Joseph Kelaghan

Development of the National Cancer Institute’s Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)

The standard approach for documenting symptomatic adverse events (AEs) in cancer clinical trials involves investigator reporting using the National Cancer Institutes (NCIs) Common Terminology Criteria for Adverse Events (CTCAE). Because this approach underdetects symptomatic AEs, the NCI issued two contracts to create a patient-reported outcome (PRO) measurement system as a companion to the CTCAE, called the PRO-CTCAE. This Commentary describes development of the PRO-CTCAE by a group of multidisciplinary investigators and patient representatives and provides an overview of qualitative and quantitative studies of its measurement properties. A systematic evaluation of all 790 AEs listed in the CTCAE identified 78 appropriate for patient self-reporting. For each of these, a PRO-CTCAE plain language term in English and one to three items characterizing the frequency, severity, and/or activity interference of the AE were created, rendering a library of 124 PRO-CTCAE items. These items were refined in a cognitive interviewing study among patients on active cancer treatment with diverse educational, racial, and geographic backgrounds. Favorable measurement properties of the items, including construct validity, reliability, responsiveness, and between-mode equivalence, were determined prospectively in a demographically diverse population of patients receiving treatments for many different tumor types. A software platform was built to administer PRO-CTCAE items to clinical trial participants via the internet or telephone interactive voice response and was refined through usability testing. Work is ongoing to translate the PRO-CTCAE into multiple languages and to determine the optimal approach for integrating the PRO-CTCAE into clinical trial workflow and AE analyses. It is envisioned that the PRO-CTCAE will enhance the precision and patient-centeredness of adverse event reporting in cancer clinical research.

Stroke and Use of Low-Dose Oral Contraceptives in Young Women A Pooled Analysis of Two US Studies

BACKGROUND AND PURPOSE The available data on low-dose oral contraceptive pill (OCP) use and stroke risk in US women are limited by small numbers. We sought more precise estimates by conducting a pooled analysis of data from 2 US population-based case-control studies. METHODS We analyzed interview data from 175 ischemic stroke cases, 198 hemorrhagic stroke cases, and 1191 control subjects 18 to 44 years of age. RESULTS For ischemic stroke, the pooled odds ratio (pOR) adjusted for stroke risk factors for current use of low-dose OCPs compared with women who had never used OCP (never users) was 0.66 (95% confidence interval [CI], 0.29 to 1.47) and compared with women not currently using OCPs (nonusers) the pOR was 1.09 (95% CI, 0.54 to 2.21). For hemorrhagic stroke, the pOR for current use of low-dose OCPs compared with never users was 0.95 (95% CI, 0.46 to 1.93) and compared with nonusers the pOR was 1.11 (95% CI, 0.61 to 2.01). The pORs for current low-dose OCP use and either stroke type were not elevated among women who were >/=35 years, cigarette smokers, obese, or not receiving medical therapy for hypertension. pORs for current low-dose OCP use were 2.08 (95% CI, 1. 19 to 3.65) for ischemic stroke and 2.15 (95% CI, 0.85 to 5.45) for hemorrhagic stroke among women reporting a history of migraine but were not elevated among women without such a history. Past OCP use (irrespective of formulation) was inversely related to ischemic stroke but unrelated to hemorrhagic stroke. CONCLUSIONS Women who use low-dose OCPs are, in the aggregate, not at increased risk of stroke. Studies are needed to clarify the risk of stroke among users who may be susceptible on the basis of age, smoking, obesity, hypertension, or migraine history.

The Relationship of Biochemical Markers of Bone Turnover to Bone Density Changes in Postmenopausal Women: Results from the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial

We assessed the associations of eight bone turnover markers (BTMs) with baseline and 1‐year percentage changes in lumbar spine and hip bone mineral density (BMD) of 293 postmenopausal women undergoing treatment with hormone replacement therapy (HRT) or placebo using squared correlation coefficients (R2). In 239 women assigned to treatment with estrogen alone or with with estrogen plus progestins (active treatment), mean percentage changes for all markers decreased significantly and remained below baseline values through 3 years of study, whereas mean percentage changes for 54 women assigned to the placebo group showed no significant change from baseline in any marker. At baseline, age and body mass index (BMI) together accounted for 16% and 25% of the variance in spine and hip BMD, respectively. The telopeptide resorption marker, cross‐linked N‐telopeptide of type I collagen (NTX), alone accounted for 12% and 8% of variance, respectively. Another telopeptide, carboxy‐terminal telopeptide of type I collagen (Crosslaps), accounted for 8% and 7% of variance, respectively. A bone‐specific alkaline phosphatase (BALP‐2) accounted for 8% of variance at the spine and 5% at the hip. No other marker accounted for more than 5% of total variance at either site; adding either baseline NTX, Crosslaps, or BAP‐2 to regressions containing age and BMI increased R2 values at the spine and hip to about 22% and 28%, respectively. In the placebo group, baseline spine BMD accounted for 4% of the variance in 1‐year spine BMD percentage change, whereas baseline values for age and BMI accounted for 1% and 0% of the variance, respectively; none of the three accounted for more than 0% of hip BMD percentage change; Crosslaps and NTX contributed 5% and 4% to the variance in 1‐year spine BMD percentage change, but other markers accounted for < 2% of variance at the spine. At the hip, another BALP (BALP‐1) accounted for 4% of variance, but no other baseline marker except NTX accounted for more than 1% of variance. In the active treatment group, baseline values for age, BMI, and spine BMD together accounted for 13% of the percentage change in spine BMD and for 4% of the BMD change at the hip. No individual or pair of baseline markers significantly enhanced these R2 values, but addition of 1‐year percentage changes in some individual markers did significantly increase it. The largest R2 value was obtained by adding the percentage change in BALP‐2, which increased the R2 in spine BMD percentage change to 20% and that at the hip to 8%. Adding baseline and change variables for all eight markers to the regression increased R2 to 28% at the spine and 12% at the hip. Restricting the set of analyses to individuals who suppressed marker activity beyond the precision error for the measurement did not improve R2s for the regressions. When baseline marker values were stratified into quartiles, only NTX and osteocalcin showed significant relationships between quartile and change in spine BMD, and these did not reach significance at the hip. When the 1‐year change in markers was stratified into quartiles, significant relationships with percentage change in spine BMD were observed only for BALP phosphatases. We conclude that BTMs are not a surrogate for BMD to identify women with low bone mass and that they offer little useful information for predicting BMD changes for individual untreated or HRT‐treated postmenopausal women.

Myocardial infarction and use of low-dose oral contraceptives: A pooled analysis of 2 US studies

BACKGROUND Population-based case-control studies to assess the relationship of low-dose oral contraceptive (OC) use with myocardial infarction (MI) were performed at 2 sites in the United States (California and Washington state). The purpose of the present study was to estimate risk of MI in relation to use of low-dose OCs in a pooled analysis combining results from the 2 sites. METHODS AND RESULTS The study included as cases women aged 18 to 44 years with incident MI who had no prior history of ischemic heart disease or cerebrovascular disease. Women in the case and control groups were interviewed in person regarding OC use and cardiovascular risk factors. The analysis included 271 MI cases and 993 controls. Compared with noncurrent users, the adjusted pooled odds ratio for MI in current OC users was 0.94 (95% CI, 0.44, 2.20) after adjustment for major risk factors and sociodemographic factors. Compared with never users, the adjusted pooled odds ratio for MI was 0.56 (0.21, 1.49) in current OC users and 0.54 (0.31, 0.95) in past OC users. Among past OC users, duration and recency of use were unrelated to MI risk as was current hormone replacement therapy. There was no evidence of interaction between OC use and age, presence of cardiovascular risk factors (hypercholesterolemia, hypertension, diabetes), obesity, or smoking. CONCLUSIONS We conclude that low-dose OCs as used in these populations are safe with respect to risk of MI in women.

Mechanical failure of the latex condom in a cohort of women at high STD risk.

BACKGROUND AND OBJECTIVES Mechanical failure may reduce the efficacy of condoms. Little is known about frequency and determinants of condom failure in groups at high risk of sexually transmitted diseases (STD). GOAL To measure condom breakage and slippage rates and evaluate potential determinants of failure among women attending a public STD clinic. STUDY DESIGN Women attending an STD clinic participated in a 6-month prospective study of barrier contraception for the prevention of STD. They completed sexual diaries that were reviewed at monthly follow-up visits. No data were collected from the male partners. Baseline characteristics of the participants and time-dependent behaviors were evaluated as potential determinants of condom failure. RESULTS Of 21,852 condoms used by 892 women, 500 broke during intercourse (2.3%) and 290 slipped (1.3%). Breakage was more common among young, black, single nulliparae who engaged in high-risk behavior. Slippage was more common among married women with children. Failure rates decreased with condom use, with coital frequency, and with use of spermicides. CONCLUSION User characteristics and experience are determinants of breakage and slippage, which are often regarded only as the effect of product design flaws. Attention to modifiable determinants of failure may improve user counseling and product labeling.

Quality-of-Life Assessment in the Symptom Management Trials of the National Cancer Institute-Supported Community Clinical Oncology Program

PURPOSE To examine how quality of life (QOL) is prospectively conceptualized, defined, and measured in the symptom management clinical trials supported by the National Cancer Institute Community Clinical Oncology Program (CCOP). METHODS All QOL research objectives, rationales, assessment instruments, symptoms treated, and types of interventions from the CCOP symptom management portfolio of clinical trials were extracted and analyzed. RESULTS QOL assessments were proposed in 68 (52%) of the 130 total CCOP symptom management trials initiated since 1987. A total of 22 global QOL instruments were identified. Both the frequency of symptom management trials and the frequency of QOL assessment have increased significantly over time. The Functional Assessment of Cancer Therapy and Uniscale instruments were the most widely used QOL instruments, included in 55% of trials assessing QOL. The conceptual framework for QOL inclusion was limited to univariate relationships between symptom relief and global improvements in QOL. No consistent associations were found between QOL assessment and either the symptoms targeted or types of interventions. CONCLUSION To advance the state of the science, research protocols need to provide more explicit rationales for assessing QOL in symptom management trials and for the selection of the QOL instrument(s) to be used. Conceptual frameworks that specify the hypothesized links between the specific symptom(s) being managed, interactions with other symptoms, different domains of QOL, and global QOL also need to be more precisely described. Methodologic and conceptual advances in QOL symptom management trials are critical to fulfill the promise of alleviating suffering and improving the QOL of cancer patients.

Translating research into evidence-based practice: the National Cancer Institute Community Clinical Oncology Program.

The recent rapid acceleration of basic science is reshaping both our clinical research system and our healthcare delivery system. The pace and growing volume of medical discoveries are yielding exciting new opportunities, yet we continue to face old challenges to maintain research progress and effectively translate research into practice. The National Institutes of Health and individual government programs increasingly are emphasizing research agendas that involve evidence development, comparative‐effectiveness research among heterogeneous populations, translational research, and accelerating the translation of research into evidence‐based practice as well as building successful research networks to support these efforts. For more than 25 years, the National Cancer Institute Community Clinical Oncology Program has successfully extended research into the community and facilitated the translation of research into evidence‐based practice. By describing its keys to success, this article provides practical guidance to cancer‐focused, provider‐based research networks as well as those in other disciplines. Cancer 2010.

Female Condom Use Among Women at High Risk Of Sexually Transmitted Disease

CONTEXT Whereas the female condom has been evaluated in many hypothetical acceptability or short-term use studies, there is little information about its suitability for the prevention of sexually transmitted diseases (STDs) or HIV over extended periods of time. METHODOLOGY As part of a six-month prospective follow-up study of 1,159 STD clinic patients, clients were interviewed during their initial visit, exposed to a behavioral intervention promoting condoms, given a physical examination and provided with instructions on completing a sexual diary. Potential predictors of trying the female condom were evaluated using logistic regression, and three condom-use groups (exclusive users of female condoms, exclusive users of male condoms and users of both types of condoms) were compared using multinomial regression. RESULTS Among 895 women who reported having engaged in vaginal intercourse during the study period, one-half had sex with only one partner, while one-quarter each had two partners or three or more partners. A total of 731 women reported using the female condom at least once during the follow-up period--85% during the first month of follow-up. Multiple logistic regression analyses indicated that employed women and those with a regular sexual partner at baseline were significantly more likely to try the female condom. By the end of the follow-up period, 8% of participants had used the female condom exclusively, 15% had used the male condom exclusively, 73% had used both types of condom and 3% had used no condoms. Twenty percent of women who tried the female condom used it only once and 13% used it twice, while 20% used 5-9 female condoms and 32% used 10 or more. Consistent condom users (N=309) were predominantly users of both types of condom (75%), and were less often exclusive users of the male condom (18%) or the female condom (7%). According to a multivariate analysis, women who used the female condom exclusively or who mixed condom types were more likely to be black, were more likely to be employed and were more likely to have a regular partner than were users of the male condom. CONCLUSIONS Women at risk of STDs find the female condom acceptable and will try it, and some use it consistently. Mixing use of female condoms and male condoms may facilitate consistent condom use. The female condom may improve an individuals options for risk reduction and help reduce the spread of STDs.

Further data supporting that paclitaxel-associated acute pain syndrome is associated with development of peripheral neuropathy†

Paclitaxel causes an acute pain syndrome (P‐APS), occurring within days after each dose and usually abating within days. Paclitaxel also causes a more classic peripheral neuropathy, which steadily increases in severity with increasing paclitaxel total doses. Little detail is available regarding the natural history of these 2 syndromes, or any relationship between them, although a recent publication does provide natural history data about weekly paclitaxel, supporting an association between the severity of P‐APS and eventual peripheral neuropathy symptoms.

Female condom and male condom failure among women at high risk of sexually transmitted diseases.

Objective: The objective of this study was to study the frequency and determinants of breakage and slippage during female and male condom use. Goal: The goal of this study was to determine condom breakage and slippage rate. Study: We conducted a 6-month prospective follow-up study of women attending 2 sexually transmitted disease clinics. Breakage and slippage rates were computed. Logistic regression was used to evaluate baseline characteristics and time-dependent behaviors. Results: A total of 869 women used condoms in 20,148 acts of intercourse. Breakage was less common for female condoms (0.1%; 95% confidence interval [CI], 0.05–0.21) than for male condoms (3.1%; 95% CI, 2.80–3.42). Slippage was more common for female condoms (5.6%; 95% CI, 5.10–6.13) than for male condoms (1.1%; 95% CI, 0.90–1.28). Rates significantly decreased with use and increased with number of previous failures. From first use to >15 uses, combined failure rate fell from 20% to 1.2% for female condoms (P <0.0001) and 9% to 2.3% for male condoms (P <0.01). Conclusions: Both condoms may provide good protection against sexually transmitted diseases. Experience determines success with either condom.