Re-irradiation of High Grade Gliomas: a Quality of Life Study

Patients with a high grade glioma have an increasing overall survival and progression free survival after initial treatment. Because of a better performance status these patients are more often eligible for re-treatment with for example radiotherapy. However, to date only a few prospective studies on re-irradiation of gliomas exist and very little is known about the effects of re-irradiation on quality of life and cognition. This trial is designed to longitudinally establish the effects of re-irradiation on quality of life, cognition and physical performance in patients with a high grade glioma. Based on the currently available information the investigators hypothesize that quality of life after re-irradiation can be kept stable until further tumour progression.

Current treatment regimes, with the addition of temozolomide, have improved progression-free survival as well as overall survival for patients with a high grade glioma. The median overall survival (MOS) for patients with a glioblastoma (GBM) is 14.6 months, with a progression free survival (PFS) of 6.9 months.

Due to longer survival and a better performance status, patients often reach a point at which re-treatment is feasible. Treatment options for recurrent glioblastoma and anaplastic glioma can include surgery, chemotherapy and re-irradiation. Re-irradiation of patients with recurrent high grade glioma is slowly becoming standard of care. It provides a comparable overall survival to palliative chemotherapy. In case of GBM there is a median time to progression after treatment of 20-27 weeks and a MOS of 26 to 60 weeks.

Patients with tumor recurrence have a significantly worse quality of life compared to patients without recurrence at the same follow-up. They experience significantly more problems with physical functioning (e.g. motor dysfunction, weakness of legs, visual disorders), work or other daily activities, mental health (e.g. future uncertainty) and general health.

With regard to re-irradiation, current available data is mostly provided by retrospective studies which often lack solid quality of life data. Endpoints include e.g. performance status, clinical (neurological) status and decreased steroid requirement after treatment. These endpoints are however inadequate to determine quality of life accurately.

Several studies have used the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire core 30 (EORTC QLQ-C30) and the brain cancer module (QLQ-BN20) scales to assess quality of life. The latter consists of 20 items including visual disorder, motor dysfunction, various disease symptoms, treatment toxicity and future uncertainty. A change of 10 points or more on these scales can be considered clinically relevant.

To date only Ernst-Stecken and colleagues have used the EORTC QLQ-C30 to prospectively evaluate the quality of life in patients with a recurrent malignant glioma after radiotherapy. In this study patients were treated with hypofractionation. The quality of life questionnaire score could be kept stable in two thirds of patients with a median follow-up of 9 months. They conclude that hypofractionated stereotactic radiotherapy is an effective treatment that helps to maintain quality of life for an acceptable period, comparable to the results found with chemotherapeutic regimes.

In patients with glioma, the tumor, radiotherapy as well as chemotherapy can disrupt cognitive function. Cognitive functioning can be evaluated by a cognitive screening instrument and/or comprehensive neuropsychological test batteries. The most well-known and convenient screening instrument is the Mini Mental-State Examination (MMSE). However, the MMSE is developed to assess dementia and does not include items related to executive function. As such, the MMSE is insufficient to assess frontal-subcortical network dysfunction associated with cognitive damage after irradiation. More sensitive cognitive tests should be administered to determine the effects of re-irradiation on cognition. There is however still little consensus on which test should be used. Although comprehensive neuropsychological test batteries are most sensitive, a brief cognitive screening is preferable in the present setting. For this trial, the investigators intend to use a number of relevant standard tests including the Hopkins Verbal Learning Test-Revised (HVLT-R, the Trail Making Test and Controlled Oral Word Association (COWA) as suggested by the Radiation Therapy Oncology Group (RTOG). The Stroop colour-word test (Stroop) is added to the battery in order to assess visual attention.

Physical functioning has a major impact on quality of life in patients with cancer. A number of studies have investigated the effects of exercise on physical functioning. They have shown, predominantly in patients with breast cancer, that exercise has beneficial effects on health and well-being. Physical performance can be measured by several means. The hand grip strength (HGS) test has been validated in previous studies for the evaluation of general health status. This test is performed with the Jamar hand dynamometer which displays hand strength in kilograms. By comparing data after re-irradiation to the data collected before the treatment the amount of muscle strength loss can be determined.

Another method of measuring physical performance is by analyzing fatigue. This is a very common symptom in cancer patients and negatively influences their quality of life. Fatigue in patients with cancer can be determined with the use of both the EORTC QLQ-C30 and the more specific Fatigue Questionnaire (EORTC QLQ-FA13).

Eligibility Criteria:
Inclusion Criteria:

* Histologically proven high-grade glioma anaplastic astrocytoma or glioblastoma
* Age ≥ 18 years
* WHO performance status ≤ 2
* Scheduled for re-irradiation of a high grade glioma
* The patient is willing and capable to comply with study procedure

Exclusion Criteria:

• Life expectancy \< 3 months