Lauren J. Rogak

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.

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.

Substance Abuse in Cancer Pain

In the oncology community, opioids recently have become the cornerstone of cancer pain management. This has led to a rapid increase in opioid prescribing in an effort to address the growing public health problem of chronic pain. A new paradigm in noncancer pain management has emerged, that of risk assessment and stratification in opioid therapy. Techniques foreign to cancer pain management have now become commonplace in the noncancer pain setting, such as the use of monitoring compliance via urine drug screens. Amidst these strides in opioid use for pain management, cancer has been changing. The survival rate has increased, and a group of these patients with chronic pain were treated with opioid therapy. With opioid exposure being longer and against the backdrop of prescription drug abuse, the question is how much of the adaptation of the risk management paradigm in chronic pain management is to be imported to cancer pain management?

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.

Harnessing Technology to Improve Clinical Trials: Study of Real-Time Informatics to Collect Data, Toxicities, Image Response Assessments, and Patient-Reported Outcomes in a Phase II Clinical Trial

PURPOSE In clinical trials, traditional monitoring methods, paper documentation, and outdated collection systems lead to inaccuracies of study information and inefficiencies in the process. Integrated electronic systems offer an opportunity to collect data in real time. PATIENTS AND METHODS We created a computer software system to collect 13 patient-reported symptomatic adverse events and patient-reported Karnofsky performance status, semi-automated RECIST measurements, and laboratory data, and we made this information available to investigators in real time at the point of care during a phase II lung cancer trial. We assessed data completeness within 48 hours of each visit. Clinician satisfaction was measured. RESULTS Forty-four patients were enrolled, for 721 total visits. At each visit, patient-reported outcomes (PROs) reflecting toxicity and disease-related symptoms were completed using a dedicated wireless laptop. All PROs were distributed in batch throughout the system within 24 hours of the visit, and abnormal laboratory data were available for review within a median of 6 hours from the time of sample collection. Manual attribution of laboratory toxicities took a median of 1 day from the time they were accessible online. Semi-automated RECIST measurements were available to clinicians online within a median of 2 days from the time of imaging. All clinicians and 88% of data managers felt there was greater accuracy using this system. CONCLUSION Existing data management systems can be harnessed to enable real-time collection and review of clinical information during trials. This approach facilitates reporting of information closer to the time of events, and improves efficiency, and the ability to make earlier clinical decisions.

Methods for Implementing and Reporting Patient-reported Outcome (PRO) Measures of Symptomatic Adverse Events in Cancer Clinical Trials

PURPOSE There is increasing interest to use patient-reported outcome (PRO) measures to evaluate symptomatic adverse events (AEs) in cancer treatment trials. However, there are currently no standard recommended approaches for integrating patient-reported AE measures into trials. METHODS Approaches are identified from previous trials for selecting AEs for solicited patient reporting, administering patient-reported AE measures, and analyzing and reporting results. FINDINGS Approaches for integrating patient-reported AE measures into cancer trials generally combine current standard methods for clinician-reported AEs and established best practices for using PRO measures. Specific AEs can be selected for a PRO questionnaire based on common and expected reactions in a given trial context, derived from literature review and qualitative/mixed-methods evaluations and should be the same set administered across all arms of a trial. A mechanism for collecting unsolicited patient-reported AEs will also ideally be included. Patients will preferably report at baseline and at the end of active treatment as well as on a frequent standardized schedule during active treatment, such as weekly from home, with a recall period corresponding to the frequency of reporting (eg, past 7 days). Less frequent reporting may be considered after an initial intensive monitoring period for trials of prolonged treatments and during long-term follow-up. Electronic PRO data collection is preferred. Backup data collection for missed PRO reports is advisable to boost response rates. Analysis can use a combination of approaches to AE and PRO data. If a high proportion of patients is experiencing baseline symptoms, systematic subtraction of these from on-study AEs should be considered to improve reporting of symptoms related to treatment. More granular longitudinal analyses of individual symptoms can also be useful. IMPLICATIONS Methods are evolving for integrating patient-reported symptomatic AEs into cancer trials. These methods are expected to further evolve as more data from trials become available.

Frequency, characteristics, and correlates of pain in a pilot study of colorectal cancer survivors 1-10 years post-treatment.

OBJECTIVE The long-term effects of disease and treatment in colorectal cancer (CRC) survivors are poorly understood. This study examined the prevalence and characteristics of pain in a sample of CRC survivors up to 10 years post-treatment. DESIGN One hundred cancer-free CRC survivors were randomly chosen from an institutional database and completed a telephone survey using the Brief Pain Inventory, Neuropathic Pain Questionnaire-Short Form, Quality of Life Cancer Survivor Summary, Brief Zung Self-Rating Depression Scale, Zung Self-Rating Anxiety Scale, and Fear of Recurrence Questionnaire. RESULTS Participants were primarily Caucasian (90%) married (69%) males (53.5%) with a mean age of 64.7 years. Chronic pain was reported in 23% of CRC survivors, with a mean moderate intensity rating (mean = 6.05, standard deviation = 2.66) on a 0-10 rating scale. Over one-third (39%) of those with pain attributed it to their cancer or treatment. Chi-square and t-test analyses showed that survivors with pain were more likely to be female, have lower income, be more depressed and more anxious, and show a higher endorsement of suicidal ideation than CRC survivors without chronic pain. On average, pain moderately interfered with daily activity. CONCLUSIONS Chronic pain is likely a burdensome problem for a small but not inconsequential minority of CRC survivors requiring a biopsychosocial treatment approach to improve recognition and treatment. Open dialogue between clinicians and survivors about physical and emotional symptoms in long-term follow-up is highly recommended.

Feasibility and clinical impact of sharing patient-reported symptom toxicities and performance status with clinical investigators during a phase 2 cancer treatment trial

Background: Clinicians can miss up to half of patients’ symptomatic toxicities in cancer clinical trials and routine practice. Although patient-reported outcome questionnaires have been developed to capture this information, it is unclear whether clinicians will make use of patient-reported outcomes to inform their own toxicity documentation, or to prompt symptom management activities. Methods: 44 lung cancer patients that participated in a phase 2 treatment trial self-reported 13 symptomatic toxicities derived from the National Cancer Institute’s Common Terminology Criteria for Adverse Events and Karnofsky Performance Status via tablet computers in waiting areas immediately preceding scheduled visits. During visits, clinicians viewed patients’ self-reported toxicity and performance status ratings on a computer interface and could agree or disagree/reassign grades (“shared” reporting). Agreement of clinicians with patient-reported grades was tabulated, and compared using weighted kappa statistics. Clinical actions in response to patient-reported severe (grade 3/4) toxicities were measured (e.g. treatment discontinuation, dose reduction, supportive medications). For comparison, 45 non-trial patients with lung cancer being treated in the same clinic by the same physicians were simultaneously enrolled in a parallel cohort study in which patients also self-reported toxicity grades but reports were not shared with clinicians (“non-shared” reporting). Results: Toxicities and performance status were reported by patients and reviewed by clinicians at (780/782) 99.7% of study visits in the phase 2 trial which used “shared” reporting. Clinicians agreed with patients 93% of the time with kappas 0.82–0.92. Clinical actions were taken in response to 67% of severe patient-reported toxicities. In the “non-shared” reporting comparison group, clinicians agreed with patients 56% of the time with kappas 0.04–0.48 (significantly worse than shared reporting for all symptoms), and clinical actions were taken in response to 44% of severe patient-reported toxicities. Conclusion: Clinicians will frequently agree with patient-reported symptoms and performance status, and will use this information to guide documentation and symptom management. (ClinicalTrials.gov: NCT00807573).

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.