Keywords::
Outcome measures in clinical trials for brain tumor patients have traditionally been confined to survival (i.e., overall and progression-free survival) and radiological response to treatment. For cancer patients, the recognition that duration of survival may not be the only goal of treatment has resulted in health-related quality of life (HRQoL) becoming an important (secondary) outcome. It is generally acknowledged that the benefits of longer survival due to tumor treatment should be weighed against side effects of treatment, which may have a negative impact on the patient’s functioning in physical, psychological and social aspects. The small number of brain tumor patients compared with other cancers, such as lung and breast cancer, and the dismal prognosis for the large majority of brain cancer patients have for a long time added to a lack of interest im patient-reported outcomes such as HRQoL in these patients. A review in 2002 demonstrated the paucity of clinical studies in brain cancer patients with HRQoL as outcome measure Citation[1].
Since then, much has changed for the positive regarding outcome measures in brain tumor patients. The finding that new (combination) treatments are of benefit for specific subgroups of primary brain tumors and that long-term survivors of brain cancer may run the risk of late treatment complications has elicited an increased interest in outcomes such as cognitive functions and HRQoL. The tumor-specific European Organization for the Research and Treatment of Cancer (EORTC) Brain Cancer Module (BN20), developed to be used with the generic EORTC Quality of Life Core Questionnaire, has successfully been applied to multicenter randomized studies in primary brain cancer to serve as a secondary outcome Citation[2–5]. In the USA, the brain subscale (Functional Assessment of Cancer Therapy [FACT]-Br) of the FACT general version (FACT-G) has similar features as the EORTC questionnaires, although the FACT modules are more focused on psychological aspects and less on symptoms Citation[6].
What have we learnt so far from these HRQoL measures used in brain tumor patients? First, by measuring HRQoL before the start of treatment, it turns out that the disease itself may have a major negative impact on the patient’s HRQoL Citation[7]. Second, tumor treatment may not only have a positive impact on duration of survival, but also on the quality of survival Citation[8]. Furthermore, HRQoL measurements used in daily clinical practice may facilitate patient counseling and also may serve as prognostic information. Having said this, practical problems with the collection and interpretation of serial HRQoL measurements are not to be ignored. Administrative failure, and lack of time and interest, mainly on the part of the doctor, may result in low compliance and a bias in the interpretation Citation[9]. In addition, timing of HRQoL assessment is of paramount importance. The minimally negative impact of combined procarbazine, lomustine and vincristine (PCV) chemotherapy on HRQoL in anaplastic oligodendroglioma patients is partly due to a too liberal timing of HRQoL measurement Citation[5]. Another issue will be the need to add new items to the existing questionnaires since new treatments, such as angiogenesis inhibitors, may cause different side effects.
Apart from these practical drawbacks, HRQoL is by definition a subjective outcome, which has specific implications for brain tumor patients. These patients do not only have cancer, but are also confronted with a progressive brain disease that will hamper their cognitive functions and, as a consequence, their notion of disease. Once cognitive functions deteriorate, brain tumor patients tend to overrate their HRQoL Citation[10]. The patient’s caregiver may then become a more reliable source of rating the patient’s HRQoL, but such a proxy measure is by definition not a patient-reported outcome.
So, if HRQoL does not give us the complete answer, which other patient-oriented outcomes measures are we in need of in brain cancer? The key clinical features for these patients are neurological functioning, cognitive deficit, epilepsy, fatigue and mood disturbances. Symptom scales are increasingly being recognized as being important in brain tumor patients, and issues such as fatigue or mood cannot be rated otherwise Citation[11]. For cognitive functioning, we dispose of standardized test batteries, covering the key cognitive domains in an objective way. Not surprisingly for brain tumor patients, the correlation between subjective cognitive symptoms and objective test results is not very high, which warrants the collection of objective data using cognitive test batteries Citation[12]. Cognitive testing has proven to be an extremely important outcome measure in low-grade glioma patients with a relatively long survival, where the immediate effects of extensive surgery and the long-term effects of radiation and other medical treatments are key issues Citation[13]. A drawback is the time-consuming procedure for both the patient and the researcher, which may hamper its use in other brain tumor patients with a more limited prognosis and often in worse clinical condition.
The Karnofsky Performance Status scale, developed for cancer patients, is frequently used in glioma patients in lack of a brain cancer-specific tool. Since the Karnofsky Performance Status scale neither reflects neurological impairment such as hemiparesis nor cognitive deficit, its use for brain tumor patients to determine performance status is limited. Possibly specific activity of daily living scales, such as an instrumental activity of daily living scale developed for dementia, should be developed for brain tumor patients Citation[14].
Apart from primary brain tumors, with gliomas having the highest incidence rates and being the most malignant, brain metastases from systemic cancer are even more frequently encountered. Progress has also been achieved in brain metastases patients with patient-reported outcome measures, which is reflected by two thorough reviews on the use of both the EORTC BN20 and the FACT-Br for HRQoL assessment in patients with brain metastases Citation[15,16]. Although both questionnaires have not been validated for brain metastases patients so far, its increasing use in brain metastases trials underscores the need for these outcome measures.
Clearly, HRQoL has become an important outcome measure in brain tumor patients, notwithstanding its limitations. Further development of both patient-reported and other patient-oriented outcomes for primary and metastastic brain tumor patients is needed for sdoctors, as well as for the patients and their families.
Financial & competing interests disclosure
MJB Taphoorn has received research grants from the Dutch Cancer Society, the EORTC Brussels and the Jacobusstichting The Hague. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
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