Download Patient-Reported Outcomes and the Evolution of Adverse Event

VOLUME 25 䡠 NUMBER 32 䡠 NOVEMBER 10 2007
JOURNAL OF CLINICAL ONCOLOGY
R E V I E W
A R T I C L E
Patient-Reported Outcomes and the Evolution of Adverse
Event Reporting in Oncology
Andy Trotti, A. Dimitrios Colevas, Ann Setser, and Ethan Basch
From the Division of Radiation Oncology, H. Lee Moffitt Cancer Center at
University of South Florida, Tampa, FL;
Division of Oncology, Stanford University, Stanford, CA; Cancer Therapy Evaluation Program, National Cancer
Institute, Bethesda, MD; and Health
Outcomes Research Group, Memorial
Sloan-Kettering Cancer Center, New
York, NY.
Submitted May 7, 2007; accepted
August 21, 2007.
Supported in part by the Radiation Therapy Oncology Group.
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this
article.
Address reprint requests to Andy Trotti,
MD, H. Lee Moffitt Cancer Center &
Research Institute, 12902 Magnolia Dr,
Mod 9 RT, Tampa, FL 33612-9416;
e-mail: [email protected].
© 2007 by American Society of Clinical
Oncology
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Adverse event (AE) reporting in oncology has evolved from informal descriptions to a highly
systematized process. The Common Terminology Criteria for Adverse Events (CTCAE) is the
predominant system for describing the severity of AEs commonly encountered in oncology clinical
trials. CTCAE clinical descriptors have been developed empirically during more than 30 years of
use. The method of data collection is clinician based. Limitations of the CTC system include
potential for incomplete reporting and limited guidance on data analysis and presentation
methods. The Medical Dictionary for Regulatory Activities (MedDRA) is a comprehensive medical
terminology system used for regulatory reporting and drug labeling. MedDRA does not provide for
severity ranking of AEs. CTC-based data presentations are the primary method of AE data
reporting used in scientific journals and oncology meetings. Patient-reported outcome instruments
(PROs) cover the subjective domain of AEs. Exploratory work suggests PROs can be used with a
high degree of patient engagement and compliance. Additional studies are needed to determine
how PROs can be used to complement current AE reporting systems. Potential models for
integrating PROs into AE reporting are described in this review. AE reporting methods will
continue to evolve in response to changing therapies and growing interest in measuring the impact
of cancer treatment on health status. Although integration of PROs into AE reporting may
ultimately improve the comprehensiveness and quality of collected data, it may also increase the
administrative burden and cost of conducting trials. Therefore, care must be used when
developing health outcomes and safety data collection plans.
J Clin Oncol 25:5121-5127. © 2007 by American Society of Clinical Oncology
0732-183X/07/2532-5121/$20.00
DOI: 10.1200/JCO.2007.12.4784
R
INTRODUCTION
Adverse event (AE) reporting is a critical component
in the conduct and evaluation of clinical trials.
Methods of AE reporting have evolved with the
complexity of cancer treatments. Reporting the subjective manifestations of AEs has historically involved clinician elicitation, interpretation, and
rating of signs and symptoms. There is growing interest in the use of patient-reported outcome tools
(PROs) to collect symptom measures directly from
the patient to improve the accuracy and efficiency of
subjective AE data collection. In this review, we describe the strengths and limitations of the current AE
reporting process, and discuss potential models for
integrating PROs into AE reporting in oncology.
EVOLUTION OF AE REPORTING IN ONCOLOGY
The methods for reporting of AEs in oncology have
evolved in response to new treatments and modalities. In the 1950s to 1970s, retrospective studies provided limited descriptions of adverse outcomes, and
severity ranking was rare.1 The routine pursuit of
clinical trials in the 1980s provided the opportunity
for formal toxicity documentation and generation
of toxicity profiles or safety reporting. Clinical trial
AE reporting is now a multistep process that begins
with a standardized terminology and grading system and ends in publication of toxicity profiles.2
Reporting has grown more structured in recent
years, including regulations for serious adverse
event (SAE) reporting and adoption of more uniform terminology.
The National Cancer Institute (NCI) Common Terminology Criteria (CTC) system is a
longstanding empirically developed dictionary,
or lexicon, designed for use in clinical trials to
aid clinicians in the detection and documentation of an array of AEs commonly encountered
in oncology.3,4 The CTC is maintained by the
NCI Cancer Therapy Evaluation Program. It is
a minimum requirement for reporting in NCIsponsored trials, and has also been widely
adopted by the pharmaceutical industry. It is the
de facto standard for reporting AEs in the oncology clinical trial literature. CTC data may be
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supplemented with other measures of adverse effects depending on
the nature of the trial.
Development of the CTC was driven by the need to document
severity and to narrow descriptions into a reasonably sized and common lexicon. Specific terms and severity descriptors were developed
by expert panel consensus process. The terms have expanded and
evolved during more than 30 years in response to the introduction of
new agents and modalities. Limitations include lack of a formal validation process, potential for under-reporting (especially for the subjective elements), and variations in end-results data presentation.5,6
Although the CTC was designed exclusively for use in clinical trials, it
is often used in routine care to guide treatment decisions including
drug dosing and supportive care interventions.
Initially called Common Toxicity Criteria (1984 to 2002), in 2003
the CTC was revised substantially and relabeled as the Common
Terminology Criteria for Adverse Events (CTCAE). The CTCAE7
includes more than 1,000 terms with improved anatomic site specificity and expanded criteria for surgical effects. The CTCAE represents the first comprehensive grading system for reporting both
acute and late effects in oncology, and was the first attempt to cover
AEs associated with all therapeutic interventions, including radiation and surgery.4
The choice of specific terms and descriptors in the CTCAE was
driven by the notion that terminology should be immediately comprehensible to those with a basic fund of medical knowledge. The
severity descriptors should correspond to common-sense notions of
mild, moderate, severe, or life-threatening events. Significant attention was paid to ensuring consistency in grading between similar
pathophysiologic processes. For example, grading descriptors for cerebrovascular and cardiac ischemia, although not identical, were intended to capture similar indicators of severity including permanent
and transient events. Similar criteria were applied to gastric versus
urinary bladder perforation, for example. However, there was no
attempt to ensure severity consistency across AEs as disparate as aminotransferase and mood alteration, for example. The severity descriptors for AEs in the metabolic/laboratory category were chosen
arbitrarily and without any intent for severity cross-comparison. For
example, a bilirubin level of greater than 10 times the upper limit of
normal will usually have more patient-discernable consequences than
an isolated aminotransferase value exceeding 20 times the upper limit
of normal, but the CTCAE assigns these abnormalities the same status
on the severity scale.
DOMAINS OF THE ADVERSE EFFECTS OF
CANCER TREATMENT
As described by Bentzen (Fig 1), the universe of adverse effects of
cancer treatment can be considered in four general domains that
contain some overlap.8 Data collection using the NCI-CTCAE system
involves three of these domains (excluding health-related quality of
life [HRQOL]/PRO tools). Movement up the y-axis involves more
specific and quantifiable end points and tests. As one moves to the
right on the y-axis, end points are more directly recognized and reported by patients. Clinician-graded symptoms are reported by patients and translated by clinicians or research staff into medical terms
and grades. Symptoms and subjective elements can also be reported
directly by the patient using HRQOL and PRO tools. Objective ele5122
Increasing Specificity
Trotti et al
NCI-common
toxicity (terminology)
criteria
Analytic
(lab/
imaging)
g))
Objective
Object
tive
(exam)
(e
exam)
Clinician-graded
Clini
symptoms
Quality of life and
patient reported
outcome tools
Increasing Patient Recognition
Fig 1. Adverse effects domains. NCI, National Cancer Institute. Adapted with
permission.8
ments are recognized and graded by clinicians using specific medical
terms and are often noted on physical examination or part of a constellation of findings or syndromes. Analytic elements are laboratory,
imaging, or other technology-based tests designed to identify and/or
quantify abnormalities that may not be appreciated using other
means. This model addresses traditional end points and methods used
in clinical trials, and in some retrospective chart reviews. Grading
descriptors for some CTCAE terms contain a mix of subjective and
objective elements. Studies regulated by the US Food and Drug Administration use US Food and Drug Administration–specific guidance and may use other standardized medical terminology systems
(see next section).
Traditional data collection methods for the symptom/subjective
elements typically involve unstructured patient interviews. These
methods may differ significantly between clinicians and specific studies. Final data capture involves clinician interpretation of patient reporting and determination of the most appropriate term and severity
grade. Thus, the subjective domain may be associated with poor interrater reliability regarding grading consistency and completeness of
capture. Symptom research has documented systematic underreporting of symptoms (in number, severity, and time of onset/resolution) by clinicians compared with patients.9,10 Thus, an
alternative approach is to collect subjective elements directly from
the patient using specific HRQOL surveys or PRO tools (discussed
later in this review).
CONTRASTING THE NCI AND US FOOD AND DRUG
ADMINISTRATION SAFETY REPORTING SYSTEMS
The two predominant AE vocabularies are the NCI CTCAE and the
Medical Dictionary for Regulatory Activities (MedDRA system).11
MedDRA is a medical terminology system developed by the International Conference on Harmonisation and is owned by the International Federation of Pharmaceutical Manufacturers and Associations
acting as trustee for the International Conference on Harmonisation
steering committee. The MedDRA system contains a large number
(⬎ 65,000) of coding terms covering a wide range of clinical information, including AEs, for all medical disciplines and covering multiple
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PROs and the CTC
medical product areas. MedDRA does not involve severity ranking of
AEs. The NCI system is a more limited dictionary of terms (⬃1,000)
commonly encountered in oncology and emphasizes severity grading
of each event, subdividing most terms into four basic grades (excluding grade zero [no event] and grade 5 [death] in some terms). CTCAE
terms (but not grades) are mapped (translated) to MedDRA.12 Although MedDRA terminology is used for regulatory reporting purposes, CTCAE-based data presentations are the primary method of
AE data reporting used in scientific medical journals and oncology
medical meetings.
The US Food and Drug Administration and NCI have different
charges: legal approval of drug claims versus support of clinical and
basic research. The US Food and Drug Administration has largely
dealt with single-agent drug approval. NCI-sponsored studies by cancer centers and cooperative groups are often concerned with evaluation of complex multimodality and multiagent treatment programs.
As a result of increasing collaborations between industry and the NCI,
there is growing overlap and simultaneous use of both dictionaries.
This also increases data collection burdens and the cost of trial conduct. Both organizations require SAE reporting as a safety reporting
process distinct from routine AE reporting. The NCI also requires
expedited reporting of unexpected and selected high-grade events
under the Adverse Event Expedited Reporting System.13
The US Food and Drug Administration provides specific guidance regarding AE data collection, data retrieval and organization, risk
assessment, data analysis, presentation for new drug applications, and
labeling. The US Food and Drug Administration accepts MedDRA
terminology as an industry standard, but does not require it in submissions or reporting. In practice, MedDRA is the terminology used
for regulatory reporting in the United States. The CTCAE is designed
as a clinical research tool. The NCI guidance focuses on terminology
applications, but provides no specific guidance on data analysis or
end-results reporting.
INCREASING COMPLEXITY OF MULTIAGENT,
MULTIMODALITY TRIALS
Most cancer agents used today were approved by the US Food and
Drug Administration on the basis of single-agent activity. Relative to
noncancer therapeutics, toxicity profiles of single agents in oncology
reveal high rates of multiple AE end points. Moreover, many cancers
are now treated with multiagent and multimodality therapies, generating even larger numbers of events.14,15 Traditional data collection
and reporting methods are strained by the volume of AE data generated by such trials. Data regarding dozens of AE end points, each
carrying four grades, quickly become difficult to summarize, interpret,
and publish.
Traditional methods of AE data summary and presentation formats were borrowed from nononcology summary methods. These
methods do not reflect the reality of multiple coincident and sequential events that often occur in oncology. The time dimensions of
events, treatment cycles, and chronic effects are customarily collapsed
into a single data point using variable forms of a worst-grade approach. Systematic under-reporting and bias using standard summary
methods has been described, potentially leading to treatment regimens appearing less toxic than they actually are.16 There are no standard methods to summarize the overall burden generated by complex
multimodality concurrent or sequential courses of treatment. Late
effects influencing the HRQOL of cancer survivors are believed to be
widely under-reported. The limitations of traditional methods to
characterize fully the toxicity burden of cancer treatments have in part
stimulated the HRQOL and PRO initiatives.
HAVE THE CTCAE CRITERIA BEEN VALIDATED?
Often the NCI is asked whether the CTCAE in general, or if specific AE
terms/grading language, have been validated. Unlike HRQOL or PRO
tools, CTCAE have not been through a formal development or validation process. However, some content validity is conferred through 30
years of widespread use and iterative improvements. In most cases,
questions regarding validation concern collection, presentation, or
interpretation of aggregate CTCAE data, rather than the CTCAE lexicon itself. CTCAE items have not been evaluated for inter-rater reliability or test-retest metrics.
Is there adequate consistency and accuracy of CTCAE data? Audits of clinical trials sponsored by NCI demonstrate that when events
from the analytic domain are recorded and supported by primary
documentation, such as a laboratory report for a metabolic/laboratory
AE, or computerized tomogram for a pulmonary embolus, the AE and
severity grade are reported accurately in the vast majority of cases.
However, in the cases of more subjective AEs, it is impossible by
audit to determine if the collection of the severity of pain, for example,
was accurate.
The question of accuracy of documentation of highly subjective
AEs such as pain is hampered to a certain extent by the lack of a gold
standard of measurement. Before one can ask whether the CTCAE is
useful as a tool for accurate capture of subjective AEs, one must ask
whose truth is to be used when making that assessment. For example,
is the physician’s report of a patient’s pain necessarily less accurate
than a patient’s self-report? If so, under what circumstances is the
patient’s report most accurate—when filling out a written questionnaire in the waiting area, when keeping a diary at home, or when
speaking to the care provider? For example, Basch et al17 have found
that for many AEs there is a high level of agreement between physician
and patient assessment. However, for highly subjective AEs such as
fatigue and dyspnea, the agreement is less strong and clinicians tend to
assign a lower severity to these than does the patient. Conversely, an
evaluation of symptoms in patients with rheumatoid arthritis treated
during a randomized controlled trial suggests that patient-reported
symptom improvement was superior to clinician-reported improvement.17,18 In fact, patients and clinicians may hold different concepts
for subjective domains that have different or complementary applications in clinical care and research. Therefore, in such cases one can
only address consistency and completeness of AE capture, rather
than accuracy.
However, even in the case of high-fidelity collection of objective
AEs such as laboratory values, final reporting of these values can be
incomplete and inconsistent. For example, a study comparing data
submitted to a regulatory sponsor versus data submitted for publication demonstrated inconsistencies in approximately 25% of all highgrade AEs.6 We know of no similar comparison using verbatim versus
MedDRA-coded AE data or PRO-type data.
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Trotti et al
PROs AND AE REPORTING
Use of PROs As Study-Specific End Point Tools
In the early development of HRQOL tools, data were collected
predominantly via staff-administered surveys. After a period of questionnaire development and validation, patient self-reporting became
the preferred method.19-25 PROs evolved from HRQOL tools to become more disease-specific and symptom oriented. PROs recently
have become the favored method for collecting symptom end point
data in trials to assess specific treatment benefits.19,26-29 These patientreported end points have now been used as the basis for drug labeling
claims for a limited number of oncology drugs including mitoxantrone (pain) and more recently eculizumab (HRQOL).30
The use of PRO end points in clinical trials is an area of increasing
interest to regulatory agencies.22,31 To clarify the role of patientreported data in the drug approval process and to refine standards for
PRO instrument development, in February 2006 the US Food and
Drug Administration issued a draft guidance on PRO Measures.32 The
NCI responded to the guidance by sponsoring the NCI Patient Reported Outcomes Assessment in Cancer Trials conference in September 2006 (described in this issue of the Journal of Clinical Oncology), at
which the position was articulated that for subjective domains the
patient’s own account should be considered the gold standard.22,32-35
Use of PROs in Routine AE Monitoring in
Clinical Trials
Unlike HRQOL and formal symptom end point assessment for
which PROs are considered standard, AE data collection is performed
exclusively by clinical staff during cancer treatment trials.2,4 Staff
members are required not only to aggregate analytic AE data (ie,
laboratory values) and objective AEs (ie, physical examination findings), but also subjective patient experiential information (ie, symptoms). In the latter case, the process of data collection is complex, with
multiple steps of information transfer and vulnerability to errors of
misinterpretation or omission (Fig 2).2,5,32,36 Alternatively, shifting to
a model in which patient-reporting is the primary mechanism for
monitoring subjective AEs may improve the quality and completeness
Patient
experiences
symptom
Clinician
interviews
patient
Standard approach:
clinician-based symptom reporting
Clinician
interprets
symptom
Clinician
writes in chart
Chart
representation
of symptom
CRA abstracts
chart
CRA
interpretation
of symptom
Data entry
by CRA
Research
database
Alternative approach:
direct patient reported outcomes (PROs)
Fig 2. Flow of symptom information in cancer treatment trials. CRA, clinical
research assistant. Reprinted with permission.36
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of collected data, provide a more comprehensive picture of the patient
experience, and improve the efficiency of clinical operations.37-39
Initial research suggests that the majority of cancer patients are
willing and able to self-report symptom AEs at clinic visits for up to a
year (including those with heavy symptom burdens), and that clinicians will accept this information as the basis for management decisions and regulatory documentation.32,36 Comparisons of patient
versus clinician CTCAE symptom reporting have found high levels of
agreement for the majority of items, with most cases of disagreement
by one point, and only rare cases in which a discrepancy would alter
clinical management or regulatory reporting.17 An ongoing study in
the NCI cooperative group, Cancer and Leukemia Group B (protocol
70501), is evaluating the feasibility and potential benefits of this approach in the setting of a multicenter treatment trial, with results
expected in late 2008.
Use of PROs in Routine Cancer Care
As with clinical trials, patient self-reporting of symptoms has
been suggested to enhance patient-clinician communication and assist in the early detection of toxicities in the routine care setting. Initial
research has demonstrated the feasibility of electronically collecting
symptoms from patients during chemotherapy and delivering printouts of this information to clinicians at appointments.40 However, at
present, patient self-reporting is not commonly used to monitor patient status during routine cancer care.
INTEGRATING PROs INTO THE CTCAE
PRO-Related CTCAE Items
The current version of the CTCAE consists of slightly more than
1,000 individual terms. For purposes of PRO tool application, these
terms can be divided into four general categories: analytic technologybased measurements (such as laboratory tests or imaging results);
objective items that rely on clinical expertise and judgment (such as
physical examination findings); subjective items that reflect patient
experience and can therefore only truly be known by the patient
(symptoms); and mixed subjective/objective items that combine
patient-reporting and clinician interpretation (such as drug reactions
experienced by patients but requiring clinician confirmation). The
latter two categories are potentially amenable to a patient-reporting
model, including the approximately 127 (12%) subjective and 128
(12%) mixed subjective/objective items in the current version of the
CTCAE (version 3.0). Thus, PROs potentially could play a role in 24%
of all AE terms. However, these terms may represent a larger portion of
all events collected, depending on the nature of the trial.
Conversion of CTCAE Items for Patient Reporting
The CTCAE was originally designed for clinician reporting, and
the language used in question items therefore includes medical jargon
and technical terminology. To provide versions of CTCAE items amenable to patient self-reporting, a layperson-friendly language adaptation of selected CTCAE subjective items (from CTCAE version 3.0)
was created using methods described in the US Food and Drug Administration guidance for ensuring content validity of PRO instruments, including patient focus groups and cognitive debriefing
sessions.41 A goal of this patient language adaptation was to preserve
the concepts represented in each response option compared with
those of the original CTCAE (Table 1). Although a high level of patient
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PROs and the CTC
Table 1. Example Adaptation of CTCAE Item Into Patient Language
Grade
NCI Description
Original Language
Patient Adaptation
1
Mild
Mild pain not interfering with function
2
Moderate
Moderate pain; pain or analgesics interfering with
function, but not interfering with ADL
3
Severe
Severe pain; pain or analgesics severely
interfering with ADL
4
Disabling
Disabling
I have had mild pain, but it does not interfere
with my normal functioning
I have had moderate pain, and my pain or my
use of pain medications interferes with my
normal functioning. But I am still able to
carry out my daily activities.
I have had severe pain, and my pain or my
use of pain medications severely interferes
with my normal daily activities
My pain has been disabling
Abbreviations: CTCAE, Common Terminology Criteria for Adverse Events; NCI, National Cancer Institute; ADL, activities of daily living.
Adapted with permission.17
acceptance and comprehension of content was observed, it was
found that reading and responding to items can be time consuming
for patients, taking an average of 4.5 minutes for 15 items, leading
to respondent questionnaire fatigue. CTCAE items include long
descriptions for each grade criterion in the original design to ensure precision, which increases the risk of incomplete questionnaires and missing data. Therefore, briefer symptom items (for
example, including only simple ordinal or visual analog scales)
ultimately may be preferable for optimizing patient response rates
(eg, self-rating of worst pain during the last 24 hours, using a
10-point scale with zero representing “no pain” and 10 representing the “worst pain imaginable”). Development and evaluations of
such briefer CTCAE PRO symptom items (and studies mapping
responses to these back to the CTCAE) are needed.
Clinician acceptance of patient toxicity symptom self-reporting
has been high, with most surveyed physicians and nurses believing
that patient self-reports are an accurate reflection of clinical status;
expressing willingness to base clinical decisions on these data; and
agreeing that PROs should be collected routinely to monitor patients
receiving chemotherapy.32,36 In an ongoing study at Memorial SloanKettering Cancer Center (New York, NY), it is being assessed whether
clinicians will alter their own symptom toxicity reporting when exposed to patient self-reports.
Potential Models
In the clinical trial setting, a potential model to integrate PROs
could include a symptom AE checklist provided to enrollees at clinic
visits (paper or electronic) with selected items drawn from the subjective and mixed subjective/objective CTCAE categories. Specific items
could be chosen to include a core set of symptoms relevant to cancer
patients receiving toxic therapies, as well as additional disease-specific
and treatment-specific items. A free-text or drop-down option could
be included to allow for patients to add other symptoms relevant to
them individually. In this paradigm, subjective items would be directly
reported by patients via toxicity reports unfiltered by clinicians,
whereas items in the mixed category would undergo clinician interpretation before reporting. Any free text items added by patients
would likely require clinician interpretation and severity grading, especially if used for regulatory reporting.
This model conceivably could be extended to the routine care
setting as well, in which real-time review of this information could be
required by clinicians to prompt discussion with patients or inform
management decisions. Furthermore, electronic home patient-
reporting could be integrated to monitor patient status between visits,
not only at the time of office appointments.
BALANCING DATA COLLECTION AND REPORTING BURDENS
The current model of AE reporting in oncology clinical trials allows for
clinician discretion in choosing which items from the CTCAE merit
reporting at any given patient visit (although some items may be
required in protocols based on expected drug-related AEs). In the
absence of specific preplanned safety questions, toxicity reporting is
largely broad and passive. Large numbers of events of all grades are
collected. Using standard summary methods, most low-grade events
are disregarded in the reporting of final results, suggesting some inefficiency in data collection efforts. Safety reporting has many stakeholders, including patients, institutional review boards, sponsors,
regulators, administrators, investigators, and industry. Multiple reporting requirements have increased data collection and reporting
burdens. The introduction of HRQOL and PRO tools may add to the
burden of data collection and reporting. Considering finite resources,
determining the optimal mix of data collection and reporting requirements is challenging. One cooperative group has initiated policies
proactively to actively manage the deluge of AE data in order to limit
data collection and reporting burdens.42
NEED FOR ADDITIONAL AE REPORTING GUIDANCE
The inherent complexity of AE outcomes in oncology makes the
development of comprehensive reporting standards extremely challenging. Currently, NCI does not have specific guidance on the methods of AE data collection, data organization, analysis, or end-results
reporting. This approach has advantages and disadvantages. Wide
variations in reporting methods have arisen, making it difficult to
compare safety outcomes among trials or cooperative groups.43 Conversely, overly specific guidance might constrain the flexibility needed
to adapt reporting to study and agent-specific issues as they arise.
Nonetheless, some additional reporting guidance would likely enhance the interpretability and comparability of AE end results.
The development and enforcement of reporting standards could
also consume considerable time and resources. Whether such guidance should come from regulators, study sponsors, administrative
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centers, or special interest groups is an open question. One recent
report suggests this should be done at the level of journal editors, using
the CONSORT model.6,44
The use of more uniform approaches focusing on the most important safety issues in the context of a given disease and given protocol may generate more reliable and useful safety data. This need is
brought into focus by the development of guidance for PROs, where
the use of prespecified data collection tools, preplanned analyses,
and formal analytic methods is expected. This model may also be
useful in the development of more specific AE data analysis and
reporting plans.
PILOT STUDY TO EVALUATE PROTOCOL-SPECIFIC SAFETY
DATA COLLECTION IN HEAD AND NECK TRIALS
In an effort to improve the consistency and completeness of AE reporting in head and neck cancer, the Radiation Therapy Oncology
Group has recently begun piloting new data collection methods using
prespecified lists of AEs to guide patient screening (Radiation Therapy
Oncology Group trials 0522 and 0615). Core acute and late head and
neck AE end points are captured and graded by clinical staff (eg,
dysphagia, mucositis, skin; chronic dysphagia, fibrosis, xerostomia,
bone necrosis) in addition to drug specific issues (epidermal growth
factor receptor–induced rash from cetuximab; bleeding from bevacizumab). Data collection of prespecified safety end points are required
for each report period to enhance the completeness of critical AE data
capture. Whether this approach will improve the completeness or
interpretability of AE data will be evaluated and reported in the future.
FUTURE DIRECTIONS AND SUMMARY
AE reporting in oncology is inherently complex. No other medical
specialty uses a specialized grading system to document severity. The
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Assessment of toxicity in cooperative oncology clinical trials: The long and short of it. J Oncol Manag
11:15-21, 2002
3. Trotti A, Byhardt R, Stetz J, et al: Common
toxicity criteria: Version 2.0: An improved reference
for grading the acute effects of cancer treatment—
Impact on radiotherapy. Int J Radiat Oncol Biol Phys
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4. Trotti A, Colevas AD, Setser A, et al: CTCAE
v3.0: Development of a comprehensive grading
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Semin Radiat Oncol 13:176-181, 2003
5. Gwede C, Saranga S, Lee J, et al: Variations in
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6. Scharf O, Colevas AD: Adverse event reporting in publications compared with sponsor database
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high level of symptom burden associated with modern cancer treatments suggests a need to capture symptoms more completely and
directly from the patient. Reporting methods should and will evolve,
in response to the needs of end users: regulators, sponsors, clinicians, and patients. How patients perceive and cope with the adverse heath effects of treatment is of interest to all stakeholders.
However, each group has a different focus and uses different end
points and methods. Use of multiple methods also increases data
collection burdens and cost.
Consideration of the use of PROs in this context provides an
opportunity to re-examine the goals, methods, and limitations of
adverse health outcome reporting in oncology. It is not feasible to
capture and report comprehensively all the details of all AEs generated
in all cancer treatments. Reporting of AEs is highly dependent on the
methods and rigor used to elicit toxicity information. The use of more
uniform methods focusing on specific safety issues in the context of a
given disease and stage should improve the utility of safety information. Direct patient reporting of symptoms has the potential to improve the completeness and fidelity of the subjective domain of the
CTCAE, or may serve as a source of stand-alone complementary
toxicity end points focusing on study-specific questions.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
The author(s) indicated no potential conflicts of interest.
AUTHOR CONTRIBUTIONS
Conception and design: Andy Trotti, Ethan Basch
Provision of study materials or patients: Ann Setser, Ethan Basch
Collection and assembly of data: Ann Setser, Ethan Basch
Data analysis and interpretation: Ann Setser, Ethan Basch
Manuscript writing: Andy Trotti, A. Dimitrios Colevas, Ann Setser,
Ethan Basch
Final approval of manuscript: Andy Trotti, A. Dimitrios Colevas
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