Ramucirumab With Eribulin Versus Eribulin in Locally Recurrent or Metastatic Breast Cancer Previously Treated With Anthracycline and Taxane Therapy: A Multicenter, Randomized, Phase II Study.

BACKGROUND: Use of antiangiogenic agents in treatment of metastatic breast cancer (MBC) remains controversial. We evaluated the efficacy and safety of ramucirumab and eribulin versus eribulin alone as third- to fifth-line therapy in women with advanced breast cancer. PATIENTS AND METHODS: In this randomized (1:1), open-label, phase II study, US women aged 18 years or older with 2 to 4 previous chemotherapy regimens for locally recurrent or MBC, previous anthracycline and taxane treatment, and Eastern Cooperative Oncology Group performance status of 0 or 1 received ramucirumab with eribulin or eribulin alone in 21-day cycles (eribulin 1.4 mg/m2 intravenously on days 1 and 8; ramucirumab 10 mg/kg intravenously on day 1). Randomization was stratified according to previous antiangiogenic therapy and triple-negative status. The primary end point was progression-free survival (PFS) in the intention to treat population. RESULTS: One hundred forty-one women were randomized to ramucirumab with eribulin (n = 71) or eribulin alone (n = 70). Median PFS for ramucirumab with eribulin was 4.4 months (95% confidence interval [CI], 3.1-6.7) compared with 4.1 months (95% CI, 3.2-5.6) for eribulin (hazard ratio [HR], 0.83; 95% CI, 0.56-1.23; P = .35). Median overall survival in patients who received ramucirumab with eribulin was 13.5 months (95% CI, 10.4-17.9) compared with 11.5 months (95% CI, 9.0-17.3) in patients who received eribulin alone (HR, 0.91; 95% CI, 0.59-1.41; P = .68); objective response rate was 21% (13 of 62 patients) for the combination and 28% (17 of 60 patients) for eribulin alone. No unexpected toxicity was identified for the combination. CONCLUSION: Ramucirumab combined with eribulin did not significantly improve PFS in advanced MBC.

Pretransplant variables associated with quality of life in liver transplant recipients.

OBJECTIVE: With an increasing number of liver transplant recipients living, understanding quality-of-life issues is essential. Our goal is to identify pretransplant variables associated with post-transplant quality of life in liver transplant recipients. METHODS: Three hundred and eight liver transplant recipients were administered the Short Form 36 and a basic demographical questionnaire. Variables associated with post-transplant quality of life were studied in a multivariate regression analysis. Interaction terms were used to examine effect modification. RESULTS: Male gender, longer pretransplant work hours and interaction term between work hours and male gender were independently associated with Physical Functioning. Work hours positively correlated with Role-Physical, while viral hepatitis and ascites were negatively associated with Role-Physical. Ascites and viral hepatitis were independently negatively associated with Bodily Pain. Encephalopathy, hepatocellular carcinoma and viral hepatitis were independently associated with General Health. Ascites was also negatively associated with Social Functioning, Role-Emotional, Bodily Pain, General Health and Vitality. Viral hepatitis was negatively correlated with Vitality and Mental Functioning. CONCLUSIONS: Pretransplant variables such as ascites, encephalopathy, hepatocellular carcinoma, viral hepatitis, work hours, time unable to work and gender were significantly associated with post-transplant quality of life in liver transplant recipients. Interventions addressing these issues may be initiated to improve the post-transplant quality of life.

Employment and quality of life in liver transplant recipients.

The purposes of liver transplantation (LT) include the extension of survival, improvement in quality of life, and the return of the recipient as a contributing member of society. Employment is one measure of the ability to return to society. The aim of this study is to determine the factors affecting employment/subemployment after LT. A total of 308 adult liver transplant recipients who were seen at the University of California, Los Angeles were administered the Medical Outcomes Short Form 36 (SF-36) and a questionnaire regarding work history and insurance coverage. Multivariate analysis were used to identify independent variables associated with posttransplantation employment. Interaction terms were used to examine effect modification. Of 308 transplant recipients, 218 (70.8%) worked prior to transplantation, and 78 (27%) worked posttransplantation. Pretransplant variables that were independently associated with posttransplantation employment included the following: lack of disability income (odds ratio [OR] = 1.86; 95% confidence interval [CI], 1.32-7.18; P = 0.36); health maintenance organization (HMO)/preferred provider organization (PPO) insurance (OR = 3.08; 95% CI, 1.32-7.18; P < 0.01); the number of hours worked (OR = 1.17; 95% CI, 1.08-1.28; P < 0.01); and the lack of diabetes mellitus (OR = 0.23; 95% CI, 0.70-0.73; P < 0.01). An interaction term between disability income and hours worked prior to transplantation (OR = 0.16; 95 % CI, 0.03-0.83; P = 0.03) was independently associated with posttransplantation employment. In a separate regression model of SF-36 responses, posttransplantation physical functioning (OR = 1.17; 95% CI, 1.10-1.26; P < 0.01) and role-physical (OR = 1.1; 95% CI, 1.02-1.16; P < 0.01) were independently associated with employment after transplantation. In conclusion, HMO or PPO insurance, lack of disability income coverage prior to transplant, the absence of diabetes mellitus, the number of hours worked prior to transplantation, and high physical functioning were associated with posttransplantation employment.

Anemia in liver transplant recipients undergoing antiviral treatment for recurrent hepatitis C.

Adherence to antiviral therapy is essential to achieve sustained virological responses in patients treated for hepatitis C. An important limitation to use of appropriate doses of ribavirin is development of anemia. The aim of this study is to identify risk factors associated with anemia in liver transplant recipients undergoing treatment for recurrent hepatitis C virus (HCV). Retrospective analysis was performed on 115 adult liver transplantation (LT) recipients who received antiviral treatment. Anemia was defined as hemoglobin of <10 gm/dL or the use of erythropoietin replacement therapy. Variables found to be significant in univariate analysis were further studied in multivariate analysis. The mean (+/- standard deviation [SD]) age of our cohort was 52.1 (+/- 8.8) yr. Anemia developed in 44 patients (38.3%). Mean (+/- SD) onset of anemia was 8.9 (+/- 6.8) weeks after initiation of antiviral therapy. A total of 30 patients (26%) required erythropoietin replacement, at a mean (+/- SD) of 7.9 (+/- 6.0) weeks after start of antiviral treatment. A total of 27 patients (24%) required ribavirin dose reduction, at a mean (+/- SD) time to dose reduction of 8.1 (+/- 6.3) weeks. In univariate analysis, body mass index (BMI) (P < 0.01), mycophenolate mofetil use (P = 0.05), trimethoprim-sulfamethoxazole (P = 0.02), and age (P = 0.02) were statistically significant. In conclusion, in multivariate analysis, BMI (P < 0.01) and age (P = 0.02) were found to be independent predictors of anemia. Anemia is common in liver transplant recipients treated for recurrent HCV. Special vigilance is required for older patients and patients with a low BMI.

The MELD score in advanced liver disease: association with clinical portal hypertension and mortality.

BACKGROUND: The Model for End-Stage Liver Disease (MELD) score is a measure of chronic liver disease severity. Patients awaiting transplantation are assessed using this score. However, it has recently been suggested that changes in MELD score may be as important as the absolute MELD score in predicting short-term survival. However, clinical factors that affect the MELD score are unknown. We sought to identify predictors of mortality for potential transplant patients and examine factors that might predict changes in MELD score. MATERIALS AND METHODS: Between January 1, 2002, and July 30, 2004, we retrospectively examined risk factors of 429 adult patients awaiting liver transplantation at the University of California at Los Angeles (UCLA). Analysis of the data was performed using demographics, manifestations of portal hypertension, time between last MELD recorded and event, and laboratory values. Significant factors in univariate analysis were further studied using Cox proportional hazards regression multivariate analysis. RESULTS: At mean follow-up of 2.15 years (+/-1.49 years), 71 patients (16.5%) had MELD scores that increased 5-10 points, 22 had changes of 10-15 points, and 14 had changes of 15-20 points. Manifestations of portal hypertension, laboratory values, and etiology of liver disease did not predict changes in MELD score. However, development of hepatic encephalopathy (HR, 3.95; P=.002; 95% CI, 1.70 to 9.42) and MELD score (HR, 1.04; P=.001; 95% CI, 1.004 to 1.08) were associated with variceal bleeding. Also, MELD score (HR, 1.07; P<.001; 95% CI, 1.05 to 1.09), refractory ascites (HR, 2.15; P=.002; 95% CI, 1.31 to 3.53), and alcoholic cirrhosis (HR, 0.40; P=.04; 95% CI, 0.18 to 0.94) were independent predictors of mortality. CONCLUSIONS: Encephalopathy and MELD score were associated with variceal bleeding. Patients with an elevated MELD score, refractory ascites, and alcoholic cirrhosis had increased mortality while on the liver transplant list. No factors predicting changes in the MELD score were identified.

MELD fails to measure quality of life in liver transplant candidates.

Previous studies have demonstrated an association between Child Turcotte-Pugh (CTP) class and impaired quality of life. However, the relationship between the model for end-stage liver disease (MELD) score and quality of life (QOL) has not been well studied. In this study, quality of life questionnaires (Medical Outcomes Short Form 36 [SF-36] and the Chronic Liver Disease Questionnaire [CLDQ]) were administered to 150 adult patients awaiting liver transplantation. We also collected demographic data and laboratory results and recorded manifestations of hepatic decompensation. The study found that all domains of the SF-36 and CLDQ were significantly lower in our patient cohort than in normal controls (P < .001). There was a moderate negative correlation between CPT class and physical components of the SF-36 (r = -.30), while there was a weak negative correlation (r = -.10) between CPT class and the mental component. There was a negative moderate correlation between CPT class and overall CLDQ (r = -.39, P < .001) and a weak correlation (r = -.20) between MELD score and overall CLDQ score. Both encephalopathy (correlation coefficient = -.713, P = .004) and ascites (correlation coefficient = -.68, P = .006) were predictive of the QOL using CLDQ (adjusted R(2) = .1494 and f = 0.000). In conclusion, in liver transplant candidates, the severity of liver disease assessed by the MELD score was not predictive of QOL. The presence of ascites and/or encephalopathy was significantly associated with poor quality of life. CTP correlates better to QOL, probably because it contains ascites and encephalopathy.

Hepatitis C positive grafts may be used in orthotopic liver transplantation: a matched analysis.

Hepatitis C (HCV)-positive liver grafts have been increasingly used in patients with decompensated liver disease from HCV because of critical shortage of available organs. Fifty-nine recipients of HCV-positive grafts were matched to patients who received HCV-negative grafts. All recipients were transplanted for HCV liver disease. Matching variables were (1) status, (2) pre-transplant creatinine, (3) recipient age, (4) donor age, (5) warm ischemia time, and (6) year of transplantation. Both unmatched and matched analyses were performed on patient survival, graft survival, and time to HCV recurrence. There was no significant statistical difference in patient, graft, or HCV recurrence-free survival between recipients of HCV-positive and HCV-negative grafts with matched and unmatched analyses (p > 0.05). The 3-year estimates of HCV disease-free survival were 12% (+/- 9%) and 19% (+/- 7%) using HCV-positive and -negative grafts, respectively. The use of HCV-positive grafts in recipients with HCV does not appear to affect patient survival, graft survival, or HCV recurrence when compared with the use of HCV-negative grafts. Our results suggest that HCV-positive grafts can be used in a HCV liver transplant recipient.

MELD score predicts 1-year patient survival post-orthotopic liver transplantation.

The Model for End-Stage Liver Disease (MELD) is an important predictor in patients awaiting orthotopic liver transplantation (OLT). However, the model's association with posttransplant patient survival is unclear. We studied 1-year patient survival in 404 adult patients who underwent OLT at the University of California Los Angeles. The hazard rates of patient survival according to the MELD strata and United Network for Organ Sharing (UNOS) statuses were assessed by Proportional Hazard Cox regression analysis. The difference in survival for MELD strata and UNOS status were compared using the Cox model. There was a significant difference in 1-year patient (P =.0006) survival using different MELD strata, whereas there was a trend according to UNOS status (P =.051). Increased rate of death was observed in recipients of OLT with higher MELD scores (> 36, hazard ratio 3.9; 95% CI 1.55, 10.27) and more urgent UNOS status (2A; hazard ratio, 1.99; 95% CI 1.07, 3.7). The MELD stratum is better associated with 1-year patient survival in liver transplant recipients than UNOS statuses. Patient survival was worse with higher MELD scores.

Discordance between ALT values and fibrosis in liver transplant recipients treated with ribavirin for recurrent hepatitis C.

Hepatitis C virus (HCV) recurrence is a serious problem after orthotopic liver transplantation (OLT). The role of ribavirin as a single agent to treat recurrent HCV is controversial. Our aim was to evaluate the correlation between alanine aminotransferase (ALT) levels and histological findings in OLT recipients treated with ribavirin monotherapy for recurrent HCV. The mean [+/- standard error (SE)] age of 11 patients was 50.1 (SE +/- 8.6) years. The estimated mean dose and duration of ribavirin treatment (+/- SE) was 661.5 (+/- 52.5) mg and 20.4 (+/- 1.7) months, respectively. Five patients required either dose reduction or erythropoietin. We found a significant decrease of mean (+/- SE) ALT value from 246 +/- 44.8 U/L to 109.4 +/- 49.1 U/L (p = 0.002) in patients treated with ribavirin. However, there was also significant worsening of interface activity (p = 0.03) and fibrosis (p = 0.02). No significant association was found between ALT values and (i) stage of hepatic fibrosis, (ii) interface activity, (iii) lobular activity and (iv) HCV RNA values. Our results suggest that HCV disease can progress despite a significant decrease in ALT values. ALT values are inadequate markers of the ribavirin monotherapy and can lead to erroneous conclusions of efficacy.