Laura Sit

Symptom Monitoring With Patient-Reported Outcomes During Routine Cancer Treatment: A Randomized Controlled Trial

PURPOSE There is growing interest to enhance symptom monitoring during routine cancer care using patient-reported outcomes, but evidence of impact on clinical outcomes is limited. METHODS We randomly assigned patients receiving routine outpatient chemotherapy for advanced solid tumors at Memorial Sloan Kettering Cancer Center to report 12 common symptoms via tablet computers or to receive usual care consisting of symptom monitoring at the discretion of clinicians. Those with home computers received weekly e-mail prompts to report between visits. Treating physicians received symptom printouts at visits, and nurses received e-mail alerts when participants reported severe or worsening symptoms. The primary outcome was change in health-related quality of life (HRQL) at 6 months compared with baseline, measured by the EuroQol EQ-5D Index. Secondary endpoints included emergency room (ER) visits, hospitalizations, and survival. RESULTS Among 766 patients allocated, HRQL improved among more participants in the intervention group than usual care (34% v 18%) and worsened among fewer (38% v 53%; P < .001). Overall, mean HRQL declined by less in the intervention group than usual care (1.4- v 7.1-point drop; P < .001). Patients receiving intervention were less frequently admitted to the ER (34% v 41%; P = .02) or hospitalized (45% v 49%; P = .08) and remained on chemotherapy longer (mean, 8.2 v 6.3 months; P = .002). Although 75% of the intervention group was alive at 1 year, 69% with usual care survived the year (P = .05), with differences also seen in quality-adjusted survival (mean of 8.7 v. 8.0 months; P = .004). Benefits were greater for participants lacking prior computer experience. Most patients receiving intervention (63%) reported severe symptoms during the study. Nurses frequently initiated clinical actions in response to e-mail alerts. CONCLUSION Clinical benefits were associated with symptom self-reporting during cancer care.

Adverse Symptom Event Reporting by Patients vs Clinicians: Relationships With Clinical Outcomes

BACKGROUND In cancer treatment trials, the standard source of adverse symptom data is clinician reporting by use of items from the National Cancer Institutes Common Terminology Criteria for Adverse Events (CTCAE). Patient self-reporting has been proposed as an additional data source, but the implications of such a shift are not understood. METHODS Patients with lung cancer receiving chemotherapy and their clinicians independently reported six CTCAE symptoms and Karnofsky Performance Status longitudinally at sequential office visits. To compare how patients vs clinicians reports relate to sentinel clinical events, a time-dependent Cox regression model was used to measure associations between reaching particular CTCAE grade severity thresholds with the risk of death and emergency room visits. To measure concordance of CTCAE reports with indices of daily health status, Kendall tau rank correlation coefficients were calculated for each symptom with EuroQoL EQ-5D questionnaire and global question scores. Statistical tests were two-sided. RESULTS A total of 163 patients were enrolled for an average of 12 months (range = 1-28 months), with a mean of 11 visits and 67 (41%) deaths. CTCAE reports were submitted by clinicians at 95% of visits and by patients at 80% of visits. Patients generally reported symptoms earlier and more frequently than clinicians. Statistically significant associations with death and emergency room admissions were seen for clinician reports of fatigue (P < .001), nausea (P = .01), constipation (P = .038), and Karnofsky Performance Status (P < .001) but not for patient reports of these items. Higher concordance with EuroQoL EQ-5D questionnaire and global question scores was observed for patient-reported symptoms than for clinician-reported symptoms. CONCLUSIONS Longitudinally collected clinician CTCAE assessments better predict unfavorable clinical events, whereas patient reports better reflect daily health status. These perspectives are complementary, each providing clinically meaningful information. Inclusion of both types of data in treatment trial results and drug labels appears to be warranted.

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.

Feasibility of Long-Term Patient Self-Reporting of Toxicities From Home via the Internet During Routine Chemotherapy

PURPOSE Patient-reported outcomes are increasingly used in routine outpatient cancer care to guide clinical decisions and enhance communication. Prior evidence suggests good patient compliance with reporting at scheduled clinic visits, but there is limited evidence about compliance with long-term longitudinal reporting between visits. PATIENTS AND METHODS Patients receiving chemotherapy for lung, gynecologic, genitourinary, or breast cancer at a tertiary cancer center, with access to a home computer and prior e-mail experience, were asked to self-report seven symptomatic toxicities via the Web between visits. E-mail reminders were sent to participants weekly; patient-reported high-grade toxicities triggered e-mail alerts to nurses; printed reports were provided to oncologists at visits. A priori threshold criteria were set to determine if this data collection approach merited further development based on monthly (≥ 75% participants reporting at least once per month on average) and weekly compliance rates (60% at least once per week). RESULTS Between September 2006 and November 2010, 286 patients were enrolled (64% were women; 88% were white; median age, 58 years). Mean follow-up was 34 weeks (range, 2 to 214). On average, monthly compliance was 83%, and weekly compliance was 62%, without attrition until the month before death. Greater compliance was associated with older age and higher education but not with performance status. Compliance was greatest during the initial 12 weeks. Symptomatic illness and technical problems were rarely barriers to compliance. CONCLUSION Monthly compliance with home Web reporting was high, but weekly compliance was lower, warranting strategies to enhance compliance in routine care settings.

Using Confirmatory Factor Analysis to Evaluate Construct Validity of the Brief Pain Inventory (BPI)

CONTEXT The Brief Pain Inventory (BPI) is a frequently used instrument designed to assess the patient-reported outcome of pain. The majority of factor analytic studies have found a two-factor (i.e., pain intensity and pain interference) structure for this instrument; however, because the BPI was developed with an a priori hypothesis of the relationship among its items, it follows that construct validity investigations should use confirmatory factor analysis (CFA). OBJECTIVES The purpose of this work was to establish the construct validity of the BPI using a CFA framework and demonstrate factorial invariance using a range of demographic variables. METHODS A retrospective CFA was completed in a sample of individuals diagnosed with HIV/AIDS and cancer (n=364; 63% male; age 21-92 years, M=51.80). A baseline one-factor model was compared against two-factor and three-factor models (i.e., pain intensity, activity interference, and affective interference) that were developed based on the hypothetical design of the instrument. RESULTS Fit indices for the three-factor model were statistically superior when compared with the one-factor model and marginally better when compared with the two-factor model. This three-factor structure was found to be invariant across disease, age, and ethnicity groups. CONCLUSION The results of this study provide evidence to support a three-factor representation of the BPI, and the originally hypothesized two-factor structure. Such findings will begin to provide clinical trialists, pharmaceutical sponsors, and regulators with confidence in the psychometric properties of this instrument when considering its inclusion in clinical research.

Electronic toxicity monitoring and patient-reported outcomes

Understanding the potential profile of adverse events associated with cancer treatment is essential in balancing safety versus benefits. Multiple stakeholders make use of this information for decision making, including patients, clinicians, researchers, regulators, and payors. Currently, adverse events are reported by clinical research staff, yet evidence suggests that this may contribute to underreporting of symptom events. Direct patient reporting via electronic interfaces offers a promising mechanism to enhance the efficiency and precision of our current approach and may complement clinician reports of adverse events. The National Cancer Institute has contracted to develop and test an item bank and software system for directly eliciting adverse symptom event information from patients in cancer clinical research, called the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events. The validity, usability, and scalability of the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events prototype are currently being examined in academic and community-based settings.

Stakeholder perspectives on implementing the National Cancer Institute’s patient-reported outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)

The National Cancer Institute (NCI) is developing a patient-reported version of its Common Terminology Criteria for Adverse Events, called the “PRO-CTCAE.” The PRO-CTCAE consists of a library of patient-reported items which can be administered in clinical trials to directly capture the patient experience of adverse events during cancer treatment, as well as a software platform for administering these items via computer or telephone. In order to better understand the impressions of stakeholders involved in cancer clinical research about the potential value of the PRO-CTCAE approach to capturing adverse event information in clinical research, as well as their perspectives about barriers and strategies for implementing the PRO-CTCAE in NCI-sponsored cancer trials, a survey was conducted. A survey including structured and open-ended questions was developed to elicit perceptions about the use of patient-reported outcomes (PROs) for adverse event reporting, and to explore logistical considerations for implementing the PRO-CTCAE in cancer trials. The survey was distributed electronically and by paper to a convenience sample of leadership and committee members in the NCI’s cooperative group network, including principal investigators, clinical investigators, research nurses, data managers, patient advocates, and representatives of the NCI and Food and Drug Administration. Between October, 2008 through February, 2009, 727 surveys were collected. Most respondents (93%) agreed that patient reporting of adverse symptoms would be useful for improving understanding of the patient experience with treatment in cancer trials, and 88%, 80%, and 76%, respectively, endorsed that administration of PRO-CTCAE items in clinical trials would improve the completeness, accuracy, and efficiency of symptom data collection. More than three fourths believed that patient reports would be useful for informing treatment dose modifications and towards FDA regulatory evaluation of drugs. Eighty-eight percent felt that patients in clinical trials would be willing to self-report adverse symptoms at clinic visits via computer, and 68% felt patients would self-report weekly from home via the internet or an automated telephone system. Lack of computers and limited space and personnel were seen as potential barriers to in-clinic self-reporting, but these were judged to be surmountable with adequate funding. The PRO-CTCAE items and software are viewed by a majority of survey respondents as a means to improve adverse event data quality and comprehensiveness, enhance clinical decision-making, and foster patient-clinician communication. Research is ongoing to assess the measurement properties and feasibility of implementing this measure in cancer clinical trials.

Measurement of Affective and Activity Pain Interference Using the Brief Pain Inventory (BPI): Cancer and Leukemia Group B 70903

OBJECTIVE The Brief Pain Inventory (BPI) was designed to yield separate scores for pain intensity and interference. It has been proposed that the pain interference factor can be further broken down into unique factors of affective (e.g., mood) and activity (e.g., work) interference. The purpose of this analysis was to confirm this affective/activity interference dichotomy. PATIENTS AND METHODS A retrospective confirmatory factor analysis was completed for a sample of 184 individuals diagnosed with castrate-resistant prostate cancer (age 40-86, mean = 65.46, 77% White non-Hispanic) who had been administered the BPI as part of Cancer and Leukemia Group B trial 9480. A one-factor model was compared against two-factor and three-factor models that were developed based on the design of the instrument. RESULTS Root mean squared error of approximation (0.075), comparative fit index (0.971), and change in chi-square, given the corresponding change in degrees of freedom (13.33, P < 0.05) values for the three-factor model (i.e., pain intensity, activity interference, and affective interference), were statistically superior in comparison with the one- and two-factor models. This three-factor structure was found to be invariant across age, mean prostate-specific antigen, and hemoglobin levels. CONCLUSIONS These results confirm that the BPI can be used to quantify the degree to which pain separately interferes with affective and activity aspects of a patients everyday life. These findings will provide clinical trialists, pharmaceutical sponsors, and regulators with confidence in the flexibility of the BPI as they consider the use of this instrument to assist with understanding the patient experience as it relates to treatment.

Software for Administering the National Cancer Institute’s Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events: Usability Study

Background The US National Cancer Institute (NCI) developed software to gather symptomatic adverse events directly from patients participating in clinical trials. The software administers surveys to patients using items from the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) through Web-based or automated telephone interfaces and facilitates the management of survey administration and the resultant data by professionals (clinicians and research associates). Objective The purpose of this study was to iteratively evaluate and improve the usability of the PRO-CTCAE software. Methods Heuristic evaluation of the software functionality was followed by semiscripted, think-aloud protocols in two consecutive rounds of usability testing among patients with cancer, clinicians, and research associates at 3 cancer centers. We conducted testing with patients both in clinics and at home (remotely) for both Web-based and telephone interfaces. Furthermore, we refined the software between rounds and retested. Results Heuristic evaluation identified deviations from the best practices across 10 standardized categories, which informed initial software improvement. Subsequently, we conducted user-based testing among 169 patients and 47 professionals. Software modifications between rounds addressed identified issues, including difficulty using radio buttons, absence of survey progress indicators, and login problems (for patients) as well as scheduling of patient surveys (for professionals). The initial System Usability Scale (SUS) score for the patient Web-based interface was 86 and 82 (P=.22) before and after modifications, respectively, whereas the task completion score was 4.47, which improved to 4.58 (P=.39) after modifications. Following modifications for professional users, the SUS scores improved from 71 to 75 (P=.47), and the mean task performance improved significantly (4.40 vs 4.02; P=.001). Conclusions Software modifications, informed by rigorous assessment, rendered a usable system, which is currently used in multiple NCI-sponsored multicenter cancer clinical trials. Trial Registration ClinicalTrials.gov NCT01031641; https://clinicaltrials.gov/ct2/show/NCT01031641 (Archived by WebCite at http://www.webcitation.org/708hTjlTl)

Burden of Sexual Dysfunction in Women with Breast Cancer.

Background: Sexual dysfunction is reported after chemotherapy and endocrine therapies, and causes a substantial burden on women with breast cancer. However, the prevalence and severity of sexual dysfunction in women undergoing therapy for both local and metastatic disease is not well defined. Improved understanding of sexual dysfunction may facilitate enhanced treatment and interventions in patients with breast cancer undergoing active treatment, and in survivors of this disease. Methods: We developed a survey that includes a previously validated questionnaire, the female sexual function index (FSFI), as well as an established measure of health-related quality of life (the EuroQol EQ-5D), and disease-specific items to characterize sexual dysfunction and its causes based on literature review and expert consultations. Anonymous administration of the surveys was conducted in outpatient clinic waiting areas of the Breast Cancer Center at Memorial Sloan-Kettering Cancer Center (MSKCC) and two community centers, under an IRB waiver of consent. Results: During November 2008 through May 2009, 509 women undergoing treatment for breast cancer of all stages were each queried once. The mean age was 51 (range 26-91). 87% reported current or past hormonal treatment, and 82% reported current or past chemotherapy (76% adjuvant; 24% for metastatic disease). Sexual dysfunction attributed to breast cancer or its treatment, defined as an FSFI score =5/10). Patients attributed their sexual dysfunction to chemotherapy in 318/373 (85%) of cases; to hormonal therapy in 221/298 (74%) of cases; and to surgery in 331/442 (66%) of cases. Other reported contributors to sexual dysfunction include a new diagnosis of breast cancer by 81% of respondents, anxiety by 82% of respondents, and change in relationship with a partner by 55% of respondents. Conclusion: Sexual dysfunction is prevalent in women treated for breast cancer and should be discussed with patients as a potential adverse effect of therapy. Assessment of sexual symptoms throughout treatment and beyond may facilitate the use of potential interventions such as lubricants, dilators, treatment modification, topical estrogens, and counseling. Future work includes a longitudinal prospective trial to further characterize the etiologies of these symptoms and a randomized controlled trial to evaluate interventions for sexual dysfunction. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1056.