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Multiple Metastases to the Brain from Primary Cancers: Whole Brain Radiotherapy
Introduction
Brain metastases from primary cancers represent a significant disease burden and common source of morbidity and mortality in the cancer population. Brain metastases, for example, are estimated to occur in 20–40% of all patients with cancer during the course of their illness ( ). In diseases such as melanoma, the incidence of brain metastases has been found to be close to 60% in autopsy studies ( ). Whole brain radiotherapy (WBRT) was historically the only treatment for patients with multiple brain metastases and now, despite many advances in radiation technology, still plays a major role in treatment. In the past couple of decades, advancements in imaging, surgical techniques, and radiation planning and delivery, the options for treatment of brain metastases have expanded. Current management options include: surgical resection, stereotactic radiosurgery (SRS), WBRT, and supportive care measures only.
Beginning in the 1970s, multiple phase III trials assessing different WBRT fractionation schedules were studied, and overall no benefit above standard dose fractionation schedules of 2000 cGy in five daily fractions or 3000 cGy in 10 daily fractions has been observed. The results of trials adding radiosensitizers have been disappointing with no additional benefit to WBRT in either local tumor response or overall survival.
Treatment recommendations for multiple brain metastases are currently in flux. Aggressive local therapy in the form of SRS or, in some cases, surgery should be considered for patients with favorable prognostic factors presenting with up to four brain metastases. These prognostic factors include the presence of symptoms, age, performance status, histology, and status of extracranial disease. The role of WBRT in patients with up to four brain metastases has been questioned as there is no survival benefit and there may be worsening neurocognitive outcomes ( ). In patients with more than four brain metastases, the standard treatment continues to be WBRT, however, ongoing studies are challenging the role of WBRT in select patients.
Whole Brain Radiation Therapy
The therapeutic effects of WBRT for brain metastasis were appreciated as far back as the 1960s, with symptomatic improvement and prolongation of life noted in a large proportion of treated patients. The RTOG has conducted numerous WBRT randomized trials answering key questions on altered dose and fractionation schedules ( ). With extended fractionation schedules (50 Gy in 20 fractions daily or 54.4 Gy at 1.6 Gy twice daily) compared to the more commonly prescribed 30 Gy in 10 fractions daily, no differences in survival, symptomatic response or duration of response were observed. Hypofractionated WBRT (10 Gy in one fraction, 12 Gy in two fractions daily, 15 Gy in two fractions over 3 days), showed a possible increased risk of herniation and death within a few days of treatment and are generally avoided. As a result, the most common WBRT fractionation schemes include 20 Gy in five fractions or 30 Gy in 10 fractions, daily ( ).
Whole Brain Radiation Therapy Technique
WBRT simulation, planning and treatment have changed over the past couple of decades with advances in computed tomography (CT) simulation, treatment planning and delivery technology. WBRT in the past was often done as a clinical mark-up without simulation. Typically≤6 MV photon beams with a right and left lateral parallel opposed field arrangement were used. The inferior border was set below a line that approximates the location of the skull base – connecting the supraorbital ridge with the mastoid tip. The superior border was set up above the cranial apex. This type of a set up, however, often led to underdosage of the middle cranial fossa. Also, the lack of computerized dosimetry would result in variation in the dose within the brain that could be as much as±20% depending on the cranial anatomy. Presently, with the availability of CT simulation, multileaf collimators (MLCs) and advanced treatment planning software, it is possible to plan and deliver more homogeneous radiation treatments that do not underdose parts of the brain and still limit the dose to organs at risk (such as the eyes).
Whole Brain Radiation Therapy Tumor Response
The few studies that have analyzed tumor response after WBRT suggest poor long-term control. analyzed CT scans in 108 patients with 336 measurable lesions following WBRT of 30 Gy in 10 fractions daily. Complete and partial response rates at up to 3 months were 24% and 35%, respectively. Response rates were dependent on histology with, for example, 37% of small cell carcinoma and 35% of breast cancer patients having a complete response while 0% of renal cell carcinoma and melanoma tumors having a complete response. Smaller tumor volume and absence of necrosis were associated with improved complete response rates. Complete response rates were 39% for solid metastases, 15% if less than 50% necrosis, and 11% if 50% or more necrosis. Complete response rates were inversely related to volume, with 52% of metastases<0.5 cm 3 having a complete response versus 0% of tumors>10 cm 3 . In a follow-up study, analyzed the CT scans of 322 patients treated with different WBRT schedules and calculated the biologically effective dose (BED). Partial remission rates improved with increasing BED. Figure 8.1 illustrates the response in a cerebellar metastases after WBRT in a patient with multiple brain metastases from lung cancer. Data from randomized trials illustrate poor longer-term control. Actuarial 1-year local control following WBRT ranges between 0% and 14% ( ). Overall, WBRT is unlikely to provide long-term control in most patients, however, favorable histology, small tumor volume and higher doses may result in improved local control.
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