Trial Information

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

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).