Reporting of health-related quality of life endpoints in National Cancer Institute-supported cancer treatment trials.

BACKGROUND: The importance of capturing and reporting health-related quality of life (HRQOL) in clinical trials has been increasingly recognized in the oncology field. As a result, the National Cancer Institute (NCI) began to provide support for correlative HRQOL studies in cancer treatment trials. The current study was conducted to assess the publication rate of HRQOL correlative studies in NCI-supported treatment trials and to identify potential factors positively or negatively associated with publication rates. METHODS: The NCI conducted a retrospective review of existing NCI databases to identify cancer treatment trials that had obtained additional NCI funding for the assessment of HRQOL and to determine the extent to which funded HRQOL studies have been completed and published in a peer-reviewed journal. RESULTS: Of the 108 included trials, 58 (54%) had a parent trial (PT) publication; of these, 36 trials (62%) had a published HRQOL result: 20 as an independent publication and 16 that were included and/or reported in the PT publication. The length of time between trial activation and closure, as well as the specific cancer, appeared to be associated with the publication rates. CONCLUSIONS: The results of the current study demonstrated that approximately 45% of the PT publications were followed by a HRQOL publication within 1 year, to allow the knowledge to be used in patient treatment decision making. The authors believe the current analysis is an important first step toward a better understand of the challenges that researchers face when reporting HRQOL endpoints.

Prevention of cisplatin-induced hearing loss in children: Informing the design of future clinical trials.

Cisplatin is an essential chemotherapeutic agent in the treatment of many pediatric cancers. Unfortunately, cisplatin-induced hearing loss (CIHL) is a common, clinically significant side effect with life-long ramifications, particularly for young children. ACCL05C1 and ACCL0431 are two recently completed Children's Oncology Group studies focused on the measurement and prevention of CIHL. The purpose of this paper was to gain insights from ACCL05C1 and ACCL0431, the first published cooperative group studies dedicated solely to CIHL, to inform the design of future pediatric otoprotection trials. Use of otoprotective agents is an attractive strategy for preventing CIHL, but their successful development must overcome a unique constellation of methodological challenges related to translating preclinical research into clinical trials that are feasible, evaluate practical interventions, and limit risk. Issues particularly important for children include use of appropriate methods for hearing assessment and CIHL severity grading, and use of trial designs that are well-informed by preclinical models and suitable for relatively small sample sizes. Increasing interest has made available new funding opportunities for expanding this urgently needed research.

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 Institute's (NCI's) 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.

Further data supporting that paclitaxel-associated acute pain syndrome is associated with development of peripheral neuropathy: North Central Cancer Treatment Group trial N08C1.

BACKGROUND: 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. METHODS: Patients entering this study were about to receive paclitaxel and carboplatin every 3 weeks. Daily questionnaires were completed for the first week after every chemotherapy dose, and European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire, Chemotherapy-Induced Peripheral Neuropathy 20-item instruments were completed weekly. RESULTS: The P-APS severity peaked on day 4 after the initial chemotherapy dose, with 12%, 29%, 23%, and 36% of patients having maximal pain scores of 0, 1 to 4, 5 or 6, or 7 to 10 during the first week after the first dose of therapy, respectively. Patients with P-APS scores of 0 to 4 with the first dose of chemotherapy had less eventual sensory neuropathy than did patients with P-APS scores of 5 to 10 (P = 0.001). With regard to the more peripheral neuropathy, sensory neuropathy was more problematic than was either motor or autonomic neuropathy. Numbness and tingling were more common components of the sensory neuropathy than was pain. CONCLUSIONS: Patients with worse P-APS severities appear to have more eventual chemotherapy-induced peripheral neuropathy. This provides support for the concept that P-APS is a form of nerve pathology.

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.

Chemoradiotherapy with or without AE-941 in stage III non-small cell lung cancer: a randomized phase III trial.

BACKGROUND AE-941 is a standardized aqueous shark cartilage extract with antiangiogenic properties that has previously been evaluated in phase I and II clinical trials. Our objective was to determine the effect of adding AE-941 to chemoradiotherapy on overall survival of patients with unresectable stage III non-small cell lung cancer (NSCLC). METHODS A randomized, double-blinded, placebo-controlled, phase III clinical trial was designed to test the efficacy of AE-941 in unresectable stage III NSCLC patients who were treated with chemoradiotherapy. Between June 5, 2000, and February 6, 2006, 379 eligible patients were enrolled in community and academic oncology centers across the United States and Canada. In February 2006, the trial was closed to new patient entry before meeting the target sample size because of insufficient accrual. All subjects received induction chemotherapy followed by concurrent chemotherapy with chest radiotherapy. Each participating center administered one of the two chemotherapy regimens, either carboplatin and paclitaxel, or cisplatin and vinorelbine. The primary endpoint was overall survival, and secondary endpoints were time to progression, progression-free survival, tumor response rate, and toxic effects. Event-time distributions were estimated by the Kaplan-Meier method. All statistical tests were two-sided. RESULTS There was no statistically significant difference in overall survival between the chemoradiotherapy plus AE-941 group (n = 188; median survival = 14.4 months, 95% confidence interval = 12.6 to 17.9 months) and the chemoradiotherapy plus placebo group (n = 191; median survival = 15.6 months, 95% confidence interval = 13.8 to 18.1 months) (P = .73). Time to progression, progression-free survival, and tumor response rates were not statistically significantly different between the AE-941 and the placebo groups. No differences between the two groups were observed in common grade 3 or higher toxic effects attributable to chemoradiotherapy. CONCLUSIONS The addition of AE-941 to chemoradiotherapy did not improve overall survival in patients with unresectable stage III NSCLC. This study does not support the use of shark cartilage-derived products as therapy for lung cancer.

Mayo Clinic and North Central Cancer Treatment Group hot flash studies: a 20-year experience.

OBJECTIVE: This project was designed to provide an overview of hot flash studies conducted over the past two decades at the Mayo Clinic and in the North Central Cancer Treatment Group. DESIGN: Prospective clinical trials performed by these investigators are illustrated, described, and discussed. RESULTS: Ten randomized, controlled (eight placebo controlled), double-blind clinical trials were conducted involving a total of 1,581 women and three placebo-controlled, double-blind clinical trials involving a total of 329 men were conducted. In addition, 14 pilot trials, having involved more than 325 participants to date, were conducted. CONCLUSIONS: Data from the pilot trials have given direction for substances that ought to be further explored in more definitive studies. In men, randomized studies demonstrate that hot flashes are markedly decreased by low doses of megestrol acetate, moderately decreased by gabapentin, but not substantially decreased by clonidine. Results from the randomized trials in women demonstrate that hot flashes are markedly decreased by relatively low doses of progestational agents (megestrol acetate and medroxyprogesterone acetate), moderately decreased by venlafaxine, mildly to moderately decreased by fluoxetine, mildly decreased by clonidine, but not substantially decreased by vitamin E, a soy phytoestrogen product, or black cohosh. Last, the data investigated in these studies support the hypothesis that, for the treatment of hot flashes in women, the results of therapeutic maneuvers are similar regardless of whether the patient has a history of breast cancer and/or is taking tamoxifen.

Health-related quality of life and symptom management research sponsored by the National Cancer Institute.

For almost 30 years, the National Cancer Institute (NCI) has sponsored health-related quality-of-life (HRQOL) measures in cancer research as a means of including the patient's experience. The scope of NCI's research in symptom management and HRQOL is described with attention to its evolution over time and the next steps, through the Clinical Trials Working Group Recommendations.

Challenges and recommendations for advancing the state-of-the-science of quality of life assessment in symptom management trials.

Major findings are presented from a workshop on Quality of Life Assessment in Cancer Symptom Management Trials, sponsored by the National Cancer Institute. Data-driven research reports focused on 3 topics, 1) the rationale and utility of health-related quality of life (HRQOL) assessment, 2) conceptual models, and 3) measurement and design issues. Recommendations for including HRQOL assessment cited the potential value of: capturing additional treatment effects (eg, fatigue + depression); describing the patient experience; predicting patient prognosis; identifying potential adverse effects; observing interactions among symptoms; calculating quality adjusted survival and cost-effectiveness; and generating new hypotheses. Recommendations for developing more fully developed conceptual models focused on maintaining clear distinctions among symptoms, function, summary measures of HRQOL, and global HRQOL assessments; identifying symptom clusters; pursuing hypotheses about whether clustering is better explained as symptom-related or as patient-related (genetic predispositions); and gaining a better understanding of the dynamic and reciprocal influences of symptoms on each other. With respect to measurement and design issues, because different HRQOL measures cover different domains with various degrees of sensitivity, there is a need to select measures that are carefully tailored to the study's hypotheses. Finally, there is a growing appreciation that trials must be powered to test for effects on secondary endpoints.

Can complementary and alternative medicine clinical cancer research be successfully accomplished? The Mayo Clinic-North Central Cancer Treatment Group experience.

Some critics question whether research on complementary and alternative modalities for patients with cancer can be done efficiently in traditional clinical settings. This article reviews a program of complementary medicine research that has been done in a traditional clinical setting over the past 30 years. Trials using complementary therapies for both symptom management and cancer treatment done by the Mayo Clinic and the North Central Cancer Treatment Group are reviewed. Twenty-seven studies have been developed using complementary therapies, addressing such issues as mucosal and epidermal toxicity, hot flashes, lymphedema, anorexia and cachexia, insomnia, cognitive dysfunction, fatigue, and cancer treatment. Nineteen of them have been completed and have had results published in peer-reviewed clinical journals, whereas two manuscripts are in press. Two other trials have recently completed accrual, and the data are being analyzed so that manuscripts can be prepared. In addition, four clinical trials are actively accruing patients. The data presented in this article demonstrate that complementary and alternative medicine research can be done in a scientifically sound manner. Well-designed and adequately powered studies can be implemented, and large numbers of patients can be accrued. The resulting research evaluations can be published in peer-reviewed medical journals.

A randomized trial of clinician-delivered interventions promoting barrier contraception for sexually transmitted disease prevention.

OBJECTIVE: The objective of this study was to compare 2 interventions promoting condoms and vaginal microbicides to prevent sexually transmitted disease (STD). STUDY: Women (N = 427) attending an STD clinic were randomly assigned to 2 clinician-delivered interventions and followed up monthly to assess condom/microbicide use and incidence of gonorrhea, chlamydia, and syphilis. RESULTS: During follow up, condom use rates were 69% (enhanced) and 49% (basic) and microbicide use rates were 44% and 29%, respectively. STD rates did not significantly differ between intervention groups. Perfect condom use (regardless of intervention arm) was associated with a 3-fold decrease in STD rates (relative risk [RR], 0.3; 95% confidence interval [CI], 0.1-0.8). Using a vaginal microbicide during > or =50% of the acts of intercourse was associated with reduced STD rates (RR, 0.5; 95% CI, 0.3-1.0) across intervention groups and condom use categories. CONCLUSIONS: The enhanced intervention increased use of condoms and vaginal microbicide; however, STD rates did not decrease because a protective effect was seen only among perfect barrier users, and the enhanced intervention only modestly increased perfect use.

Research-design issues in cancer-symptom-management trials using complementary and alternative medicine: lessons from the National Cancer Institute Community Clinical Oncology Program experience.

PURPOSE: To identify major research-design issues in proposals submitted by investigators in the Community Clinical Oncology Program (CCOP) for clinical trials of complementary and alternative medicine (CAM) for cancer-symptom management. METHODS: We conducted content analysis of all scientific reviews of concepts and protocols submitted by the CCOP to the National Cancer Institute (NCI) to identify research challenges in conducting clinical trials designed to evaluate CAM interventions for cancer-symptom management. RESULTS: Since the inception of the NCI Office of Cancer Complementary and Alternative Medicine in 1998, a total of 46 symptom-management studies using CAM interventions have been proposed by CCOP investigators, with 20 studies now in progress comprising 22% of the current total CCOP symptom-management portfolio. Proposals fell into four categories: complex natural products; nutritional therapeutics; mind-body interventions; and alternative medical systems. The most significant research-design issues arose as a consequence of the lack of preclinical data for CAM interventions and the lack of quality-control standards comparable with those used in regulating new pharmaceutical agents. CONCLUSION: Across the different types of CAM interventions, the most common problems found in proposed research designs are related to unwarranted assumptions about the consistency and standardization of CAM interventions, the need for data-based justifications for the study hypotheses, and the need to implement appropriate quality control and monitoring procedures during the course of the trial. To advance the state of the science, future research must address these critical issues if CAM interventions are to be evaluated rigorously and have a consequent impact on clinical practice and general public awareness.

An intervention to promote the female condom to sexually transmitted disease clinic patients.

This article describes a 1-hour behavioral intervention designed to promote female condoms and safer sex to women at a high risk for sexually transmitted diseases (STDs). The intervention includes a promotional videotape; a skills-oriented counseling session with a nurse clinician; assorted take-home items, including a videotape for men; and free supplies of female and male condoms. Designed for women ages 18 to 34 attending public STD clinics, the intervention is developed using a systematic process of formative evaluation influenced by principles of social marketing and drawing on the social cognitive theory. The effect of the intervention on female and male condom use is evaluated using a pretest-posttest design with 1,159 women. Most elements of the intervention could be replicated in settings other than STD clinics and delivered by persons other than nurse clinicians.

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.

Participation and retention in a study of female condom use among women at high STD risk.

PURPOSE: Differential participation and retention can bias the findings of a follow-up study. This problem was evaluated in a study of barrier contraception among women at high STD risk. The goal of this study was to identify predictors of participation and retention and determine whether they could influence study results. METHODS: Six-month follow-up study of women attending STD clinics. Determinants of participation and retention were evaluated using logistic and proportional hazards models. RESULTS: Agreement to participate was associated with young age, black race, low education and income, older age at first intercourse, the number of lifetime partners, and STD history. Early attrition was associated with young age, non-black race, higher income, lack of interest/commitment to using the female condom, high coital frequency, no STD history, not using a birth control method at baseline, and with inconsistent condom use, high coital frequency, and pregnancy during follow up. CONCLUSIONS: There was little evidence that differential participation influenced the validity of the study. Differential attrition may have biased behavioral measures of intervention effectiveness, but not necessarily measures of condom use effectiveness.

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.