Brain cancer (BC) constitutes a heterogeneous group of diseases, accounting for 1–2% of all primary cancers in adults (1). These neoplasms (primary or secondary) are characterized by severe and complex symptoms, usually associated with a poor prognosis (1, 2). There is no definite cure for most patients. Therefore, a reasonable primary aim of treatment is to extend survival with effective symptom relief (2, 3).

Efforts with emerging new therapeutic strategies are mainly focused on prolonging survival (4). However, BC is associated to symptoms and complications that negatively impact patients' Health-related quality of life (HRQL). BC may directly provoke disabling symptoms including headache, sensory-motor dysfunction, seizures, mood disorders, personality changes, and cognitive dysfunction (5). Consequently, the clinical benefits of treatment should be evaluated not only according to the classical outcome measures (objective response or survival) but also by ensuring HRQL improvement, and must be weighed against treatment side-effects (5–7).

The clinical consequences of disease can be identified by physical examination and evaluated with neurological and neuropsychological tests. Patients' opinions on their own HRQL differ substantially from the opinions of proxies or health-care personnel. Hence, two instruments have been developed to measure HRQL in the specific case of BC: the FACT-Br, Peds-FACT-BrS, and the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ) BN20 (8–11). The MDASI-BT is a symptom inventory designed to measure symptoms and not for HRQL assessment (12).

The QLQ-BN20 measures focus more specifically on function and symptoms, while the FACT-Br assessments cover more psychosocial aspects of the disease. Therefore, the QLQ-BN20 is superior when assessing the treatment outcome and may provide more information in trials that focus on functional endpoints, whereas FACT-Br could be more useful in patients with positive functional capacity but psychosocial concerns, although no instrument is superior to the other (13). Both must be considered as complementary.

The QLQ-BN20 instrument comprises 11 symptom scales that cover the more common complains in patients with BC and it was designed to be used with the core questionnaire QLQ-C30. This core instrument comprises five functional scales, and nine symptom scales plus a global HRQL scale. Both have been translated and validated into several languages and have been extensively used in the medical literature. However, available information on the subject published in Latin-American countries is scarce. The aim of this study was to validate the Mexican-Spanish version of the QLQ-C30 and QLQ-BN20 questionnaires in patients with BC.

In this study, the Mexican-Spanish version of the QLQ-BN20 instrument along with its core instrument QLQ-C30 has been psychometrically and clinically validated as we found them reliable and valid.

The main traditional outcome measures in oncology research are the frequency of objective responses after therapy, progression-free survival, or OS. However, many brain neoplasms are incurable, and maintenance or improvement of patients' HRQL are, at least, as important as increases in the progression-free survival or OS. On the other hand, a patient-centered approach complementing the decision-making process in Neuro-Oncology is feasible and desirable. Most patients with BC can participate actively in the decisions on their management options if relevant information is presented in a clear and reasonable manner. When informed, most patients are able to identify concepts of HRQL, the capability to maintain functional independence and the influence of treatment on survival as the most relevant factors in determining their decision (21). As physicians, we must be prepared to facilitate this process.

In a 20-year period, only five Randomized clinical trials (RCT) included HRQL evaluations as primary or secondary outcome measurements. However, the quality of reporting HRQL data has not considerably improved (22). In these contexts, the availability of valid instruments to accurately measure HRQL is mandatory. In general terms, the psychometric characteristics of our study were similar to the original report and other validation reports (23, 24).

The original QLQ-BN20 instrument was developed in multilingual and multicultural settings in Europe (including European-Spanish) and has proven to be valid and reliable (11, 25). Our study is the first validation protocol of the instrument in the Mexican-Spanish language, performed in a Cancer Center in Latin America. Similar psychometric findings are described in other validation studies but the association of several HRQL scales and relevant clinical variables has not been previously reported (11, 23–26). In known-group comparisons, the association of the QLQ-BN20 instrument with the ECOG performance status scale, RPA and OS are described.

The main pitfalls of our study are that responsiveness to cancer treatment was not investigated as long as we have performed one HRQL evaluation for each patient, and our relatively small sample size (n = 119), when compared with the original report from the EORTC (n = 891) (11).

Floor and ceiling values are 0–100 in all scales except in the Cognitive scale of the QLQ-C30 (Table 1). In general terms, most patients report high functional and low symptom scales (Table 1), reflecting a population with a recent diagnosis and low disease burden. Convergent and divergent validity is adequate for both instruments, as shown in Table 2, and as similarly reported in the other four validation studies (11, 23–26). The reliability of the Cognitive scale of the QLQ-C30 is below 0.7 and this finding is similar to the Korean validation study (24), while the other three validation studies did not mention the values of the QLQ-C30 scales (11, 23, 25, 26). Low Cronbach α values in terms of Cognitive scale's reliability are frequent in the literature in patients with diverse types of cancer. Examples of this finding include the original EORTC report of the QLQ-C30 instrument (27), and the original Mexican-Spanish validation study of the QLQ-C30 instrument (14). All multi-item scales of the QLQ-BN20 presented fair Cronbach α values as in the other three validation reports (11, 23–26). Certain QLQ-BN20 mean scale scores revealed important associations with ECOG, RPA and OS (Tables 3, 4 and Figure 1). No comparison is possible because to our knowledge, these findings have not been previously reported.

Although, there is currently no available cure for advanced BC, survival rates have been increasing over the last few years, so this tool is useful in assessing the development of an effective treatment that improves HRQL (5). The QLQ-BN20 instrument has been cited in 42 publications in PubMed since 2009 and has been used in clinical trials to measure HRQL in BC patients undergoing chemotherapy (Ch) and/or radiotherapy (RT). A recent study compared two treatment outcomes in glioblastoma patients: one received RT alone, while the other group of patients was treated with RT plus adjuvant temozolomide; QLQ-C30 and QLQ-BN20 were used to assess the patients at follow-up and results showed similar HRQL in the two groups with minimal differences in the nausea/vomiting and constipation scales, which were worse in the Ch / RT group than in the RT only group. Nevertheless, the use of adjuvant temozolomide therapy further prolonged patient survival compared to the RT only group (28).

In clinical trials, statistically significant changes in HRQL can be observed by increasing the sample size or in the scenario of multiple comparisons (such as comparison of multiple HRQL scale scores). However, these changes may not be clinically relevant. The meaning of the minimal clinical important difference is pertinent in the design of clinical trials, when proposing an adequate sample size and in the correct interpretation of results. The minimal clinical important difference can be defined as the smallest difference in the mean score which is clinically important (as in between groups or paired comparison designs). In a recent study, a decrease of 6.1 units or 13.8 units was required to represent clinically relevant deterioration of the Seizures or Weakness of legs variables, respectively (29).

In another study of BC patients, 5.2 units change represented the minimal clinically important deterioration in the motor dysfunction scale. Similarly, 9.1 units change represented clinically important improvement in the communication deficit (30).

In general terms, the authors consider that any 10-unit change or difference in the mean score represents a clinically important difference.

Most patients do not report problems with the cognitive functioning scale. This problem may result from their sociocultural background. At the INCan hospital, we mainly treat patients with a low income, illiteracy, a low education level and poor working possibilities.

Distinguishing patients with glioma from those with meningioma was not tested in this study because of the great variability of histopathology diagnoses in the cohort. This is a validation study, so we did not test the impact of different treatments on HRQL. This question and others could be investigated in future research studies, including the usefulness of these instruments in revealing subtle differences associated to novel treatments in randomized clinical trials.

In conclusion, the Mexican-Spanish version of the QLQ-BN20 instrument is a valid and reliable test that can be used in clinical studies that include patients with primary or metastatic BC. Some HRQL items were associated with the OS and could be used as prognostic factors or might contribute to assemble prognostic models as aids in treatment trade-offs.

BC-D and LO-O conception and design of the study and analysis and interpretation of data and draft and revise the article. NL-M recruiting patients, acquisition of data, cleaning of the database. All authors have approved the final version to be submitted.