Treatment Patterns of Long-Acting Somatostatin Analogs for Neuroendocrine Tumors.

Background: Long-acting somatostatin analog therapy (LA-SSA) is recommended as first-line therapy for treatment of unresectable or metastatic neuroendocrine tumors (NETs). Understanding treatment sequencing and dosing patterns of LA-SSA is essential for clinical decision-making to provide value-based management of NETs. Objective: To describe treatment patterns of LA-SSA among patients with NETs and subgroups with carcinoid syndrome (CS) in the United States. Methods: This retrospective study utilized claims data from MarketScan® databases to identify patients with NETs and newly treated with LA-SSA between January 1, 2015, and October 31, 2020. Patients were stratified by index LA-SSA (lanreotide and octreotide long-acting release [LAR]). Reported 28-day doses were based on claim fields for days' supply/drug quantity or units of service. Dose escalation was defined as increases in quantity or frequency. Continuous variables, categorical variables, and Kaplan-Meier estimated treatment durations were compared using t-tests, chi-square/Fisher's tests, and log-rank tests, respectively. Results: The study included 241 lanreotide and 521 octreotide LAR patients. Compared with octreotide LAR patients, treatment duration was longer for lanreotide patients (median, 41.3 vs 26.8 months; log-rank p=.004). Fewer lanreotide patients received rescue treatment with short-acting octreotide (7.9% vs 14.4%; p=.011), and a first (6.2% vs 27.3%) and second dose escalation (0.8% vs 5.2%; both p<.05). Among patients with doses reported, fewer lanreotide patients received above-label doses (2.5% [5/202] vs 14.4% [60/416]; p<.001). Among patients who ended treatment during follow-up, fewer lanreotide patients transitioned to another LA-SSA (18.9% [17/90] vs 33.6% [92/274]; p=.008). Similar treatment patterns were observed in CS subgroups. Results for switched treatment patterns were limited due to insufficient sample sizes. Discussion: Real-world treatment patterns of LA-SSA were assessed using more recent administrative claims data. Compared with octreotide LAR patients, lanreotide patients were more likely to remain longer on initial treatment and starting dose without dose escalations and less likely to use rescue treatment and transition to another LA-SSA after discontinuation of the index treatment. Conclusions: Findings from this claims study suggest a potential clinical benefit of lanreotide in NET management.

Prior irinotecan exposure does not preclude benefit to liposomal irinotecan in patients with metastatic pancreatic ductal adenocarcinoma.

BACKGROUND: Subgroup analyses of the NAPOLI-1 study identified that among patients who were irinotecan naïve prior to entering the clinical trial, a survival benefit was observed between the study arm and control arm. This treatment benefit was not observed among those previously exposed to irinotecan. This study sought to understand the impact of prior exposure to irinotecan on clinical outcomes among patients treated with liposomal irinotecan in the real-world setting. METHODS: This retrospective observational study utilized a nationwide electronic health record (EHR)-derived deidentified database. Data for adult patients with mPDAC treated with liposomal irinotecan-based regimens between January 2016 and October 2020 were analyzed. Patient characteristics, overall survival (OS), and progression-free survival (PFS) were assessed. Cox proportional hazard methods were used to calculate hazard ratios (HRs). HRs were adjusted for demographics and relevant clinical covariates. RESULTS: Six hundred and seventy-five patients with mPDAC treated with a liposomal irinotecan-based regimen were included. The unadjusted OS HR was 1.3 (95% CI: 1.1-1.6, p < 0.001) and unadjusted PFS was HR 1.4 (95% CI: 1.2-1.7, p < 0.001). After adjustment for baseline characteristics, the adjusted OS HR was 1.0 (95% CI: 0.8-1.3, p = 0.8836) and the adjusted PFS HR was 1.1 (95% CI: 0.8-1.4, p = 0.5626). CONCLUSIONS: Prior irinotecan was not found to be a significant predictor of patient outcomes in those later treated with liposomal irinotecan. Thus, the results may inform the rationale for utilizing liposomal irinotecan combination therapy following prior irinotecan exposure in mPDAC, in particular where the prior irinotecan exposure was more distant in time.

Costs by Site of Service for Commercially-Insured Patients with Metastatic Pancreatic Cancer Receiving Guideline-Recommended Chemotherapy: Comparing Community Oncology and Hospital Outpatient Settings.

Purpose: Compare total cost of care (TCOC) for commercially-insured patients with metastatic pancreatic cancer receiving FDA-approved/NCCN Category 1 preferred regimens in community oncology or hospital outpatient settings. Patients and Methods: We used the 2016-2019 MarketScan® and Milliman Consolidated Health Cost Guidelines Sources Database (CHSD) administrative claims data to compare utilization of healthcare services and expenditures for commercially-insured patients receiving chemotherapy in community oncology or hospital outpatient settings. We identified patients with metastatic pancreatic cancer using ICD-10 diagnosis codes in 2016-2019 MarketScan® and Milliman Consolidated Health Cost Guidelines Sources Database files. Patients were assigned to cohorts based on where they received the plurality of chemotherapy services: community oncology or hospital outpatient settings. Total cost of care (TCOC) and healthcare resource utilization metrics were calculated per line of therapy (LOT) for patients receiving similar chemotherapy regimens in each cohort, and differences between cohorts were evaluated using t-testing and chi-squared statistical methods. Results: Although cohorts had similar demographics, chemotherapy regimen use, and length of therapy, the mean TCOC among all patients receiving chemotherapy in hospital outpatient settings was 41% higher compared to community oncology settings. Median TCOC was 35% higher in hospital outpatient settings than in community oncology settings. Mean admissions and readmissions per beneficiary were 7% and 16% higher, respectively, for thse treated in hospital outpatient versus community oncology settings. We observed no differences in the use of emergency department or hospice care between the cohorts. Conclusion: Our study indicates that patients receiving chemotherapy at community oncology centers are associated with better or equivalent outcomes and lower costs than patients receiving the same regimen in a hospital outpatient setting.

Real-world Impact of Age at Diagnosis on Treatment Patterns and Survival Outcomes of Patients with Metastatic Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Sixty-eight percent of patients with pancreatic ductal adenocarcinoma (PDAC) are 65 years and older. Older adults are under-represented in clinical trials and their care is complicated with multiple age-related conditions. Research suggests that older patients can experience meaningful responses to treatment for PDAC. The objective of this study was to evaluate the characteristics, rate of treatment, and survival outcomes of patients with metastatic PDAC (mPDAC) based on age at diagnosis. MATERIALS AND METHODS: Data were extracted for patients diagnosed with mPDAC between January 1, 2015, and March 31, 2020, from the Flatiron Health database. Patients were stratified into 3 age groups: <70 years old, 70-79 years, and ≥80 years. The proportion of patients who received first-line therapy, the types of regimens received in the metastatic setting, overall survival (OS) from the start of treatment were evaluated. RESULTS: Of the 8382 patients included, 71.3% (n = 5973) received treatment. Among patients who received treatment 55.5% (n = 3313) were aged <70 years at diagnosis, 33.0% (n = 1972) were 70-79 years, and 11.5% (n = 688) were ≥80 years. Patients ≥80 years of age were more likely to receive gemcitabine monotherapy and less likely to receive FOLFIRINOX. Among first-line treated patients, median OS significantly decreased with age. However, when comparing patients treated with the same first-line regimen, no significant differences in median OS were observed by age. CONCLUSIONS: This study highlights that older adults with mPDAC can benefit substantially by receiving appropriate levels of treatment.

Impact of the COVID-19 Pandemic on Management of Patients with Metastatic Pancreatic Ductal Adenocarcinoma in the United States.

BACKGROUND: The purpose of this study was to understand how the COVID-19 pandemic has affected health care patterns and outcomes for patients diagnosed with metastatic pancreatic ductal adenocarcinoma (mPDAC) in 2020 compared with those diagnosed with mPDAC in 2019. PATIENTS AND METHODS: We used the Flatiron Health database to identify adults diagnosed with mPDAC from March 1 to September 30, 2019 (pre-COVID-19 cohort) and March 1 to September 30, 2020 (post-COVID-19 cohort). Between-cohort comparisons included demographic and clinical characteristics and year-over-year data for diagnosis of mPDAC, newly treated patients, time to and types of first-line therapy, and adverse events (AEs) during first-line therapy. Overall survival (OS) and milestone survival rates were evaluated. Kaplan-Meier methods were used to assess OS. RESULTS: Pre-COVID-19 (n = 923) and post-COVID-19 (n = 796) cohorts had similar baseline demographic characteristics. A smaller proportion of patients in the pre-COVID-19 cohort were initially diagnosed with stage IV disease versus the post-COVID-19 cohort (62.2% vs 69.7%). Between 2019 and 2020, there was a 13.8% decrease in diagnosis of mPDAC and a 13.0% decrease in newly treated patients. Median (interquartile range) times to first-line treatment were similar (21 [13-40] and 19 [12-32] days). Median OS (months) was significantly longer in the pre-COVID-19 cohort (8·4 [95% CI: 7·5, 9·0]) versus the post-COVID-19 cohort (6·1 [95% CI: 5·4, 6·9]; P < .001). Survival rates were higher in the pre-COVID-19 versus post-COVID-19 cohorts. CONCLUSIONS: During the pandemic, patients were initially diagnosed with PDAC at more advanced stages. While patients in both cohorts appeared to receive similar care, survival outcomes were adversely affected.

Real-world safety and supportive care use of second-line 5-fluorouracil-based regimens among patients with metastatic pancreatic ductal adenocarcinoma.

OBJECTIVE: Chemotherapy-related adverse events (AEs) can negatively impact the care of patients. The prevention and management of AEs often require additional medications. This study evaluated the percentages of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) undergoing second-line therapy with 5-fluorouracil (5-FU)-based regimens that experienced AEs during treatment and received medication to manage those AEs. METHODS: We conducted a retrospective observational analysis utilizing the Flatiron Health database of adult patients with mPDAC who started second-line therapy between January 2016 and August 2020. The occurrence of diarrhea, fatigue, nausea and vomiting, neuropathy, and hematologic AEs including G3/G4 anemia, neutropenia, and thrombocytopenia was assessed. The use of concomitant medications including atropine and granulocyte colony stimulating factor (G-CSF) was assessed. RESULTS: Of the 825 eligible patients, 29.0% (n = 239) received FOLFIRINOX, 24.0% (n = 198) received FOLFOX, 6.8% (n = 56) received FOLFIRI, and 40.2% (n = 332) received liposomal irinotecan-based regimens. FOLFIRI and FOLFIRINOX regimens were associated with the highest rates of anemia (16.1% and 15.5%), neutropenia (19.6% and 22.6%), and thrombocytopenia (14.3% and 9.6%). The liposomal irinotecan and FOLFOX regimens were associated with lower rates of anemia (11.8% and 12.1%), neutropenia (12.4% and 14.7%), and thrombocytopenia (2.4% and 8.1%). G-CSF use was observed among 63.6%, 34.9%, 33.9%, and 44.9% of patients treated with FOLFIRINOX, FOLFOX, FOLFIRI, and liposomal irinotecan-based regimens, respectively. Diarrhea was observed among 12.5%, 4.5%, 12.5%, and 10.2% of patients who were treated with FOLFIRINOX, FOLFOX, FOLFIRI, and liposomal irinotecan-based regimens, respectively. Nausea and vomiting occurred in 14.9%, 12.6%, 10.5%, and 13.1% of patients treated with FOLFIRINOX, FOLFOX, FOLFIRI, and liposomal irinotecan-based regimens, respectively. Atropine use was higher in patients treated with FOLFIRINOX and FOLFIRI (90.8% and 94.6%, respectively) than in patients treated with liposomal irinotecan-based regimens (75.6%). CONCLUSIONS: In patients with mPDAC who received second-line therapy, those who received liposomal irinotecan-based regimens had the lowest rates of anemia, neutropenia, and thrombocytopenia compared to FOLFIRI, FOLFIRINOX, and FOLFOX, while requiring a similar or lower level of medication to treat and manage those adverse events. Patients treated with FOLFIRI received the highest dose of pegfilgrastim to manage neutropenia. The results of this real-world analysis are consistent with prior evaluations of patients with mPDAC and highlight the importance of managing adverse events and associated cost implications.

Real-world prognostic factors for survival among treated patients with metastatic pancreatic ductal adenocarcinoma.

BACKGROUND: Many real-world studies of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) are restricted to single centers, limiting the generalizability of their insights. This study aimed to identify important population-based predictors for survival in patients diagnosed with mPDAC in a broader setting. METHODS: Data between 1 January 2017 and 31 December 2019 were extracted from the Flatiron Health EHR database. Treatment-specific predictive models were generated for patients treated with first-line gemcitabine+nab-paclitaxel (GNP), FOLFIRINOX, gemcitabine monotherapy (gem-mono), and second-line liposomal irinotecan-based regimens. The holdout method was used for cross-validation. Age at diagnosis, sex, BMI, smoking status, and ECOG performance score were included in all models with additional demographic, clinical characteristics, and hematological function assessed for inclusion. RESULTS: Of the 3625 patients, 43% received GNP, 26% received FOLFIRINOX, 7% received gem-mono, and 23% received other regimens; 40% (n = 1448) advanced to the second line. Among all first-line patients, the following were included in the final model: prior surgery, white blood cell (WBC) counts, serum albumin (SA), liver function tests (LFTs), serum bilirubin, serum carbohydrate antigen 19-9, and ascites. Models for patients receiving specific therapies differed from the overall model, GNP (ascites removed), FOLFIRINOX (stage at initial diagnosis added), and gem-mono (LFTs omitted). Alkaline phosphatase (ALP), SA, and WBC counts were important predictors of survival among patients treated with second-line liposomal irinotecan. Across all regimens, the strongest predictors of survival were ECOG score, SA, and ALP. CONCLUSIONS: In this real-world study of patients with mPDAC, important population prognostic factors of survival were identified in a large cohort of patients receiving systemic treatment.

The Association of Real-World CA 19-9 Level Monitoring Patterns and Clinical Outcomes Among Patients With Metastatic Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Pancreatic cancer is expected to be the third deadliest cancer in the US in 2021. Evaluation of treatment response in patients with mPDAC necessitates scheduled clinical and radiographic assessments along with monitoring serum CA 19-9 levels. Currently available single-institution data examining the importance of CA 19-9 monitoring cannot be generalized to real-world settings. We investigated the impact of serum CA 19-9 monitoring and its association with clinical outcomes in patients with mPDAC in a population-based setting. METHODS: Data were extracted from the Flatiron Health electronic health record (EHR)-derived de-identified database for patients diagnosed with mPDAC between January 1, 2015, and June 30, 2020. Serum CA 19-9 levels at baseline - defined as the values obtained ≤ 60 days prior to treatment initiation - and during treatment were extracted. CA 19-9 levels > 40 IU/mL were considered elevated. Survival outcomes were compared based on testing frequency, baseline CA 19-9 levels, and change in CA 19-9. RESULTS: 6,118 patients with mPDAC who received treatment were included in the analysis. The median age at diagnosis was 68 years (IQR: 61-75). Patients with normal baseline CA 19-9 experienced longer median survival than patients with elevated levels [1L: 8.8 months (95% CI: 7.9 - 10) vs. 7.2 months (6.8 - 7.5), p < 0.001; 2L: 7.2 months (6.1 - 9.2) vs. 5.2 months (4.9 - 5.6), p < 0.001; 3L: 6.1 months (5.4 - 9.1) vs. 3.9 months (3.4 - 4.3), p < 0.001]. Patients with decreasing/stable CA 19-9 during treatment experienced longer survival than patients who experienced an increase in CA 19-9 levels [1L: 10.9 months (10.5 - 11.3) vs. 5.4 months (5.1 - 5.9), p < 0.0001; 2L: 8.2 months (7.7 - 8.5) vs. 4.3 months (4.1 - 4.7), p < 0.001; 3L: 7.5 months (6.6 - 9.2) vs. 3.7 months (3.4 - 4.3), p < 0.001]. CONCLUSIONS: In one of the largest, contemporary, real-world studies of patients with mPDAC, elevated CA 19-9 level at treatment initiation demonstrated a prognostic impact. Routine serial monitoring of CA 19-9 levels during treatment may be warranted, in addition to clinical and radiographic assessment, and may translate into better patient outcomes. Further validation studies are needed to understand the generalizability of these results.

Clinical Outcomes Among Patients With Metastatic Pancreatic Ductal Adenocarcinoma Treated With Liposomal Irinotecan.

BACKGROUND: The NAPOLI-1 trial demonstrated that liposomal irinotecan in combination with fluorouracil (5-FU) and leucovorin (LV) prolonged survival with a manageable safety profile in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy. Real-world data on clinical outcomes associated with liposomal irinotecan in NAPOLI-1-based regimens is needed to further substantiate this. METHODS: This real-world, retrospective chart review study included patients with mPDAC who received NAPOLI-1-based regimens from six academic centers in the United States. Liposomal irinotecan initiation defined the index date. Overall survival (OS) and progression-free survival (PFS) were assessed with Kaplan-Meier methodology. RESULTS: There were 374 patients evaluated; median age was 68 years, and 51% were female. Among 326 patients with baseline ECOG information, approximately 74% had ECOG score <2. Liposomal irinotecan was administered as a doublet with 5-FU in a NAPOLI-1-based regimen in the first line (1L; 16%), 2L (42%), and 3L+ (42%) of the metastatic setting. For patients treated in 1L, 2L, and 3L+, median [95% confidence interval (CI)] OS was 8.0 [5.1, 11.2], 7.3 [5.3, 8.8], and 4.6 [4.0, 5.7] months, and median [95% CI] PFS was 4.2 [2.2, 6.6], 3.0 [2.6, 3.7], and 2.0 [1.7, 2.2] months, respectively. CONCLUSIONS: Patients in a real-world setting treated with NAPOLI-1-based liposomal irinotecan doublet regimens at academic centers were older with poorer performance status compared to trial patients yet had similar outcomes and efficacy. Furthermore, liposomal irinotecan was frequently used in the 3L+ setting where no treatment has been approved and provided clinical benefit.

Real-World Cost of Care for Commercially Insured versus Medicare Patients with Metastatic Pancreatic Cancer Who Received Guideline-Recommended Therapies.

BACKGROUND: Much of the literature about the costs of metastatic pancreatic cancer is focused on the Medicare population, but the cost in the commercially insured population is not well-documented. Differences in treatment patterns between commercially insured and Medicare patients with metastatic pancreatic cancer can provide insights into healthcare utilization and the total cost of care. OBJECTIVE: To compare the total cost of care for commercially insured versus Medicare patients with metastatic pancreatic cancer who are receiving National Comprehensive Cancer Network (NCCN)-recommended treatment regimens. METHODS: We identified 3904 patients (mean age at diagnosis, 56 years) with metastatic pancreatic cancer using International Classification of Diseases, Ninth/Tenth Revision diagnosis codes in claims data in the 2014-2018 MarketScan commercial database and 28,063 patients (mean age at diagnosis, 73 years) with metastatic pancreatic cancer in the 2014-2017 Medicare Parts A, B, and D 100% research identifiable data files. We calculated the total cost of care and resource utilization by NCCN-recommended (category 1) treatment regimen, including 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX); gemcitabine plus nab-paclitaxel; gemcitabine monotherapy; and liposomal irinotecan. All patients had ≥2 claims with a pancreatic cancer diagnosis more than 30 days apart and ≥1 subsequent claims with a secondary malignancy diagnosis for metastatic disease. RESULTS: The mean total cost of care was 186% higher in the commercially insured cohort than in the Medicare cohort. Excluding gemcitabine monotherapy, the total cost of care for patients with metastatic pancreatic cancer was similar between the regimens used in each cohort, ranging from $95,426 to $116,325 in the commercial insurance group and from $39,777 to $40,390 in the Medicare group. The components of hospital-based inpatient and outpatient costs varied between similar regimens in both cohorts. The inpatient admission patterns of patients' regimens were consistent across the 2 cohorts, with patients receiving gemcitabine monotherapy or liposomal irinotecan having the lowest overall number of admissions in each cohort. CONCLUSIONS: The treatment patterns varied across the regimens but were largely consistent between the commercially insured and the Medicare patients who received the same regimen for metastatic pancreatic cancer; the ratio of total cost of care was 3:1 (commercially insured to Medicare). The total costs of care were similar across the regimens in each cohort, but the components of the total cost varied. These results can inform clinical guidelines and pathways for pancreatic cancer therapy as new evidence and treatment options emerge, and in the context of increasing value-based care models.

Real-world outcomes associated with liposomal irinotecan dose reductions in metastatic pancreatic ductal adenocarcinoma.

Aim: This study sought to understand the association between liposomal irinotecan dose reductions (DRs) and clinical outcomes among patients with metastatic pancreatic ductal adenocarcinoma. Materials & methods: A retrospective study of adult patients with metastatic pancreatic ductal adenocarcinoma treated with liposomal irinotecan in the Flatiron Health database was conducted to assess treatment and clinical outcomes. Results: DRs occurred in 28.4% of the 320 patients in the study. Patients with DRs had longer overall survival (7.7 [95% CI: 6.2-10.2]) vs 3.6 [3.2-4.1] months) and time to discontinuation (4.2 [3.0-4.9] vs 1.4 [1.0-1.5] months) than patients without DRs. Results were consistent in a validation analysis requiring three cycles of treatment. Conclusion: Liposomal irinotecan DRs were associated with improved clinical outcomes compared with patients without DRs.

Comparing real-world evidence among patients with metastatic pancreatic ductal adenocarcinoma treated with liposomal irinotecan.

There are questions surrounding the real-world effectiveness of chemotherapeutic treatments for pancreatic ductal adenocarcinoma. This literature review compared the clinical characteristics and outcomes of available real-world evidence (RWE) for liposomal irinotecan in combination with 5-fluorouracil (5-FU) and leucovorin (LV), a treatment regimen indicated for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who previously progressed on gemcitabine-based therapy. A targeted literature search was conducted in the PubMed Central® and Embase® databases to identify available RWE regarding patients with mPDAC receiving liposomal irinotecan published within the last 5 years (January 2014-September 2019). Data were extracted for prior lines of therapy, performance status, overall survival (OS), progression-free survival (PFS), duration of exposure, and adverse events. Six studies met inclusion criteria. A comparison of baseline patient characteristics and results with the included evidence reveals a clinically fragile, real-world patient population in terms of age (range: 61-68), prior lines of therapy with 34-61% of patients receiving ⩾2 lines of lines of prior therapy and performance status [49.8-100% of patients with Eastern Cooperative Oncology Group (ECOG) 0-1]. Studies observed wide OS (range: 5.3-9.4 months) and similar PFS (range: 2.3-4.1 months), with two studies measuring duration of exposure (7.3 weeks, 3.1 months). Patients analyzed by RWE studies tended to be older with significant disease progression, poor performance status, and more heavily pretreated compared with the phase III registrational trial (NAPOLI-1). Despite this, patients treated with liposomal irinotecan + 5-FU/LV therapy had similar outcomes as those in NAPOLI-1.

Reducing nihilism in metastatic pancreatic ductal adenocarcinoma: Treatment, sequencing, and effects on survival outcomes.

BACKGROUND: Real-world practice patterns, treatment sequencing, and outcomes in patients with metastatic pancreatic cancer remain unclear. Previous research indicates that the likelihood of patients with metastatic pancreatic cancer receiving or continuing cancer-directed therapy is low-a phenomenon called nihilism. This retrospective, descriptive analysis examined clinical characteristics, treatment patterns, and outcomes for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). METHODS: Treatment patterns were examined using electronic health records from the Flatiron Health database covering the period from January 1, 2014, to June 30, 2019. Real-world overall survival [rwOS]) was compared for a subgroup of patients receiving treatment and a matched subgroup not receiving treatment. RESULTS: Of 7666 patients, 5687 (74.2%) received at least one line of systemic therapy. A greater proportion of patients receiving treatment than not receiving treatment had an initial diagnosis of stage IV disease (68.8% vs 61.2%, respectively). Among patients receiving an initial therapy, fewer than half (38.2%; 2174/5687) received second-line treatment, mostly because they died, and only 34.3% (745/2174) of those receiving second-line treatment advanced to third-line treatment. The rwOS for patients receiving at least one line of systemic therapy was 8.1 months versus 2.6 months for matched patients not receiving treatment (hazard ratio, 0.41; 95% confidence interval, 0.38-0.45; 1470 patients per group). CONCLUSIONS: Systemic therapy provided significant clinical benefit for patients who were eligible and chose to receive it, particularly when treatment was consistent with guideline recommendations. The large proportion of patients initiating treatment suggests that nihilism with mPDAC is diminishing.

Correction to: In Vivo Pharmacokinetics of Bromfenac Ophthalmic Solution 0.075%, Bromfenac Ophthalmic Solution 0.07%, and Nepafenac/Amfenac Ophthalmic Suspension 0.3% in Rabbits.

In the original publication, units were incorrectly published in the results section as micrograms (µg/mL).

An ex vivo human aqueous humor-concentration comparison of two commercial bromfenac formulations.

PURPOSE: The purpose of this study was to quantify the concentration of bromfenac in the aqueous humor utilizing high-performance liquid chromatography mass spectrometry between two commercial nonsteroidal anti-inflammatory drugs, using aqueous humor concentrations to characterize pharmacokinetic proportional differences between 0.075% bromfenac ophthalmic solution in DuraSite (BromSite®) and 0.09% bromfenac ophthalmic solution (Bromday®). METHODS: In this multicenter, randomized, double-masked, two-arm, parallel-group, comparative, Phase II clinical trial, subjects were assigned to receive bromfenac in DuraSite or bromfenac ophthalmic solution in a 1:1 ratio. One drop of the masked test article was instilled into the study eye once a day for 2 days prior to and 3 hours prior (last instillation) to the subject's cataract surgery. Aqueous humor samples were collected upon initial cataract incision for analysis of bromfenac levels. The primary end point was aqueous humor concentration of bromfenac at Day 3, at the initiation of cataract surgery. Aqueous humor samples were collected and analyzed for bromfenac levels. RESULTS: A total of 60 subjects completed the study, 30 in each group. The mean bromfenac aqueous humor concentration in subjects who received bromfenac in DuraSite was more than twice (49.33±41.87 ng/mL, P=0.004) that of subjects who received bromfenac ophthalmic solution (23.65±16.31 ng/mL) after three doses. CONCLUSION: Mean bromfenac aqueous humor concentration in subjects receiving the DuraSite-containing bromfenac in DuraSite (0.075%) was significantly higher compared to subjects receiving bromfenac ophthalmic solution (0.09%) after 3 days of dosing.

In Vivo Pharmacokinetics of Bromfenac Ophthalmic Solution 0.075%, Bromfenac Ophthalmic Solution 0.07%, and Nepafenac/Amfenac Ophthalmic Suspension 0.3% in Rabbits.

INTRODUCTION: Little is known of the ocular distribution characteristics of currently branded non-steroidal anti-inflammatory drugs (NSAIDs) in the United States. This study was designed to predict the ocular bioavailability characteristics in humans using Dutch Belted rabbits as a surrogate. Commercially available, topically-applied NSAIDs containing bromfenac or nepafenac/amfenac were evaluated. METHODS: 126 healthy adult Dutch Belted rabbits were randomly assigned to three treatment cohorts (BromSite® twice daily [BID] in the right eye, BromSite® once daily [QD] in the right eye, Prolensa® QD in the right eye and Ilevro™ QD in the left eye) and 7 post-dosing time points (0.5, 1, 2, 4, 8, 12, 24 h after final instillation). The study eyes received 40 µL of the assigned drug for a consecutive 9 days. Samples of aqueous humor, iris-ciliary body, choroid, sclera, and retina were harvested from the study eyes at the assigned time point after the last dose on the 9th day. NSAID content in ocular tissues was analyzed using high-performance liquid chromatography (HPLC), and area under the curve (AUC0.5-24h), maximum concentration (Cmax), and time to maximum concentration (Tmax) were determined. RESULTS: Peak NSAID concentrations were reached within 1-3 h in the anterior segment and within 1-3 h in the posterior segment after last dose. Throughout the ocular tissues, both AUC and Cmax for BromSite® (BID and QD) were consistently higher than respective NSAID concentrations of Prolensa® QD and Ilevro® QD. When comparing BromSite® BID to QD, the BID regimen produced generally higher but statistically similar bromfenac concentrations throughout the ocular tissues except in the aqueous humor and iris-ciliary body, where the AUC BID was statistically significantly higher with BromSite® BID. CONCLUSION: As a surrogate to human ocular bioavailability, BromSite® demonstrated significantly greater NSAID compared to Prolensa® QD and Ilevro® QD. The DuraSite® component of BromSite® appears to enhance ocular penetration throughout both anterior and posterior tissues. FUNDING: Sun Pharmaceutical Industries Ltd.

Evaluation of clinical efficacy and safety of tobramycin/dexamethasone ophthalmic suspension 0.3%/0.05% compared to azithromycin ophthalmic solution 1% in the treatment of moderate to severe acute blepharitis/blepharoconjunctivitis.

OBJECTIVE: To evaluate the clinical efficacy and safety of tobramycin/dexamethasone (TobraDex ST ; 'ST') ophthalmic suspension 0.3%/0.05% compared to azithromycin (Azasite) ophthalmic solution (1%) in the treatment of moderate to severe blepharitis/blepharoconjunctivitis. RESEARCH DESIGN AND METHODS: The study was a multicenter, randomized, investigator-masked, and active-controlled, 15-day study. Enrolled in the study were 122 adult subjects (at least 18 years of age) diagnosed with moderate to severe blepharitis/blepharoconjunctivitis, defined by a minimum score of at least '1' for one of the lid signs, one of the conjunctival signs, and one of the symptoms in at least one eye and a minimum global score (total signs and symptoms score) of '5' in the same eye. One group of 61 subjects received ST with instructions to dose 1 drop four times daily (QID) for 14 days. The other group of 61 subjects received azithromycin and dosed with 1 drop twice daily (BID) for 2 days followed by once daily (QD) dosing for 12 days. Visits were conducted at Day 1 (baseline), Day 8 and Day 15. The a priori primary outcome parameter of the study was the seven-item global score defined as the total score of lid margin redness, bulbar conjunctival redness, palpebral conjunctival redness, ocular discharge (0-3 scale), and lid swelling, itchy eyelids, and gritty eyes (0-4 scale). The study utilized standardized, validated photograph control scales developed by Ora, Inc. (Andover, MA). CLINICAL TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov under the registry number NCT01102244. RESULTS: A statistically significant lower mean global score (p = 0.0002) was observed in subjects treated with ST compared to subjects treated with azithromycin at Day 8. No serious adverse events were reported during the course of the study in either group. CONCLUSION: ST provides a fast and effective treatment of acute blepharitis compared to azithromycin. Initial therapy with the combination of tobramycin/dexamethasone provides faster inflammation relief than azithromycin for moderate to severe blepharitis/blepharoconjunctivitis.

Conjunctival concentrations of a new ophthalmic solution formulation of moxifloxacin 0.5% in cataract surgery patients.

PURPOSE: To compare the conjunctival concentrations of moxifloxacin after instillation of a single drop of moxifloxacin ophthalmic solution, 0.5% (Moxi) or a new 0.5% ophthalmic solution formulation (MAF) containing a retention-enhancing agent in patients undergoing cataract surgery. METHODS: This was a randomized, double-masked, parallel-group study. One hundred thirty patients scheduled for routine phacoemulsification and intraocular lens implantation were randomized to both treatment and post-dose sample collection time points. A single topical drop of Moxi or MAF was instilled in the study eye. At the designated time (0.25, 0.5, 1, 3, or 5 h post-dose), 2 conjunctival biopsy samples were obtained (N = 11-13 per treatment condition). Concentrations of moxifloxacin were determined using a validated ultra-performance liquid chromatography method. Moxifloxacin exposure [maximum mean moxifloxacin concentrations (C(max)) and area under the concentration-time curve (AUC)] was estimated from the observed concentration-time data. RESULTS: The conjunctival moxifloxacin C(max), 43.8 µg/g, for MAF was achieved at 0.25 h. This was 1.8-fold higher than the C(max) for Moxi (24.1 µg/g), which was reached at 0.5 h post-dose. MAF AUC(0-3) was significantly greater than the AUC(0-3) of Moxi [50.5 (µg·h)/g vs. 27.1 (µg·h)/g; P < 0.05]. The conjunctival moxifloxacin C(max) for MAF was 337- to 730-fold greater than the reported minimum inhibitory concentration (MIC(90)) values for Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae. The C(max):MIC(90) ratios for Moxi ranged from 185 to 402. Conjunctival AUC(0-24):MIC(90) ratios ranged from 777 to 1,683 for MAF and from 625 to 1,355 for Moxi. CONCLUSIONS: The new MAF ophthalmic formulation of moxifloxacin provided higher peak levels of moxifloxacin in the conjunctiva tissue, and larger total tissue exposure than the current, commercially available formulation. The superior penetration of MAF observed in this study could translate into greater eradication of bacteria.

Kinetics of kill of bacterial conjunctivitis isolates with moxifloxacin, a fluoroquinolone, compared with the aminoglycosides tobramycin and gentamicin.

PURPOSE: To compare the kinetics and speed of kill of Streptococcus pneumoniae and Haemophilus influenzae on exposure to three topical ophthalmic antibiotic solutions. MATERIALS AND METHODS: Bacterial conjunctivitis isolates of S. pneumoniae and H. influenzae were exposed to 1:1000 dilutions of moxifloxacin 0.5%, tobramycin 0.3%, gentamicin 0.3%, and water (control). At 15, 30, 60, 120, and 180 minutes after exposure, aliquots were collected, cells were cultured, and viable cell counts were determined using standard microbiological methods. RESULTS: Moxifloxacin achieved 99.9% kill (3-log reduction) at approximately 2 hours for S. pneumoniae and at 15 minutes for H. influenzae. Tobramycin and gentamicin did not achieve 3-log reduction of S. pneumoniae during the 180-minute study period. An increase in bacterial growth was noted for these isolates. Gentamicin took more than 120 minutes to achieve the 3-log reduction of H. influenzae and tobramycin did not reach the 3-log reduction of this pathogen during the 180-minute study period. CONCLUSION: Moxifloxacin killed S. pneumoniae and H. influenzae in vitro faster than tobramycin and gentamicin, suggesting its potential clinical benefit as a first-line treatment for bacterial conjunctivitis to minimize patient symptoms and to limit the contagiousness of the disease.