Efficacy
The management of brain metastasis can be complex and involve a number of treatment modalities. The main goal of WBRT is to palliate the symptoms of brain metastases and surrounding oedema, and to prevent deterioration of neurologic function. There is limited evidence that patients with brain metastases of any histology and poor performance status will benefit from WBRT. All randomised studies have included a mix of histologies with a predominance of non small cell lung cancer and in an era of older systemic therapies.
WBRT alone
WBRT alone has a role in the management of brain metastases in patients who are not suitable for surgery and/or stereotactic radiosurgery. The evidence supporting the use of WBRT (as opposed to no brain radiation therapy) for patients unsuitable for surgical resection or SRS is largely historical. In poor performance status patients, consider best supportive care alone as a less toxic alternative to WBRT. This is supported by the outcomes of the QUARTZ trial which found that omitting WBRT did not significantly affect quality of life or overall survival.r
The key evidence supporting the use of this protocol comes from the Tsao et al.2012Cochrane review of WBRT for the treatment of multiple brain metastases.r This included 39 trials and 10,835 patients. Coia et al. also provides the historical summary of evidence which underpins the use of WBRT for palliation including clinical endpoints, tumour histology, dose fractionation schedules and prognostic factors.r
For the endpoint of overall survival, randomised studies have shown that 20 Gy in 5 fractions is neither inferior or superior to higher prescription doses.rr The majority of the published studies have used 30 Gy in 10 fractions in their control arms.
Adjuvant WBRT after local therapy
Adjuvant WBRT after local therapy or surgery results in better intracranial control but no overall survival benefit and worse neurocognition and quality of life.rrrrrrr Adjuvant WBRT is generally not indicated. If adjuvant radiation therapy is omitted, active surveillance is important e.g. 3-monthly MRI surveillance.
Post-operative WBRT
Patchell et al. randomised post-operative patients with single brain metastasis to receive either WBRT (50.4 Gy in 28 fractions) or no further treatment.r The radiation therapy group had less frequent recurrence of tumour anywhere in the brain (18% vs 70%, respectively; p <0.001). WBRT prevented recurrence both at the original metastasis site (10% vs 46%; p <.001) and at other sites in the brain (14% vs 37%; p <0.01). WBRT patients were also less likely to die of neurologic causes (14% vs 44%; p = 0.003). However, there was no significant difference in either overall survival or duration of functional independence.
Brown et al. published results of NCCTG N107C/CEC 3, a phase III study of postoperative SRS vs. WBRT (n=194).r Patients with one resected brain metastasis were randomised to receive either SRS (12-20 Gy in 1 fraction) or WBRT (30 Gy in 10 fractions). After a median follow-up on 11.1 months, SRS was shown to be less toxic compared to WBRT with a longer median cognitive-deterioration-free survival (3.7 months vs 3.0 months) and resulted in less cognitive deterioration (52% vs 85%). There was no difference in overall survival between the two groups (12.2 months for SRS vs 11.6 months for WBRT).
Hong et al. reported on a study of melanoma patients that received adjuvant WBRT following local treatment of one to three brain metastases which showed no improvement in intracranial control or survival benefit.r
Local therapy and WBRT
Kocher et al. reported on the EORTC 22952-26001 study where patients with 1-3 brain metastases were treated with local therapy (SRS or surgery) and then randomised patients to either receive WBRT (30 Gy in 10 fractions) or observation only.r The primary endpoint was time to WHO performance status >2 and there was no significant difference between the two arms; 10 months in the observation arm vs 9.5 months in the WBRT arm (p = 0.71). The 2-year relapse rate at the initial and new sites for both surgery and SRS groups and the rate of neurological death were significantly reduced in the WBRT arm. However, there was no significant difference in other endpoints such as duration of functional independence or overall survival.
Hippocampal sparing techniques
Brown et al. reported on the NCC 001 trial of hippocampal sparing WBRT (HA-WBRT) treatment compared to WBRT, both with the addition of memantine.rWith a median follow up of 7.9 months, they reported that compared to WBRT treatment, HA-WBRT reduced neurocognitive decline, fatigue, speech difficulties and cognitive symptoms, with no difference in OS, toxicity or PFS. They concluded that HA-WBRT may be suitable in conjunction with memantine for patients requiring WBRT with controlled systemic disease who are predicted to live longer than 4 months.