Incidence of skin and soft tissue infections in ambulatory and inpatient settings, 2005-2010.

BACKGROUND: The emergence of community-associated methicillin-resistant S. aureus was associated with dramatically increased skin and soft tissue infection (SSTI) incidence in the first few years of the 21(st) century in the U.S. However, subsequent trends are poorly understood. METHODS: We examined ambulatory and inpatient data of over 48 million persons years aged 0-64 years from the HealthCore Integrated Research Database (HIRD) between 2005 and 2010. Data were extracted from medical, pharmacy, and eligibility databases. We quantified SSTI incidence, type, and complications and comparative incidence trends for urinary tract infections (UTIs) and pneumonia. RESULTS: A total of 2,301,803 SSTIs were identified. Most SSTIs (95 %) were treated in the ambulatory setting and most (60 %) were categorized as abscesses or cellulitis. During the study period, SSTI incidence remained relatively stable from 47.9 (95 % CI: 47.8-48.1) cases/1,000 PY in 2005 to 48.5 cases/1,000 PY (95 % CI: 48.3-48.6) in 2010). Persons aged 45-64 years had the highest incidence of both ambulatory-treated and inpatient-treated SSTIs (51.2 (95 % CI: 51.1-51.3) and 3.87 (95 % CI: 3.84-3.90) cases/1,000 PY, respectively). SSTI complications such as myositis, gangrene, and sepsis occurred in 0.93 % (95 % CI: 0.92-0.94 %) and 16.92 % (95 % CI: 16.87-16.97 %) of ambulatory-treated and inpatient-treated patients, respectively. SSTI incidence was approximately twice that of UTIs and tenfold of that of pneumonia. CONCLUSIONS: Among our large, diverse population of persons less than 65 years, SSTI incidence 2005 through 2010 has remained relatively constant at approximately 4.8 SSTIs per 100 person years, suggesting that previously observed increases in SSTI incidence remain sustained.

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.

Validation of a claims-based diagnostic code for Stevens-Johnson syndrome in a commercially insured population.

PURPOSE: To validate the administrative claims identification of a diagnosis of Stevens-Johnson syndrome (SJS) using medical records as the "gold standard" in a large, commercially insured US population. METHODS: Patients with >1 medical claim with the International Classification of Diseases, Ninth Revision, Clinical Modification code 695.1x between 1 July 2000 and 31 May 2007 were queried in the HealthCore Integrated Research Database(SM) , which contains administrative claims data for 14 commercial health insurance plans. Trained nurses and pharmacists abstracted pertinent information from the identified patients' medical records, which were then reviewed by two independent dermatologists to identify criteria to determine SJS diagnosis. Positive predictive values (PPVs) based on the claims and chart data were computed for all the cases. RESULTS: Medical charts for 200 claims-identified cases, with the International Classification of Diseases, Ninth Revision, Clinical Modification code 695.1x, were abstracted and reviewed by the dermatologists. A total of five cases (PPV = 2.50%, 95%CI = 0.8%-5.7%) were determined to be SJS with clinical certainty. PPVs varied with data stratification: PPV for inpatient claims only (PPV = 2.00%, 95%CI = 0.24%-7.04%), inpatient claims with 695.1x in first diagnosis field (PPV = 4.11%, 95%CI = 0.86%-11.54%), and final decisions of either clinical certainty or probable cases of SJS (PPV = 6.00%, 95%CI = 3.14%-10.25%). CONCLUSION: These findings demonstrate the difficulties associated with identifying rare disorders, which lack specific diagnostic criteria, within administrative claims databases. They underscore the challenges of using claims data to monitor ill-defined clinical conditions as well as the need to validate claims-identified cases with information from other sources, such as medical charts. Copyright © 2012 John Wiley & Sons, Ltd.

The prognostic significance of patient-reported outcomes in pancreatic cancer cachexia.

Data from a clinical study of 86 pancreatic cancer patients with involuntary, significant weight loss (cachexia) were used to explore the relationship between patient-reported outcomes (PROs) and survival. In all, 28 pancreatic cancer patients with cachexia were given gemcitabine (Gemzar) plus 3 mg/kg of infliximab (Remicade), 28 were given gemcitabine plus 5 mg/kg of infliximab, and 30 were given gemcitabine plus placebo in a double-blinded, phase II, multicenter trial. PRO endpoints included scores from the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Functional Assessment of Anorexia/ Cachexia Therapy (FAACT), Brief Pain Inventory (BPI), and the Short-Form 36 general health survey (SF-36). Population mean scores at baseline indicated fatigue problems (FACIT-F), nutritional health issues (FAACT), and mild-to-moderate pain (BPI "worst pain" score). Baseline normalized SF-36 values for physical functioning, vitality, and mental health indicated substantial impairment. Baseline fatigue and physical-functioning scores predicted survival as well as, or better than, baseline Karnofsky Performance Status or hemoglobin level. A cut-point in the FACIT-F score (median < or = 30) strongly predicted mortality; patients with greater fatigue had a lower median overall survival than did those with less fatigue. These findings supported several features of an a priori clinical-benefit model. Patient-reported fatigue provided powerful prognostic information; tracking of this symptom may be useful for treatment planning and medical monitoring of advanced-stage pancreatic cancer patients with cachexia. These results must be confirmed by larger trials.

Comparing Biologic Cost Per Treated Patient Across Indications Among Adult US Managed Care Patients: A Retrospective Cohort Study.

BACKGROUND: The relative cost of biologics in the treatment of autoimmune disorders, including rheumatoid arthritis, psoriatic arthritis, psoriasis, and ankylosing spondylitis, is a key consideration for managed care payers. OBJECTIVES: Our objective was to estimate biologic costs and treatment patterns in US managed care patients with rheumatoid arthritis, psoriatic arthritis, psoriasis, and/or ankylosing spondylitis. METHODS: This retrospective study used administrative claims data from the HealthCore Integrated Research Database (HIRDSM) for adults with rheumatoid arthritis, psoriatic arthritis, psoriasis, and/or ankylosing spondylitis who received abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab, rituximab, tocilizumab, or ustekinumab between 1 July 2009 and 31 January 2013. Biologic costs (based on drug utilization) and treatment patterns (discontinued, restarted after a >45-day gap, switched to another biologic, or persisted without switching or stopping) were analyzed for the first year post-index. RESULTS: Most of the 24,460 patients received etanercept (48 %), adalimumab (29 %), or infliximab (12 %) as the index biologic. On the index date, 44 % were new to biologic therapy and 56 % were continuing biologic therapy. Biologic cost per treated patient for 1 year was as follows: etanercept $US24,859, adalimumab $US26,537, and infliximab $US26,468. Treatment patterns across indications for etanercept, adalimumab, and infliximab were as follows: persistent (52, 49, 67 %), restarted (23, 21, 12 %), switched (12, 13, 11 %), and discontinued (14, 18, 10 %). CONCLUSIONS: These findings from a large health benefits organization in the USA are similar to those of several previous cost analyses assessing different populations, which demonstrates the external validity of the results from the previous studies, both over time and across large populations.

Biologic Cost per Effectively Treated Rheumatoid Arthritis Patient in a Large Managed Care Population: A Retrospective Cohort Study.

Background: Until recently, the lack of clinical outcomes information for rheumatoid arthritis (RA) in administrative claims databases limited their use in comparative effectiveness research. A validated claims-based algorithm has been developed to estimate the effectiveness of biologics for RA, allowing for estimation of cost and effectiveness in the same database. Objectives: To implement a validated claims-based effectiveness algorithm in a US managed care claims database to compute the 1-year biologic cost per effectively treated patient among first-line biologics approved for moderate-to-severe RA (abatacept, adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab). Methods: This retrospective cohort study used administrative claims data for individuals in the HealthCore Integrated Research Database (HIRDSM). The first claim for a first-line biologic between July 1, 2009, and January 31, 2013, after 6 months of continuous enrollment, was defined as the index event and date. Patients were aged 18-63 years on the index date and had at least one claim for RA in the 6-month pre- index period. Biologic costs included plan and patient paid amounts on claims for the biologic drug and administration. The algorithm defined effectiveness during the 12-month post-index period as achieving all six of the following: high adherence (medication possession ratio ≥80% or infusions consistent with the product label); no increase in biologic dose or decrease in dosing interval; no new biologic; no new nonbiologic disease-modifying antirheumatic drug; no new or increased oral glucocorticoid use; and ≤1 glucocorticoid injection. Cost per effectively treated patient was calculated as the total biologic cost (drug and administration) divided by the number of patients categorized by the algorithm as effectively treated. Results: The cohort comprised 4844 patients (mean age 48.6 years, 76.4% female). Average first-year biologic cost ranged from $14 795 (golimumab) to $19 520 (abatacept). Average first-year biologic cost per effectively treated patient was significantly lower for etanercept ($50 217) than for golimumab ($56 427, p<0.001) adalimumab ($56 879, p<0.001), abatacept ($68 062, p<0.001), certolizumab pegol ($76 427, p<0.001), and infliximab ($95 126, p<0.001). Conclusions: In this application of a validated claims-based algorithm to a large managed care population, etanercept had the lowest 1-year biologic cost per effectively treated patient among first-line biologics.

What pretreatment prostate-specific antigen level warrants long-term androgen deprivation?

PURPOSE: Several large randomized prospective studies have demonstrated a survival benefit with the addition of long-term androgen deprivation to definitive radiotherapy for patients with Gleason score 8-10 or T3-T4 prostate cancer. However, these studies were performed before the routine use of prostate-specific antigen (PSA) measurement. The purpose of this study was to determine what pretreatment (initial) PSA (iPSA) level, if any, warrants the addition of long-term androgen deprivation in the PSA era. METHODS AND MATERIALS: The data set evaluated consisted of 1003 prostate cancer patients treated definitively with three-dimensional conformal radiotherapy between May 1, 1989 and November 30, 1999 (median follow-up, 61 months). Specifically excluded were patients with T3-T4 disease or Gleason score greater than 7 or those who had undergone androgen deprivation as a part of their initial therapy. The median radiation dose was 76 Gy. Patients were randomly split into two data sets, with the first (n = 487) used to evaluate the optimal iPSA cutpoint for which a statistically significant difference in outcome was noted. The second data set (n = 516) served as a validation data set for the initial modeling. The analysis of the optimal iPSA cutpoint was based on a recursive partitioning approach for censored data using the log-rank test for nodal separation of freedom from biochemical failure (FFBF) as defined by the American Society for Therapeutic Radiology and Oncology definition. Cox multivariate regression analysis was used to confirm independent predictors of outcome among the clinical and treatment-related factors: iPSA (grouped as defined by the recursive partitioning analysis), Gleason score (2-6 vs. 7), T stage (T1c-T2a vs. T2b-T2c), and total radiation dose (continuous). RESULTS: The recursive partitioning analysis data set resulted in an optimal iPSA cutpoint of 35 ng/mL, such that the 5-year Kaplan-Meier estimate of FFBF was 80%, 69%, and 19% for iPSA groups of 0-9.9, 10-35, and >35 ng/mL, respectively. The validation data set demonstrated the optimal iPSA cutpoint to be 30 ng/mL. Conservatively choosing 30 ng/mL as the optimal cutpoint, the 5-year FFBF estimate for the entire 1003 patients was 82%, 69%, and 20% for iPSA groups 0-9.9 (n = 630), 10-30 (n = 329), and >30 (n = 44) ng/mL, respectively. On multivariate regression analysis, with the iPSA grouped as above, the Gleason score and radiation dose were independent predictors of outcome in this patient group (all p < 0.001). On univariate analysis, a higher radiation dose improved FFBF when the iPSA level was between 10 and 30 ng/mL (p = 0.001) but not when the iPSA level was >30 or <10 ng/mL. CONCLUSION: Recursive partitioning techniques defined an iPSA cutpoint of 30 ng/mL for delineating intermediate vs. high risk. Patients with a PSA level >30 ng/mL in the absence of Gleason score >7 or T3 disease do poorly when treated with radiotherapy alone and should be considered for long-term androgen deprivation or other aggressive systemic therapy.

Pattern of local recurrence after conservative surgery and whole-breast irradiation.

PURPOSE: Most recurrences in the breast after conservative surgery and whole-breast irradiation have been reported to occur within the same quadrant as the initial primary tumor. We analyzed the long-term risk of recurrence by area of the breast after whole-breast irradiation. MATERIALS AND METHODS: In all, 1,990 women with Stage 0-II breast cancer were treated with conservative surgery and whole-breast irradiation from 1970-1998. Stage was ductal carcinoma in situ in 237, T1 in 1273, and T2 in 480 patients. Of 120 local recurrences, 71 were classified as true local (confined to the original quadrant) and 49 as elsewhere (involving outside the original quadrant). Kaplan-Meier methodology was used to calculate 5-year, 10-year, and 15-year rates of recurrence (95% confidence intervals in parentheses). The median follow-up is 80 months. RESULTS: There was no apparent difference in the 15-year rate of true local vs. elsewhere recurrence, but the time to recurrence was different. The rate of true local recurrence was 2%, 5%, and 7% (5-9%) at 5, 10, and 15 years, respectively. The recurrences elsewhere in the breast were rare at 5 (1%) and 10 (2%) years, but increased to 6 (3-9%) at 15 years. This 15-year rate of elsewhere recurrence was half the rate of contralateral breast cancers of 13% (10-16%). CONCLUSIONS: Recurrence elsewhere in the breast is rare for the first 10 years, but by 15 years is nearly equal to true local recurrence even after whole-breast irradiation. The 15-year rate of elsewhere recurrence was half the rate of contralateral breast cancers. This may indicate a therapeutic effect of whole-breast radiation for other areas of the breast. Very long follow-up will be needed for partial breast irradiation with or without tamoxifen to show that the risk of elsewhere recurrence is not significantly different than after whole-breast irradiation.

Defining biochemical failure after radiotherapy with and without androgen deprivation for prostate cancer.

PURPOSE: To compare several characteristics of alternative definitions of biochemical failure (BF) in men with extended follow-up after radiotherapy (RT) with or with androgen deprivation therapy (ADT) for prostate cancer. METHODS AND MATERIALS: From December 1, 1991, to April 30, 1998, 688 men with Stage T1c-T3NX-N0M0 prostate cancer received RT alone (n = 586) or RT plus ADT (n = 102) with a minimal follow-up of 4 years and five or more "ADT-free" posttreatment prostate-specific antigen levels. BF was defined by three methods: (1) the ASTRO definition (three consecutive rises in prostate-specific antigen level); (2) a modified American Society for Therapeutic Radiology Oncology (ASTRO) definition requiring two additional consecutive rises when a decline immediately subsequent to three consecutive rises occurred; and (3) the "Houston" or nadir plus 2-ng/mL definition (a rise of at least 2 ng/mL greater than the nadir). The sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy were determined for each using clinical progression as the endpoint. Furthermore, the misclassification rates for a steadily rising prostate-specific antigen level, ability to satisfy the proportional hazards (RT with or without ADT), effects of short follow-up, and intervals to the diagnosis of BF were compared. RESULTS: The misclassification rate for BF using the nadir plus 2-ng/mL definition was 2% for RT alone and 0% for RT plus ADT compared with 0% and 0% for the modified ASTRO definition, and 5% and 23% for the ASTRO definition, respectively. The hazard rates for RT alone and RT plus ADT were proportional only for the nadir plus 2 ng/mL definition and seemingly unaffected by the length of follow-up. For RT with or without ADT, the nadir plus 2 ng/mL definition was the most specific (RT, 80% vs. RT plus ADT, 75%) with the greatest positive predictive value (RT, 36% vs. RT plus ADT, 25%) and overall accuracy (RT, 81% vs. RT plus ADT, 77%). A greater proportion of BF was diagnosed in the first 2 years of follow-up with the nadir plus 2 ng/mL definition compared with the ASTRO definition (13% vs. 5%, p = 0.0138, chi-square test). CONCLUSION: The nadir plus 2 ng/mL definition was the best predictor of sustained, true, biochemical, and clinical failure, and was not affected by the use of ADT or follow-up length.

Importance of physical examination in the absence of a mammographic abnormality for the detection of early-stage breast cancer.

PURPOSE: A recent trial called into question the efficacy of breast self-examination. We studied the characteristics and outcome of women in whom physical examination (PE) was their sole method of breast cancer detection. PATIENTS AND METHODS: From 1970 to 1998, 1752 women with stage I/II breast cancer underwent breast-conserving surgery and radiation. Two hundred sixty patients (15%) had abnormal PE finding as their sole method of cancer detection at the time of diagnosis, 723 (41%) had only mammographic findings, and 762 (43%) had both. RESULTS: Detection by PE was associated with younger age, larger tumor size, positive axillary nodes, and use of chemotherapy. For women < 40 years of age, PE was the sole method of detection in 40% of cases. The patients for whom PE was the sole method of detection had equivalent 10-year locoregional control and overall survival (OS) compared with patients whose cancer was detected by mammography. Detection by PE was not an independent predictor for outcome on multivariate analysis. The use of tamoxifen (P = 0.0089) was the sole predictor for improved locoregional control. Tumor stage (P = 0.0001), nodal status (P = 0.039), age (P = 0.0112) and lymphovascular invasion (P = 0.0399) were negative predictors of OS. CONCLUSION: Although associated with younger age, larger tumors, and more frequent node positivity, in this study detection by PE did not confer worse outcome. This may be because of the increased use of chemotherapy in these patients. Physical examination remains an important method of detection of breast cancer, particularly for younger women for whom mammography is less sensitive and not performed as frequently.

Cost and consequences of noncompliance to oral bisphosphonate treatment.

BACKGROUND: Despite the favorable efficacy, safety, and cost-effectiveness profile of bisphosphonate (BIS) treatment for osteoporosis (OP), patient compliance remains suboptimal. A longer follow-up period could help to better characterize patient behavior as well as the predictors of noncompliance because of the extended durations of osteoporosis and time to a fracture. OBJECTIVE: To determine health care outcomes associated with compliance and noncompliance to BIS therapy in women diagnosed with OP. METHODS: This retrospective claims study focused on women with OP, who were aged 55 years and older and using oral BIS treatment. Patients were identified within the HealthCore Integrated Research Environment (HIRE) between January 1, 2007, through June 30, 2010. Patients were required to have ≥ 12 months of pre-index eligibility and ≥ 24 months of post-index health plan eligibility. Post-index eligibility was split into 2 periods: (1) the compliance time period (the first 12-month post-index period, in which compliance was determined) and (2) the cost and consequences time period (13- to 24-month post-index period during which time health care resource utilization, cost, and outcomes were assessed). Noncompliance was defined as medical possession ratio (MPR) less than 70%. Descriptive statistics described outcome variables for the study population. A logistic regression model determined variables predictive of compliance. Further, a generalized linear model was used to examine associations between all-cause or OP-related medical/total costs and to estimate health care utilization. RESULTS: Of patients overall (N = 27,905), 59% were noncompliant, and 62% discontinued medication. Among noncompliant patients, 6.7% switched BIS therapy (after 64 days average); 97% discontinued (87 days average); and 21% restarted medication (218 days average). Of noncompliant patients, 14% had greater than 1 inpatient visits; 16% had greater than 1 emergency room visits; 94% had greater than 1 outpatient visits; and 95% had greater than 1 office visits. Logistic regression results indicated that under aged 65 years (P = 0.012) predicted noncompliance. Relative to the compliant group, noncompliant patients had higher fracture rates at post-index second year, 3.3% vs. 2.4%, and combined second and third years, 6.0% vs. 4.8%, respectively. Compared with noncompliant patients, compliant patients had 9% (P = 0.007) lower OP-related costs, 3% lower all-cause costs during the second post-index year, and 11% (P = 0.016) lower OP-related costs. Mean 13- to 24-month post-index period all-cause costs were $7,237 for noncompliant patients versus $6,758 for compliant patients (P = 0.008). CONCLUSIONS: These results indicate high noncompliance rates in this population of older females. OP medication compliance was associated with lower fracture rates, OP- and all-cause costs, and health care utilization. These findings highlight the financial implications and treatment outcomes of BIS medication noncompliance within a female osteoporotic population.

Adherence to rotavirus vaccination quality measures in a commercially insured population.

BACKGROUND: This retrospective study determined the level of compliance to rotavirus vaccination guidelines within a large, commercially insured US population, as well as compliance with PI, ACIP and HEDIS measures for rotavirus vaccination. METHODS: Medical and pharmacy claims were obtained from the HealthCore Integrated Research Database. Enrolled children were stratified into PI, ACIP and HEDIS cohorts. The PI cohort was subdivided into RV5 and RV1 cohorts due to the differences in dosing schedules and patients with mixed dosing were excluded from the these two cohorts. Patients identified in the HEDIS cohort were linked to the administering physicians. RESULTS: Of 162,614 patients in PI cohort, 27% did not receive rotavirus vaccinations, 24% (RV5) and 15% (RV1) had incomplete doses (p < 0.0001; RV1 vs. RV5). A total of 76% of patients completed RV5 series but not on schedule, 54% completed on schedule. A total of 85% of patients completed the RV1 series at any time, 69% completed on schedule. Among health plans, 53% of patients completed the series, 22% (RV5) and 15% (RV1) had incomplete doses (p < 0.0001). Of 2,086 physicians who treated ≥ 10 patients within the plan (regardless of vaccination status), 78% had > 50% of patients complete, 22% had > 90% of patients completed. CONCLUSION: Despite both two effective rotavirus vaccines and national immunization recommendations, rotavirus vaccination remains underutilized for infants.

Skin and soft tissue infections and associated complications among commercially insured patients aged 0-64 years with and without diabetes in the U.S.

INTRODUCTION: Skin and soft tissue infections (SSTIs) are common infections occurring in ambulatory and inpatient settings. The extent of complications associated with these infections by diabetes status is not well established. METHODS: Using a very large repository database, we examined medical and pharmacy claims of individuals aged 0-64 between 2005 and 2010 enrolled in U.S. health plans. Diabetes, SSTIs, and SSTI-associated complications were identified by ICD-9 codes. SSTIs were stratified by clinical category and setting of initial diagnosis. RESULTS: We identified 2,227,401 SSTI episodes, 10% of which occurred in diabetic individuals. Most SSTIs were initially diagnosed in ambulatory settings independent from diabetes status. Abscess/cellulitis was the more common SSTI group in diabetic and non-diabetic individuals (66% and 59%, respectively). There were differences in the frequencies of SSTI categories between diabetic and non-diabetic individuals (p<0.01). Among SSTIs diagnosed in ambulatory settings, the SSTI-associated complication rate was over five times higher in people with diabetes than in people without diabetes (4.9% vs. 0.8%, p<0.01) and SSTI-associated hospitalizations were 4.9% and 1.1% in patients with and without diabetes, respectively. Among SSTIs diagnosed in the inpatient setting, bacteremia/endocarditis/septicemia/sepsis was the most common associated complication occurring in 25% and 16% of SSTIs in patients with and without diabetes, respectively (p<0.01). CONCLUSIONS: Among persons with SSTIs, we found SSTI-associated complications were five times higher and SSTI-associated hospitalizations were four times higher, in patients with diabetes compared to those without diabetes. SSTI prevention efforts in individuals with diabetes may have significant impact on morbidity and healthcare resource utilization.

Early steps in the development of a claims-based targeted healthcare safety monitoring system and application to three empirical examples.

BACKGROUND: Several efforts are under way to develop and test methods for prospective drug safety monitoring using large, electronic claims databases. Prospective monitoring systems must incorporate signalling algorithms and techniques to mitigate confounding in order to minimize false positive and false negative signals due to chance and bias. OBJECTIVE: The aim of the study was to describe a prototypical targeted active safety monitoring system and apply the framework to three empirical examples. METHODS: We performed sequential, targeted safety monitoring in three known drug/adverse event (AE) pairs: (i) paroxetine/upper gastrointestinal (UGI) bleed; (ii) lisinopril/angioedema; (iii) ciprofloxacin/Achilles tendon rupture (ATR). Data on new users of the drugs of interest were extracted from the HealthCore Integrated Research Database. New users were matched by propensity score to new users of comparator drugs in each example. Analyses were conducted sequentially to emulate prospective monitoring. Two signalling rules--a maximum sequential probability ratio test and an effect estimate-based approach--were applied to sequential, matched cohorts to identify signals within the system. RESULTS: Signals were identified for all three examples: paroxetine/UGI bleed in the seventh monitoring cycle, within 2 calendar years of sequential data; lisinopril/angioedema in the second cycle, within the first monitoring year; ciprofloxacin/ATR in the tenth cycle, within the fifth year. CONCLUSION: In this proof of concept, our targeted, active monitoring system provides an alternative to systems currently in the literature. Our system employs a sequential, propensity score-matched framework and signalling rules for prospective drug safety monitoring and identified signals for all three adverse drug reactions evaluated.

Intensity modulated radiation therapy (IMRT) decreases acute skin toxicity for women receiving radiation for breast cancer.

OBJECTIVE: To determine the clinically observed incidence and severity of acute skin toxicity with breast intensity modulated radiation therapy (IMRT), and compare the results with a matched cohort of patients treated by conventional radiation therapy. Our hypothesis is that measures to decrease dose inhomogeneity within the breast and skin with IMRT will improve acute skin toxicity. MATERIALS AND METHODS: The study population consists of 73 women with early stage breast cancer treated with breast-conserving surgery and IMRT. The IMRT technique involves an iteration method for optimization to generate the IMRT plan, Monte Carlo dose calculation, and a step-and-shoot technique using multileaf collimation for beam delivery. Other aspects of the technique including the clinical definition of the clinical target volume by the physician, patient positioning, tangential beam orientation, dose and field sizes were unchanged compared conventional tangential radiation. These patients were matched one-to-one to a control group of 60 women treated with conventional photon radiation by using their bra size and chest wall separation. The study end point was acute skin toxicity. RESULTS: There were no observed differences in the acute toxicity based upon common terminology criteria for adverse events (CTC) for acute radiation dermatitis. There was no desquamation in 42% of IMRT patients, dry desquamation in 37% and moist desquamation in 21%. The degree of desquamation was greater for conventional patients compared with IMRT patients -52% grade 0, 10% grade 1, and 38% grade 2 (P = 0.001). Subgroup analysis showed desquamation was significantly lower with IMRT for small (P = 0.038) and large breast sizes (P = 0.037), but not medium sizes (P = 0.454). For large breast sizes, the incidence of moist desquamation grade 2 was 48% with IMRT compared with 79% in controls. Significant predictors of moist desquamation on stepwise logistic regression were use of IMRT (P = 0.0011) and breast size (P < 0.0001). CONCLUSIONS: IMRT is associated with a decrease in severity of acute desquamation compared with a matched control group treated with conventional radiation therapy. As with conventional radiation, breast size remains the most important prognostic factor for acute skin toxicity. The CTC grading system for acute radiation dermatitis is not sensitive when applied to modern breast cancer treatment because of its dependence of subjective rating of erythema and inability to gauge variations in desquamation. Further study of patient symptoms, quality of life, and cosmesis is needed to evaluate the benefit of IMRT for breast cancer.

Does a delay in external beam radiation therapy after tissue diagnosis affect outcome for men with prostate carcinoma?

BACKGROUND: Physicians involved in the care of men diagnosed with prostate carcinoma must assess the urgency of treatment. For those men who choose external beam radiation therapy (EBRT), the delay from the time of biopsy to treatment may be stressful. There are limited data on the consequences of radiation treatment delay. The purpose of the current study was to evaluate the effect of time to treatment (TTT) on outcomes. METHODS: The authors of the current study analyzed 1322 patients who were treated with EBRT alone. Overall survival (OS), cause specific survival (CSS), distant metastasis (DM), and freedom from biochemical failure (FFBF) were calculated. TTT was first analyzed at 4 intervals: < 3, 3-6, 6-9 and > 9 months, and at the median TTT. Cox multivariate analysis (MVA) was then performed with 2002 American Joint Commission on Cancer T-stage, Gleason score, prostate specific antigen (PSA), radiation dose, and TTT as covariates. RESULTS: There were no statistical differences in OS, CSS, DM, or FFBF among men whose EBRT began < 3, 3-6, 6-9, or > 9 months after diagnosis. This was also true at the median TTT of 3.1 months. A subgroup analysis was performed in which patients were stratified into low-, intermediate- and high-risk groups based on pretreatment PSA, Gleason score and AJCC T-stage. FFBF, and DM were calculated above and below the median TTT of 3.1 months. In this analysis, there was no statistically significant difference in FFBF or DM within the risk groups. CONCLUSIONS: Within the limits of the current study, data indicate that a treatment delay, even in high-risk patients, has little effect on clinical or biochemical outcome.