to March 2016, 281 patients were enrolled (142 EPC, 139 SOC); 218 completed FACT-G at 12 weeks. Baseline demographic and clinical characteristics were similar for the two groups. Values of FACT-G at baseline and 12 weeks were 72.3 (SD 12.6) and 70.1 (SD 15.5) for patients enrolled in the EPC arm, vs. 71.7 (SD 14.7) and 69.6 (SD 15.5) for the SOC arm, but the change scores did not differ significantly between groups. In the multivariable analysis, adjusting for QoL at baseline, two potential prospective prognostic factors were statistically significant: lung cancer (P=0.03) and interaction of living without a partner and intervention arm (P=0.01). Dying within 6 months (P<0.001) was also statistically significant. CONCLUSIONS: In this study, EPC did not improve QoL in advanced cancer patients, but our findings highlight aspects which may guide future research on EPC.

Problems and needs in patients with incurable esophageal and pancreaticobiliary cancer: a descriptive study.

Patients with incurable esophageal cancer (EC) or pancreaticobiliary cancer (PBC) often have multiple symptoms and their quality of life is poor. We investigated which problems these patients experience and how often care is expected for these problems to provide optimal professional care. Fifty-seven patients with incurable EC (N = 24) or PBC (N = 33) from our outpatient clinic completed the validated "Problems and Needs for Palliative Care" (PNPC) questionnaire and two disease-specific quality of life questionnaires, European Organization for Research and Treatment in Cancer (EORTC). Although patients in general had several problems, physical, emotional, and loss of autonomy (LOA) problems were most common. For these physical and emotional problems, patients also expected professional care, although to a lesser extent for LOA problems. Inadequate care was received for fatigue, fear, frustration, and uncertainty. We conclude that an individualized approach based on problems related to physical, emotional, and LOA issues and anticipated problems with healthcare providers has priority in the follow-up policy of patients with incurable upper gastrointestinal cancer. Caregivers should be alert to discuss needs for fatigue, feelings of fear, frustration, and uncertainty.

Measuring post-traumatic growth in people diagnosed with hepatobiliary cancer: directions for future research.

PURPOSE/OBJECTIVES: To highlight and provide preliminary data regarding issues in the measurement of post-traumatic growth in people diagnosed with primary or metastatic hepatobiliary cancer. DESIGN: Prospective. SETTING: A large medical center in Pittsburgh, PA. SAMPLE: 120 patients with hepatobiliary cancer. METHODS: Participants were administered a battery of questionnaires, including the Post-Traumatic Growth Inventory (PTGI), Center for Epidemiological Studies-Depression scale, and the Functional Assessment of Cancer Therapy-Hepatobiliary module. Family caregivers also rated patients' post-traumatic growth. Qualitative data collected from patients included positive and negative changes associated with their cancer diagnoses. MAIN RESEARCH VARIABLES: Post-traumatic growth, depression, quality of life, and caregiver ratings of patients' post-traumatic growth. FINDINGS: The results revealed that the PTGI is a reliable instrument in people diagnosed with cancer. The level of post-traumatic growth varies depending on hepatobiliary cancer type. The onset and process of post-traumatic growth differed based on the method of measurement employed (qualitative versus quantitative). Agreement on the PTGI was high between patients and caregivers, suggesting that the patients' growth was observable to others. Post-traumatic growth was not found to be associated with depressive symptoms, quality of life, or survival in patients diagnosed with hepatobiliary cancer. CONCLUSIONS: The results of this study underscore the need to understand differences in the measurement and the process of post-traumatic growth in people with cancer. IMPLICATIONS FOR NURSING: For some patients, post-traumatic growth as a result of a cancer diagnosis may be associated with positive cognitive, emotional, and behavioral changes that influence mental and physical health. For patients who experience post-traumatic growth, healthcare providers may be able to facilitate behavior changes to enhance health.

Quality of life after liver resection for hepatobiliary malignancies.

BACKGROUND: Few prospective longitudinal studies have used a validated quality of life (QOL) instrument in patients undergoing liver resection for hepatobiliary malignancy. METHODS: Patients undergoing liver resection for hepatobiliary tumours in a 1-year period were enrolled. The cancer-specific European Organization for Research and Treatment of Cancer core questionnaire (EORTC QLQ-C30) was completed before operation, and at 6, 12 and 36-48 months after surgery. QOL over time was analysed in relation to several clinical factors. RESULTS: A total of 103 patients were enrolled. Patient compliance was at least 75 per cent at all stages. Most functional scales and the global QOL scale showed a non-significant trend towards deterioration at 6 months and a return to preoperative level at 12 months. Physical functioning and dyspnoea deteriorated significantly at 6 months (P = 0.020 and P = 0.004 respectively) and did not recover by 12 months (P = 0.002 and P < 0.001 respectively). Pain and fatigue showed clinically significant deterioration over 12 months, which was not statistically significant. Survivors without recurrence at 36-48 months showed better QOL than those with recurrent disease. CONCLUSION: Major liver resection is associated with acceptable QOL outcomes, and QOL continues to improve in the long term in those without recurrence.

[Evaluation of Chinese version of the Functional Assessment of Cancer Therapy-Hepatobiliary questionnaire].

OBJECTIVE: To evaluate the effectiveness of the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) questionnaire in measuring the quality of life in patients with primary hepatic carcinoma (PHC) in China. METHODS: FACT-Hep questionnaire was translated into Chinese and revised properly. From September 2005 to April 2006, one hundred and eighty patients with primary liver carcinoma were admitted and measured by using the Chinese version of FACT-Hep questionnaire, and the reliabilities, validities and responsibilities of the questionnaire were assessed. RESULTS: Correlation coefficient was higher between items and dimension of their corresponding domain (0.5933+/-0.1652) than that between the items and other domains (0.2749+/-0.1922). Six principal constituents were extracted by factor analysis and represented all domains of the questionnaire. The combinations of components were consistent with what was expected. The correlation coefficient of criterion-related validity was 0.828. The test-retest reliability correlation coefficients of physical, social/family, emotion, function, symptom and total questionnaire were 0.731, 0.334, 0.953, 0.786, 0.785 and 0.801 respectively, and the values of Cronbach's alpha were 0.7397, 0.4193, 0.7914, 0.8250, 0.8399 and 0.9161, respectively. There were statistical differences in scores of FACT-Hep questionnaire in different PHC stages or in different Child-Pugh classes (P<0.05). CONCLUSION: The FACT-Hep questionnaire can measure the quality of life in patients with PHC with good reliability, validity and responsiveness; it can be used in assessing the disease-specific health-related quality of life of patients with hepatobiliary cancers.

Depression, immunity, and survival in patients with hepatobiliary carcinoma.

PURPOSE: The aims of the present study were to assess the prevalence of depressive symptoms at diagnosis, test the association between depressive symptoms and survival, and preliminarily test a mediational model of depression, immunity, and survival in patients with hepatobiliary carcinoma (HBC). PATIENTS AND METHODS: One hundred one patients diagnosed with HBC were prospectively studied. Depressive symptoms were measured at diagnosis using the Center for Epidemiological Studies Depression Scale (CES-D). Sociodemographic and disease-specific data were gathered from the patients' charts. In a subsample of patients, stress; alcohol, tobacco, and drug use; sleep quality; physical activity; social support; natural killer (NK) cell number and cytotoxicity; and plasma levels of interleukin (IL) -4, IL-5, tumor necrosis factor alpha, and interferon gamma were measured. Survival was measured from date of diagnosis to death. RESULTS: At diagnosis, 37% of patients reported a CES-D score of > or = 16 (clinical range). Using Cox regression analysis, sociodemographic and disease-specific variables and CES-D score significantly predicted survival (Breslow chi2 = 32.4, P = .006). Only vascular invasion (P = .001) and CES-D score > or = 16 (P = .03) were significant predictors. In a subsample of 23 patients, patients who reported a CES-D score of > or = 16 were found to have significantly lower NK cell numbers than patients who reported a CES-D score of less than 16 (F1,21 = 9.39, P = .003). A robust trend was found in which NK cell number was associated with survival. A mediational model linking depressive symptoms and survival, with NK cell number as a mediator, was preliminarily supported. CONCLUSION: Secondary to the high prevalence of depressive symptoms and impact on survival, psychological and pharmacologic interventions should be designed and implemented in patients diagnosed with HBC.

Preliminary results of an individually tailored psychosocial intervention for patients with advanced hepatobiliary carcinoma.

BACKGROUND: A plethora of research now exists documenting the benefits of psychosocial interventions for cancer patients; however, no studies have been conducted with people diagnosed with hepatobiliary carcinoma. METHODS: A total of 28 patients agreed to participate in the study in which 14 patients were randomized to the intervention arm of the study and 14 patients to an attention-standard of care arm. Evaluation of the benefits of the intervention was performed using the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep), the Center for Epidemiological Studies-Depression, the State Trait Anxiety Index (STAI) to assess anxiety, peripheral blood leukocytes to measure immune system modulation, and survival. RESULTS: Results indicate that patients who were randomly assigned to the intervention arm of the study reported clinically, but not statistically, significant improvements on symptoms of depression and anxiety, disease-related symptoms and treatment side effects, health-related quality of life (HRQL), and modest improvements in peripheral blood leukocytes and survival when compared with the standard of care group. CONCLUSIONS: The findings of this study suggest that the individually tailored intervention was feasible and preliminary data suggested that the intervention may improve patients' HRQL, mood, and had modest improvements in immune system functioning and survival. Further research is needed with a larger sample size to test the statistical significance and generalizability of the individually tailored intervention.

Measuring health-related quality of life in patients with hepatobiliary cancers: the functional assessment of cancer therapy-hepatobiliary questionnaire.

PURPOSE: This is the first report on the development and initial validation of the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) questionnaire, a 45-item self-report instrument designed to measure health-related quality of life (HRQL) in patients with hepatobiliary cancers. The FACT-Hep consists of the 27-item FACT-G, which assesses generic HRQL concerns, and the newly validated 18-item Hepatobiliary Subscale (HS), which assesses disease-specific issues. PATIENTS AND METHODS: The development of the HS followed a four-phase process of item generation, item reduction, scale construction, and reliability/validity testing. Two independent samples were studied: item generation (sample 1; n = 30) and reliability/validity testing (sample 2; n = 51). RESULTS: In sample 2, all subscales and aggregated scores showed high internal consistency at initial assessment (Cronbach's alpha range, 0.72 to 0.94) and retesting (Cronbach's alpha range, 0.81 to 0.94). Measurement stability over a 3- to 7-day period was also high for all aggregated scales (test-retest correlation range, 0.84 to 0.91; intraclass correlation coefficient range, 0.82 to 0.90). Convergent and divergent validity were demonstrated by examining relationships between FACT subscales and mood, social support, and social desirability. Finally, when performance status and treatment status were used to divide sample 2, the HS differentiated groups to a degree comparable to the Physical and Functional Well-Being subscales of the FACT-G, thereby contributing favorably to a 32-item Trial Outcome Index. In addition to the 18 validated, scored items in the HS, seven treatment-related items may be appended, if clinically indicated, as a separate subscale. CONCLUSION: The 45-item FACT-Hep can be used independently as a brief measure of disease-related symptoms and functioning. Alone or paired with the FACT-G, the HS has promise for use in assessing the disease-specific HRQL of patients with hepatobiliary cancers.

Surgical palliative treatment in bilio-pancreatic malignancy.

Most patients with bilio-pancreatic malignancy are no candidate for curative resection and will need palliative treatment. Palliation in these patients is focussed on relief symptoms such as obstructive jaundice, duodenal obstruction and pain. It has been suggested that non surgical treatment (stenting) is the optimal palliation for patients with short survival and surgical bypass for those surviving more than 6 months. Unfortunately valid criteria for estimating survival are not available except for metastases. A prognostic score chart to predict survival probabilities for 3,6 and 9 months after diagnosis has been developed. The use of this prognostic score chart may help clinicians to select optimal palliative treatment for individual patients. Surgical biliary drainage can be performed by a simple cholecystoenterostomy; a choledochoduodenostomy or a choledocho/hepaticojejunostomy with Roux-Y jejunal limb reconstruction. The present data available in the literature do not give sufficient guidance to make a well deliberated selection between the different types of bypass surgery but choledochojejunostomy is generally preferred. Gastroentero-stomy is performed routinely during the biliary bypass procedure in our institution because gastric outlet obstruction has been described between 9-21% of the patients who underwent only a surgical biliary bypass but there is still controversy. Recently it was also suggested that there is an indication to perform palliative resections. No results are available to justify resections as a debulking procedure.