Discussion
In this study, we showed that the proportion of randomised phase III trials that included QoL as a study endpoint has increased in recent years, though it remains suboptimal, particularly in trials promoted by academic sponsors.
In many cases, although collected according to study protocol, QoL data are not presented in the primary publication. This under-reporting was already relevant some years ago,7 but the trend is worsening in recent years, with a frequent delay in the availability of QoL results. For instance, even if the rate of industry-sponsored trials including QoL among endpoints has increased in the last 5 years, this was not followed by an increase in reporting of QoL results, which on the contrary has decreased in 2017–2021 compared with the previous 5 years. The same concept also applies to trials testing immunotherapy or conducted in advanced disease, among others. It should be highlighted that the drop in the presence of QoL results in primary publications was particularly relevant for trials including patients with lung cancer (45.8% in 2012–2016 compared with 25.0% in 2017–2021). Of course, regulatory agencies may evaluate QoL results although still unpublished, but we believe that the concomitant publication of QoL results together with other outcomes is very useful not only for decision makers, but for the entire scientific community (including clinicians and patients) to evaluate the value of a new treatment.
By performing a multivariate analysis on the whole 10-year dataset, we investigated the factors (both related to the study and journal characteristics) associated with a higher chance of inclusion of QoL among study endpoints and presence of QoL results in the primary publication. Of note, journal IF was associated with the inclusion of QoL among endpoints and with the presence of QoL results in the first publication. However, these associations were in opposite directions: studies published in journals with higher IF had higher frequency of QoL among endpoints (multivariate OR for journals with high IF compared with those with low IF 4.13, 95% CI 2.59 to 6.56), but higher IF was associated with lower inclusion of QoL results in the first publication (multivariate OR 0.37, 95% CI 0.19 to 0.75). In other words, if we consider the journal IF as a surrogate of the quality and the relevance of the trial, high-quality trials do include QoL in study protocol, but those journals do not ask for those results when the study is submitted for publication. This is particularly evident for trials testing immunotherapy, as previously shown by a dedicated analysis.15 In this study, immunotherapy studies confirmed a high rate of inclusion of QoL among endpoints, but a very disappointing rate of presence of QoL data in the primary publication.
As expected, the proportion of trials including QoL among endpoints was significantly lower in trials conducted in early stages compared with advanced disease, although in the last 5 years this proportion showed an improvement in both subgroups. Disease setting showed a significant association at multivariate analysis, with both inclusion of QoL among endpoints and presence of QoL data in the primary publication. The attention to QoL was higher in patients with advanced disease: indeed, in this setting, tumour-related symptoms can have a relevant impact on QoL, and the burden of treatment-related adverse events is not negligible, especially if treatment is associated with a modest efficacy. In patients receiving adjuvant treatment, with a curative aim, investigators often suppose that the benefit in terms of chance of cure should outweigh the negative, hopefully transient, detrimental effect.
We were already disappointed in the previous analysis by the high proportion of academic trials that did not include QoL as a study endpoint. In this update, the gap between industry-sponsored and academic studies was even higher: while the proportion of trials including QoL among industry-sponsored studies significantly improved in recent years (moving from 60.3% to 82.3%, OR 3.06), this was not the case for the academic counterpart (from 46.4% in 2012–2016 to 47.5% in 2017–2021, OR 1.05). In the multivariate analysis conducted over the 10-year period, study sponsor remained statistically significant (OR of QoL inclusion for industry-sponsored vs academic trials 1.48, 95% CI 1.01 to 2.17). In other words, pharmaceutical companies are responding to regulatory agencies’ invitation to increase the production of QoL data during a treatment’s clinical development, while academic research continues to underestimate the importance of PROs and QoL in clinical trials. We acknowledge that this can be related to technical and methodological challenges: academic trials are often conducted with far less resources compared with industry-sponsored trials, and the administration, collection and analysis of QoL questionnaires could be considered as a ‘burden’ mining the feasibility of the trial. However, we hope that the increased awareness of the relevance of QoL will determine an improvement also in academic research, coherently with the its philosophy, aiming to optimise treatment choices and patients’ QoL.
One reason for not including QoL as an endpoint could be the concern that, in order to be methodologically reliable, QoL data should be generated in a blinded setting rather than in an open-label design.9 If this was actually the case, this could partially explain the suboptimal QoL inclusion in academic research, considering that the conduction of placebo-controlled trials can be particularly challenging for academic investigators. In our analysis, masking was significantly associated with the probability of QoL results in the study publication at multivariate analysis (OR 1.52, 95% CI 1.07 to 2.18). However, we believe that QoL data are worth to be collected even if the trial is open-label. In a review of 538 randomised trials with a patient-reported endpoint conducted in the most prevalent cancers, there was no significant association of the treatment concealment (blinded vs open-label) with the proportion of trials favouring the experimental treatment (adjusted OR 1.19, 95% CI 0.79 to 1.79; p=0.40).16 These findings support the validity of QoL results derived from open-label oncology trials.
The limited word-count imposed by most scientific journals may be one of the factors hindering QoL reporting in the primary publication. Limiting the reporting of QoL results to the global/total QoL score due to space restrictions may limit the interpretation of the QoL profile of the treatments under study. In fact, results of the various QoL items and domains, along with different modalities of analysis and presentation of results (eg, mean changes, proportion of responders, time to QoL deterioration), are important to understand treatment impact on QoL and to personalise treatment choices and management. We believe that scientific journals should consider synchronous publications dedicated to PROs, in order to offer a timely and complete evaluation of new treatments. Alternatively, authors should be encouraged to add details of PROs results in the supplemental data, which usually have no word-count restriction, although this solution is at risk of limiting the visibility of PRO results.
We acknowledge some limitations of our study. First, our analysis is limited to 11 major journals and cannot be considered a systematic review of the literature. Some phase III trials published in different journals, even of high relevance and quality, are not considered in our study. However, considering our finding that studies including QoL among endpoints are published more often in journals with higher IF, it is reasonable that the inclusion of other journals (including those with lower IF) could have further reduced the proportion of studies including QoL; therefore, this limitation is conservative as for the matter of the analysis. In addition, we decided to conduct the update on the same 11 journals already included in our previous study, to obtain a homogeneous comparison between the two periods, and the journals included are among those most read by the oncological community. We believe that, despite this important limitation, our review is useful in providing a picture of the relevance of QoL in oncology literature. Second, this analysis, like the previous one, is limited to full text publications. We did not consider the presentation of QoL results as abstracts, posters and/or oral presentations, at scientific meetings, although those usually precedes the definitive publication and could allow the availability of QoL data for the scientific community for some of the trials classified as under-reported in our analysis. However, we believe that the full text, peer-reviewed publication should be the reference for the evaluation of the methodological quality of a clinical trial. In addition, there is no scientific reason for not including QoL data in the primary study publication, considering that those data are collected during the treatment, and should be mature at the moment of primary analysis. Third, we did not investigate the modality of collection (paper-based vs electronic) within each study. Recent years are witnessing an increasing use of electronic collection of PROs, which allows a prompt availability of data for the analysis. Whether the use of electronic PROs may be associated with higher PROs reporting still needs further investigation. Lastly, we acknowledge that the year of publication is an imprecise surrogate for the year of study design and that the length of accrual for academic trials could be, at least in principle, longer than for industry-sponsored trials due usually to more limited resources. This can affect the comparison of time trends according to sponsorship, at least for the inclusion of QoL among study endpoints, but not for the presentation of results.
In conclusion, we showed that the proportion of oncology trials including QoL among endpoints increased in 2017–2021 compared with 2012–2016, and this is an encouraging result, although QoL remains underrated in many trials. Furthermore, the proportion of trials reporting QoL results in primary publications remains suboptimal, necessitating discussion within the scientific community, which includes not only investigators but also journal editors and peer-reviewers. We believe that more needs to be done to ensure that the scientific community and also patients can access data of PROs and QoL at an appropriate time. At the moment, journal editors, who could make the provision of PROs and QoL for clinical trials a requirement for publication, may hold the key for the improvement of the timely presentation of patient-reported results.