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Improving the Capture of Adverse Event Data in Clinical Trials: The Role of the International Atomic Energy Agency
Int. J. Radiation Oncology Biol. Phys., Vol. 69, No. 4, pp. 1218–1221, 2007 Copyright Ó 2007 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/07/$–see front matter
doi:10.1016/j.ijrobp.2007.04.054
CLINICAL INVESTIGATION
Normal Tissue
IMPROVING THE CAPTURE OF ADVERSE EVENT DATA IN CLINICAL TRIALS: THE ROLE OF THE INTERNATIONAL ATOMIC ENERGY AGENCY ¨ ZLEM U. ATAMAN, M.D., PH.D.,z SUSAN E. DAVIDSON, M.D.,* ANDY TROTTI, M.D.,y O x k JINSIL SEONG, M.D., PH.D., FEN NEE LAU, M.D., NEIRO W. DA MOTTA, M.D., PH.D.,{ # AND BRANISLAV JEREMIC, M.D., PH.D. * Department of Clinical Oncology, Christie Hospital NHS Trust, Manchester, United Kingdom; y Division of Radiation Oncology, H. Lee Moffitt Cancer Center, University of South Florida, Tampa, FL; z Dokuz Eylul University Oncology Institute, Izmir, Turkey; x Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University Medical College, Seoul, South Korea; k Institute of Radiotherapy and Oncology, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia; { Fundac¸ao Faculdade Federal de Ciencias Medicas de Porto Alegre, Servico de Radioterapia, Porto Alegre, Brazil; and # International Atomic Energy Agency, Vienna, Austria Purpose: To report meetings of the Applied Radiation Biology and Radiotherapy section of the International Atomic Energy Agency (IAEA), organized to discuss issues surrounding, and develop initiatives to improve, the recording of adverse events (AE) in clinical trials. Methods and Materials: A first meeting was held in Atlanta, GA (October 2004). A second meeting was held in Denver, CO (October 2005) and focused on AE data capture. The National Cancer Institute Common Terminology Criteria for Adverse Events, version 3 (CTCAE) was suggested during the first meeting as the preferred common platform for the collection and reporting of AE data in its clinical trials. The second meeting identified and reviewed the current weaknesses and variations in the capture of AE data, and proposals to improve the quality and consistency of data capture were discussed. Results: There is heterogeneity in the collection of AE data between both institutions and individual clinicians. The use of multiple scoring systems hampers comparisons of treatment outcomes between centers and trials. There is often insufficient detail on normal tissue treatment effects, which leads to an underestimate of toxicity. Implementation of improved data capture was suggested for one of the ongoing IAEA clinical trials. Conclusions: There is a need to compare the quality and completeness of data between institutions and the efficacy of structured/directed vs. traditional passive data collection. Data collection using the CTCAE (with or without a questionnaire) will be investigated in an IAEA multinational trial of radiochemotherapy and high-dose-rate brachytherapy in cervical cancer. Ó 2007 Elsevier Inc. Adverse events reporting, CTCAE.
INTRODUCTION
was held in Denver, CO in 2005 to focus on initiatives to improve AE reporting. This article summarizes the issues surrounding AE data collection and reporting that were discussed at the meetings and the development of a study to compare passive with active data collection methods in an IAEA randomized trial.
An International Atomic Energy Agency (IAEA) Technical Meeting on Adverse Events held in 2004 in Atlanta, GA suggested the Common Terminology Criteria for Adverse Events version 3.0 (CTCAE) as the preferred common platform for the collection and reporting of adverse event (AE) data in its clinical trials (1). The IAEA is interested in increasing awareness worldwide of the need to improve the capture and recording of AE data after radiotherapy through its ongoing projects. Because it has the potential to provide a rapid framework for testing hypotheses and exploring approaches for improving AE reporting, a second meeting in this series
CURRENT ISSUES IN ADVERSE EVENTS REPORTING There are a number of issues that need addressing to improve the reporting of AEs in clinical trials. These are the use of diverse grading systems, inconsistencies in the
The International Atomic Energy Agency (IAEA) Consultant’s meeting was held October 15, 2005, Denver, CO. The IAEA provided financial support for this meeting. Conflict of interest: none. Received Feb 13, 2007, and in revised form April 25, 2007. Accepted for publication April 29, 2007.
Reprint requests to: Susan E. Davidson, M.D., Department of Clinical Oncology, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, United Kingdom. Tel: (+44) 161446-3410; Fax: (+44) 161-44-8014; E-mail: Susan.Davidson@ christie-tr.nwest.nhs.uk 1218
Improving the capture of AE data in clinical trials d S. E. DAVIDSON et al.
time points used in reporting effects, variation in methods for data collection, differences between patient and clinical staff perceptions of toxicity, and the need for tools that can be used in different countries. It is well recognized that there are limitations in the different grading systems used between centers and trials, which lead to underreporting of treatment morbidity (2). There may not be sufficient detail in the scoring systems used or sufficient time allowed for follow-up to detect late normal tissue effects. In 2003 the CTCAE was published online and for the first time a system was available for recording both acute and late effects (1, 3).The development of a single comprehensive grading system suitable for use with all cancer treatment modalities is a key advance, but other aspects of the reporting process need to be improved. There are strengths and limitations to the use of the CTCAE. One strength is its incorporation of Late Effects on Normal Tissues (LENT) Subjective, Objective, Management, Analytic (SOMA) items so that it comprises more than 1000 items of potential normal tissue effects. One of the limitations of the application of the CTCAE is inconsistencies in the timing of recording data. Late-effect data from a randomized trial of radiochemotherapy in advanced head-and-neck cancer were shown to vary not only according to the scoring system used but also the time point used to report toxicity (4). There is a recognized need for the development of methods for improving data collection. Data collection methods are variable and cumbersome. Information can be transferred verbally from patient to clinician, interpreted and recorded by the clinician, and information extracted and entered manually into a database. During this process information can be altered and lost (5). Grade 3 and 4 events are more likely to be reported than Grade 1 and 2. A review of the National Cancer Institute’s Clinical Data Update System (CDUS) for studies that used the Common Toxicity Criteria version 2 for reporting AEs revealed underrepresentation of Grade 1 and 2 toxicities in published articles. Only 58% of Grade 1 and 2 investigational-agent AEs in CDUS were reported in articles, whereas three articles failed to report any Grade 1 and 2 AEs (6). This issue was recognized in an audit of cervical cancer patients who underwent radiotherapy in 1993 in the United Kingdom (UK). Grade 3 toxicity was chosen to report toxicity because it involved surgery as part of the management and would therefore be recorded in the patients’ case records (7). The relationship between observer- and patient-based toxicity reporting has received little attention in oncology. It was the LENT SOMA scales that first attempted to incorporate both patient- and clinician-recorded AE data. Subsequently the CTCAE included these items. Published work has shown a difference between patient and physician scores and that patient-recorded symptoms can add to current methods for AE reporting (8). For example, by including patient views, bowel urgency was shown to be a problem in 10–37% of patients after pelvic radiotherapy for prostate cancer, and this is a symptom not included in the Radiation Therapy Oncology Group late effects system (9, 10). Jensen et al. (11) described a study that explored the relationship between observer-based toxicity scoring and patient-
1219
assessed symptom severity after treatment for head-and-neck cancer. The DAHANCA (the Danish Head and Neck Study Group) scoring technique was effective in assessing objective treatment-induced toxicity in head-and-neck cancer patients but insensitive and nonspecific with regard to patient-assessed subjective endpoints (European Organization for the Research and Treatment of Cancer [EORTC] quality-of-life questionnaire). The DAHANCA study observed objective symptoms, such as edema, atrophy, and fibrosis, correlated poorly with quality-of-life endpoints. This finding is likely to apply to other observer-based scoring systems. In a study of >700 patients receiving palliative care, Stephens et al. (12) compared the scores of physicians and patients obtained using the same scales. There was 78% agreement in scores but 15% underestimation of symptoms by the treating physician. The questionnaires were completed by patients before physician consultation, but ‘‘the doctors did not usually refer to this.’’ However, because the patient scores were available at the time of physician scoring, this may have led to some overestimation of the agreement. A qualityof-life measure has been used as a surrogate endpoint for treatment toxicity in some studies but is not justified. Although quality-of-life measurements are important, they measure how patients live with the consequences rather than the toxicity of treatment (13). One study was carried out to look at the accuracy of clinicians reporting chemotherapy AEs by comparing the EORTC Core 30 quality-of-life questionnaire (C30) with physicians’ reporting of the same symptoms in patients receiving chemotherapy for metastatic prostate cancer (14). There was only 32% agreement on new or worsened symptoms between patients and physicians: even in a tightly controlled clinical trial, physician reporting was neither sensitive nor specific in detecting common chemotherapy AEs. However, one limitation of this study was the use of C30 because this is a quality-of-life questionnaire allowing examination of only eight AEs rather than a comprehensive AE scoring system. The findings suggest that patient self-reporting should complement rather than replace physician assessments. Basch et al. (8) reported work using a questionnaire with 11 common CTCAE symptoms, which was given to 400 patients with lung and prostate cancer undergoing chemotherapy and also to the physicians or nurses involved in their care. The results of the patient and physician/nurse responses were compared. For most symptoms agreement was high between patients and physicians, with discrepancies differing by only one grade. Patients tended to score a greater severity of symptoms than did clinicians. Agreement was higher for observable symptoms, such as vomiting and diarrhea, and less for subjective symptoms, such as fatigue and shortness of breath. In this study the differences between patients and physicians would have rarely altered treatment decisions. The investigators stated that their strategy should be studied in a less urban, less educated, and less affluent population. The important issue of collecting AE data in multinational trials involving patients in developing countries where literacy may be low has not been addressed. There is a clear
1220
I. J. Radiation Oncology d Biology d Physics
need for more work translating toxicity scales into multiple languages and investigating the feasibility of their use in clinical trials. FUTURE INITIATIVES FOR IMPROVING AE REPORTING One way of addressing the need to improve the capture of AE data is to use prospectively completed questionnaires (8, 15, 16). A questionnaire approach has been used in Manchester, UK since 1998 to collect LENT SOMA data. The approach is associated with good compliance and low interscorer variability (16). Patient-completed questionnaires can be used to obtain detailed AE data in a standardized and uniform way within a busy cancer center (17, 18). Electronic methods to facilitate AE data collection may promote more uniform data collection and reporting practices (1). It is a method that has been used in quality-of-life research and is well received by patients and associated with good reliability and completeness of data collection (19, 20). Basch et al. (21) used a web-based assessment using seven common symptoms from the CTCAE for 80 gynecologic cancers to report symptoms with chemotherapy. However, the majority of the patients held a college degree, and assessment of this approach is needed in the clinical trial setting that incorporates a wider socioeconomic range of the population. There is also a need for multilingual methods of data capture. An important aim of follow-up after treatment for cancer is to detect various events associated with disease recurrence or metastatic spread or severe treatment-related complications as early as possible. Each tumor type may show a specific pattern and timing of these events related to different prognostic factors. A working group of the European Society for Therapeutic Radiology and Oncology was funded by the European Union for a project—Recording providing Education, and Ameliorating the Consequences of Treatment (REACT)—and carried out a study to propose a way of defining an optimal timing schedule for follow-up after treatment, based on the analysis of failure patterns determined from follow-up data from prospective clinical trials (22). Questions that need addressing in future studies were formulated by the IAEA meeting participants as follows: 1. Can a CTCAE questionnaire approach be used in a multicenter, multinational study? 2. Will CTCAE questionnaires improve the collection of normal tissue toxicity data compared with toxicity tables? 3. Is the method of data collection important (manual compared with electronic or patient compared with doctor or nurse)? 4. Does electronic data capture at the point of care improve the efficiency of collecting data compared with completing paper proformas? 5. Is electronic data capture seen as an advantage over conventional data acquisition, and is it feasible in a multicentered study? 6. What is the optimum frequency of patient assessments?
Volume 69, Number 4, 2007
OPPORTUNITY FOR EVALUATING POTENTIAL IMPROVEMENT IN AE REPORTING IN AN IAEA TRIAL The IAEA is currently supporting a coordinated research project on a clinical/radiobiology study of virally induced cancers’ response to radiotherapy. The trial in patients with locally advanced cervical cancer involves six countries (Brazil, Peru, India, South Africa, Pakistan, and Macedonia) and has four arms testing two different fractionation schedules for high-dose-rate brachytherapy (7 Gy 4 and 9 Gy 2) given with external beam radiotherapy with and without concurrent weekly cisplatin. The Radiation Therapy Oncology Group Early and Late Toxicity Scales and the CTCAE are being used to report treatment toxicity. The study began in February 2006, will run for 4 to 5 years, and has a planned recruitment of more than 600 patients with approximately 150 patients in each arm. A new component (improvement in AE data capture) was developed during the Denver meeting to evaluate methods for improving AE data collection. This addition will explore the feasibility of using questionnaires for CTCAE data collection. The questionnaires can be viewed on the Christie Hospital website: http://www.christie.nhs.uk/pro/ depts/clinical_oncology/lent_soma/iaea_crp_cx_hdr.aspx. Because literacy is a problem for many patients in the participating centers, the questionnaires would not be selfadministered. The questionnaires would be used to structure the physician’s interview with patients to aid the physician in recording patients’ symptoms and treatment effects in a reproducible and reliable way. Therefore, these would not be classified as patient-reported outcome forms and would not have to undergo further testing that would be required for a patient-reported outcome. These questionnaires have been used in Manchester, UK with large numbers of patients (nearly 1200 patients with cancers at different sites to date) in face-to-face interviews, in which the questionnaire structures the interview, and these are completed as patients are recruited into local studies. Language translation of the questionnaires will involve extensive work to test meaning and acceptability and translation back into English—a process used by the EORTC in the translation of their quality-of-life questionnaires (23). The feasibility of the proposed addition will be assessed in each center. It needs to be established that a structured interview approach improves compliance and the quality of AE data collected compared with passive data collection. Qualitative data, such as the time taken for structured interviews, can be assessed along with convenience of use. SUMMARY The adoption of the National Cancer Institute CTCAE system should facilitate the reporting of AE comparisons between trials and centers and promote a more complete recognition and reporting of AEs after radiation therapy (24). It is increasingly recognized that both physician- and
Improving the capture of AE data in clinical trials d S. E. DAVIDSON et al.
patient-recorded symptoms should be recorded and that a questionnaire approach facilitates the collection of AE data. The ways in which AE data are recorded within the
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clinic need to be addressed and is to be the subject of a future coordinated research project to establish the most reliable method of data collection.
REFERENCES 1. Chen Y, Trotti A, Coleman CN, et al. Adverse event reporting and developments in radiation biology after normal tissue injury: International Atomic Energy Agency consultation. Int J Radiat Oncol Biol Phys 2006;64:1442–1451. 2. Bentzen SM. Towards evidence based radiation oncology: Improving the design, analysis, and reporting of clinical outcome studies in radiotherapy. Radiother Oncol 1998;46:5–18. 3. National Cancer Institute. CTC v2.0 and common terminology criteria for adverse events v3.0 (CTCAE). Available at: http:// ctep.cancer.gov/reporting/ctc.html. Accessed May 6, 2007. 4. Denis F, Garaud P, Bardet E, et al. Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. J Clin Oncol 2004;22:69–76. 5. Gwede CK, Johnson DJ, Daniels SS, et al. Assessment of toxicity in cooperative oncology clinical trials: The long and short of it. J Oncol Manag 2002;11:15–21. 6. Scharf O, Colevas AD. Adverse event reporting in publications compared with sponsor database for cancer clinical trials. J Clin Oncol 2006;24:3933–3938. 7. Denton AS, Bond SJ, Matthews S, et al. National audit of the management and outcome of carcinoma of the cervix treated with radiotherapy in 1993. Clin Oncol (R Coll Radiol) 2000; 12:347–353. 8. Basch E, Iasonos A, McDonough T, et al. Patient versus clinician symptom reporting using the National Cancer Institute Common Terminology Criteria for Adverse Events: Results of a questionnaire-based study. Lancet Oncol 2006;7:903–909. 9. Livsey JE, Routledge J, Burns M, et al. Scoring of treatmentrelated late effects in prostate cancer. Radiother Oncol 2002; 65:109–121. 10. Olopade FA, Norman A, Blake P, et al. A modified Inflammatory Bowel Disease questionnaire and the Vaizey Incontinence questionnaire are simple ways to identify patients with significant gastrointestinal symptoms after pelvic radiotherapy. Br J Cancer 2005;92:1663–1670. 11. Jensen K, Bonde Jensen A, Grau C. The relationship between observer-based toxicity scoring and patient assessed symptom severity after treatment for head and neck cancer. A correlative cross sectional study of the DAHANCA toxicity scoring system and the EORTC quality of life questionnaires. Radiother Oncol 2006;78:298–305. 12. Stephens RJ, Hopwood P, Girling DJ, et al. Randomized trials with quality of life endpoints: Are doctors’ ratings of patients’
13. 14.
15.
16.
17.
18. 19.
20. 21. 22.
23.
24.
physical symptoms interchangeable with patients’ self-ratings? Qual Life Res 1997;6:225–236. Baumann M, Bentzen SM. Clinical manifestations of normaltissue damage. In: Steel GG, editor. Basic clinical radiobiology. London: Arnold; 2002. p. 105–119. Fromme EK, Eilers KM, Mori M, et al. How accurate is clinician reporting of chemotherapy adverse effects? A comparison with patient-reported symptoms from the Quality-of-Life Questionnaire C30. J Clin Oncol 2004;22:3485–3490. Davidson SE, Burns M, Routledge J, et al. Short report: A morbidity scoring system for Clinical Oncology practice: Questionnaires produced from the LENT SOMA scoring system. Clin Oncol (R Coll Radiol) 2002;14:68–69. Routledge JA, Burns MP, Swindell R, et al. Evaluation of the LENT-SOMA scales for the prospective assessment of treatment morbidity in cervical carcinoma. Int J Radiat Oncol Biol Phys 2003;56:502–510. Davidson SE, Burns MP, Routledge JA, et al. Assessment of morbidity in carcinoma of the cervix: A comparison of the LENT SOMA scales and the Franco-Italian glossary. Radiother Oncol 2003;69:195–200. Chassagne D, Sismondi P, Horiot JC, et al. A glossary for reporting complications of treatment in gynecological cancers. Radiother Oncol 1993;26:195–202. Drummond HE, Ghosh S, Ferguson A, et al. Electronic quality of life questionnaires: A comparison of pen-based electronic questionnaires with conventional paper in a gastrointestinal study. Qual Life Res 1995;4:21–26. Velikova G, Wright EP, Smith AB, et al. Automated collection of quality-of-life data: A comparison of paper and computer touch-screen questionnaires. J Clin Oncol 1999;17:998–1007. Basch E, Artz D, Dulko D, et al. Patient online self-reporting of toxicity symptoms during chemotherapy. J Clin Oncol 2005;23: 3552–3561. Ataman OU, Barrett A, Filleron T, et al. Optimization of followup timing from study of patterns of first failure after primary treatment. An example from patients with NSCLC: A study of the REACT working group of ESTRO. Radiother Oncol 2006;78:95–100. Cull A, Sprangers M, Bjordal K, et al. EORTC quality of life study group translation procedure. In. Brussels; 1998. pp. 1–31. Available at: www/eortc.be/home/gol/manuals. Accessed May 6, 2007. Trotti A, Colevas AD, Setser A, et al. CTCAE v3.0: Development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 2003;13:176–181.
doi:10.1016/j.ijrobp.2007.04.054
CLINICAL INVESTIGATION
Normal Tissue
IMPROVING THE CAPTURE OF ADVERSE EVENT DATA IN CLINICAL TRIALS: THE ROLE OF THE INTERNATIONAL ATOMIC ENERGY AGENCY ¨ ZLEM U. ATAMAN, M.D., PH.D.,z SUSAN E. DAVIDSON, M.D.,* ANDY TROTTI, M.D.,y O x k JINSIL SEONG, M.D., PH.D., FEN NEE LAU, M.D., NEIRO W. DA MOTTA, M.D., PH.D.,{ # AND BRANISLAV JEREMIC, M.D., PH.D. * Department of Clinical Oncology, Christie Hospital NHS Trust, Manchester, United Kingdom; y Division of Radiation Oncology, H. Lee Moffitt Cancer Center, University of South Florida, Tampa, FL; z Dokuz Eylul University Oncology Institute, Izmir, Turkey; x Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University Medical College, Seoul, South Korea; k Institute of Radiotherapy and Oncology, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia; { Fundac¸ao Faculdade Federal de Ciencias Medicas de Porto Alegre, Servico de Radioterapia, Porto Alegre, Brazil; and # International Atomic Energy Agency, Vienna, Austria Purpose: To report meetings of the Applied Radiation Biology and Radiotherapy section of the International Atomic Energy Agency (IAEA), organized to discuss issues surrounding, and develop initiatives to improve, the recording of adverse events (AE) in clinical trials. Methods and Materials: A first meeting was held in Atlanta, GA (October 2004). A second meeting was held in Denver, CO (October 2005) and focused on AE data capture. The National Cancer Institute Common Terminology Criteria for Adverse Events, version 3 (CTCAE) was suggested during the first meeting as the preferred common platform for the collection and reporting of AE data in its clinical trials. The second meeting identified and reviewed the current weaknesses and variations in the capture of AE data, and proposals to improve the quality and consistency of data capture were discussed. Results: There is heterogeneity in the collection of AE data between both institutions and individual clinicians. The use of multiple scoring systems hampers comparisons of treatment outcomes between centers and trials. There is often insufficient detail on normal tissue treatment effects, which leads to an underestimate of toxicity. Implementation of improved data capture was suggested for one of the ongoing IAEA clinical trials. Conclusions: There is a need to compare the quality and completeness of data between institutions and the efficacy of structured/directed vs. traditional passive data collection. Data collection using the CTCAE (with or without a questionnaire) will be investigated in an IAEA multinational trial of radiochemotherapy and high-dose-rate brachytherapy in cervical cancer. Ó 2007 Elsevier Inc. Adverse events reporting, CTCAE.
INTRODUCTION
was held in Denver, CO in 2005 to focus on initiatives to improve AE reporting. This article summarizes the issues surrounding AE data collection and reporting that were discussed at the meetings and the development of a study to compare passive with active data collection methods in an IAEA randomized trial.
An International Atomic Energy Agency (IAEA) Technical Meeting on Adverse Events held in 2004 in Atlanta, GA suggested the Common Terminology Criteria for Adverse Events version 3.0 (CTCAE) as the preferred common platform for the collection and reporting of adverse event (AE) data in its clinical trials (1). The IAEA is interested in increasing awareness worldwide of the need to improve the capture and recording of AE data after radiotherapy through its ongoing projects. Because it has the potential to provide a rapid framework for testing hypotheses and exploring approaches for improving AE reporting, a second meeting in this series
CURRENT ISSUES IN ADVERSE EVENTS REPORTING There are a number of issues that need addressing to improve the reporting of AEs in clinical trials. These are the use of diverse grading systems, inconsistencies in the
The International Atomic Energy Agency (IAEA) Consultant’s meeting was held October 15, 2005, Denver, CO. The IAEA provided financial support for this meeting. Conflict of interest: none. Received Feb 13, 2007, and in revised form April 25, 2007. Accepted for publication April 29, 2007.
Reprint requests to: Susan E. Davidson, M.D., Department of Clinical Oncology, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, United Kingdom. Tel: (+44) 161446-3410; Fax: (+44) 161-44-8014; E-mail: Susan.Davidson@ christie-tr.nwest.nhs.uk 1218
Improving the capture of AE data in clinical trials d S. E. DAVIDSON et al.
time points used in reporting effects, variation in methods for data collection, differences between patient and clinical staff perceptions of toxicity, and the need for tools that can be used in different countries. It is well recognized that there are limitations in the different grading systems used between centers and trials, which lead to underreporting of treatment morbidity (2). There may not be sufficient detail in the scoring systems used or sufficient time allowed for follow-up to detect late normal tissue effects. In 2003 the CTCAE was published online and for the first time a system was available for recording both acute and late effects (1, 3).The development of a single comprehensive grading system suitable for use with all cancer treatment modalities is a key advance, but other aspects of the reporting process need to be improved. There are strengths and limitations to the use of the CTCAE. One strength is its incorporation of Late Effects on Normal Tissues (LENT) Subjective, Objective, Management, Analytic (SOMA) items so that it comprises more than 1000 items of potential normal tissue effects. One of the limitations of the application of the CTCAE is inconsistencies in the timing of recording data. Late-effect data from a randomized trial of radiochemotherapy in advanced head-and-neck cancer were shown to vary not only according to the scoring system used but also the time point used to report toxicity (4). There is a recognized need for the development of methods for improving data collection. Data collection methods are variable and cumbersome. Information can be transferred verbally from patient to clinician, interpreted and recorded by the clinician, and information extracted and entered manually into a database. During this process information can be altered and lost (5). Grade 3 and 4 events are more likely to be reported than Grade 1 and 2. A review of the National Cancer Institute’s Clinical Data Update System (CDUS) for studies that used the Common Toxicity Criteria version 2 for reporting AEs revealed underrepresentation of Grade 1 and 2 toxicities in published articles. Only 58% of Grade 1 and 2 investigational-agent AEs in CDUS were reported in articles, whereas three articles failed to report any Grade 1 and 2 AEs (6). This issue was recognized in an audit of cervical cancer patients who underwent radiotherapy in 1993 in the United Kingdom (UK). Grade 3 toxicity was chosen to report toxicity because it involved surgery as part of the management and would therefore be recorded in the patients’ case records (7). The relationship between observer- and patient-based toxicity reporting has received little attention in oncology. It was the LENT SOMA scales that first attempted to incorporate both patient- and clinician-recorded AE data. Subsequently the CTCAE included these items. Published work has shown a difference between patient and physician scores and that patient-recorded symptoms can add to current methods for AE reporting (8). For example, by including patient views, bowel urgency was shown to be a problem in 10–37% of patients after pelvic radiotherapy for prostate cancer, and this is a symptom not included in the Radiation Therapy Oncology Group late effects system (9, 10). Jensen et al. (11) described a study that explored the relationship between observer-based toxicity scoring and patient-
1219
assessed symptom severity after treatment for head-and-neck cancer. The DAHANCA (the Danish Head and Neck Study Group) scoring technique was effective in assessing objective treatment-induced toxicity in head-and-neck cancer patients but insensitive and nonspecific with regard to patient-assessed subjective endpoints (European Organization for the Research and Treatment of Cancer [EORTC] quality-of-life questionnaire). The DAHANCA study observed objective symptoms, such as edema, atrophy, and fibrosis, correlated poorly with quality-of-life endpoints. This finding is likely to apply to other observer-based scoring systems. In a study of >700 patients receiving palliative care, Stephens et al. (12) compared the scores of physicians and patients obtained using the same scales. There was 78% agreement in scores but 15% underestimation of symptoms by the treating physician. The questionnaires were completed by patients before physician consultation, but ‘‘the doctors did not usually refer to this.’’ However, because the patient scores were available at the time of physician scoring, this may have led to some overestimation of the agreement. A qualityof-life measure has been used as a surrogate endpoint for treatment toxicity in some studies but is not justified. Although quality-of-life measurements are important, they measure how patients live with the consequences rather than the toxicity of treatment (13). One study was carried out to look at the accuracy of clinicians reporting chemotherapy AEs by comparing the EORTC Core 30 quality-of-life questionnaire (C30) with physicians’ reporting of the same symptoms in patients receiving chemotherapy for metastatic prostate cancer (14). There was only 32% agreement on new or worsened symptoms between patients and physicians: even in a tightly controlled clinical trial, physician reporting was neither sensitive nor specific in detecting common chemotherapy AEs. However, one limitation of this study was the use of C30 because this is a quality-of-life questionnaire allowing examination of only eight AEs rather than a comprehensive AE scoring system. The findings suggest that patient self-reporting should complement rather than replace physician assessments. Basch et al. (8) reported work using a questionnaire with 11 common CTCAE symptoms, which was given to 400 patients with lung and prostate cancer undergoing chemotherapy and also to the physicians or nurses involved in their care. The results of the patient and physician/nurse responses were compared. For most symptoms agreement was high between patients and physicians, with discrepancies differing by only one grade. Patients tended to score a greater severity of symptoms than did clinicians. Agreement was higher for observable symptoms, such as vomiting and diarrhea, and less for subjective symptoms, such as fatigue and shortness of breath. In this study the differences between patients and physicians would have rarely altered treatment decisions. The investigators stated that their strategy should be studied in a less urban, less educated, and less affluent population. The important issue of collecting AE data in multinational trials involving patients in developing countries where literacy may be low has not been addressed. There is a clear
1220
I. J. Radiation Oncology d Biology d Physics
need for more work translating toxicity scales into multiple languages and investigating the feasibility of their use in clinical trials. FUTURE INITIATIVES FOR IMPROVING AE REPORTING One way of addressing the need to improve the capture of AE data is to use prospectively completed questionnaires (8, 15, 16). A questionnaire approach has been used in Manchester, UK since 1998 to collect LENT SOMA data. The approach is associated with good compliance and low interscorer variability (16). Patient-completed questionnaires can be used to obtain detailed AE data in a standardized and uniform way within a busy cancer center (17, 18). Electronic methods to facilitate AE data collection may promote more uniform data collection and reporting practices (1). It is a method that has been used in quality-of-life research and is well received by patients and associated with good reliability and completeness of data collection (19, 20). Basch et al. (21) used a web-based assessment using seven common symptoms from the CTCAE for 80 gynecologic cancers to report symptoms with chemotherapy. However, the majority of the patients held a college degree, and assessment of this approach is needed in the clinical trial setting that incorporates a wider socioeconomic range of the population. There is also a need for multilingual methods of data capture. An important aim of follow-up after treatment for cancer is to detect various events associated with disease recurrence or metastatic spread or severe treatment-related complications as early as possible. Each tumor type may show a specific pattern and timing of these events related to different prognostic factors. A working group of the European Society for Therapeutic Radiology and Oncology was funded by the European Union for a project—Recording providing Education, and Ameliorating the Consequences of Treatment (REACT)—and carried out a study to propose a way of defining an optimal timing schedule for follow-up after treatment, based on the analysis of failure patterns determined from follow-up data from prospective clinical trials (22). Questions that need addressing in future studies were formulated by the IAEA meeting participants as follows: 1. Can a CTCAE questionnaire approach be used in a multicenter, multinational study? 2. Will CTCAE questionnaires improve the collection of normal tissue toxicity data compared with toxicity tables? 3. Is the method of data collection important (manual compared with electronic or patient compared with doctor or nurse)? 4. Does electronic data capture at the point of care improve the efficiency of collecting data compared with completing paper proformas? 5. Is electronic data capture seen as an advantage over conventional data acquisition, and is it feasible in a multicentered study? 6. What is the optimum frequency of patient assessments?
Volume 69, Number 4, 2007
OPPORTUNITY FOR EVALUATING POTENTIAL IMPROVEMENT IN AE REPORTING IN AN IAEA TRIAL The IAEA is currently supporting a coordinated research project on a clinical/radiobiology study of virally induced cancers’ response to radiotherapy. The trial in patients with locally advanced cervical cancer involves six countries (Brazil, Peru, India, South Africa, Pakistan, and Macedonia) and has four arms testing two different fractionation schedules for high-dose-rate brachytherapy (7 Gy 4 and 9 Gy 2) given with external beam radiotherapy with and without concurrent weekly cisplatin. The Radiation Therapy Oncology Group Early and Late Toxicity Scales and the CTCAE are being used to report treatment toxicity. The study began in February 2006, will run for 4 to 5 years, and has a planned recruitment of more than 600 patients with approximately 150 patients in each arm. A new component (improvement in AE data capture) was developed during the Denver meeting to evaluate methods for improving AE data collection. This addition will explore the feasibility of using questionnaires for CTCAE data collection. The questionnaires can be viewed on the Christie Hospital website: http://www.christie.nhs.uk/pro/ depts/clinical_oncology/lent_soma/iaea_crp_cx_hdr.aspx. Because literacy is a problem for many patients in the participating centers, the questionnaires would not be selfadministered. The questionnaires would be used to structure the physician’s interview with patients to aid the physician in recording patients’ symptoms and treatment effects in a reproducible and reliable way. Therefore, these would not be classified as patient-reported outcome forms and would not have to undergo further testing that would be required for a patient-reported outcome. These questionnaires have been used in Manchester, UK with large numbers of patients (nearly 1200 patients with cancers at different sites to date) in face-to-face interviews, in which the questionnaire structures the interview, and these are completed as patients are recruited into local studies. Language translation of the questionnaires will involve extensive work to test meaning and acceptability and translation back into English—a process used by the EORTC in the translation of their quality-of-life questionnaires (23). The feasibility of the proposed addition will be assessed in each center. It needs to be established that a structured interview approach improves compliance and the quality of AE data collected compared with passive data collection. Qualitative data, such as the time taken for structured interviews, can be assessed along with convenience of use. SUMMARY The adoption of the National Cancer Institute CTCAE system should facilitate the reporting of AE comparisons between trials and centers and promote a more complete recognition and reporting of AEs after radiation therapy (24). It is increasingly recognized that both physician- and
Improving the capture of AE data in clinical trials d S. E. DAVIDSON et al.
patient-recorded symptoms should be recorded and that a questionnaire approach facilitates the collection of AE data. The ways in which AE data are recorded within the
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clinic need to be addressed and is to be the subject of a future coordinated research project to establish the most reliable method of data collection.
REFERENCES 1. Chen Y, Trotti A, Coleman CN, et al. Adverse event reporting and developments in radiation biology after normal tissue injury: International Atomic Energy Agency consultation. Int J Radiat Oncol Biol Phys 2006;64:1442–1451. 2. Bentzen SM. Towards evidence based radiation oncology: Improving the design, analysis, and reporting of clinical outcome studies in radiotherapy. Radiother Oncol 1998;46:5–18. 3. National Cancer Institute. CTC v2.0 and common terminology criteria for adverse events v3.0 (CTCAE). Available at: http:// ctep.cancer.gov/reporting/ctc.html. Accessed May 6, 2007. 4. Denis F, Garaud P, Bardet E, et al. Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. J Clin Oncol 2004;22:69–76. 5. Gwede CK, Johnson DJ, Daniels SS, et al. Assessment of toxicity in cooperative oncology clinical trials: The long and short of it. J Oncol Manag 2002;11:15–21. 6. Scharf O, Colevas AD. Adverse event reporting in publications compared with sponsor database for cancer clinical trials. J Clin Oncol 2006;24:3933–3938. 7. Denton AS, Bond SJ, Matthews S, et al. National audit of the management and outcome of carcinoma of the cervix treated with radiotherapy in 1993. Clin Oncol (R Coll Radiol) 2000; 12:347–353. 8. Basch E, Iasonos A, McDonough T, et al. Patient versus clinician symptom reporting using the National Cancer Institute Common Terminology Criteria for Adverse Events: Results of a questionnaire-based study. Lancet Oncol 2006;7:903–909. 9. Livsey JE, Routledge J, Burns M, et al. Scoring of treatmentrelated late effects in prostate cancer. Radiother Oncol 2002; 65:109–121. 10. Olopade FA, Norman A, Blake P, et al. A modified Inflammatory Bowel Disease questionnaire and the Vaizey Incontinence questionnaire are simple ways to identify patients with significant gastrointestinal symptoms after pelvic radiotherapy. Br J Cancer 2005;92:1663–1670. 11. Jensen K, Bonde Jensen A, Grau C. The relationship between observer-based toxicity scoring and patient assessed symptom severity after treatment for head and neck cancer. A correlative cross sectional study of the DAHANCA toxicity scoring system and the EORTC quality of life questionnaires. Radiother Oncol 2006;78:298–305. 12. Stephens RJ, Hopwood P, Girling DJ, et al. Randomized trials with quality of life endpoints: Are doctors’ ratings of patients’
13. 14.
15.
16.
17.
18. 19.
20. 21. 22.
23.
24.
physical symptoms interchangeable with patients’ self-ratings? Qual Life Res 1997;6:225–236. Baumann M, Bentzen SM. Clinical manifestations of normaltissue damage. In: Steel GG, editor. Basic clinical radiobiology. London: Arnold; 2002. p. 105–119. Fromme EK, Eilers KM, Mori M, et al. How accurate is clinician reporting of chemotherapy adverse effects? A comparison with patient-reported symptoms from the Quality-of-Life Questionnaire C30. J Clin Oncol 2004;22:3485–3490. Davidson SE, Burns M, Routledge J, et al. Short report: A morbidity scoring system for Clinical Oncology practice: Questionnaires produced from the LENT SOMA scoring system. Clin Oncol (R Coll Radiol) 2002;14:68–69. Routledge JA, Burns MP, Swindell R, et al. Evaluation of the LENT-SOMA scales for the prospective assessment of treatment morbidity in cervical carcinoma. Int J Radiat Oncol Biol Phys 2003;56:502–510. Davidson SE, Burns MP, Routledge JA, et al. Assessment of morbidity in carcinoma of the cervix: A comparison of the LENT SOMA scales and the Franco-Italian glossary. Radiother Oncol 2003;69:195–200. Chassagne D, Sismondi P, Horiot JC, et al. A glossary for reporting complications of treatment in gynecological cancers. Radiother Oncol 1993;26:195–202. Drummond HE, Ghosh S, Ferguson A, et al. Electronic quality of life questionnaires: A comparison of pen-based electronic questionnaires with conventional paper in a gastrointestinal study. Qual Life Res 1995;4:21–26. Velikova G, Wright EP, Smith AB, et al. Automated collection of quality-of-life data: A comparison of paper and computer touch-screen questionnaires. J Clin Oncol 1999;17:998–1007. Basch E, Artz D, Dulko D, et al. Patient online self-reporting of toxicity symptoms during chemotherapy. J Clin Oncol 2005;23: 3552–3561. Ataman OU, Barrett A, Filleron T, et al. Optimization of followup timing from study of patterns of first failure after primary treatment. An example from patients with NSCLC: A study of the REACT working group of ESTRO. Radiother Oncol 2006;78:95–100. Cull A, Sprangers M, Bjordal K, et al. EORTC quality of life study group translation procedure. In. Brussels; 1998. pp. 1–31. Available at: www/eortc.be/home/gol/manuals. Accessed May 6, 2007. Trotti A, Colevas AD, Setser A, et al. CTCAE v3.0: Development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 2003;13:176–181.