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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
Lessons Learned in the Assessment of Health-Related
Quality of Life: Selected Examples From the National
Cancer Institute of Canada Clinical Trials Group
Michael Brundage, David Osoba, Andrea Bezjak, Dongsheng Tu, Michael Palmer, and Joseph Pater
From the Departments of Oncology and
Community Health and Epidemiology,
and National Cancer Institute of Canada
Clinical Trials Group Queen’s Cancer
Research Institute, Queens University,
Kingston; Department of Radiation
Oncology, Princess Margaret Hospital;
University Health Network, University
of Toronto, Toronto, Ontario; and QOL
Consulting, West Vancouver, British
Columbia, Canada.
Submitted February 26, 2007; accepted
June 15, 2007.
Supported in part by the National
Cancer Institute of Canada.
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this
article.
Address reprint requests to Michael
Brundage, MD, MSc, Cancer Clinic of
Southeastern Ontario at Kingston
General Hospital, 25 King St W, Kingston, Ontario, Canada, K7L 5P9; e-mail:
[email protected].
© 2007 by American Society of Clinical
Oncology
0732-183X/07/2532-5078/$20.00
DOI: 10.1200/JCO.2007.11.4645
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In this article, we provide a brief historical review of the development of patient-reported outcome
measurement, analysis, and reporting in clinical trials of the National Cancer Institute of Canada
Clinical Trials Group (NCIC CTG). In doing so, we examine selected lessons learned in furthering
the quality of these data and their application to clinical practice. We conclude that sequential
institution of key policies within the NCIC CTG and the development of a collective philosophy
within the group has enabled the routine incorporation of health-related quality of life into clinical
trial protocols according to robust scientific principles; that collection of quality data is possible in
a variety of circumstances (although not universally so); that patient-reported data on subjective
experiences is likely to be more reliable and valid than conventional toxicity information; and
that simple analyses that report group trends as well as individual patient response rates are
preferred.
J Clin Oncol 25:5078-5081. © 2007 by American Society of Clinical Oncology
INTRODUCTION
The purpose of this article is to provide a Canadian
cooperative clinical trials group perspective on issues central to the application of patient-reported
outcome (PRO) assessment in cancer clinical trials.
The National Cancer Institute of Canada Clinical
Trials Group (NCIC CTG) is Canada’s largest cancer clinical trials group, and it is from the perspective
of the NCIC CTG that we provide experiences
and comments relevant to the Patient-Reported
Outcomes Assessment in Cancer Trials (PROACT)
themes.Inthesixsectionsofthisarticle,wefirstprovide
abriefhistoryanddescriptionoftheorganizationofthe
NCIC CTG and then provide historical and current
perspectives pertaining to the main PROACT themes
addressing the decision to collect PRO data, data collectionandplannedanalyses,fieldoperations,andfinal
data analysis and interpretation. Finally, we provide
examples of ancillary or complementary research undertaken by researchers at the NCIC CTG that has
contributed to the group’s current strategies for incorporating PROs in clinical trials.
QUALITY OF LIFE COMMITTEE OF THE
NCIC CTG
The NCIC CTG was established in 1980 as a clinical
research program of the National Cancer Institute of
Canada. The group’s mission is to develop and conduct clinical trials aimed at improving the treatment
and prevention of cancer with the ultimate goal of
reducing cancer morbidity and mortality from
this disease. Under direction of Dr J. Pater, the
NCIC CTG has grown into a cooperative effort of
more than 80 Canadian centers with full membership participation.
The Quality of Life (QOL) Committee has been
an NCIC CTG standing committee since 1987, born
out of recognition of the potential value of using
validated measures of multidimensional PROs in
clinical trials of cancer therapies. Subsequently,
health-related QOL (HRQOL) assessment in the
CTG has evolved, in keeping with developing
understanding within the discipline. The main mandate of the QOL Committee is to provide methodologic and practical support for collection of
HRQOL data in clinical trials conducted by NCIC
CTG. The QOL Committee presently consists of 17
members, who were invited as a result of their expertise in QOL research, with representation of the diversity of professional, cancer site–specific, and
geographic backgrounds of NCIC CTG investigators. The members include medical, radiation, and
surgical oncologists; social scientists; a senior biostatistician; a clinical research associate (CRA) representative; and representatives of the NCIC CTG
central office. In the sections that follow, we describe
further details of the committee’s activities.
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NCIC CTG Perspective
DECISION TO COLLECT PRO DATA
Members of the QOL Committee influence the decision to collect
PRO data in two related ways, as contributing members of the disease
site executive and as clinical trial QOL coordinators for specific trials.
In general, the decision to collect PRO data in a specific trial is made by
the trial principle investigator in consultation with the QOL Committee liaison for that disease site and with appropriate input from the trial
physician coordinator (a member of the CTG central office faculty).
Should there be consensus that the trial will include a QOL end point,
the QOL Committee member then becomes the QOL coordinator for
that study. By QOL end point, we refer to PRO assessments that have
been guided by the QOL Committee and that include measures provided by validated QOL instruments and, where relevant, trial-specific
symptom checklists. In addition, the committee helps oversee the use
of patient symptom diaries and measures of psychological distress (the
latter more recently in conjunction with a psychosocial behavioral
working group).
Over the evolution of our experience with QOL outcome measurement, the CTG has implemented several policies that have influenced this general decision process. For example, in keeping with our
belief that QOL is an integral end point in most randomized studies,
the CTG executive approved a policy in 1989 stating that “there should
be a statement about the anticipated impact on quality of life with
every proposed phase III clinical trial and whether or not quality of life
measures will be incorporated in the protocol.”1 As described in more
detail by Osoba et al,2 this policy was successful in bringing QOL to the
attention of all investigators considering clinical trial protocol proposals. Furthermore, implementation of the policy required investigators
to address potential adverse or beneficial consequences of the study
interventions that might be best assessed by direct reporting by patients and, thus, enhance the interpretation of the overall study results.
Consequently, 52 (92%) of 57 phase III trials led by the CTG since
1990 have included an HRQOL end point. A second example of
effective CTG policy implementation is the past strategic decision to
include a QOL Committee liaison member on the executive of each
disease site committee. As a result, QOL Committee members had the
opportunity to educate the clinician investigator leaders regarding
opportunities to incorporate QOL measurement into clinical trials
under development or under consideration by that site group. This
process resulted in QOL elements of study protocols being integrated
earlier into the trial development process than had been previously
experienced. These and other policies, taken together, have shaped
and defined expectations of clinical investigators and QOL Committee members alike, allowing the integration of HRQOL measurement
as a fundamental element of clinical trial development.
Several other strategic decisions have complemented the implementation of these policies. For example, the CTG focus on using the
European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 instrument3 and collaborating with its
developers to contribute to its validation4 has increased familiarity of
the CTG members with the instrument’s administration, analysis, and
interpretation. The organizational infrastructure of the group has
allowed for effective integration of the QOL Committee members
with the disease site groups, and the QOL Committee has had the
opportunity to set its own strategic plan in the context of the overall
CTG direction. This evolution of the CTG members’ general attitudes
toward the value of PRO data has facilitated ongoing decisions to use,
or not use, PRO approaches in a given clinical trial setting.
PLANNING DATA COLLECTION AND ANALYSIS
In an effort to develop standards for the incorporation of PROs across
clinical trials within the CTG, the QOL Committee provided guidelines for CTG investigators regarding the inclusion of HRQOL assessments.1 For example, the guidelines stated that the HRQOL
components should be a part of the main protocol and not an add-on
study. They further provided explicit instructions for the sections of
the protocol dealing with the study rationale, HRQOL research hypothesis, the clinical objectives of HRQOL assessment, and research
elements such as sample size requirements, instrument description
and rationale, instructions for administration of the instrument(s),
timing of assessments, planned analysis, and the wording for the
consent form. The guidelines, while undergoing revision and
modification over time, have provided the committee with a consistent framework for debating appropriate standards of HRQOL research practice within the CTG. Interested readers may find the
original guidelines published by Osoba1 in 1992 and discussed further
in 1998.5
FIELD OPERATIONS
As with other cooperative clinical trials groups, field operations for the
NCIC CTG have evolved substantially over time. The first clinical trial
to collect HRQOL information (BR.56) was designed to compare
chemotherapy for advanced non–small-cell lung cancer with best
supportive care without chemotherapy. Despite good intentions of
investigators who agreed to including the PRO in this study, compliance was poor (⬍ 25% of patients). Accordingly, a scientific session
was held at a subsequent annual meeting of NCIC CTG investigators
to stimulate interest in HRQOL and to re-examine the best approach
to incorporating PROs into CTG study protocols. Since then, several
educational activities for both clinicians and CRAs in the field have
helped to move forward the PRO agenda of the group.7 These activities have included plenary scientific sessions at annual group meetings, poster sessions, a dedicated section in the CTG newsletter
devoted to HRQOL, and trial-specific educational sessions designed to address perceived or anticipated operational issues before
protocol activation.7
Examples of changes implemented by the CTG as a result of these
deliberations include the following: a policy to integrate a complete
HRQOL assessment as part of baseline documentation required before random assignment; a policy to make this assessment required for
all patients able to read English or French but to allow patients not able
to complete these forms (as a result of language barriers) to still
participate in study protocols; and routine educational sessions with
CRAs to review the rationale for PRO end point inclusion, PRO
instrument characteristics, questionnaire administration details, timing of assessments, and special considerations at the time of activating
each clinical trial protocol including HRQOL end points.7 As such,
we experienced a paradigm shift over time where early concerns regarding patient burden with completing PRO questionnaires were
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Brundage et al
replaced by an understanding that patients were willing to, able to, and
generally enthusiastic about participating in these assessments.2
In parallel with the implementation of these field operations, the
CTG implemented central office quality assurance measures that further enhanced the collection of quality PRO data. A rigorous central
office process for ensuring that new protocols were complete in terms
of PRO measures was developed. Furthermore, participating center
CRAs were routinely queried regarding late or missing expected forms
becase these were considered equivalent in importance to the conventional clinical trial data expected at each assessment.8 The CTG Central Office, in collaboration with the QOL Committee, developed
processes for monitoring the implementation of these policies, such as
systematically reviewing the completion rate for baseline questionnaires over 16 clinical trials in a variety of disease sites, demonstrating
a compliance of 97% for 2,556 patients at baseline.9 Finally, more
recently, the Central Office has developed an electronic process to
regularly inform each QOL coordinator about the compliance (expected v received PRO data forms at all study evaluation time points)
for each active trial in that coordinator’s portfolio. This process enables the early identification of patient assessment time points where
PRO submission compliance rates are lower than expected, thereby
providing the opportunity for intervention on operational issues at the
earliest possible time.
The NCIC CTG recommends a relatively simple, clinically practical analysis that consists of four steps.14 After calculating the questionnaire completion rates and the baseline scores, the individual
change scores from baseline are determined, and the treatment groups
are statistically compared under the null hypothesis that change scores
are no different between groups. In addition, the proportions of patients who have reported a predetermined clinically significant change
score (using a 10-point threshold or other appropriate cut point) are
calculated, and the differences in the number of patients who have
benefited in each treatment group are tested for statistical significance.
An advantage of this approach of calculating the proportion of patients with an HRQOL response is that patients with missing data may
still be included in an intent-to-treat analysis by considering them as
nonresponders. Moreover, criteria for duration of response can be
applied on the basis of individual patient change scores. These approaches have been compared on summary statistical measures,15 and
further research is required to explore how these approaches compare
with more complex statistical analysis such as linear mixed regression
models, growth curve analyses, or newer strategies such as patient
assessment using item response theory coupled with computer adaptive testing.
DATA ANALYSIS AND INTERPRETATION
Research supervised or led by NCIC CTG physician coordinators and
members of the QOL Committee has furthered the group’s collective
efforts in PRO research in several ways. Although we do not attempt to comprehensively review these research efforts here, we
provide examples of how research regarding QOL methodology
and/or clinical application has been relevant to the overall NCIC
CTG research agenda.
Early in the experience of the group with HRQOL measurement,
we were able to demonstrate that non–laboratory-based conventional
toxicity measurement was subject to significant interobserver variation in its recording, even by experienced nurse CRAs.16 These efforts
were useful in highlighting for clinicians the potential advantages of
patients directly reporting their own subjective toxicity events. Early
demonstrations of high compliance in patients completing QOL assessments and the success of educational interventions helped to sustain feasibility.7,17 The demonstrations of HRQOL scores as an
independent prognostic factor for survival18 and as sensitive to specified time frame of consideration in the questionnaire19 helped to
underscore the independent validity of these measures for clinicians.
The added value of HRQOL information to conventional clinical
trial end points was further demonstrated by HRQOL data defining
clinical benefit of study interventions (eg, in trials of antiemetics in
emetogenic chemotherapeutic regimens)10; by the demonstrated convergence of HRQOL-related benefit to improvement demonstrated in
survival end points (eg, improved symptom control or patient wellbeing in palliative treatments yielding survival advantages)20,21; and by
detecting and characterizing adverse effects of adjuvant treatment.22
Further research demonstrated that, within a given clinical trial, conventional toxicity information often yielded findings that differed
from those reported by patients.23,24 Our qualitative25 and quantitative26 research into communicating the results of the NCIC CTG trials
to patient or lay consumers of HRQOL information provided a clinically feasible strategy for reporting these data to patients in decision
As operational issues within the NCIC CTG and methodologic understanding within the discipline of HRQOL measurement have evolved,
so too has the approach of the CTG to HRQOL analysis and reporting
of HRQOL data. Initially, analyses focused on between-group (intervention allocation) mean scores for each QOL domain. With recognition of the influence of missing data not at random (survivor bias), our
focus shifted to between-group mean change scores using repeatedmeasures approaches.10 We recognized that such analyses are limited
to those patients reporting both baseline and follow-up data and, thus,
are limited to a subset of trial participants, risking bias that would
influence the generalizability of results. More recently, the CTG has
had interest in describing the proportions of patient participants who
are clinically improved or deteriorated with respect to HRQOL domains at particular assessment time points compared with baseline
scores. As has been described in detail elsewhere, there exists a variety
of approaches to determining the magnitude of change in score that
constitutes a valid cut point for defining a specific patient as clinically
changed for either the better or worse.11-13 Clearly cut points that are
too low risk false-positive identification of responders as a result of
chance variance in scores, whereas cut points that are too high run the
risk of being insensitive to clinically meaningful responses. Because no
gold standard exists, the current CTG pragmatic approach is to use, for
100-point HRQOL scales, a cut point of 10 points in improvement or
deterioration in defining response scores.14 We selected this 10-point
threshold as appropriate for initial analyses based on our desire to
minimize false-positive responses, given data from several sources,
including patients’ reporting of significant subjective differences in
their status,11 as well as the work of others regarding non–anchorbased assessment methods.13 We recognize that specific clinical contexts and other instruments may call for a modified cut point.
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ANCILLARY RESEARCH OF THE QOL COMMITTEE MEMBERS
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NCIC CTG Perspective
aids or educational materials. Finally, our contributions to determining minimally important clinical changes in patients’ status
were critical to the development of anchor-based methods for data
analysis and to clinician understanding of the data generated by
these trials.11
universally so); that patient-reported data on subjective experiences
are likely to be more reliable and valid than conventional toxicity
information; and that simple analyses that report group trends as well
as individual patient response rates are preferred.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
CONCLUSION
We have provided a brief historical review of the development of PRO
measurement, analysis, and reporting in clinical trials of the NCIC
CTG. In doing so, we have provided lessons learned in furthering the
quality of these data and their application to clinical practice. We
conclude that institution of group policy and collective philosophy has
enabled the routine incorporation of HRQOL into clinical trial protocols according to robust scientific principles; that collection of quality data is possible in a variety of circumstances (although not
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The author(s) indicated no potential conflicts of interest.
AUTHOR CONTRIBUTIONS
Conception and design: Michael Brundage, David Osoba, Andrea
Bezjak, Dongsheng Tu, Michael Palmer, Joseph Pater
Manuscript writing: Michael Brundage, David Osoba, Andrea Bezjak
Final approval of manuscript: Michael Brundage, David Osoba, Andrea
Bezjak, Dongsheng Tu, Michael Palmer, Joseph Pater
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