Annals of Oncology Advance Access originally published online on January 27, 2007
Annals of Oncology 2007 18(4):775-781; doi:10.1093/annonc/mdl494
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© 2007 European Society for Medical Oncology
quality of life and supportive care |
Has the quality of health-related quality of life reporting in cancer clinical trials improved over time? Towards bridging the gap with clinical decision making
1 European Organisation for Research and Treatment of Cancer (EORTC) Data Center, Quality of Life Unit, Brussels, Belgium
2 QOL Consultant, West Vancouver, British Columbia, Canada
3 Cancer Research Center of Hawaii, University of Hawaii, Honolulu, HI, USA
4 Academic Medical Center, Department of Medical Psychology, University of Amsterdam, Amsterdam, The Netherlands
* Correspondence to: Dr F. Efficace, Mediterranean Institute of Hematology (IME), GIMEMA Data Center, Via Benevento, 6, 00161 Rome, Italy. Phone: +39 06 441 639850; Fax: +39 06 440 2516. E-mail: f.efficace{at}fondazioneime.org
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Abstract |
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Background: Previous work highlighted a number of methodological constraints when reporting health-related quality of life (HRQOL) outcomes from randomized controlled trials (RCTs). Given this, the objective of this study was to investigate whether the quality of such HRQOL reports has improved over time.
Materials and methods: On the basis of a predefined set of criteria, 159 RCTs with a HRQOL end point, published between 1990 and 2004 were identified and analyzed. Each study was evaluated by a number of issues (e.g. sample size and industry sponsorship) and by the ‘minimum standard checklist for evaluating HRQOL outcomes in cancer clinical trials’.
Results: The quality of HRQOL reports, as measured by the overall checklist score, was independently related to more recently published studies (P < 0.0001). This relationship was independent of industry funded, HRQOL end point (primary versus secondary), cancer disease site, size of the study and HRQOL difference between treatment arms. While only 39.3% of studies published between 1990 and 2000 (89/159 RCTs) were identified as being probably robust, thus likely to support clinical decision making, this percentage was 64.3% for studies published after 2000 (70/159 RCTs).
Conclusion: Since we found a significant learning curve in HRQOL trial reporting since 1990, it can be expected that HRQOL data will increasingly impact on clinical decision making and treatment policies in the near future.
Key words: Cancer, clinical decision-making, clinical trial, quality of life
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introduction |
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The need to evaluate the impact of disease and treatment on health-related quality of life (HRQOL) is increasingly acknowledged as crucial for evaluating the overall treatment effectiveness in cancer clinical trials. Information about side-effects, symptoms and treatment options are important to cancer patients as they enable them to make informed treatment decisions. Cancer patients require information not only related to survival estimates, but also regarding HRQOL issues [1]. Providing patients with such information, from a methodologically sound research basis, is therefore of paramount importance. Including HRQOL as an end point in a clinical trial setting could provide invaluable information related to functional ability as well as treatment side-effects from the patients' perspective. Assessing HRQOL, however, requires making a number of challenging decisions with regard, for example, to data collection, appropriate timing of assessment, adequate statistical analysis as well as outcome interpretation [2]. In addition, specific information regarding the psychometric robustness of the tool has to be taken into account when selecting a questionnaire for a specific trial population.
Previous work has highlighted a number of drawbacks when reporting HRQOL results of cancer clinical trials in various cancer disease sites [3–6]. It is, however, possible that such criticism regarding the adequacy of HRQOL reporting may be premature due to the fact that these evaluations were on the basis of older studies [7]. Methodological limitations have also been shown to be the major barrier for the Food and Drug Administration oncology drug applications on the basis of HRQOL end points [8]. Moreover, inadequate or poorly designed and reported HRQOL investigations in the context of randomized controlled trials (RCTs) can mislead clinical decision making, as it will hamper a clear appraisal of the validity of the outcomes. While several guidelines have recently been published to help investigators addressing a number of issues when measuring HRQOL in clinical trials [2], no data exist regarding the quality of such assessment over time in cancer research. As it is of paramount importance that the accuracy of the reporting of key HRQOL methodological factors increases, in order to allow health care providers to make informed decisions about the value of HRQOL outcomes, the main objective of this study was to investigate whether there has been a learning curve in terms of the quality of HRQOL assessment in RCT reports.
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materials and methods |
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systematic literature search
A literature search for studies meeting the criteria reported below was undertaken on several databases including Medline, Cancerlit and the Cochrane Controlled Trials Register. A hand search of the references section of electronically identified articles was also carried out. Given the lack of necessary information in conference abstracts, they were excluded. The majority of the studies analyzed in this research were previously identified in a series of systematic reviews dealing with HRQOL methodological issues in RCTs of breast, colorectal, non-small-cell lung cancer (NSCLC) and prostate cancer. Details on searching strategy have been previously reported [3–6].
criteria for considering studies
types of participants.
Adult patients diagnosed with breast, colorectal, NSCLC and prostate cancer. In North America as well as in Northern and Western Europe these represent the top four major cancer disease sites in terms of incidence [9]. No restriction was applied in terms of disease stage.
types of intervention.
Interventions included any RCTs comparing medical treatment regardless of the intervention type—radiotherapy, chemotherapy and surgical procedures. Studies dealing with psychological intervention, complementary and alternative medicine approaches or any kind of interventions other than conventional medical treatments were excluded.
types of outcome measures examined.
Any study including HRQOL as an end point was considered. Studies exclusively using proxy-based questionnaires (i.e. completed by clinicians or significant others) were excluded. Only HRQOL self-reported patient measures were taken into account. HRQOL was defined as a multidimensional construct [10]. However, studies covering at least two HRQOL domains (e.g. physical, social, psychological) and/or those only evaluating global HRQOL were also eligible.
types of studies.
All RCTs comparing different medical treatment modalities published between 1990 and 2004 and enrolling overall at least 100 patients were analyzed. The search was restricted to RCTs as they represent the gold standard by which health care professionals make decisions about treatment effectiveness [11].
methods of evaluation of HRQOL reports and data collection
Two reviewers (AB and FE) independently analyzed all identified RCTs meeting the criteria. The evaluation was on the basis of a predefined data-extraction form including information regarding the design of the trial and the HRQOL assessment methodology used. When disagreement about the analysis of a study occurred, the reviewers revisited the paper to reconcile any differences until consensus was achieved. The studies were then stored on an electronic database at the Quality of Life Unit at the European Organisation for Research and Treatment of Cancer (EORTC) Data Center in Brussels. An electronic database was specifically developed for the purpose of this research to store data collected from literature reviews. A full list of articles included in the database is available from the authors.
As the aim of this research was to investigate the level of HRQOL reporting, each RCT was evaluated according the ‘minimum standard checklist for evaluating HRQOL outcomes in cancer clinical trials’ [12]. This checklist was specifically intended for reviewing and facilitating a critical appraisal and interpretation of HRQOL outcome reports and also for guiding investigators when writing the HRQOL report from a clinical trial. It consists of 11 basic items that can be scored as ‘yes’ (giving a score of one) or ‘no’ (giving a score of zero), the higher the score the higher the robustness of the outcomes. Two items, namely, ‘a priori hypothesis stated’ and ‘cultural validity verified’ can also be evaluated as not/applicable. Each report could then receive a score ranging from zero to a maximum of 11. The checklist was developed on the basis of good practice in conducting a HRQOL evaluation. The items were originally selected from the literature by consensus of HRQOL researchers with international expertise in oncology and further ranked, to determine the relative importance by an additional independent panel of 30 experts in the field of HRQOL in oncology (including clinicians, psychologists and statisticians). The items are grouped into four key categories related to the HRQOL assessment: conceptual, measurement, methodology and interpretation. Although the items are self-explanatory, the specific criteria for assessing each item and additional details on the development process have been previously reported [12].
data analysis
As previously indicated [12], studies scoring at least eight on this checklist including three mandatory items (i.e. baseline compliance, missing data and psychometric properties reported) could be considered as ‘probably robust’, thus being likely to possibly have an impact on clinical decision making. Hence, all studies were classified into ‘probably robust’ (as defined above), ‘limited’ (scoring higher than four but either lower than eight or not including all three mandatory items), and ‘very limited’ (all other studies, i.e. scoring four or lower on the checklist score). The frequency distribution for this checklist score categorization as well as for the arbitrary classification for date of publication (chosen a priori as before and after 2000) is presented for descriptive purposes only. In univariate analysis, a linear regression model with adjusted checklist score (i.e. raw score divided by the number of applicable questions) as dependent variable and with time as continuous independent covariate was fitted. A general multivariate linear regression model was also used to examine the effect of time on the adjusted checklist score while controlling for possible confounding factors. Factors included: industry funded (yes versus no), HRQOL end point (primary versus secondary), year of publication (continuous), disease site (prostate versus breast; prostate versus colorectal; prostate versus NSCLC), number of patients enrolled into the trial (continuous) and HRQOL difference between treatment arms (yes versus no). The latter was defined as any statistical difference between treatment arms at any given time point assessment during the trial (even if this only occurred in one HRQOL domain). Statistically significant variables were identified at the 1% level via Wald-type Chi-square tests for linear regression. All statistical analyses were two-sided and were carried out using SAS version 9.1 for Windows (SAS Institute Inc., Cary, NC).
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results |
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One hundred and fifty-nine RCTs enrolling 58 635 patients were identified from 1990 to 2004 and were available for analysis (Table 1).
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reporting of the checklist categories over time (Table 2)
conceptual issues.
Overall, 28.9% of the studies reported an a priori hypothesis. The percentage of the trials addressing this issue was, however, higher for those published between 2001 and 2004 (35.7%) as compared with the studies published before 2001 (23.6%). While one-third (33.7%) of the RCTs before 2001 provided a rationale for selecting a specific HRQOL questionnaire, the percentage was higher for the studies published more recently (65.7%).
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measurement issues.
Nearly all of the RCTs have used a validated questionnaire (94.3%) covering at least the main domains relevant to a generic cancer population (96.9%). The most frequently used HRQOL measures were the EORTC questionnaires being used in 76 studies (48%). Other questionnaires frequently used were the Rotterdam Symptom Checklist and the Functional Assessment of Cancer Therapy (FACT) being used in 17 studies (11%) and 15 studies (9%), respectively. For the remaining items an improvement was also noted for the reports published after 2000. In all of the above, reporting was higher in the years 2001–2004 than in the earlier period.
methodological issues.
While only 24.7% of the reports published between 1990 and 2000 specified who and/or in which clinical setting the HRQOL instrument was administered, >38% of the reports published after 2000 reported this issue. Nearly all of the studies documented the HRQOL timing of assessment. Some 31% and 30% of studies published before 2001 failed to provide any detail on missing data and baseline compliance, respectively. For both these two key aspects, however, these percentages dropped to only 17% for the reports published after 2000.
interpretation issues.
The major drawback was related to the limited progress in addressing the clinical significance of the HRQOL outcomes, as only 24.5% of all the studies provided information related to clinical significance. This percentage was, however, 34.3% for the reports published after 2000 as compared with 16.9% for those published earlier. Nearly all of the studies (93.1%) discussed the HRQOL findings regardless of the results in at least one sentence.
overall checklist score over time
The percentage of studies judged as ‘probably robust’ was 64.3% for those published between 2001 and 2004 while it was only 39.3% for those published earlier (Figure 1). The remainder of the studies done from 2001 to 2004 were evaluated as being ‘limited’ with none being ‘very limited’. From 1990 to 2000 there were, however, 15.7% of studies that gave ‘very limited’ information.
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A linear regression analysis showed a statistically significant trend for the adjusted checklist score over time (ß = 0.025; P < 0.0001). The scatter plot is reported in Figure 2. A wide variability, however, was also evident even within the same year of publication. This relationship remained significant independent of other possible confounding factors (P < 0.0001). A multivariate regression analysis was run, using the adjusted checklist score as the dependent variable, and the following additional covariates: industry funded, HRQOL end point, disease site, number of patients enrolled into the trial and HRQOL difference between treatment arms. Of these, only disease site was significant together with year of publication at the 1% level. Details are reported in Table 3. Since the studies conducted in various disease sites seemed to vary in terms of quality of HRQOL reports, we further investigated this issue and noted that the ones conducted in NSCLC had higher checklist scores (Table 4).
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discussion |
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TopAbstractintroductionmaterials and methodsresultsdiscussionAcknowledgementsReferences |
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The main finding of this research is that a significant improvement has occurred since 1990 in terms of the quality of HRQOL reporting. This trend was independent of the sample size of the study, the industry sponsorship, the use of HRQOL as a primary or secondary end point in the trial, the specific disease site investigated and the evidence of a HRQOL difference between treatment arms. This evidence has been shown in 159 RCTs conducted in the top four major cancer disease sites, in terms of incidence, in North America as well as in Northern and Western Europe [9]. The percentage of the studies evaluated as being probably robust, thus likely to be reliable and possibly better informing clinical decision making, was 64.3% for those published after 2000, in contrast to only 39.3% for those published earlier (Figure 1). Overall, this result confirms the remarkable progress that has been made in a relatively short period of time in this field [13]. This evaluation was on the basis of a previously developed checklist specifically devised for reviewing and facilitating a critical appraisal and interpretation of HRQOL outcome reports from clinical trials. The strength of this pragmatic tool is that it is on the basis of the cancer literature and only focuses on issues related to HRQOL reporting [12].
While investigating the reasons underlying the quality improvement over time lies beyond the scope of this paper, and a number of reasons could account for this evidence, it is possible to provide some tentative explanations. Although some major guidelines on how to conduct and incorporate HRQOL as an end point into clinical trial protocols were published in the early 1990s [14, 15], the majority of these were published in or after 1997 [16–19]. It is also worthy of note that some frequently used HRQOL psychometric robust questionnaires devised for a generic cancer population, such as the EORTC QLQ-C30 or the FACT-G were only published in 1993 [20, 21]. In addition, several other commonly used cancer site-specific measures, such as the EORTC QLQ-BR23 and the FACT-B were published later in 1996 and 1997, respectively [22, 23]. Thus, it might be possible that the relatively poor level of HRQOL reporting of previously published manuscripts could stem from the general unfamiliarity of clinical researchers in oncology with HRQOL issues as well as the lack of methodologically sound HRQOL cancer questionnaires.
Since a difference was noted in the accuracy of HRQOL reports conducted among the cancer disease sites investigated, it is possible that the learning curve identified mainly reflects the improvement of studies conducted within a specific cancer disease site (Tables 3 and 4). However, because of the small number of studies in each category and possible lack of power in the additional analysis, we did not further investigate this issue. Rather, the aim of this paper was to provide an overall picture of the quality of HRQOL research in oncology.
Measuring HRQOL in a clinical trial setting requires making a number of important decisions, including the selection of the most appropriate questionnaire, the methods of administration and data collection [2]. The statistical analysis and interpretation of HRQOL results are also crucial aspects of this process [24]. As an example, the Clinical Trials Group of the National Cancer Institute of Canada has recently proposed a simple and practical guide that may aid in the analysis and interpretation of HRQOL data [7].
On one hand, our findings show an overall improvement in the level of reporting of all the checklist items over time, while on the other they also highlight some areas that deserve further attention. For example, the current findings identify the lack of an a priori hypothesis as a major limitation (overall only 29% of the studies reported this aspect). Our findings also indicate the lack of documentation of missing data as a further possible limitation as, overall, 25% of the studies conducted failed to provide any details on the proportion of patients who dropped out during the course of the trial. Recent studies have addressed handling missing data in a comprehensive way and are likely to assist investigators when exploring this issue [25–27]. There is room for improvement in addressing the clinical significance of HRQOL outcomes since, overall, only 24% the RCTs addressed this issue. Recent work, which has investigated this aspect in a comprehensive way, is likely to help researchers when addressing the interpretability of the results [18, 28–32]. As has been noted for all the items of the checklist, however, the number of studies addressing these issues was higher for those published after 2000 as compared with previous years.
A recent editorial published in the Journal of Clinical Oncology [33] pointed out that it is ‘disappointing’ that despite the fact that thousands of patients have been enrolled in cancer clinical trials with a HRQOL component, ‘there are relatively few examples of formal quality-of-life measurement that have influenced individual patient decision making or treatment policies’ (p.2215). The issue raised in this editorial represents a challenging topic for all investigators involved in HRQOL cancer research. While a number of reasons could account for the arguments brought up in the editorial, the present findings indicate that the reason could merely stem from the generally poor level of methodological rigor in the HRQOL assessment of many previously conducted RCTs.
Our study has some limitations. We did not take into account unpublished reports. There is evidence that some HRQOL analyses were not reported because of a very low compliance rate [34]. It is, however, not possible to find out exactly how many studies were not submitted for publication or were rejected because of administrative and methodological problems. Since we focused on only the four major disease sites, our results should only be interpreted in the context of these sites. Another potential limitation is that since our checklist is on the basis of minimum criteria, it may not be sensitive enough to pick up the more subtle trends of the quality of HRQOL reports. If this were the case, however, our data would represent an underestimate of the real trend. If the accuracy of the reporting continues to improve, the checklist items could be expanded in the future by adding more demanding and comprehensive criteria.
Since we found a substantial quality improvement in the HRQOL reporting of RCTs over time, it can be expected that HRQOL data will increasingly impact on clinical decision making and treatment policies in the near future. Blazeby et al. [35] have recently shown, for example, that HRQOL data informed clinical decision making providing robust and additional information in a number of surgical trials in oncology. The authors also pointed out that if HRQOL is an appropriate outcome in a given clinical trial, the results will always contribute to clinical decision making if HRQOL is assessed robustly [35].
It is clear that Journal policies will also have a major role in continuing to raise the standard of HRQOL reporting by requiring, for example, more demanding criteria for publishing HRQOL reports. In this respect, the adoption of some basic and pragmatic criteria, such as the ones contained in the checklist used in this paper, could be of help in the editorial process.
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This publication is supported in part by grants number 2U10 CA11488-31 through 5U10 CA11488-35 from the National Cancer Institute (Bethesda, MD). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. Presented in part at the 12th Annual Conference of the International Society for Quality of Life Research, San Francisco, CA, 19–22 October 2005.
Received for publication September 18, 2006. Revision received November 20, 2006. Accepted for publication December 7, 2006.
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