Neurocognitive impairment and patient–proxy agreement on health-related quality of life evaluations in recurrent high-grade glioma patients

Since aggressive brain tumors are associated with a dismal prognosis, it is pivotal to evaluate and monitor health-related quality of life in these patients during the disease course. In addition to neurological deficits, these patients often have impaired neurocognitive functioning, which is associated with missing, or possibly inadequate, health-related quality of life evaluations and consequently necessitates involvement of proxies to obtain such information. With this study we investigated to what extent patients’ health-related quality of life reported by proxies reflects the patients’ self-reports. We found that proxies’ evaluation of the patients’ health-related quality of life was weakly associated with patients’ self-reports, regardless of them having neurocognitive deficits or not. We therefore suggest using proxy’s evaluations of high-grade glioma patients’ function with caution.

The prognosis for high-grade glioma patients is quite dire, with a median survival time of 15 months and a usually rapid decline in general health. Therefore, it is not surprising that health-related quality of life (HRQOL) has become an important secondary outcome measure in high-grade glioma clinical trials, as a measure of patients’ functioning [1]. Traditional clinical trial outcomes such as progression-free survival or overall survival do not provide a complete picture of the patient’s functioning and well-being. Therefore, outcomes such as HRQOL and neurocognitive functioning are now typically included in brain tumor clinical trials, to better capture functioning and well-being. Unfortunately, many brain tumor clinical trials still suffer from a substantial amount of missing HRQOL data over time. [2] Restricting analyses only to patients able to offer complete patient-reported outcomes (PROs) might introduce a bias in clinical trials, since important HRQOL evaluations of patients with poor neurological and/or neurocognitive functioning might be missing [3]. A possible solution to this problem has been proposed in resorting to evaluations offered by partners, relatives, or informal caregivers, collectively referred to as “proxies” as substitute data in the analysis of missing scores reported by patients.

However, it is unclear to what extent proxy-reported outcomes are representative of the patients’ self-perceived outcomes. Previous studies in low-grade glioma patients showed that the level of neurocognitive functioning determines the degree of patient–proxy agreement. Moderate to high patient–proxy agreement was found in neurocognitively intact patients, while in patients with neurocognitive impairment, patient and proxy ratings differed regarding emotional functioning [4‐7]. In general, there seems to be agreement between patients and proxies concerning physical functioning and symptoms [6], but the same cannot be said regarding less visible issues, such as mood and emotional functioning [8].

Furthermore, the debate concerning the subjectivity of HRQOL is still open. While HRQOL ratings are by definition subjective and should in principle be reported by the patient him- or herself [9], HGG patients often face neurological and neurocognitive deterioration that could force clinicians to resort to proxy ratings because of the inability of the patient to do so.

The aim of this study is to investigate patient–proxy HRQOL agreement in a large sample of patients with recurrent HGG. Previous findings of a study conducted on low-grade glioma patients, in which part of the authors involved in the present study collaborated, suggest neurocognitive impairment as an influencing factor for HRQOL patient–proxy agreement. Therefore, we divided patients participating in two EORTC-coordinated clinical trials in neurocognitively impaired and intact and used an approach similar to the one previously implemented in the study by Ediebah and colleagues. Our pre-trial hypothesis was that we expected neurocognitively impaired patients to have lower levels of patient–proxy agreement than neurocognitively intact patients [4‐7].

The initial sample of EORTC trials 26101 and 26091 combined consisted of 731 patients. Most patients had prior chemotherapy and radiotherapy and, in both trials, evaluation prior to randomization and every 12 weeks thereafter included neurocognitive, HRQOL, and full clinical assessment.

In addition to the criteria set for inclusion in the two clinical trials shortly described underneath [10, 11], only HGG patients (i.e., WHO grade III and grade IV) were selected for this study. Since data have been collected prior to 2016, the 2007 WHO tumor classification was used, selecting only WHO grade III and IV tumors [12]. All variables were measured within two weeks prior to randomization. We determined a time window of ± 7 days between neurocognitive functioning (NCF) evaluation and QLQ-C30 and QLQ-BN20 administration to assure concurrent measurements, given the one-week time frame of the QLQ questions.

EORTC trial 26101 (EudraCT number 2009–017,422-39) was a randomized phase III trial investigating whether the combination of lomustine plus bevacizumab compared to lomustine alone would result in better overall survival in glioblastoma patients with first progression [10]. EORTC 26091 (EudraCT number 2010–023,218-30) was a randomized, open-label phase II trial comparing temozolomide alone to the combination of temozolomide and bevacizumab in patients with a first recurrence of a locally diagnosed WHO grade II or III glioma without 1p/19q co-deletion [11].

From the initial cohort of 731 patients and 601 proxies, 127 patients were excluded due to completely or extensively missing NCF, QLQ-C30, and/or QLQ-BN20 evaluations and 103 patients did not meet the histological criteria of WHO grade III and IV high-grade gliomas. After the exclusion of those patients with extensively missing data and their significant others together with them, a total of 501 patients were selected: 470 with first recurrence of glioblastoma (EORTC 26101) and 31 patients with first recurrence of a locally diagnosed WHO grade II or III glioma without 1p/19q co-deletion (EORTC 26091). Patients included for the current analyses (n = 501) had a median age of 56 years (21–82) and 202 (37.3%) were female. Further detailed clinical information can be found in Table 1.

In this study, we aimed at assessing patient–proxy HRQOL agreement in a large sample of high-grade glioma (HGG) patients with and without neurocognitive impairment. To achieve this, we compared the baseline scores of patients and proxies from the EORTC trial 26101 and 26091 on the QLQ-C30 and QLQ-BN20 questionnaires. Our findings primarily suggest that in general there is little agreement between HGG patients and proxies on generic and disease-specific HRQOL outcomes.

These results are only partially in line with other studies on patient–proxy agreement in brain cancer patients. [7, 24] Indeed, when looking at the general agreement of HGG patients with their proxies and comparing it to the results published by Brown and colleagues in a similar population and by Sneeuw and colleagues on a generic cancer population, the agreement reported in our sample is lower. Using a similar statistical approach, the first study reported an ICC between patients and proxies greater than 0.5 on 80% of the measurements; the second showed ICCs ranging from 0.46 to 0.73, indicating a moderate to good level of agreement between patients and proxies. In our study, the agreement ranged from 0.08 to 0.46, with only two scales surpassing the 0.40 threshold that indicates the transition from poor/fair to moderate agreement.

According to the literature comparing patients and proxies evaluations in brain tumor patients [4, 6, 23, 24], neurocognitive impairment is considered to affect patient–proxy agreement. Therefore, we expected neurocognitive impairment to be an influencing factor. However, the findings of the present study do not offer such crystal-clear difference between cognitively impaired and intact patients. While it is true that intact patients showed moderate level of agreement and impaired patients reached a similar level of agreement on only two subscales, the difference between the two groups was not as profound as in other studies. Even though the number of scales showing moderate agreement was higher in neurocognitively intact patients, the lower and upper limit of Lin’s CCC range across all scales did not differ much between neurocognitively impaired and intact patients.

Results obtained using the Wilcoxon signed-rank test, as well as those using the Bland–Altman limits of agreement follow a similar pattern, respectively, with less scales showing significant differences and more scales with good levels of agreement for cognitively intact patients than impaired ones, without determining a clear difference.

It is hard to determine whether our expectations were met since neurocognitively impaired patients showed lower levels of patient–proxy agreement than neurocognitively intact patients, but agreement was poor altogether, independently from patients’ neurocognitive functioning. The results stress how HRQOL evaluation from patients and proxies are far from aligned and this offers the chance to discuss how this divergence can be interpreted. Perfect patient–proxy agreement is unlikely, and differences in scores, depending on the direction of the difference, determine the interpretation: patients showing higher functioning scores and lower symptoms scores than proxies are considered to underestimate their condition and proxies scoring lower on functioning scales and higher on symptoms scales than patients are considered to overestimate patients’ status. The opposite interpretation is possible as well, with proxies underestimating or overestimating patient’s functioning and symptoms.

We believe that this way of interpreting the difference in scoring is inadequate, since it implies that one of the two perspectives must be wrong. Clearly, this deviates from the purpose itself of evaluating HRQOL which is a subjective concept by nature. We expected the present study to confirm, as reported in the literature, agreement between patients and proxy, or perhaps smaller differences on those scales concerning aspects of physical functioning and symptoms [6], and discrepancy or greater differences over scales and symptoms related to mood and emotional functioning [8]. The difference in mean scores of patients and proxies observed in this study support this pattern. Indeed, we believe that it could be easier for a proxy to recognize patient’s physical distress or functioning impairment in the activities of daily living rather than perceive mood changes or being emotionally empathic.

Altogether the lack of patient–proxy agreement over HRQOL reflected in the results of the present study, and the importance of not considering a patient untrustworthy solely due to its condition stress the lack of a tool to establish PROs reliability.

It is important to mention that there are several limitations to this study. The fact that treatment course and disease duration prior to inclusion may have been different between patients in the two trials might have impacted sample homogeneity. Additionally, a selection bias due to missing NCF data might have affected the results.

Data concerning the level of kinship of proxies was not recorded at the EORTC headquarters. At the time of the design of these studies, it was regarded to be counterproductive to register demographic data on the proxies, as that would have required informed consent by the proxy as well, possibly negatively influencing recruitment rates of these EORTC studies. No information about specific procedures used to assess tests which were independently completed was recorded. However, in each institution, one person was appointed as the responsible for the local organization of HRQOL data collection. This could have been a physician, data manager, (research) nurse, or a psychologist.

The percentage of mean differences between dyads (0, 10, 20, or more than 20) might have been influenced by the number of possible scores on a scale. [23] Furthermore, no direct measure of mood, which has been shown to offer even more insight into patient–proxy levels of agreement, was collected [8]. Generalizability might be limited due to the selection bias which characterizes clinical trial populations in general. Finally and importantly, our definition of impairment is arbitrary. It is possible that by grading the extent of neurocognitive impairment in levels rather than in a dichotomic variable, results might be different, unfortunately in our case this was not possible. Nevertheless, a sensitivity analysis raising the threshold for neurocognitive dysfunction per test (> 2 SD) was performed. By exacerbating the definition of neurocognitive impairment from what is commonly considered the impairment threshold in the clinical environment, we hoped to include only those with an impaired performance even if on only one of the NCF tests. Results show how raising the neurocognitive impairment threshold produced little difference compared to the methodology implemented in the present study and suggests that the threshold adopted in the present study does not limit its message.

The aim of this study was to assess patient–proxy HRQOL agreement in a large sample of high-grade glioma (HGG) patients with and without neurocognitive impairment. The intrinsic subjectivity of health-related quality of life evaluation makes it difficult to establish what the ‘truth’ is. Our initial assumption was based on a syllogism for which a cognitive intact patient could be considered a reliable source of his/her own quality of life and a caregiver should be a reliable observer, at least for those scales describing functioning aspects and observable symptoms.

However, the question that would follow is a predictable one: Would it be legitimate not to rely on patients evaluation of his/her own well-being due to neurocognitive impairment?

The results of this study suggest that the level of patient–proxy agreement in HGG patients is low in general. When patients were divided into cognitively impaired and intact, these latter showed agreement with their proxies on more scales of the questionnaires, but the level of agreement remained low, suggesting, in contrast with previous literature that cognitive impairment might influence but not preclude agreement. We hope that future studies will tackle the lack of a quantitative measure of reliability of PROs in patients at risk for neurocognitive impairment. Moreover, in light of these findings, we would suggest to cautiously consider the use of proxy’s evaluation in lieu of PROs at least until a measure to establish reliability is developed.