Whole brain radiaiton therapy has been used to treat patients with multiple brain metastases for decades. To date, no trial has demonstrated a survival advantage. The median survival following whole brain radiation is around 4 to 6 months. Gaspar described a recursive partition analysis scheme for brain metastases based on age, performance status and control of primary disease. (see RPA discussion) The RTOG and others have looked at ways to improve survival, including the addition of SRS, or alternatively treating with different dose/fractionation schemes, use of steroids either exclusively or combined with radiation.
Median survival with brain metastases is short. It does vary based on whether or not the primary disease is controlled and the histology of the original disease. The RTOG RPA/GPA series discussed primary disease based and clinical characteristics based prognosis, but in the worst case scenario (advanced age, uncontrolled primary, poor performance status), median survival is on the close order of 2 months. In the best scenario, (young, good performance, controlled primary, favorable primary pathology and site) median survival can be longer than a year.
A more or less standard whole brain radiation treatment is a set of 6 MV photon beams arranged in an opposed lateral combination. Many dose/fraction schemes are in use. Among these are:
There is concern for the development of late leukoencephalopathy of radiation therapy. Original studies by Patchel looked at post-radiation symptoms but did not do comprehensive neurocognitive studies prior to radiation to assess a baseline state post radiation. The post-radiation analysis may not be fully reflective of true radiation effects in those studies. Three randomized trials have demonstrated the benefit of whole brain radiation to focal therapy in patients with limited intracranial metastases. Patchell reported local control of 90% v. 54%, improved extra-cranial control and cumulative intracranial control (82% v. 30%) compared to surgical resection alone. Patients in the WBRT arms were less likely to suffer neurologic death and resulting loss of quality of remaining life from intracranial progression. This trial was not designed nor powered to detect a survival difference and was designed only for intracranial control analysis.
A Japanese study (JROSG) looked at patients with 1-4 metastases randomized to SRS, WBRT+SRS. The WBRT arm had superior control, superior distant intracranial control, and total intracranial control.
An EORTC study corroborates the findings of the other trials (EORTC 22952-26001) demonstrated an improved progression free survival of 4.6 v. 3.4 months, lower neurologic death rates (28% v. 44%), improved lesion control and improved intracranial control compared with surgery or SRS alone.
Initial studies did not perform high quality neurocognitive assessments prior to initiating whole brain radiation therapy. These studies did not stratify by previous craniotomy, chemotherapy, narcotics, steriods, presence of metastases and prior radiation therapy. DeAngelis reported 11% severe dementia rate in patients who were treated with WBRT and survived a minimum of 1 year post WBRT. The study itself was small and 5 patients of 47 were treated. Of these 5 three were treated with 5 or 6 Gy/fraction, one was treated with 6 Gy/fraction and concurrent doxorubicin. One was treated at 3 Gy/fraction but with concurrent radiosensitization with lonidamine. No patients who were treated with standard fractionation radiotherapy in the absence of concurrent systemic therapy developed dementia.
The RTOG NSCLC prophylactic cranial irradiation study treated patients to 30 Gy in 15 fractions was controlled for no intracranial disease, controlled primary disease in stage IIIA/B lung cancer. Quality of life and neurocognitive assessment pre- and post-radiation showed no statistically significant difference in quality of life at 6 and 12 months. There was a greater decline on MMSI at 3 months in the irradiated patients, but this resolved by 6 months, and involved delayed and immediate recall. Cognitive risk is not age dependent, memory decline was relatively frequent, involving both immediate and delayed recall.
In a 2009 literature review by Y. R. Lawrence (doi:10.1016/j.ijrobp.2009.02.091 / PII: S0360-3016(09)03287-8) Lawrence noted that the incidence and severity of cognitive decline is dose and volume dependent, can be increased by chemotherapy, age, diabetes and spatial factors. He states that teh evidence supporting RT-induced neurocognitive injury is weak and notes that there was evidence of neurocognitive dysfunction present in patients even prior to any radiation therapy. The effects are noted more in treatments ≥ 3 - 6 Gy/fraction. Four studies showed no cognitive difference at ≤ 2 years followup. Young age has consistently been shown to be a risk factor for neurocognitive decline with radition therapy. Lawrence concludes that a BED3 of 120 Gy or less is associated with a 5% risk of radionecrosis.
Whole brain radiation therapy is the mainstay of treatment of intracranial metastases. Dosing schemes discussed above have been used, but most commonly, 30 Gy in 10 fractions and 37.5 Gy in 15 fractions are used. Shorter course radiation in those with clearly limited life expectancy are sometimes reasonable, but at a clearly increased risk of neurocognitive impairment (20 Gy in 5 fractions @ 4 Gy/fraction). A German review of practice and outcomes demonstrated increased risk of neurocognitive issue with fraction sizes > 3 Gy/day, consistent with other studies.
There is no strong evidence to support the use of chemotherapy or radiosensitizing agents with concurrent radiotherapy and the original DeAngelis study reported a patient with lonidamine and 3 Gy/fraction with severe neurocognitive decline, while others treated with 3 Gy/fraction alone had no such effect.
SRS and Surgery have lesser roles in patients with multiple metastases. Some retrospective studies have suggested that it can offer survival benefit but its role remains controversial.
Whole brain radiation therapy is an effective palliative tool for patients with multiple brain metastases, Half have an improvement in neurologic symptoms, but a majority do not achieve local control and succumb to progression in the brain. The role of SRS in single metastases is clear, and likely in 1-3 mets, but beyond that is unclear and cannot replace the benefits of WBRT per the Japanese trial.
A 50 year old man has a history of NSCLC (adenocarcinoma) initailly staged T2N0M0, after comprehensive staging workup. He underwent a lobectomy, clear margins and has done well for 6 months. An MRI was obtained in followup which demonstrated two intracranial metastases, both resectable. One is in the right frontal hemisphere, the other in the right lateral cerebellum. The frontal lesion is 3 cm and the cerebellar lesion is < 1 cm. These are imaging findings only with no clinical findings. A further staging workup has not revealed other evidence of metastases. What are the treatment options, prognosis and recommendations?