Prospective Longitudinal Patient-Reported Satisfaction and Health-Related Quality of Life following DIEP Flap Breast Reconstruction: Effects of Reconstruction Timing.

BACKGROUND: Without reconstruction, mastectomy alone can produce significant detrimental effects on health-related quality of life. The magnitude of quality-of-life benefits following breast reconstruction may be unique based on timing of reconstruction. Facilitated by the BREAST-Q questionnaire, characterization of how reconstruction timing differentially affects patient-reported quality of life is essential for improved evidence-based clinical practice. METHODS: Consecutive DIEP flap breast reconstruction patients prospectively completed BREAST-Q questionnaires preoperatively and at two different time intervals postoperatively. The first (postoperative time point A) and second (postoperative time point B) postoperative questionnaires were completed 1 month postoperatively and following breast revision/symmetry procedures, respectively. Postoperative flap and donor-site complications were recorded prospectively. Stratified by timing (immediate versus delayed) of reconstruction, preoperative clinical data, operative morbidity, and BREAST-Q scores were compared at all time points. RESULTS: Between July of 2012 and August of 2016, 73 patients underwent 130 DIEP flap breast reconstructions. Collectively, breast satisfaction, psychosocial well-being, and sexual well-being scores significantly (p < 0.001) increased postoperatively versus baseline. Chest and abdominal physical well-being scores returned to baseline levels by postoperative time point B. Preoperatively, patients undergoing delayed breast reconstruction reported significantly (p < 0.05) lower breast satisfaction, psychosocial well-being, and sexual well-being scores compared to immediate reconstruction patients. Postoperatively, delayed and immediate reconstruction patients reported similar quality-of-life scores. Outcome satisfaction and flap and donor-site morbidity were similar between groups irrespective of timing of reconstruction. CONCLUSIONS: In this prospective study, patient-reported outcomes demonstrate significant improvements in breast satisfaction, psychosocial well-being, and sexual well-being among patients following DIEP flap reconstruction. Moreover, preoperative differences in quality-of-life scores among delayed/immediate reconstruction patients were eliminated postoperatively. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

Case Volume-Dependent Changes in Operative Morbidity following Free Flap Breast Reconstruction: A 15-Year Single-Center Analysis.

BACKGROUND: Operative morbidity is a common yet modifiable feature of complex surgical procedures. With increasing case volume, improvement in morbidity has been reported through designated procedural processes and greater repetition. Defined as a volume-outcome association, improvement in breast reconstruction morbidity with increasing free flap volume requires further characterization. METHODS: A retrospective analysis was conducted among consecutive free flap patients using a two-microsurgeon model between January of 2002 and December of 2017. Patient demographics and operative characteristics were obtained from medical records. Complications including unplanned surgical intervention (take-back) and flap loss were obtained from prospectively kept databases. Individual surgeon operative volume was estimated by considering overall practice volume and correcting for the number of surgeons at any given time. RESULTS: During the study period, 3949 patients met inclusion criteria. A total of 6607 breasts underwent reconstruction with 6675 free flaps. Mean patient age was 50 ± 9.4 years and mean body mass index was 28.8 ± 5.0 kg/m2. Bilateral reconstruction was performed on 2633 patients (66.5 percent), with 4626 breasts (70.5 percent) reconstructed in the immediate setting. Overall, breast and donor-site complications were reported in 507 breasts (7.7 percent) and 607 cases (15.4 percent), respectively. Take-back was required in 375 cases (9.5 percent), with complete flap loss occurring in 57 cases (0.9 percent). Based on annual flaps per surgeon, the incidence of complications decreased with increasing volume (slope = -0.12; p = 0.056). CONCLUSION: Through procedural efficiency and execution of defined clinical processes using a two-microsurgeon model, increases in microsurgical breast reconstruction case volume result in decreased morbidity. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Serum microRNA profiles among dioxin exposed veterans with monoclonal gammopathy of undetermined significance.

Previously an increased risk for monoclonal gammopathy of undetermined significance (MGUS), a precursor of multiple myeloma (MM), was reported among Vietnam veterans exposed to Agent Orange and its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Dysregulated expression of certain microRNAs (miRNAs) was demonstrated in MGUS and MM. Given the important role of miRNAs in cellular homeostasis, the aim of this study was to determine if there was an association between serum levels of selected miRNAs and TCDD in 47 MGUS cases identified in our previous investigation using serum specimens and exposure data archived by the Air Force Health Study (AFHS). A total of 13 miRNA levels (let-7a, let-7i, miR-16, miR-20a, miR-21, miR-34a, miR-106b, miR-146a, miR-181a, miR-192, miR-205, miR-335, and miR-361) was measured in serum stored during the 2002 AFHS follow-up and the relationship to lipid-adjusted serum TCDD levels in 1987 was determined. miR-34a showed the strongest relationship with TCDD; after age-adjustment, this positive association was more pronounced. In contrast, the other 12 miRNAs displayed absolute values of age adjusted coefficient estimates below 1.16 and non-significant p-values. The observed strong positive association between high body burdens of TCDD and miR-34a, a tumor suppressor regulated by p53, in this MGUS population warrants clarification of the TCDD-miR-34a relationship and its role in the pathogenesis of MGUS and risk for MM.

Cardiovascular Risk Assessment Varies Widely by Calculator and Race/Ethnicity in a Majority Latinx Cohort Living with HIV.

Comparison of cardiovascular disease (CVD) risk calculators in Latinx majority populations living with HIV can assist clinicians in selecting a calculator and interpreting results. 10-year CVD risks were estimated for 652 patients seen ≥ 2 times over 12 months in a public clinic using three risk calculators: Atherosclerotic CVD risk Calculator (ASCVD), Framingham Risk Calculator (FRC), and Data Collection on Adverse Effects of Anti-HIV Drugs Study (D:A:D) Calculator. Median estimated 10-year CVD risk in this population was highest using FRC (11%), followed by D:A:D (10%), and lowest with ASCVD (5%; p < 0.001). However, D:A:D classified 44.3% in a high/very high risk category compared to FRC (20.7%) and ASCVD (33.4%) (all p < 0.001). ASCVD risk estimates differed significantly by race/ethnicity (p < 0.001). Risk varied widely across three risk calculators and by race/ethnicity, and providers should be aware of these differences when choosing a calculator for use in majority minority populations.

Prospective Longitudinal Patient-Reported Satisfaction and Health-Related Quality of Life following DIEP Flap Breast Reconstruction: Relationship with Body Mass Index.

BACKGROUND: Breast reconstruction plays a significant role in breast cancer treatment recovery. Introduction of the BREAST-Q questionnaire has facilitated quantifying patient-reported quality-of-life measures, promoting improved evidence-based clinical practice. Information regarding the effects of body mass index on patient-reported outcomes and health-related quality of life is significantly lacking. METHODS: Consecutive deep inferior epigastric perforator (DIEP) flap breast reconstruction patients prospectively completed BREAST-Q questionnaires preoperatively and at two points postoperatively. The first (postoperative time point A) and second (postoperative time point B) postoperative questionnaires were completed 1 month postoperatively and following breast revision, respectively. Postoperative flap and donor-site complications were recorded prospectively. BREAST-Q scores were compared at all time points and stratified by body mass index group (≤25, >25 to 29.9, 30 to 34.9, and ≥35 kg/m). RESULTS: Between July of 2012 and August of 2016, 73 patients underwent 130 DIEP flap breast reconstructions. Breast satisfaction and psychosocial and sexual well-being scores increased significantly postoperatively. Chest and abdominal physical well-being scores returned to baseline levels by postoperative point B. Preoperatively, stratified by body mass index, breast satisfaction and psychosocial well-being scores were significantly lower among patients with body mass index of 35 or higher and of more than 30, respectively. After reconstruction, not only were breast satisfaction, psychosocial, and sexual well-being scores significantly improved in all body mass index groups versus baseline, but also between-body mass index group differences were no longer present. Outcome satisfaction, flap, and donor-site morbidity were similar irrespective of body mass index. CONCLUSIONS: Patient-reported outcomes demonstrate significant improvements in breast satisfaction and psychosocial and sexual well-being among patients following DIEP flap reconstruction. Preoperative differences in quality-of-life scores were improved in patients with obesity (body mass index ≥30 kg/m). CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

Internal Mammary Lymph Node Biopsy During Free-Flap Breast Reconstruction: Optimizing Adjuvant Breast Cancer Treatment Through Comprehensive Staging.

BACKGROUND: Accurate breast cancer staging is essential for optimal management of adjuvant therapies. While breast lymphatic drainage involves both axillary and internal mammary (IM) lymph node (LN) basins, IM LN sampling is not routinely advocated. The current study analyzes the incidence of IM LN metastases sampled during free flap breast reconstruction and subsequent changes in adjuvant treatment. METHODS: A retrospective analysis of patients with positive IM LN biopsies during free flap breast reconstruction was performed. Pre-reconstruction surgical and adjuvant therapies as well as staging and prognostic data were recorded. Change in adjuvant therapies based solely on IM LN positivity was determined. RESULTS: IM LN metastases were found on 28 (1.3%) out of 2057 patients and comprised the study population. Mean age was 49 years with pre-reconstruction chemotherapy or radiation administered in 50 or 54% of cases, respectively. Five (18%) patients had previously undergone lumpectomy with axillary sampling. Mean tumor size was 3.1 cm with tumor location evenly distributed among all four quadrants. Ten (36%) patients had isolated IM LN metastases Patients with both axillary and IM disease had larger lesions, increased prevalence of pre-reconstruction chemotherapy and radiation. Based exclusively on positive IM LN disease, 17 (63%) patients had a change in adjuvant therapy. CONCLUSION: Despite the low incidence of IM LN metastases, IM LN biopsy during free flap breast reconstruction is recommended. In 36% of cases, nodal metastases were isolated to the IM nodes. Identification of IM metastases influenced adjuvant therapies in a majority of cases.

Prescription Opioid Use is Associated with Virologic Failure in People Living with HIV.

Prescription opioid misuse is a rising epidemic in the U.S., and people living with HIV are at increased risk. We assessed the association between prescription opioid use and virologic failure in HIV+ patients in the South Texas HIV Cohort. We found prescription opioid use was significantly associated with virologic failure, after adjustment for age, race, gender, insurance status, years living with HIV, reported HIV risk factor, chronic hepatitis C virus infection, current substance abuse, and care engagement. These findings suggest that opioid analgesic use may have negative consequences beyond misuse in people living with HIV.

Left Versus Right: Does Location Matter for Refractory Metastatic Colorectal Cancer Patients in Phase 1 Clinical Trials?

PURPOSE: Location of the primary tumor is prognostic and predictive of efficacy with VEGF-inhibitors (I) versus EGFR-I given first-line to metastatic colorectal cancer (mCRC) patients. However, little is known regarding the effect of location on prognosis and prediction in refractory mCRC. We assessed the efficacy of VEGF-I and EGFR-I in regards to location of the primary tumor in patients with refractory mCRC enrolled in early phase studies. METHODS: A historical cohort analysis of mCRC patients, including 44 phase I trials our institution, from March 2004 to September 2012. Median Progression free survival (mPFS) and overall survival (mOS) were estimated from Kaplan-Meier curves and groups were statistically compared with the log-rank test. RESULTS: One hundred thirty-nine patients with a median age 59 (33-81). 73.9% received 3+ lines of therapy. All KRAS wild-type patients had received prior EGFR-I. LOCATION: right 20.9%, left 61.9%, and transverse 4.3%. For survival analysis, transverse CRC were included with right. Of the 112 patients, mOS was left (N = 80) 6.6 months versus right (N = 32) 5.9 months, P = 0.18. mPFS was left (n = 86) 2.0 months versus right (N = 35) 2.0 months, P = 0.76. In subgroup analysis, survival was significant for KRAS wild-type patients with left-sided mCRC had mOS of 6.2 months with other agents versus 9.4 months with EGFR-I (P = 0.03). CONCLUSIONS: In phase 1 clinical trials, although location alone was not prognostic in heavily pretreated patients, left-sided mCRC had improved survival with EGFR-I. Despite progression on EGFR-I, left-sided KRAS wild mCRC patients should be considered for phase 1 studies of agents targeting growth factor pathways.

Health Care Access, Utilization, and Cancer Screening Among Low-Income Latina Women.

INTRODUCTION: Cancer screening reduces mortality rates for breast, cervical, and colon cancer. Yet cancer screening rates for Latina women are lower than for non-Latino Whites, and below Healthy People 2020 goals. Additionally, Latinos face many health care access barriers. This study examined health care access and utilization in relation to cancer screening among low-income Latina women recruited from a high-risk area and enrolled in a navigation-plus-education intervention. METHODS: Latina women considered rarely or never screened for breast, cervical, or colorectal cancer were recruited from community-based organizations and events (N = 691). We gathered self-reported survey data on insurance status, usual source of care, health care utilization, and cancer screening behavior. We conducted multivariable logistic regression models to estimate odds ratios of receipt of at least one cancer screening test. RESULTS: Overall, 28% of women received at least one cancer screening test. Results indicated that women without insurance (odds ratio [OR] = 2.08; confidence interval [CI] = 1.09, 3.98) and without a doctor's visit in the past year (OR = 2.02; CI = 1.28, 3.18), compared with their counterparts, had greater odds of receiving at least one screening test. CONCLUSION: Findings highlight the continued need to explore ways to support uninsured individuals' screening efforts and further investigate barriers among insured women who are not up-to-date with screenings.

Mycoplasma pneumoniae and health outcomes in children with asthma.

BACKGROUND: Acute infections with Mycoplasma pneumoniae (Mp) have been associated with worsening asthma in children. Mp can be present in the respiratory tract for extended periods; it is unknown whether the long-term persistence of Mp in the respiratory tract affects long-term asthma control. OBJECTIVE: To determine the effect of Mp on asthma control. METHODS: We enrolled 31 pediatric subjects 3 to 10 years of age with persistent asthma who completed up to 8 visits over a 24-month period. We detected Mp by antigen capture and polymerase chain reaction. Primary outcome measurements included symptom scores, quality of life, medication scores, oral corticosteroid use, health care usage, school absences, and exhaled breath condensate pH. RESULTS: Low levels of Mp community-acquired respiratory distress syndrome toxin were detected in 20 subjects (64.5%) at enrollment. Subjects with Mp positivity at a given visit had a .579 probability of remaining Mp positive at the subsequent visit, whereas those with Mp negativity had a .348 probability of becoming Mp positive at the following visit. The incidence of Mp overall was higher in the spring and summer months. Overall, we found no significant relation between the detection of Mp and worse outcome measurements at the same visit or at subsequent visits. CONCLUSION: The long-term persistence of Mp in the respiratory tract is common in children with asthma. However, the detection of Mp was not associated significantly with worse asthma symptoms, quality of life, health care usage, school absences, or exhaled breath condensate pH in this pediatric asthma cohort.

Missed Initial Medical Visits: Predictors, Timing, and Implications for Retention in HIV Care.

HIV disproportionately affects racial/ethnic minorities and individuals living in the southern United States, and missed clinic visits account for much of this disparity. We sought to evaluate: (1) predictors of missed initial HIV medical visits, (2) time to initial visit, and (3) the association between initial visit attendance and retention in HIV care. Chart reviews were conducted for 200 consecutive HIV-infected patients (100 in Dallas, 100 in San Antonio) completing case management (CM) intake. Of these, 52 (26%) missed their initial visit, with 22 (11%) never presenting for care. Mean age was 40 years, 85% were men, >70% were of minority race/ethnicity, and 28% had a new HIV diagnosis. Unemployment (OR [95% CI] = 2.33 [1.04-5.24], p = 0.04) and lower attendance of CM visits (OR = 3.08 [1.43-6.66], p = 0.004) were associated with missing the initial medical visit. A shorter time to visit completion was associated with CD4 ≤ 200 (HR 1.90 [1.25-2.88], p = 0.003), Dallas study site (HR = 1.48 [1.03-2.14], p = 0.04), and recent hospitalization (HR = 2.18 [1.38-3.43], p < 0.001). Patients who did not complete their initial medical visit within 90 days of intake were unlikely to engage in care. Initial medical visit attendance was associated with higher proportion of visits attended (p = 0.04) and fewer gaps in care (p = 0.01). Missed medical visits were common among HIV patients initiating or reinitiating care in Texas. Employment and CM involvement predicted initial medical visit attendance, which was associated with retention in care. New, early engagement strategies are needed to decrease missed visits and reduce HIV health disparities.

The influence of trauma and patient characteristics on provider burnout in VA post-traumatic stress disorder specialty programmes.

OBJECTIVE: Prolonged exposure (PE) and cognitive processing therapy (CPT) - post-traumatic stress disorder (PTSD) treatments now available at the Veterans Health Administration (VHA) - expose the provider to graphic traumatic material. Little is known about the impact of traumatic material on VHA providers. The purpose of this study was to examine the relationship between trauma content, patient characteristics, and burnout among VHA PTSD Clinical Team (PCT) providers. It was hypothesized that trauma content and patient characteristics would significantly predict burnout in this population. DESIGN: This cross-sectional study consisted of 137 participants. The sample was mostly female (67%), Caucasian (non-Hispanic; 81%), and married (70%) with a mean age of 44.3 years (SD = 11.3). METHODS: Participants completed an electronic survey that assessed demographics, patient characteristics (i.e., anger, personality disorder, malingering), trauma content characteristics (e.g., killing of women and children) as well as burnout as measured by the Maslach Burnout Inventory-General Survey (MBI-GS; Maslach et al., 1996, Burnout inventory manual. Palo Alto: Consulting Psychologist Press). RESULTS: Over half of the study population reported being bothered by trauma content; however, trauma content did not predict burnout. Treating patients with personality disorders and suspected malingering predicted burnout in PCT providers. High numbers (77%) reported perceiving that emotional exhaustion impacted the quality of care they provided. CONCLUSION: These findings suggest an important role of burnout assessment, prevention, and treatment strategies at the VHA. PRACTITIONER POINTS: This paper addresses the impact of provider burnout on perceived quality of care. This paper also addresses potential predictors of burnout in PCT settings. This paper outlines potential remedies to provider burnout in the VHA.

Agent Orange Exposure and Monoclonal Gammopathy of Undetermined Significance: An Operation Ranch Hand Veteran Cohort Study.

IMPORTANCE: Multiple myeloma has been classified as exhibiting "limited or suggestive evidence" of an association with exposure to herbicides in Vietnam War veterans. Occupational studies have shown that other pesticides (ie, insecticides, herbicides, fungicides) are associated with excess risk of multiple myeloma and its precursor state, monoclonal gammopathy of undetermined significance (MGUS); however, to our knowledge, no studies have uncovered such an association in Vietnam War veterans. OBJECTIVE: To examine the relationship between MGUS and exposure to Agent Orange, including its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in Vietnam War veterans. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective cohort study conducted in 2013 to 2014, testing for MGUS in serum specimens collected and stored in 2002 by the Air Force Health Study (AFHS). The relevant exposure data collected by the AFHS was also used. We tested all specimens in 2013 without knowledge of the exposure status. The AFHS included former US Air Force personnel who participated in Operation Ranch Hand (Ranch Hand veterans) and other US Air Force personnel who had similar duties in Southeast Asia during the same time period (1962 to 1971) but were not involved in herbicide spray missions (comparison veterans). Agent Orange was used by the US Air Force personnel who conducted aerial spray missions of herbicides (Operation Ranch Hand) in Vietnam from 1962 to 1971. We included 479 Ranch Hand veterans and 479 comparison veterans who participated in the 2002 follow-up examination of AFHS. EXPOSURES: Agent Orange and TCDD. Serum TCDD levels were measured in 1987, 1992, 1997, and 2002. MAIN OUTCOMES AND MEASURES: Risk of MGUS measured by prevalence, odds ratios (ORs), and 95% CIs. RESULTS: The 479 Ranch Hand veterans and 479 comparison veterans had similar demographic and lifestyle characteristics and medical histories. The crude prevalence of overall MGUS was 7.1% (34 of 479) in Ranch Hand veterans and 3.1% (15 of 479) in comparison veterans. This translated into a 2.4-fold increased risk for MGUS in Ranch Hand veterans than comparison veterans after adjusting for age, race, BMI in 2002, and the change in BMI between 2002 and the time of blood draw for TCDD measurement (adjusted OR, 2.37; 95% CI, 1.27-4.44; P=.007). CONCLUSIONS AND RELEVANCE: Operation Ranch Hand veterans have a significantly increased risk of MGUS, supporting an association between Agent Orange exposure and multiple myeloma.

Comparative dosing and efficacy of sorafenib in hepatocellular cancer patients with varying liver dysfunction.

BACKGROUND: Sorafenib is the only FDA-approved systemic therapy for advanced hepatocellular carcinoma (HCC). In clinical practice, dose reductions are often required, although there are limited efficacy data related to dose modifications. Given the prevalence of HCC in South Texas, we assessed the efficacy and safety of sorafenib therapy in relation to dose and Child Pugh (CP) score. METHODS: A retrospective analysis was done of advanced HCC patients, starting sorafenib at 400 mg twice daily, or at physician discretion at 400 mg daily, with the goal of titrating to twice daily. Overall survival (OS) and progression-free survival (PFS) were assessed. RESULTS: Among 107 patients, median OS (mOS) was 10.2 months; median PFS (mPFS) was 5.2 months. mOS for sorafenib 400 mg/day was 6.6 vs. 800 mg/day was 12.8 months [hazard ratio (HR), 0.59; P=0.04]; mPFS was 3.5 vs. 5.9 months, respectively (HR, 0.66; P=0.07). For Child Pugh A class (CP-A) patients, mOS was 15.8 months for 400 mg/day vs. 12.8 months for 800 mg/day (HR, 1.48; P=0.35); mPFS was 9.0 vs. 5.9 months, respectively (HR, 1.23; P=0.56). For Child Pugh B class (CP-B) patients, mOS was 5.0 months for 400 mg/day vs. 11.2 months for 800 mg/day (HR, 0.33; P=0.002); mPFS was 2.1 vs. 5.6 months, respectively (HR, 0.41; P=0.006). No differences in adverse events (AEs) were observed in CP-A vs. CP-B. CONCLUSIONS: Patients with CP-A or CP-B advanced HCC should be offered sorafenib at 400 mg twice daily with optimal management of AEs in order to improve survival.

How concerns for bisphosphonate-induced osteonecrosis of the jaw affect clinical practice among dentists: a study from the South Texas Oral Health Network.

Bisphosphonate-induced osteonecrosis of the jaw (BONJ) represents a growing concern for dentists and patients in that it may alter clinical care. This study assessed the knowledge and perceptions of practicing dentists in relation to the risk of BONJ and how their knowledge and perceptions influence their decisions when developing treatment plans. For this study, a sample of dentists (n = 93) in South Texas completed a 38-item survey about BONJ knowledge and perception and their current clinical practices for patients undergoing bisphosphonate therapy. Knowledge score groupings reflected differences between low knowledge and high knowledge dentists in terms of their behavior concerning medical history, alternative treatments offered, and routine blood testing for patients on bisphosphonate therapy.

Utilization of evidence-based psychotherapies in Veterans Affairs posttraumatic stress disorder outpatient clinics.

In response to the growing numbers of veterans with posttraumatic stress disorder (PTSD), the Department of Veterans Affairs (VA) has sought to make evidence-based psychotherapies for PTSD available at every VA facility. We conducted a national survey of providers within VA PTSD clinical teams (PCTs) to describe utilization of prolonged exposure (PE) and cognitive processing therapy (CPT) and to identify individual and organizational factors associated with treatment uptake and adherence. Participants (N = 128) completed an electronic survey assessing reported utilization of PE and CPT treatments, adherence to treatment manuals, and characteristics of the provider and workplace environment. Participants reported conducting a weekly mean of 4.5 hours of PE, 3.9 hours of CPT (individual format), 1.3 hours of CPT (group format), and 13.4 hours of supportive care. Perceived effectiveness of PE and CPT were significantly associated with utilization of and adherence to those treatments. Reported number of hours conducting supportive care was positively associated with feeling the clinic was not sufficiently staffed (p = .05). Adherence to the PE treatment manual was positively associated with receiving emotional support from coworkers (p < .01). Provider attitudes and organizational factors such as staffing and work relationships may have an important impact on treatment selection and the quality of PTSD care provided in VA PCTs.

Phase II study evaluating the efficacy, safety, and pharmacodynamic correlative study of dual antiangiogenic inhibition using bevacizumab in combination with sorafenib in patients with advanced malignant melanoma.

PURPOSE: Melanomas are vascular tumors with a high incidence of BRAF mutations driving tumor proliferation. Complete inhibition of vascular endothelial growth factor (VEGF) signaling has potential for enhanced antitumor efficacy. METHODS: Patients with advanced melanoma and adequate organ function were eligible. Sorafenib was given orally at 200 mg BiD for 5 days every week; bevacizumab was administered 5 mg/kg intravenously every 14 days. The primary objective was to determine clinical biological activity. The secondary objectives were safety, tolerability, and time to progression (TTP). Pharmacodynamic analysis included serum VEGF and soluble VEGF receptor-1 and VEGF receptor-2 performed at baseline, C1D15 and C2D1. The study was terminated during the first stage of a Simon two-stage design, after 14 of planned 21 subjects were enrolled. RESULTS: Of the 14 patients who received treatment, no objective tumor responses were observed. Stable disease (SD) ≥16 weeks was observed in 57 % patients, including three patients with SD lasting ≥1 year. Median TTP was 32 weeks. The most frequently reported drug-related adverse events (AEs) were hand-foot syndrome (57.1 %), fatigue (57.1 %), hypertension (64.3 %), and proteinuria (35.7). Grade 3/4 drug-related AEs were hypertension (14.2 %), hand-foot syndrome, proteinuria, and thrombocytopenia (7 % each). Patients with low VEGF (<300 pg/ml) experienced longer TTP than those with high VEGF [median 50 vs. 15 weeks, p = 0.02). A similar pattern was seen for VEGFR1 and VEGFR2, although it did not reach statistical significance. CONCLUSIONS: Combined VEGF/VEGFR blockade using bevacizumab with sorafenib shows clinical activity. The linkage between VEGF levels and time to tumor progression needs further exploration.

Should we move beyond VEGF inhibition in metastatic colorectal cancer? Lessons from early phase clinical trials.

Data from recent clinical trials utilizing bevacizumab or other anti-VEGF agents in patients with metastatic colorectal cancer (mCRC) show improvements in progression-free survival (PFS) but modest, if any, improvements in overall survival (OS). Despite modest improvements, use of bevacizumab beyond first and second progression is routinely done in clinical practice. Recently, the CORRECT trial using regorafenib, a multi-kinase inhibitor with VEGF inhibitory properties, reported modest improvements in PFS and OS when compared to placebo, leading to FDA approval in the third-line setting. Prior to regorafenib, heavily pre-treated patients were often enrolled onto early phase clinical trials with many of these studies reporting efficacy amongst patients with mCRC; however, a collective efficacy analysis of mCRC patients enrolled into early phase clinical trials stratified by class of agents and their mechanism of action has not been done. To assess this, we performed an analysis of efficacy and stratified these findings based on VEGF inhibition versus non-VEGF inhibition in mCRC patients enrolled onto phase I trials at our institution from 3/2004-9/2012. Similar to many reported clinical studies, our data showed that VEGF inhibitors have a statistically significant improvement in PFS when compared to non-VEGF targeting agents; however, no differences in OS were observed between these two different classes of agents. We were not able to identify predictive biomarkers that correlate with efficacy of VEGF inhibitors. This should be further explored in prospective studies in order to identify active agents in this heavily pre-treated population that improve efficacy while minimizing cost and toxicity.