Evaluation of Repeated Whole Brain Radiotherapy Versus Best Supportive Care for Multiple Brain Metastases.

Brain Metastasases

Whole Brain Radiotherapy (WBRT) has been established as the treatment standard in patients with multiple cerebral metastases from solid tumors. However, intracerebral recurrence is possible and a repeated WBRT may be indicated to improve intracerebral tumor control. Each institutsion offers different dosing regimens, which have all been published to be safe and effective. Some favor best supportive care only. The current study protocol is aimed at evaluating primarily the toxicity as well as secondarily the local and loco-regional tumor control, overall survival and QoL after repeated WBRT using 2 different dose concepts (20 Gy in 10 Fx vs. 30 Gy in 15 Fx) compared to BSC.

According to Nussbaum et al., 24-45% of cancer patients develop cerebral metastases during the course of the disease. Brain metastases are generally associated with a poor prognosis and high morbidity. Published median survival rates after WBRT are between 2 and 7 months. Standard of care in multiple BM is WBRT delivered as 30 Gy in 10 fractions, leading to modest palliation with a median survival of 3 to 5 months. Prognostic factors include the RPA-classification, performance status, response to steroids and evidence of systemic disease. Unfortunately, intracerebral recurrence happens. For example, in the cohort of Meyners et al.(2010) on WBRT in relatively radioresistant tumors, median time to recurrence was 4.5months and the local control rates at 6 and 12 months post radiationem were 37% and 15%, respectively. Furthermore, the treatment of intracerebral recurrence after previous WBRT is challenging. In case of \</= 3 recurrent BM, surgery or radiosurgery (RS) are options. One other option, especially in case of \>3 recurrent BM is repeated WBRT. In this setting, one of the first reports on repeated WBRT was published by Cooper et al. in 1990. The authors reported on repeated WBRT (n=52) consisting of 25 Gy in 10 fractions. Response to reirradiation was seen in 42% of the patients. Furthermore, the patients improved by at least one level in their neurologic function status. Survival after second therapy averaged 5 months. In the report by Wong et al. (1996) median dose of retreatment (n=86) was 20 Gy. Resolution of symptoms was achieved in 27% of patients, partial improvement in 43% and no improvement or worsening of symptoms was seen in 29% of patients. The majority of patients had no significant toxicity secondary to re-irradiation. Five patients had radiographic abnormalities of their brain consistent with radiation-related changes. One patient had symptoms of dementia that was thought to be caused by radiotherapy. Sadikov et al. (2007) reported on 72 patients who underwent repeated WBRT for recurrent or progressive BM. The median survival after re-irradiation was 4.1 months. One patient was reported as having memory impairment and pituitary insufficiency after 5 months of progression-free survival. In the report by Mayer et al. on re-irradiation tolerance of the human brain -in this analysis focused on recurrent glioma-, the authors concluded that radiation-induced brain tissue necrosis is found to occur at normalized tolerance doses of cumulative \> 100 Gy. The current study protocol is aimed at evaluating primarily the toxicity as well as secondarily the local and loco-regional tumor control, overall survival and QoL after repeated WBRT using 2 different dose concepts (20 Gy in 10 Fx vs. 30 Gy in 15 Fx) compared to BSC. In the present trial, the primary endpoint toxicity as well as the secondary endpoints QoL, loco-regional progression-free survival, overall survival and imaging response in patients previously treated with WBRT requiring repeated WBRT for intracerebral tumor progression will be evaluated.

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