The Aetion Coalition to Advance Real-World Evidence through Randomized Controlled Trial Emulation Initiative: Oncology.

Legislative and technological advancements over the past decade have given rise to the proliferation of healthcare data generated from routine clinical practice, often referred to as real-world data (RWD). These data have piqued the interest of healthcare stakeholders due to their potential utility in generating evidence to support clinical and regulatory decision making. In the oncology setting, studies leveraging RWD offer distinct advantages that are complementary to randomized controlled trials (RCTs). They also permit the conduct of investigations that may not be possible through prospective designs due to ethics or feasibility. Despite its promise, the use of RWD for the generation of clinical evidence remains controversial due to concerns of unmeasured confounding and other sources of bias that must be carefully addressed in the study design and analysis. To facilitate a better understanding of when RWD can provide reliable conclusions on drug effectiveness, we seek to conduct 10 RWD-based studies that emulate RCTs in oncology using a systematic, protocol-driven approach described herein. Results of this investigation will help inform clinical, scientific, and regulatory stakeholders on the applications of RWD in the context of product labeling expansion, drug safety, and comparative effectiveness in oncology.

Prognosis and oncogenomic profiling of patients with tropomyosin receptor kinase fusion cancer in the 100,000 genomes project.

INTRODUCTION: Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers in various tumor types. Limited data exist on the overall survival (OS) of patients with tumors with NTRK gene fusions and on the co-occurrence of NTRK fusions with other oncogenic drivers. MATERIALS AND METHODS: This retrospective study included patients enrolled in the Genomics England 100,000 Genomes Project who had linked clinical data from UK databases. Patients who had undergone tumor whole genome sequencing between March 2016 and July 2019 were included. Patients with and without NTRK fusions were matched. OS was analyzed along with oncogenic alterations in ALK, BRAF, EGFR, ERBB2, KRAS, and ROS1, and tumor mutation burden (TMB) and microsatellite instability (MSI). RESULTS: Of 15,223 patients analyzed, 38 (0.25%) had NTRK gene fusions in 11 tumor types, the most common were breast cancer, colorectal cancer (CRC), and sarcoma. Median OS was not reached in both the NTRK gene fusion-positive and -negative groups (hazard ratio 1.47, 95% CI 0.39-5.57, P = 0.572). A KRAS mutation was identified in two (5%) patients with NTRK gene fusions, and both had hepatobiliary cancer. High TMB and MSI were both more common in patients with NTRK gene fusions, due to the CRC subset. While there was a higher risk of death in patients with NTRK gene fusions compared to those without, the difference was not statistically significant. CONCLUSION: This study supports the hypothesis that NTRK gene fusions are primary oncogenic drivers and the co-occurrence of NTRK gene fusions with other oncogenic alterations is rare.

Real-world patient characteristics associated with survival of 2 years or more after radium-223 treatment for metastatic castration-resistant prostate cancer (EPIX study).

BACKGROUND: The real-world EPIX study was conducted to gather information about the characteristics of patients with metastatic castration-resistant prostate cancer (mCRPC) who survived ≥2 years after treatment with the alpha-emitter radium-223. METHODS: This retrospective study of electronic health records in the US Flatiron database (NCT04516161) included patients with mCRPC treated with radium-223 between January 2013 and June 2019. Median overall survival (OS) and prostate-specific antigen (PSA) response (≥50% reduction) from start of radium-223 treatment were the primary and secondary endpoints, respectively. Patient characteristics were compared between those who survived ≥2 years versus <2 years, including a subgroup who survived <6 months. RESULTS: In the 1180 patients identified, median OS was 12.9 months (95% CI: 12.1-13.7), and 13% of patients with data at 6 months had a PSA response. The survival groups included 775 patients (65.7%) who survived <2 years (including 264 (22.4%) who survived <6 months) and 185 patients (15.7%) who survived ≥2 years; 220 patients (18.6%) had incomplete follow-up data and were censored. On multivariate analysis, age >75 years, Eastern Cooperative Oncology Group performance status (ECOG PS) 2-4, visceral metastases, prior symptomatic skeletal events (SSEs), and prior chemotherapy were independently prognostic of reduced OS. For patients with survival ≥2 years versus <2 years, median age was 71 versus 75 years, 4% versus 14% had ECOG PS 2-4, 4% versus 10% had visceral metastases, 38% versus 44% had prior SSEs, and 16% versus 32% had prior chemotherapy. CONCLUSIONS: In this study of men with mCRPC treated in real-world clinical practice, median OS was consistent with that seen in the phase 3 ALSYMPCA trial. Patients who survived ≥2 years after the start of radium-223 were younger and had better ECOG PS, lower disease burden, and less use of prior chemotherapy than those who survived <2 years.

Real-world outcomes of second novel hormonal therapy or radium-223 following first novel hormonal therapy for mCRPC.

Aim: To evaluate real-world clinical outcomes of radium-223 or alternative novel hormonal therapy (NHT) following first-line NHT for metastatic castration-resistant prostate cancer (mCRPC). Patients & methods: Retrospective analysis of the US Flatiron database (ClinicalTrials.gov identifier: NCT03896984). Results: In the radium-223 cohort (n = 120) versus the alternative NHT cohort (n = 226), proportionally more patients had prior symptomatic skeletal events and bone-only metastases, and first-line NHT duration was shorter. Following second-line therapy, 49 versus 39% of patients received subsequent life-prolonging therapy; of these, 47 versus 76% received taxane. Median overall survival was 10.8 versus 11.2 months. Conclusion: Real-world patients with mCRPC had similar median overall survival following second-line radium-223 or alternative NHT after first-line NHT. Many patients received subsequent therapy, with less taxane use after radium-223.

Lay abstract Patients with metastatic castration-resistant prostate cancer are often first treated with novel hormonal therapy (NHT) using abiraterone or enzalutamide. To aid decisions about what treatment to use next, we reviewed information about patients who were treated with an alternative NHT (226 patients) or the nuclear medicine radium-223 (120 patients) after the first NHT. Most patients given radium-223 had cancer that had spread to their bones only, whereas many patients given an alternative NHT had cancer in their bones and other parts of their body. Around one in four patients given radium-223 and one in five given an alternative NHT had symptoms related to their bone metastases after starting treatment. Five in every ten patients given radium-223 received further therapy, including chemotherapy in 50% of these patients, while four in every ten patients given an alternative NHT received further therapy, including chemotherapy in 75%. On average, patients lived for almost a year after starting radium-223 or an alternative NHT.

TRK Fusion Cancer: Patient Characteristics and Survival Analysis in the Real-World Setting.

BACKGROUND: Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers in various tumor types. While NTRK gene fusions are predictive of benefit from tropomyosin receptor kinase inhibitors regardless of tumor type, the prognostic significance of NTRK gene fusions in a pan-tumor setting remains unclear. OBJECTIVE: This study evaluated the characteristics and prognosis of tropomyosin receptor kinase fusion cancer in the real-world setting. PATIENTS AND METHODS: This retrospective study used a de-identified clinico-genomic database and included patients with cancer who had comprehensive genomic profiling between January 2011 and July 2018. Patients were classified as having cancer with NTRK gene fusions or NTRK wild-type genes. Patients were matched with a 1:4 ratio (NTRK fusion:NTRK wild-type) using the Mahalanobis distance method on demographic and clinical characteristics, including age and Eastern Cooperative Oncology Group performance status. Descriptive analysis of clinical and molecular characteristics was conducted. Kaplan-Meier estimator and Cox regression were used for overall survival analysis. RESULTS: Median overall survival was 12.5 months (95% confidence interval 9.5-not estimable) and 16.5 months (95% confidence interval 12.5-22.5) in the NTRK gene fusion (n = 27) and NTRK wild-type cohorts (n = 107), respectively (hazard ratio 1.44; 95% confidence interval 0.61-3.37; p = 0.648). Co-occurrence of select targetable biomarkers including ALK, BRAF, ERBB2, EGFR, ROS1, and KRAS was lower in cancers with NTRK gene fusions than in NTRK wild-type cancers. CONCLUSIONS: Although the hazard ratio for overall survival suggested a higher risk of death for patients with NTRK gene fusions, the difference was not statistically significant. Co-occurrence of NTRK gene fusions and other actionable biomarkers was uncommon.

Concurrent or layered treatment with radium-223 and enzalutamide or abiraterone/prednisone: real-world clinical outcomes in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: In this study, we evaluated real-world data on radium-223 plus abiraterone/prednisone or enzalutamide. Previously, the ERA 223 trial (NCT02043678) demonstrated increased fracture risk with concurrent treatment with radium-223 and abiraterone plus prednisone/prednisolone in patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: We used the Flatiron Health database to perform a retrospective study of patients with mCRPC treated with radium-223. Treatment with radium-223 plus abiraterone/prednisone or enzalutamide was defined as concurrent if both drugs started within 30 days of one another, or layered when the second drug started ≥30 days after the first. The index date was defined as the day of the first radium-223 dose. Outcome measures included symptomatic skeletal events (SSEs), overall survival (OS), and patterns of treatments received. RESULTS: Of the 625 patients treated with radium-223, 22% received it together with abiraterone/prednisone and 27% with enzalutamide. When these agents were combined, they were often initiated in a layered fashion (73% layered, 23% concurrent). Prior or concomitant bone health agents (BHAs) were received by 67% and 55% of patients, respectively. Median follow-up was 9 months. Overall, incidence rates for SSEs and pathologic fractures were 0.35 and 0.11 patients per person-year, respectively. Median OS from mCRPC diagnosis was 28.1 months. CONCLUSIONS: In this real-world setting, combination treatments with radium-223 and abiraterone/prednisone or enzalutamide were common. These agents were more commonly given in a layered than a concurrent fashion. Incidence rates for SSEs were reduced when BHAs were used; however, BHAs were underutilized.

Treatment Patterns and Outcomes in Patients With Metastatic Castration-resistant Prostate Cancer in a Real-world Clinical Practice Setting in the United States.

BACKGROUND: Clinical trials have demonstrated the efficacy of several life-prolonging therapies for metastatic castration-resistant prostate cancer (mCRPC); however, real-world data on their use, survival effect, and safety are limited. Using electronic health record data from the Flatiron Health database, we studied real-world treatment patterns and health outcomes in patients with mCRPC. PATIENTS AND METHODS: We conducted a retrospective, non-interventional cohort analysis of electronic health record data of patients with confirmed mCRPC between January 2013 and September 2017. The primary objective was to describe real-world treatment patterns, including treatment type, duration, and sequencing. Secondary objectives included describing patient characteristics and clinical outcomes. RESULTS: Of 2559 patients with mCRPC, 1980 (77%) received at least 1 line of life-prolonging therapy (abiraterone, enzalutamide, docetaxel, cabazitaxel, sipuleucel-T, or radium-223). Of patients receiving first-line therapy, 49% received second-line therapy, and of these, 43% received third-line therapy. Abiraterone/prednisone and enzalutamide accounted for 65% of first-line therapies and 54% of second-line therapies. Docetaxel was the most common third-line therapy (24%). Back-to-back use of abiraterone/prednisone and enzalutamide was common. Radium-223 monotherapy use was 2% in the first-line setting, 3% in the second-line setting, and 8% in the third-line setting. The median overall survival was longer in patients who received life-prolonging therapies (23.7 months; 95% confidence interval: 22.3-25.1 months) than in those who did not (10.1 months; 95% confidence interval: 9.1-11.5 months). CONCLUSION: These real-world insights on over 2500 patients with mCRPC supplement findings from randomized controlled trials and may help to inform clinical trial design, treatment guidelines, and clinical decision-making.

Relative dose intensity of first-line chemotherapy and overall survival in patients with advanced non-small-cell lung cancer.

PURPOSE: The effects of chemotherapy dose intensity on survival in patients with advanced non-small-cell lung cancer (NSCLC) are poorly understood. We retrospectively analyzed dose delays/reduction, relative dose intensity (RDI), and the association between chemotherapy intensity and survival in advanced NSCLC. METHODS: This retrospective cohort study included adults with advanced lung cancer who received first-line myelosuppressive platinum-based chemotherapy (January 2007-December 2010) in ~ 230 US Oncology Network community practices. Dose delays ≥ 7 days, dose reductions ≥ 15%, and RDI relative to standard regimens were described. Overall survival (OS) was measured using Kaplan-Meier and Cox proportional hazard (PH) models. RESULTS: Among 3866 patients with advanced NSCLC, 32.4% experienced dose delays ≥ 7 days, 50.1% experienced dose reductions ≥ 15%, and 40.4% had RDI < 85%. Reduced RDI was also common regardless of baseline ECOG PS (ECOG PS ≥ 2, 56.2%; ECOG PS 0, 33.6%) and tumor subgroup (squamous cell carcinoma, 52.2%; adenocarcinoma, 36.0%). When stratified by chemotherapy intensity measures, significant OS differences were observed only for dose delays. Median (95% CI) OS was 1.02 years (0.96-1.12) for dose delays ≥ 7 days and 0.71 years (0.66-0.77) for dose delays < 7 days. In multivariable Cox PH analysis, dose delays ≥ 7 days (HR = 0.71; 95% CI = 0.63-0.80) and RDI ≥ 85% (HR = 1.18; 95% CI = 1.05-1.32) were significantly associated with decreased mortality. CONCLUSIONS: Dose delays, dose reductions, and reduced RDI were common, and dose delays ≥ 7 days and high RDI were significantly associated with decreased mortality. These results can help identify potential risk factors and characterize the effect of chemotherapy dose modification strategies on mortality.

Compliance with clinical guidelines and adherence to antiretroviral therapy among patients living with HIV.

Objective: Evaluation of provider compliance with antiretroviral (ARV) treatment guidelines and patient adherence to ARVs is important for HIV care quality assessment; however, there are few current real-world data for guideline compliance and ARV adherence in the US. This study evaluated provider compliance with US Department of Health and Human Services (DHHS) guidelines and patient adherence to ARVs in a US population of patients with HIV.Methods: This was a retrospective claims study of adults with HIV-1 receiving ARV treatment between January 2010-December 2014. Follow-up began at first ARV treatment and ended at health plan disenrollment or study end. ARV regimens for treatment-naïve patients were categorized as "preferred/recommended", "alternative", or "non-preferred/recommended/alternative" according to DHHS guidelines. ARV adherence was evaluated using proportion of days covered (PDC) and medication possession ratio (MPR).Results: The analysis included 25,320 patients (84.4% male, mean age 45.3 years) and 39,071 regimens. Preferred/recommended regimens were most common during each study year, but the proportion of non-preferred/recommended/alternative regimens was substantial (15.9-20.6%). Only 53.6% of patients had optimal adherence by PDC ≥0.95, and 57.9% by MPR ≥0.95. Guideline non-compliance and sub-optimal adherence were more prevalent among female vs male patients (22.6% vs 14.8% [in 2014] and 65.9% vs 53.7%, respectively).Conclusions: Provider non-compliance with DHHS guidelines and sub-optimal ARV adherence among patients with HIV remain common in real-world practice, particularly for female patients. Healthcare providers should follow the latest clinical guidelines to ensure that patients receive recommended therapy, and address non-adherence when selecting ARV regimens.

Risk Factors, Health Care Resource Utilization, and Costs Associated with Nonadherence to Antiretrovirals in Medicaid-Insured Patients with HIV.

BACKGROUND: Adherence to antiretrovirals (ARVs) is critical to achieving durable virologic suppression. OBJECTIVE: To investigate risk factors of poor adherence and the effect of suboptimal adherence on health care resource utilization (HCRU) and costs in Medicaid patients. METHODS: A retrospective longitudinal study was conducted using Medicaid data. Adults (aged ≥ 18 years) with human immunodeficiency virus (HIV)-1 initiating selected ARVs (index date) were identified. Adherence was measured using medication possession ratio (MPR) and proportion of days covered (PDC) at 6 and 12 months post-index. Risk factors of poor adherence (PDC < 80%) were assessed using a logistic regression. HCRU and costs were compared between suboptimal (80% ≤ PDC < 95%) and optimal (PDC ≥ 95%) adherence groups using Poisson and ordinary least square models, respectively. RESULTS: In total, 3,477 patients were identified. Using MPR, 1,282 (39.0%) of the evaluable patients had poor adherence; 667 (20.2%) had suboptimal adherence; and 1,342 (40.8%) had optimal adherence versus 1,342 (51.1%), 509 (19.0%), and 804 (30.0%), respectively, using PDC at 6 months. PDC at 12 months was even lower. Younger age (OR = 1.58; 95% CI = 1.18-2.11; P = 0.002), noncapitated coverage (OR = 1.40; 95% CI = 1.16-1.69; P < 0.001), dual Medicaid/Medicare coverage (OR = 5.98; 95% CI = 4.39-8.16; P < 0.001), no baseline ARV treatment (OR = 1.98; 95% CI = 1.62-2.41; P < 0.001), and baseline asymptomatic HIV (OR = 1.37; 95% CI = 1.13-1.68; P = 0.002) were associated with higher risk of poor adherence. Suboptimal adherence patients had higher total number of days spent in a hospital (incidence rate ratio [IRR] = 1.62; 95% CI = 1.13-2.19; P = 0.008), total number of long-term care admissions (IRR = 3.11; 95% CI = 1.26-7.39; P = 0.008), total medical costs (mean monthly cost difference = $339; 95% CI = $153-$536; P < 0.001), and inpatient costs (mean monthly cost difference = $259; 95% CI = $122-$418; P < 0.001) compared with patients with optimal adherence. CONCLUSIONS: Nonadherence to ARVs was observed in 60%-80% of Medicaid patients, depending on the adherence measure used, and was associated with incremental HCRU and costs. Age, insurance type and coverage, previous ARV treatment, and HIV symptoms were predictors of adherence. Treatment options that enhance adherence and prevent developing virologic failure with drug resistance should be considered for HIV patients. DISCLOSURES: This study was supported by Janssen Scientific Affairs, which was involved in the study design, data collection, data analysis, manuscript preparation, and publication decisions. Emond, Lafeuille, Romdhani, and Lefebvre are employees of Analysis Group, a consulting company that received research grants from Janssen Scientific Affairs to conduct this study. Dunn, Woodruff, Pesa, and Tandon are current employees and stockholders of Johnson & Johnson, owner of Janssen Scientific Affairs. Jiao was an employee of Janssen at the time of the study. Emond has received grants from Novartis, Regeneron, Aegerion, Lundbeck, Bristol-Myers Squibb, Bayer, Millennium, Allergan, AbbVie, and GlaxoSmithKline unrelated to this study. Part of the material in this study was presented at the Academy of Managed Care Pharmacy 2017 Annual Meeting; March 27-30, 2017; Denver, CO, and at the 9th International AIDS Society Conference; July 23-26, 2017; Paris, France.

Predictors of Long-Term Response With Pazopanib in Patients With Advanced Renal-Cell Carcinoma.

BACKGROUND: Pazopanib is among the current standards of care for first-line treatment of patients with unresectable advanced renal-cell carcinoma (aRCC) or metastatic renal-cell carcinoma. This real-world study aimed to characterize those with long-term response to pazopanib in the treatment of aRCC in a community oncology setting, and to identify predictors of long-term response. PATIENTS AND METHODS: aRCC patients treated with first-line pazopanib were classified as having long-term or non-long-term response (progression-free survival [PFS] of ≥ 18 or < 18 months, respectively). Baseline patient demographics and clinical characteristics were evaluated and compared between the 2 groups. Differences in PFS and overall survival were also evaluated. RESULTS: A total of 153 eligible patients were identified, of which 33 (21.6%) and 120 (78.4%) patients were identified as having disease with long-term and non-long-term response, respectively. The median PFS for those with long-term response was 27.2 months (95% confidence interval [CI], 23.0-35.2) versus 6.9 months (95% CI, 5.0-8.6) for those with non-long-term response. Median overall survival was not reached (NR) for those with long-term response (95% CI, NR to 39.1) compared to 15.3 months (95% CI, 12.3-21.6) for those with non-long-term response. Baseline Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 (vs. ECOG PS of 1 and ≥ 2) and history of nephrectomy were identified as significant predictors of long-term response to pazopanib. CONCLUSION: In aRCC patients treated with first-line pazopanib, 22% had a long-term response. Significant predictors of long-term response included an ECOG PS of 0 and a history of nephrectomy.

Chemotherapy Dose Intensity and Overall Survival Among Patients With Advanced Breast or Ovarian Cancer.

BACKGROUND: The effects of chemotherapy dose intensity on patient outcomes in advanced cancer are not well understood. We studied the association between chemotherapy relative dose intensity (RDI) and overall survival (OS) among patients with advanced breast or ovarian cancer. PATIENTS AND METHODS: This retrospective cohort study included adults with advanced breast or ovarian cancer who received first-line myelosuppressive chemotherapy (January 2007 to December 2010) in US Oncology Network community practices. Dose delays ≥ 7 days, dose reductions ≥ 15%, and RDI relative to standard regimens were described. OS was measured by the Kaplan-Meier method and Cox proportional hazards models. RESULTS: Among 874 patients with advanced breast cancer, 33.2% experienced dose delays ≥ 7 days, 48.7% experienced dose reductions ≥ 15%, and 38.9% had RDI < 85%. In the multivariable Cox proportional hazards model, Eastern Cooperative Oncology Group performance status 1/2 versus 0 (hazard ratio [HR] = 1.45; 95% confidence interval [CI], 1.15-1.82) and triple-negative status (HR = 3.14; 95% CI, 1.15-8.62) were significantly associated with mortality. Among 170 patients with advanced ovarian cancer, 43.5% experienced dose delays ≥ 7 days, 48.2% experienced dose reductions ≥ 15%, and 46.5% had RDI < 85%. In the multivariable Cox proportional hazards model, dose reductions ≥ 15% (HR = 1.94; 95% CI, 1.09-3.46) and other tumor histology (vs. nonserous adenocarcinoma; HR = 3.55; 95% CI, 1.38-9.09) were significantly associated with mortality. CONCLUSION: Dose delays, dose reductions, and reduced RDI were common. In advanced breast cancer, health status and triple-negative disease were significantly associated with mortality. In advanced ovarian cancer, dose reductions and tumor histology were significantly associated with mortality. These results can help identify potential risk factors and characterize the effect of chemotherapy dose modification strategies on mortality.

Treatment Patterns and Clinical Outcomes in Patients With Metastatic Gastroenteropancreatic Neuroendocrine Tumors Treated in the Community Practice Setting in the United States.

OBJECTIVE: This study was conducted to understand treatment patterns and clinical outcomes in metastatic gastroenteropancreatic neuroendocrine tumor patients treated in a large community oncology network. METHODS: This retrospective study used the McKesson Specialty Health/US Oncology Network iKnowMed electronic health record database with supplemental chart review. Eligibility criteria included a metastatic neuroendocrine tumor diagnosis between January 1, 2008, and to December 31, 2012; at least 2 US Oncology Network visits; and age at least 18 years. Follow-up was through October 31, 2014. RESULTS: Among the 229 patients identified, median age was 64.0 years, 52.4% were male, 69.4% were white, and 62.9% were overweight/obese. Primary tumor sites included small bowel (47.6%), pancreas (31.4%), and stomach/colorectum (21.0%). There were 16.2% under observation without treatment, 52.4% received only somatostatin analogs (SSAs), and 31.4% received chemotherapy/targeted therapy during treatment. In the first-line setting (n = 192), 77% received SSAs, 12% received chemotherapy, and 10.9% received targeted therapy. Fifty percent of patients receiving octreotide had a relative dose intensity of less than 85%, and 16.7% received above-label dose. Toxicities of SSAs included diarrhea (18.2%), abdominal pain (16.9%), and fatigue (13.5%). Median overall survival from diagnosis was 68.0 months (95% confidence interval, 57.1 to not reached). CONCLUSIONS: Most metastatic gastroenteropancreatic neuroendocrine tumor patients received systemic treatment with SSAs. Patient treatment used an individualized dosing approach. Overall survival and toxicity were consistent with the published literature.

Axitinib in metastatic renal cell carcinoma: patient characteristics and treatment patterns in US community oncology centers.

AIM: To study patient characteristics and treatment patterns in real-world axitinib use for metastatic renal cell carcinoma. PATIENTS & METHODS: We conducted a retrospective analysis of second- or third-line axitinib use between 1 January 2012 and 31 October 2014 in 135 metastatic renal cell carcinoma patients using the US Oncology Network database. RESULTS: Overall, 86.7% had clear cell histology, 57.8% had stage III/IV disease at diagnosis and 55.6% were poor risk by Heng criteria. Median treatment duration was 4.6 months (range: 0.03-35.49); 80.7% initiated axitinib at 5 mg/day twice daily, and 67.4% maintained this dose. Overall, 77.8% discontinued treatment, mainly due to disease progression (50.5%) and toxicity (21.9%). CONCLUSION: Axitinib usage patterns were consistent with the National Comprehensive Cancer Network Guidelines®. Ease of use among community oncologists and patient tolerance are key features of axitinib.

HER2-Positive Metastatic Breast Cancer Patients Receiving Pertuzumab in a Community Oncology Practice Setting: Treatment Patterns and Outcomes.

BACKGROUND: Pertuzumab (Perjeta®), a HER2/neu receptor antagonist, was approved by the US Food and Drug Administration in June 2012 for use in the first-line setting for patients with HER2-positive metastatic breast cancer (mBC). OBJECTIVE: This retrospective study investigated the clinical and demographic characteristics, treatment patterns, safety, and clinical outcomes for patients with HER2-positive mBC who received pertuzumab in the first-line setting in US community oncology practices. METHODS: Patients with HER2-positive mBC, who initiated pertuzumab within 60 days of mBC diagnosis between June 2012 and June 2014, followed through December 2014, had ≥2 visits within the McKesson Specialty Health/US Oncology Network, and were not on clinical trials during the study period, were eligible. This study utilized iKnowMed electronic health records, Claims Data Warehouse, and Social Security Death Index. Progression-free survival (PFS) was assessed by Kaplan-Meier methods. RESULTS: A total of 266 patients met the selection criteria. A vast majority of the patients (249/266, 93.6%) received a trastuzumab + pertuzumab + taxane (H + P + T) regimen. The number of patients with prior adjuvant/neoadjuvant therapy was higher than the CLEOPATRA trial, but age (median 57 years) and percentage of visceral disease (74.8%) were similar. The most common adverse events were fatigue (50.8%), diarrhea (44.7%), nausea (35.3%), peripheral neuropathy (33.5%), neutropenia (24.9%), and rash (24.4%). The median PFS was 16.9 months (95% CI 14.2-19.7). CONCLUSIONS: In this retrospective study of patients with HER2-positive mBC receiving pertuzumab in the first-line setting, most patients were treated with H + P + T. The safety and PFS of H + P + T were consistent with those observed in the pivotal trial.

Treatment pattern by hormone receptors and HER2 status in patients with metastatic breast cancer in the UK, Germany, France, Spain and Italy (EU-5): results from a physician survey.

BACKGROUND: The differences in country-specific treatment patterns across Europe for metastatic breast cancer (mBC) patients have not been extensively studied. This study compared the treatment choices in aggregate, as well as by biomarker status, between various lines of therapy in clinical practice in the EU-5 countries among newly diagnosed mBC patients. MATERIALS & METHODS: The IMS LifeLink™ Oncology Analyzer database, based on surveys of practicing oncologists, was used to identify mBC patients aged ≥21 years. In this database, sample-level data are projected to national-level estimates for each country using a sample projection technique. RESULTS: The prevalence of hormone receptors (71-74%) is quite similar across different countries, while HER2 overexpression varies from 22 (France) to 34% (Italy); chemotherapy combined with HER2-targeted medicine was the mainstay of treatment for HER2(+) patients. The use of HER2-targeted medicine and bevacizumab greatly varied: while they were most frequently used in France, they were least frequently used in the UK. Fewer treatment options existed for triple-negative patients and patients with HER2(+) disease following trastuzumab treatment. Chemotherapy was the treatment choice for triple-negative patients, as these patients do not respond to hormonal therapy and HER2-targeted medicine. CONCLUSION: This study found that, while a trastuzumab-based regimen is the preferred option for treating HER2(+) mBC patients in the EU-5, variations in this personalized medicine approach exist between different EU-5 countries. However, fewer treatment options exist for triple-negative and HER2(+) patients after trastuzumab treatment, highlighting the unmet need for these patient subgroups.

Seasonal spring peaks of suicide in victims with and without prior history of hospitalization for mood disorders.

BACKGROUND: Seasonal spring peaks of suicide are highly replicated, but their origin is poorly understood. As the peak of suicide in spring could be a consequence of decompensation of mood disorders in spring, we hypothesized that prior history of mood disorders is predictively associated with suicide in spring. METHODS: We analyzed the monthly rates of suicide based upon all 37,987 suicide cases in the Danish Cause of Death Registry from 1970 to 2001. History of mood disorder was obtained from the Danish Psychiatric Central Register and socioeconomical data from the Integrated Database for Labour Market Research. The monthly rate ratio of suicide relative to December was estimated using a Poisson regression. Seasonality of suicide between individuals with versus without hospitalization for mood disorders was compared using conditional logistic regression analyses with adjustment for income, marital status, place of residence, and method of suicide. RESULTS: A statistically significant spring peak in suicide was observed in both groups. A history of mood disorders was associated with an increased risk of suicide in spring (for males: RR=1.18, 95% CI 1.07-1.31; for females: RR=1.20, 95% CI 1.10-1.32). LIMITATIONS: History of axis II disorders was not analyzed. Danish socioeconomical realities have only limited generalizability. CONCLUSIONS: The results support the need to further investigate if exacerbation of mood disorders in spring triggers seasonal peaks of suicide. Identifying triggers for seasonal spring peaks in suicide may lead to uncovering novel risk factors and therapeutic targets for suicide prevention.

Thoracoscopic approach for spine deformities.

BACKGROUND: We reviewed our experience using anterior thoracoscopic procedures in the correction of severe idiopathic scoliosis and kyphotic deformities to evaluate the feasibility and effectiveness of such procedures. STUDY DESIGN: Twenty-four patients who underwent thoracoscopic surgical correction of the spine between March 1995 and December 2001 were retrospectively reviewed. A team consisting of one orthopaedic surgeon and one thoracic surgeon performed anterior thoracoscopic soft tissue release, disc excision, and bone grafting followed on the same day with posterior instrumentation and correction of deformity. RESULTS: There were 16 female and 8 male patients, with a median age of 16 years (range 11 to 47 years) with idiopathic scoliosis (20 patients) or kyphotic deformity (4 patients). The average time for the thoracoscopy was 125 minutes (range 60 to 175 minutes). Blood loss averaged 135 mL (range 20 to 350 mL), and a median number of five discs (range two to eight) were excised. The median ICU time was 2 days (range 1 to 8 days), and the median length of hospital stay was 6 days (range 4 to 11 days). One patient required conversion to an open procedure because of arterial bleeding from the cancellous bone (T5). Postoperative complications occurred in four patients (atelectasis, pneumothorax, pneumonia, and wound infection in one patient each). All patients had an uneventful hospital course after treatment. CONCLUSIONS: Thoracoscopic anterior procedures can be used safely and effectively in the treatment of idiopathic scoliosis and kyphotic deformity. This minimally invasive approach might decrease procedure-related trauma, operative time, blood loss, and length of hospitalization and may also alleviate postthoracotomy pain.

Immunohistochemistry analysis of micrometastasis in pretreatment lymph nodes from patients with esophageal cancer.

BACKGROUND: With recent advances in neoadjuvant therapy in esophageal cancer, pretreatment lymph node staging has become increasingly important in stratifying patients to appropriate treatment regimens and for prognostication. Immunohistochemical analysis (IHC) using epithelial markers has been shown to identify micrometastases in histologically negative lymph nodes. We performed this study to evaluate if IHC analysis in thoracoscopic/laparoscopic (Ts/Ls) pretreatment staging lymph nodes can reveal additional diagnostic information to routine histopathology. METHODS: Specimens of 106 patients with esophageal cancer who had pretreatment Ts/Ls staging were retrospectively studied. Lymph node biopsies were obtained for IHC staining using cytokeratin (CK) of AE1/AE3. IHC staining for p53, an apoptosis protein associated with poor prognosis in esophageal cancer, was also performed. RESULTS: 331 Ts/Ls staging lymph node biopsies were collected from 106 patients. A total of 15.4% (51/331) of the lymph nodes or 34.9% (37/106) of patients were found to have metastatic deposits by routine histology. All the histologically positive lymph nodes were CK positive. Among the remaining 280 histologically negative lymph nodes, 11(3.9%) were found to have micrometastasis by CK staining. Three patients (4.3%, 3/69) were upstaged from N0 to N1. They died of early recurrences after treatment. A total of 67.6% (25/37) of the patients with histologically positive lymph node were p53 positive. No histologically negative lymph node was found to be p53 positive in this series. CONCLUSIONS: Immunohistochemical analysis for CK can detect micrometastatic involvement of lymph nodes that are missed on routine pathologic examination, and, therefore, can improve lymph node staging. Its clinical significance in esophageal cancer warrants further study.

Leukotriene A4 hydrolase in rat and human esophageal adenocarcinomas and inhibitory effects of bestatin.

BACKGROUND: Esophageal adenocarcinoma (EAC) is increasing at the most rapid rate of any cancer in the United States. An esophagogastroduodenal anastomosis (EGDA) surgical model in rats mimics human gastroesophageal reflux and results in EAC. Leukotriene A4 hydrolase (LTA4H), a protein overexpressed in EAC in this model, is a rate-limiting enzyme in the biosynthesis of leukotriene B4 (LTB4), a potent inflammatory mediator. We used this model and human EAC and non-tumor tissues to elucidate the expression pattern of LTA4H and to evaluate it as a target for chemoprevention. METHODS: LTA4H expression was examined by western blotting and immunohistochemistry. The functional role of LTA4H in carcinogenesis was investigated by use of an LTA4H inhibitor, bestatin, in the rat EGDA model. All statistical tests were two-sided. RESULTS: LTA4H was overexpressed in all 10 rat EACs examined, compared with its level in normal rat tissue; it was also overexpressed in four of six human EAC tumor samples, compared with its level in adjacent non-tumor tissue. In tissue sections from 20 EGDA rats and 92 patients (86 with EAC, one with dysplasia, and five with columnar-lined esophagus), LTA4H was expressed in infiltrating inflammatory cells and overexpressed in the columnar cells of preinvasive lesions and cancers, especially in well-differentiated EACs, as compared with the basal cells of the normal esophageal squamous epithelium. Bestatin statistically significantly inhibited LTB4 biosynthesis in the esophageal tissues of EGDA rats (without bestatin = 8.28 ng/mg of protein; with bestatin = 4.68 ng/mg of protein; difference = 3.60, 95% CI = 1.59 to 5.61; P = .002) and reduced the incidence of EAC in the EGDA rats from 57.7% (15 of 26 rats) to 26.1% (6 of 23 rats) (difference = 31.6%, 95% CI = 0.3% to 56.2%; P = .042). CONCLUSION: LTA4H overexpression appears to be an early event in esophageal adenocarcinogenesis and is a potential target for the chemoprevention of EAC.