Patient-reported health-related quality of life, work productivity, and activity impairment during treatment with ALO-02 (extended-release oxycodone and sequestered naltrexone) for moderate-to-severe chronic low back pain.

BACKGROUND: The efficacy of ALO-02, an abuse-deterrent formulation containing extended-release oxycodone and sequestered naltrexone, in the treatment of chronic low back pain (CLBP) was studied in a 12-week randomized controlled trial. Primary efficacy endpoint results have been published previously (Rauck et al., 2015). The current paper focuses on patient-reported outcomes for health-related quality of life (HRQL), work productivity, and activity impairment that were assessed during this study. METHODS: This was a double-blind, placebo-controlled, randomized withdrawal study in patients with moderate-to-severe CLBP. After a screening period (≤2 weeks), patients entered an open-label titration period (4-6 weeks). Treatment responders were then randomized to a double-blind placebo-controlled treatment period (12 weeks). HRQL was assessed using changes in the Short Form-36 v2 Health Survey (SF-36v2) and the EuroQol-5 Dimensions Health Questionnaire 3-Level version (EQ-5D-3L). Work productivity and regular activities were evaluated using the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI:SHP). RESULTS: A total of 410 patients received ALO-02 during the open-label titration period, of which 280 (intent-to-treat (ITT) population) were treated during the double-blind placebo-controlled treatment period (placebo, n = 134; ALO-02, n = 146). Significant improvement was observed for all SF-36v2 subscales and component scores (p < 0.005) and the EQ-5D-3L summary index and visual analog scale (p < 0.0001) during the titration period. Improvement was also significant (p < 0.0001) for all WPAI:SHP outcomes except 'work time missed due to CLBP' for the titration period. Significant differences favoring ALO-02 compared with placebo were only observed for the SF-36v2 Bodily Pain subscale (p ≤ 0.0232; ITT population) during the double-blind treatment period and the overall study period (screening to the end of the double-blind treatment period). The percentage change in activity impairment due to low back pain subscale of the WPAI:SHP significantly favored ALO-02 compared with placebo for the ITT population when considering the overall study period (p = 0.0040). CONCLUSIONS: HRQL, work productivity, and activity impairment may be improved with ALO-02 treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT01571362 , registered April 3, 2012.

Enhancing Risk Assessment in Patients Receiving Chronic Opioid Analgesic Therapy Using Natural Language Processing.

OBJECTIVES: Clinical guidelines for the use of opioids in chronic noncancer pain recommend assessing risk for aberrant drug-related behaviors prior to initiating opioid therapy. Despite recent dramatic increases in prescription opioid misuse and abuse, use of screening tools by clinicians continues to be underutilized. This research evaluated natural language processing (NLP) together with other data extraction techniques for risk assessment of patients considered for opioid therapy as a means of predicting opioid abuse. DESIGN: Using a retrospective cohort of 3,668 chronic noncancer pain patients with at least one opioid agreement between January 1, 2007, and December 31, 2012, we examined the availability of electronic health record structured and unstructured data to populate the Opioid Risk Tool (ORT) and other selected outcomes. Clinician-documented opioid agreement violations in the clinical notes were determined using NLP techniques followed by manual review of the notes. RESULTS: Confirmed through manual review, the NLP algorithm had 96.1% sensitivity, 92.8% specificity, and 92.6% positive predictive value in identifying opioid agreement violation. At the time of most recent opioid agreement, automated ORT identified 42.8% of patients as at low risk, 28.2% as at moderate risk, and 29.0% as at high risk for opioid abuse. During a year following the agreement, 22.5% of patients had opioid agreement violations. Patients classified as high risk were three times more likely to violate opioid agreements compared with those with low/moderate risk. CONCLUSION: Our findings suggest that NLP techniques have potential utility to support clinicians in screening chronic noncancer pain patients considered for long-term opioid therapy.

A systematic review of the effectiveness of policies restricting access to pregabalin.

BACKGROUND: Formularies often employ restriction policies to reduce pharmacy costs. Pregabalin, an alpha-2-delta ligand, is approved for treatment of fibromyalgia (FM); neuropathic pain (NeP) due to postherpetic neuralgia (PHN), diabetic peripheral neuropathy (pDPN), spinal cord injury; and as adjunct therapy for partial onset seizures. Pregabalin is endorsed as first-line therapy for these indications by several US and EU medical professional societies. However, restriction policies such as prior authorization (PA) and step therapy (ST) often favor less costly generic pain medications over pregabalin. METHODS: A structured literature search (PubMed, past 11 years) was conducted to evaluate whether restriction policies against pregabalin support real-world economic and healthcare utilization benefits. RESULTS: Search criteria identified three claims analyses and a modeling study that evaluated patients with NeP and/or FM with and without PA restrictions; three other studies included patients with FM and NeP in plans with ST requirements, and one evaluated a mail order requirement program. All studies evaluated outcomes during follow-up periods of 6 months or longer. Overall, PA, ST, and mail order restriction policies effectively reduced pregabalin usage, but the effects were inconsistent with reducing pharmacy costs and were non-significant for total disease-related medical costs. Two studies (one PA; one ST) reported significantly higher disease-related costs in restricted plans. The modeling study failed to demonstrate cost savings with PA. Opioid usage was higher in PA-restricted plans (two studies). The US Centers for Disease Control and Prevention and several professional NeP guidelines recommend opioid use only in cases when other non-opioid pain therapies have proven ineffective. New US Government taskforce guidelines now seek to reduce opioid exposure. Additionally, in both ST studies, gabapentin utilization (a common ST edit) was significantly increased. Both studies had substantial proportions of FM and pDPN patients and the only pain condition gabapentin is approved to treat in the United States is PHN. CONCLUSION: PA and ST restriction policies significantly decrease utilization of pregabalin, but do not consistently demonstrate cost savings for US health plans. More research is needed to evaluate whether these policies may lead to increased opioid usage as found in some studies. TRIAL REGISTRATION: N/A.

Burden of illness in fibromyalgia patients with comorbid depression.

OBJECTIVES: To assess the burden of fibromyalgia (FM) in patients with FM taking antidepressant medication for comorbid depression. METHODS: Symptom burden, impact on work and activity, and healthcare resource utilisation (HCRU) was examined at randomisation in patients enrolled in a clinical trial. Symptom burden was estimated based on self-reported health status measures. The Work Productivity and Activity Impairment: Specific Health Problem scale adapted to FM and a separate HCRU questionnaire were completed. The relationship between FM severity and burden was evaluated. RESULTS: The total population analysed comprised 193 patients; 71 (36.8%) had moderate FM and 119 (61.7%) severe FM. Patients had moderate pain, severe impairment in functioning due to FM, sleep disruption, mild anxiety, and mild depression. In the 7 days preceding randomisation, an average of 58.0% overall work impairment was reported, with 15.2% of working hours missed and 54.0% productivity while at work. In the 3 months preceding randomisation, on average, 5.0 visits per patient were made to healthcare professionals. Physical treatments were used by 34.7% and supplements by 31.6% of patients. Prescription and non-prescription medications, as well as professional services providing help with activities of daily living (ADL) that are impacted by FM, were used by >75% of patients. In addition, 50.4 hours of unpaid help was provided for ADL assistance. Total out-of-pocket expenditures were US$307.1, €410.4, or C$211.3, depending on location. FM burden worsened with increasing FM severity. CONCLUSIONS: This study demonstrates the significant burden of FM in patients with comorbid depression treated with an antidepressant.

Evaluating Guideline-recommended Pain Medication Use Among Patients with Newly Diagnosed Fibromyalgia.

OBJECTIVES: To compare pain medication treatment changes across cohorts of newly diagnosed patients with fibromyalgia (FM) treated with guideline-recommended medications or opioids. METHODS AND DESIGN: Retrospective claims data analysis examined adult commercial health plan members newly diagnosed with FM (initial diagnosis = index date) from January 2008 to February 2012. Patients had 6-month pre-index and 12-month postindex periods and received pain medication within 6 months postindex; cohorts were based on the first postindex medication. Guideline-recommended medication cohorts were anti-epileptic drug (AED), serotonin-norepinephrine reuptake inhibitor (SNRI), selective serotonin reuptake inhibitor (SSRI), and tricyclic antidepressant (TCA). Short-acting and long-acting opioid (SAO, LAO) cohorts were also identified. Pairwise comparisons with the SAO cohort were conducted. Cox proportional hazards regressions modeled the likelihood of receiving guideline-recommended therapy. RESULTS: The final sample was 96,175 patients (mean age 47.3 years; 72.5% female), distributed into SAO (57%), SSRI (22%), AED (10%), SNRI (6%), TCA (3%), and LAO (2%) cohorts. The SAO cohort had the most discontinuation (49% vs. 6% to 22%, P < 0.01) and the least augmentation (29% vs. 35% to 50%, P < 0.01). Regression analyses indicated that patients with (vs. without) pre-index guideline-recommended medications were 2 to 4 times more likely to receive them postindex. Patients in the opioid cohorts were about half as likely to receive subsequent guideline-recommended medications. CONCLUSIONS: Opioid use was widespread among patients with FM. Once patients received opioids postdiagnosis, the likelihood of receiving guideline-recommended medications was small. These real-world results indicate an opportunity may exist for improved FM management using recommended therapies in clinical practice.

The Comparative Burden of Chronic Widespread Pain and Fibromyalgia in the United States.

BACKGROUND/PURPOSE: Little information exists on the comparative patient and economic burden of chronic widespread pain (CWP) and fibromyalgia (FM) in the United States. METHODS: This multistage, observational study included an online screening survey of a large geographically diverse US sample to assess CWP status, a physician/site visit to determine FM diagnosis, and an online subject questionnaire to capture clinical characteristics, pain, health status, functioning, sleep, healthcare resource use (HRU), productivity, and costs. Based on the screener and physician evaluation, mutually exclusive groups of subjects without CWP (CWP-), with CWP but without FM (CWP+), and with confirmed FM were identified. RESULTS: Disease burden was examined in 472 subjects (125 CWP-, 176 CWP+, 171 FM). Age, race, and ethnicity were similar across groups. Mean body mass index and number of comorbidities increased from CWP- to CWP+ to FM (P = 0.0044, P < 0.0001, respectively). From CWP- to CWP+ to FM, there were reductions in health status (EQ-5D, SF-12) and sleep outcomes (MOS-SS, SSQ) (all P < 0.05). Pain severity, interference with function (BPI-SF), and overall work impairment (WPAI:SHP) increased from CWP- to CWP+ to FM (all P < 0.0001). Higher proportions of CWP+ (52.8%) and FM subjects (62.6%) were taking pain-related prescription medications relative to CWP- subjects (32.8%; P < 0.0001). Significant differences in total direct and indirect costs across the three groups (both P < 0.0001) were observed, with highest costs among FM subjects. CONCLUSION: Fibromyalgia subjects were characterized by the greatest disease burden with more comorbidities and pain-related medications, poorer health status, function, sleep, lower productivity, and higher costs.

Prior authorization in the treatment of patients with pDPN and FM.

PURPOSE: To determine prior authorization (PA) impact on healthcare utilization, costs, and pharmacologic treatment patterns for painful diabetic peripheral neuropathy (pDPN) and fibromyalgia (FM). METHODS: This retrospective, observational, longitudinal cohort study used medical and pharmacy claims data. Newly diagnosed patients treated for FM or pDPN between 7/1/2007 and 12/31/2011 were included. PA and no PA groups were matched by propensity score 4:1. Medical resource utilization, direct medical and pharmacy costs, and treatment pattern differences were compared. Pre and postindex differences between PA and no PA cohorts were determined by difference in difference analysis. RESULTS: Analysis of 2,315 FM patients (1,852 PA; 463 no PA) demonstrated greater increases in postindex all-cause costs ($197; P = 0.6673) and disease-related costs ($72; P = 0.4186) in the PA cohort. Analysis of 1,300 pDPN patients (1,040 PA; 260 no PA) demonstrated postindex all-cause cost increases of $1,155 more in the no PA cohort (P = 0.6248); disease-related costs decreased $2,809 more in the no PA cohort (P = 0.4312). Treatment patterns were similar between cohorts; opioid usage was higher in the FM PA cohort (P = 0.0082). CONCLUSIONS: There was no evidence of statistically significant differences between PA and no PA cohorts in either FM or pDPN populations for total all-cause or disease-related costs.

Patient experience and unmet needs in high-risk nonmuscle-invasive bladder cancer: Insights from qualitative interviews and a cross-sectional survey.

OBJECTIVES: To evaluate patient experience, unmet needs, and burden among patients with high-risk nonmuscle-invasive bladder cancer (HR-NMIBC) treated with Bacillus Calmette-Guérin (BCG). METHODS: This cross-sectional study included HR-NMIBC patients who received BCG treatment in the past 3 years. The study, preceded by a focused literature review, was conducted in 2 phases: 1) qualitative interviews with 32 patients in the United States (US), France, Germany, and United Kingdom (UK) and 2) quantitative survey of 150 patients in the US. Both phases of the study assessed patient characteristics, treatment history, experience, and perceptions, as well as side effects, pain, discomfort, and time burden associated with BCG treatment. The quantitative survey included additional items related to BCG treatment satisfaction, health-related quality of life (HRQoL), productivity, and healthcare resource utilization. Descriptive statistics and bivariate subgroup comparisons were reported. RESULTS: All patients in both study phases received transurethral resection of the bladder tumor (TURBT). Nearly all patients reported keeping their bladder/avoiding radical cystectomy (RC) was important (99%). Results from the quantitative survey reported a substantial impact to cancer-specific HRQoL of patients, with lower mean scores on physical (64.7), social (62.8), and role functioning (56.7) as measured by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-30). Most patients (69%) were satisfied overall with BCG treatment, although satisfaction declined with increased number of side effects, higher numbers of BCG administrations, and greater discomfort (all P < 0.05). CONCLUSIONS: Most HR-NMIBC patients were satisfied overall with BCG treatment. Approximately half of the patients had stopped BCG treatment, notably, most during the induction phase, suggesting nonadherence to guidelines which recommend maintenance treatment after induction. Future treatments should focus on delaying or avoiding recurrence and cystectomy while reducing patient discomfort and discontinuation prior to completing the recommended course of treatment.

The Cost-Effectiveness of Lorlatinib Versus Chemotherapy as a Second- or Third-Line Treatment in Anaplastic Lymphoma Kinase (ALK)-Positive Non-small-cell Lung Cancer in Sweden.

BACKGROUND: Lorlatinib is a third-generation anaplastic lymphoma kinase (ALK)/c-ros oncogene 1 (ROS1) tyrosine kinase inhibitor (TKI) with efficacy in patients with ALK-rearranged non-small-cell lung cancer (NSCLC) previously treated with a second-generation ALK inhibitor or with first- and second-generation ALK inhibitors. We examined the cost-effectiveness of second- or third-line+ (2L+ or 3L+) lorlatinib in Sweden, versus chemotherapy. METHODS: A partitioned survival model with three health states (progression free, progressed, or death) was used. Lorlatinib relative efficacy versus chemotherapy was derived using unanchored matching adjusted indirect treatment comparisons from a phase 2 clinical trial. Utility data were derived from the same trial and published studies. Costs (year 2019) were obtained from Swedish national data. Costs and benefits were discounted at 3% per annum using a societal perspective (base case). Model robustness was evaluated with deterministic and probabilistic sensitivity analyses. RESULTS: For 2L+, the average discounted total quality-adjusted life year (QALY) gain was 1.29 years. Total incremental costs were Swedish krona (SEK) 731,791, resulting in an incremental cost-effectiveness ratio (ICER) of SEK 566,278 per QALY gained. Non-discounted survival gain amounted to 1.94 years. For 3L+, the average discounted total QALY gain was 1.25 years. Total incremental costs were SEK 754,801, resulting in an ICER of SEK 603,934 per QALY gained. Non-discounted survival gain was 1.88 years. Sensitivity analyses were consistent. CONCLUSIONS: ICERs ranged from SEK 421,000 to SEK 384,066 less than the boundary for a cost-effective treatment for a high-severity disease in Sweden (SEK 988,000), suggesting 2L+ or 3L+ lorlatinib is a cost-effective treatment for ALK-positive NSCLC versus chemotherapy.

Real-world treatment patterns and outcomes in PD-L1-positive non-small cell lung cancer.

Aim: We report real-world treatment patterns and outcomes in patients with PD-L1+ non-small-cell lung cancer (NSCLC). Methods: This retrospective, observational study using the ConcertAI Oncology Dataset (Symphony AI, CA, USA), included patients with PD-L1+ (≥1% expression) metastatic NSCLC who began first-line (1L) treatment between 2016 and 2019. Treatment outcomes were assessed by treatment class (immune checkpoint inhibitor [ICI] monotherapy, ICI combinations or chemotherapy). Results: In total, 128 (25.5%), 237 (47.3%) and 136 patients (27.1%) received 1L chemotherapy, 1L ICI monotherapy and 1L ICI combinations, respectively. ICI combinations and monotherapy had improved clinical outcomes versus chemotherapy. Adjusted analyses showed no significant difference in outcome between ICI monotherapy and ICI combinations. Conclusion: ICI-based treatments are being increasingly adopted into clinical practice and were associated with better outcomes versus chemotherapy.

Retrospective Observational Study of ALK-Inhibitor Therapy Sequencing and Outcomes in Patients with ALK-Positive Non-small Cell Lung Cancer.

BACKGROUND: Data are sparse concerning the sequential use of multiple anaplastic lymphoma kinase (ALK) inhibitors for ALK-positive locally advanced or metastatic non-small cell lung cancer (NSCLC). OBJECTIVE: This study investigated sequencing and outcomes among patients receiving multiple ALK inhibitors. PATIENTS AND METHODS: This was a retrospective observational cohort study of adult patients with ALK-positive NSCLC treated with available first- and second-generation ALK inhibitors from 1 September 2011 to 31 December 2017. Duration of therapy (DOT) and overall survival (OS) were assessed with the Kaplan-Meier method. A multivariable linear regression analysis was performed to assess if DOT with a preceding ALK inhibitor was predictive of DOT for subsequent ALK inhibitor treatments. RESULTS: A total of 410 patients were analyzed: 57% received 1 ALK inhibitor; 35%, 2 ALK inhibitors; and 8%, 3-4 ALK inhibitors. Among those receiving > 1 ALK inhibitor (n = 177), 60% received a crizotinib-led sequence and 39% an alectinib-led sequence. Nearly 60% of the overall population received chemotherapy prior to their first ALK inhibitor. Median OS for the study population was 28 months, 15 months in patients who received 1 ALK inhibitor, 42 months in patients who received 2 ALK inhibitors, and 56 months in patients who received 3-4 ALK inhibitors. Longer DOT of the first ALK inhibitor was associated with increased DOT of the second (p < 0.0001), and longer DOT of the second ALK inhibitor was associated with increased DOT of the third (p < 0.0001). CONCLUSIONS: This study provides initial information on real-world treatment patterns following the introduction of new ALK inhibitors, and supports the use of sequential ALK therapies.

Humanistic and Economic Burden of Non-Muscle Invasive Bladder Cancer: Results of Two Systematic Literature Reviews.

PURPOSE: Non-muscle invasive bladder cancer (NMIBC) is a malignancy restricted to the inner lining of the bladder. Intravesical Bacillus Calmette-Guerin (BCG) following transurethral resection of the bladder tumor is the mainstay first-line treatment for high-risk NMIBC patients. Two systematic literature reviews (SLRs) were conducted to further assess the current evidence on BCG use in NMIBC and the humanistic and economic burden of disease. METHODS: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, Embase® and MEDLINE® were searched using the Ovid platform to identify interventional or real-world evidence studies on the health-related quality of life (HRQoL) and economic burden in NMIBC. Limited evidence was found from initial economic SLR searches in NMIBC, so additional targeted searches for bladder cancer were conducted to expand findings. RESULTS: Fifty-nine publications were included in the HRQoL SLR, of which 23 reported HRQoL and symptoms in NMIBC. At diagnosis, HRQoL was comparable with population norms but worsened considerably 2 years following diagnosis. Maintenance therapy with intravesical BCG was associated with reduced HRQoL, and treatment-related adverse events (AEs) resembled typical NMIBC symptoms. Twenty-two studies reported decreasing BCG compliance over time. Common AEs with BCG were frequent urination, lower urinary tract symptoms, pain, and hematuria. Forty-two publications were included in the economic SLR, of which nine assessed healthcare costs and resource use in NMIBC or bladder cancer. High-risk disease and high-intensity treatment were associated with increased healthcare costs. CONCLUSION: NMIBC has a considerable symptomatic, HRQoL, and economic burden. Symptoms persisted and HRQoL worsened despite intravesical BCG treatment. NMIBC is a costly disease, with higher healthcare costs associated with increased risk of disease progression and recurrence. There is a high unmet need for safe and effective treatments that reduce the risk of disease progression and recurrence, provide symptomatic relief, and improve HRQoL for patients.

Treatment Sequencing in Patients with Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer in Japan: A Real-World Observational Study.

INTRODUCTION: The anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) alectinib was approved in Japan in 2014 for the treatment of ALK fusion gene-positive advanced non-small cell lung cancer (NSCLC). With the approvals of crizotinib in 2012 and ceritinib in 2017, Japan became the first country with multiple ALK TKIs available for first-line or later use in patients with ALK-positive advanced NSCLC. Here, we collected and evaluated real-world data on ALK TKI clinical usage patterns and sequencing in patients with ALK-positive NSCLC in Japan. METHODS: This retrospective observational study used the Japanese Medical Data Vision database to analyze data from patients with a confirmed diagnosis of lung cancer who visited a healthcare facility in the database between April 2010 and March 2017, underwent an ALK test, received a prescription for an ALK TKI, and were at least 18 years old as of the date of the first ALK TKI prescription. There were no exclusion criteria. Descriptive analyses of demographics, baseline characteristics, ALK TKI treatment patterns and sequences, non-ALK TKI treatments received before, during, and after ALK TKI treatment, and treatment durations were reported. RESULTS: A total of 378 patients met the inclusion criteria and were evaluated in mutually exclusive groups of patients receiving one, two, or three ALK TKIs. The initial ALK TKI prescribed was crizotinib for 52.1% of patients and alectinib for 47.9% of patients; however, the proportion of patients receiving alectinib as the initial ALK TKI increased over time following the Japanese approval of alectinib in 2014. Of the 117 patients who received two or three ALK TKIs, 106 received crizotinib as the first ALK TKI and 11 received alectinib. Before the date of the patient's first ALK TKI prescription, 153 of 378 patients (40.5%) had received chemotherapy. Of 104 patients who discontinued ALK therapy, 46.2% received chemotherapy and 5.8% received immunotherapy as their next treatment. CONCLUSION: At the time of this analysis, most patients who received more than one ALK TKI received crizotinib as the initial ALK TKI. Additional ALK TKIs have since been approved in Japan as first-line or later therapeutic options for patients with ALK-positive NSCLC, but the optimal sequence of ALK TKI usage remains undetermined. As new data continue to emerge, additional research will be warranted to evaluate ALK TKI sequences that do not include crizotinib as the first therapy in this patient population.

Impact of lorlatinib on patient-reported outcomes in patients with advanced ALK-positive or ROS1-positive non-small cell lung cancer.

OBJECTIVES: To evaluate patient-reported outcomes (PROs) from a phase 1/2 study (NCT01970865) in patients with anaplastic lymphoma kinase (ALK)- or ROS1-positive advanced non-small cell lung cancer (NSCLC) treated with lorlatinib 100 mg once daily. MATERIALS AND METHODS: PRO measures, including global quality of life (QoL), functioning domains and symptoms, were assessed by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and the 13-item Lung Cancer (QLQ-LC13) module. Mean changes of absolute scores from baseline were assessed. Percentages of patients showing improvement, stability or worsening on each scale were reported, with a change of ≥10 points considered clinically meaningful (CM). RESULTS: 255 patients completed baseline and ≥1 post-baseline PRO assessment. Most patients had CM improvement (42.4 %) or stable (38.0 %) scores for global QoL. Functioning domains with the greatest proportion of patients with improved scores were role (37.6 %) and emotional (36.9 %); only one domain had more patients showing worsening than improving function (cognitive [24.3 % vs 22.4 %]). Most patients showed improved or stable scores for disease-related symptoms. No QLQ-C30 symptom domains had more patients worsening than improving. Symptoms on the QLQ-C30 scale with the greatest proportion of patients with improved scores were fatigue (49.4 %) and insomnia (46.3 %). Four QLQ-LC13 domains had more patients worsening than improving (two most affected were peripheral neuropathy [37.3 % vs 13.7 %] and alopecia [19.2 % vs 13.3 %]). Symptoms on the QLQ-LC13 scale with the greatest proportion of patients with improved scores were cough (42.7 %) and pain in other parts (32.9 %). CONCLUSIONS: Lorlatinib treatment showed CM improvement from baseline in global QOL that was maintained over time. Additionally, there were improvements in physical, emotional, social, and role functioning. Improvements were shown in appetite loss and key symptoms such as pain, dyspnea, cough and fatigue; a worsening in peripheral neuropathy was noted.

Systematic review of sequencing of ALK inhibitors in ALK-positive non-small-cell lung cancer.

The objective of this study was to understand outcomes of patients treated with ALK inhibitors, especially when ALK inhibitors are followed by other ALK inhibitors. A systematic literature review was conducted in PubMed, Embase, and Cochrane through July 17, 2017. Conference abstracts (three meetings in past 2 years) also were searched. Of 504 unique publications, 80 met inclusion criteria (47 clinical trials, 33 observational studies). Observational studies have the potential to provide information for ALK inhibitors used sequentially. Ten observational studies reported median overall survival of crizotinib-led sequences ranging from 30.3 to 63.75 months from initiation of crizotinib; 49.4-89.6 months from metastatic non-small-cell lung cancer diagnosis; and 15.5-22.0 months from initiation of the second-generation ALK inhibitor after initial crizotinib. Sequencing of ALK inhibitors may benefit patients progressing on initial ALK inhibitors.

Cost of opioid medication abuse with and without tampering in the USA.

OBJECTIVE: To provide per-patient estimates of the economic burden for opioid medication abuse with and without tampering. PATIENTS AND METHODS: Adults in the US who participated in the 2010 and/or 2011 National Health and Wellness Survey were resurveyed to provide information on use and abuse of prescription opioids in the previous 3 months. Participants (N=20,885) were categorized as those who abused and tampered (n=107), abused without tampering (n=118), those who reported using of opioids as prescribed (n=981), and non-opioid controls (n=19,679). Average wages from the Bureau of Labor Statistics and health care unit costs from the Truven MarketScan database were applied to self-reported work impairment (absenteeism, presenteeism, and overall work impairment) and health care resource utilization (health care provider visits, emergency room visits, hospitalizations, and drug rehabilitation) to estimate indirect and direct medical costs, respectively. Estimated mean costs for these groups were compared using analysis of variance, and generalized linear models were used to compare costs adjusted for confounders. RESULTS: Those who abused and tampered had significantly higher mean indirect (work impairment: $3,614 vs $2,938, p<0.05) and direct (health care use: $23,328 vs $4,514, p<0.001) costs over 3 months than those who abused without tampering. This included higher mean incremental costs for non-opioid-related medical visits ($14,180 vs $2,236, p<0.001), opioid-related medical visits ($8,790 vs $2,223, p<0.001), and drug rehabilitation ($358 vs $55, p<0.001). Increased total direct costs were associated with tampering after adjusting for confounders (p<0.001). Median incremental costs were also higher among those who tampered. CONCLUSION: Tampering with prescription opioid medications is associated with significantly increased medical costs compared to abuse without tampering. Reducing tampering may provide net health care savings.

Real-World Use and Outcomes of ALK-Positive Crizotinib-Treated Metastatic NSCLC in US Community Oncology Practices: A Retrospective Observational Study.

INTRODUCTION: Around 3⁻5% of non-small cell lung cancers (NSCLC) are ALK-positive. Crizotinib was the first approved ALK inhibitor from clinical trials. However, there are less data on the utilization and patient outcomes associated with crizotinib in real-world clinical practice. METHODS: This was a retrospective, observational study of adult crizotinib-treated ALK-positive metastatic NSCLC patients who received treatment between 1 September 2011 and 31 October 2014, with follow up through 31 December 2015. Data were obtained via programmatic queries of the US Oncology Network/McKesson Specialty Health electronic health record database, supplemented with chart abstraction. Overall survival (OS) and time to treatment failure (TTF) were estimated from crizotinib initiation using the Kaplan⁻Meier (KM) method. RESULTS: Of the n = 199 ALK-positive crizotinib-treated patients meeting eligibility criteria, crizotinib was prescribed as first line (1 L) in n = 123 (61.8%). The majority (88.9%) had confirmed adenocarcinoma histology and 32.2% had brain metastases at initial diagnosis. Median age at crizotinib initiation was 60.2 years (range 27.1⁻88.2); 54.8% were never smokers, 33.7% were former smokers. Treatment of 250 mg, twice daily, was most commonly prescribed (89.5%) with the dose unchanged from an initial dose in 79.4% of patients. The primary discontinuation reason was progression (n = 91, 58.7%). Patients (3.2%) were identified as discontinuing crizotinib as a result of treatment-related toxicity. With median follow-up time of 13.0 months (min⁻max = 0.03⁻46.6), median OS from crizotinib initiation was 33.8 months (95% CI = 24.3⁻38.8). Median TTF was 10.4 months. CONCLUSIONS: Crizotinib usage evaluated within the real-world setting is consistent with prior phase III clinical trial data, and illustrates the real-world effectiveness of crizotinib.

Natural Language Processing-Identified Problem Opioid Use and Its Associated Health Care Costs.

Use of prescription opioids and problems of abuse and addiction have increased over the past decade. Claims-based studies have documented substantial economic burden of opioid abuse. This study utilized electronic health record (EHR) data to identify chronic opioid therapy (COT) patients with problem opioid use (POU) and compared costs with those for COT patients without POU. This study utilized EHR and claims data from an integrated health care system. Patients received COT (≥70 days' supply in ≥1 calendar quarter, 2006-2012). Natural language processing (NLP) identified notations of opioid addiction, abuse, misuse, or overuse, and manual validation was performed. Cases had evidence of POU (index = first POU notation), and controls, sampled 9:1, did not. Health care resource utilization was measured and costs estimated using Medicare reimbursement rates. A longitudinal analysis of costs was conducted using generalized estimating equations. Adjusted analyses controlled for baseline age, gender, region, specific comorbidities, and a comorbidity index. The analysis population included 1,125 cases and 10,128 controls. Unadjusted costs were higher for cases in all three years. After controlling for covariates, total costs remained higher in cases and were significantly higher in the first year of follow-up ($38,064 vs. $31,674, P = .0048). The largest cost difference was observed in the first month of follow-up. COT patients with POU experienced significantly higher costs compared with COT patients without POU in the first year of follow-up. The greatest difference in costs was observed around identification of POU.

Results of PROFILE 1029, a Phase III Comparison of First-Line Crizotinib versus Chemotherapy in East Asian Patients with ALK-Positive Advanced Non-Small Cell Lung Cancer.

INTRODUCTION: The phase III randomized PROFILE 1014 study demonstrated superiority of crizotinib to first-line chemotherapy in prolonging progression-free survival (PFS) in previously untreated patients with ALK receptor tyrosine kinase gene (ALK)-positive advanced nonsquamous NSCLC. This result was consistent with that in the smaller subset of East Asian patients in PROFILE 1014. The subsequent study reported here prospectively evaluated crizotinib in a larger East Asian patient population. METHODS: In this open-label phase III study (PROFILE 1029), patients were randomized 1:1 to receive orally administered crizotinib 250 mg twice daily continuously (3-week cycles) or intravenously administered chemotherapy (pemetrexed 500 mg/m2, plus cisplatin 75 mg/m2, or carboplatin [at a dose to produce area under the concentration-time curve of 5-6 mg·min/mL]) every 3 weeks for a maximum of six cycles. PFS confirmed by independent radiology review was the primary end point. RESULTS: Crizotinib significantly prolonged PFS (hazard ratio, 0.402; 95% confidence interval [CI]: 0.286-0.565; p < 0.001). The median PFS was 11.1 months with crizotinib and 6.8 months with chemotherapy. The objective response rate was 87.5% (95% CI: 79.6-93.2%) with crizotinib versus 45.6% (95% CI: 35.8-55.7%) with chemotherapy (p < 0.001). The most common adverse events were increased transaminase levels, diarrhea, and vision disorders with crizotinib and leukopenia, neutropenia, and anemia with chemotherapy. Significantly greater improvements from baseline in patient-reported outcomes were seen in crizotinib-treated versus chemotherapy-treated patients. CONCLUSIONS: First-line crizotinib significantly improved PFS, objective response rate, and patient-reported outcomes compared with standard platinum-based chemotherapy in East Asian patients with ALK-positive advanced NSCLC, which is similar to the results from PROFILE 1014. The safety profiles of crizotinib and chemotherapy were consistent with those previously published.

Relation between prenatal lipid-soluble micronutrient status, environmental pollutant exposure, and birth outcomes.

BACKGROUND: Adverse postnatal health effects have been associated with compromised fetal growth, which makes it essential to understand its determinants. Significant effects of environmental pollutants on birth outcomes have been observed in our study population, and nutritional status may be an additional factor influencing fetal development and effects of environmental toxins. OBJECTIVE: The objective of the study was to examine the relations between birth outcomes and lipid-soluble plasma micronutrient concentrations and to explore interactions between micronutrients and environmental pollutant exposure in newborns in Krakow, Poland. DESIGN: In this prospective cohort study, retinol, alpha-tocopherol, and carotenoids were measured in maternal and cord blood samples obtained at delivery (251 maternal-newborn pairs), and birth weight, birth length, head circumference (HC), and gestational age were evaluated. Linear regression analysis was used to estimate the effects of micronutrients while covariates were controlled for. Interaction terms assessed whether the effects of polycyclic aromatic hydrocarbons (PAHs), common environmental pollutants, varied by nutrient status. RESULTS: Infants whose mothers had low plasma alpha-tocopherol concentrations (below the median) weighed 92.9 g less and had 0.41-cm smaller HCs than did infants whose mothers had high alpha-tocopherol concentrations. Infants with low plasma retinol (below the median) weighed 125.9 g less and had 0.31-cm smaller HCs. There was no evidence of an interaction between PAHs and micronutrients, although power was limited. CONCLUSION: Maternal alpha-tocopherol and cord retinol concentrations were significantly and positively associated with BW and HC. These micronutrients may have direct effects or may be markers for other underlying determinants of these pregnancy outcomes.