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.

Response to treatment after WBRT in a patient with multiple brain metastases from lung cancer. (Left) A 3.6 by 3.1 cm left cerebellar tumor is present before treatment. (Right), 2 months post-WBRT of 30 Gy in 10 daily fractions, the tumor shrunk to 2.5 by 2.0 cm. The patient also had an improvement in gait.

Expected Survival after Whole Brain Radiation Therapy

Survival after WBRT varies from a few weeks to a few years. The RTOG has published two widely used and validated indices, the recursive partition analysis (RPA) ( ) and the graded prognostic assessment (GPA) ( ). The RPA ( Table 8.1 ) categorizes patients into three classes based on age, Karnosky performance status (KPS) and control of extracranial disease. Class 1 patients (KPS≥70, age<65, and controlled primary with no extracranial metastases) have the best median survival of 7.1 months, while Class 3 patients (KPS<70) have the worst median survival of 2.3 months. Class 2 patients (all others) have an intermediate median survival of 4.2 months. The GPA was developed to account for the number of brain metastases and remove the subjective factor of control of systemic disease. The GPA evaluates the factors of age, KPS, presence or absence of extracranial metastases and number of metastases (one, two to three, and more than three), and assigns a score for each and the overall sum predicts for median survival. The diagnosis-specific GPA (DS-GPA) improves on the GPA and utilizes histology as a key factor that predicts survival. For example, the significant prognostic factors for non-small cell lung cancer (NSCLC) and SCLC include the original four factors whereas, for breast and gastrointestinal cancers, the only significant prognostic factor is KPS ( ).

Whole Brain Radiation Therapy and Surgery

The combination of surgery and WBRT in the treatment of brain metastases, in particular solitary metastases, has been well established. Three prospective randomized trials have evaluated the addition of surgery in addition to WBRT. Two of the three studies support the addition of surgery to WBRT in selected patients with good performance status, controlled extracranial disease, and a single brain metastasis. Patients had improved local control, increased duration of functional independence, and increased median survival. Factors found to be associated with longer survival included younger age, no extracranial disease, surgical resection, and longer interval from primary diagnosis to diagnosis of brain metastasis ( ).

The addition of WBRT following surgical resection has been addressed in two randomized trials. The first study by had 95 adults with solitary brain metastases treated with complete surgical resection and randomly assigned to observation versus postoperative WBRT (50.4 Gy in 28 fractions). The WBRT arm was found to have a significantly decreased risk of local failure (10% vs 46% for observation), distant brain failure (14% vs 37%), and any brain failure (18% vs 70%), longer median time to local failure (more than 52 vs 27 weeks), and longer median time to any brain failure (more than 70 vs 26). Patients randomized to WBRT were significantly less likely to die neurologic deaths (14% vs 44%), though they had similar median survival and length of functional independence. The second trial by the EORTC randomized patients to WBRT (30 Gy in 10 fractions daily) or observation with one to three brain metastases treated with either surgery or radiosurgery. One-hundred and sixty patients underwent surgery, with 79 patients allocated to observation, and 81 allocated to adjuvant WBRT. WBRT reduced 2-year relapse at initial sites from 59% to 27%, and at new sites from 42% to 23%. WBRT reduced the frequency of salvage treatment, and death from intracranial progression ( ).

Whole Brain Radiation Therapy and Radiosurgery

Radiosurgery plays an important role in the treatment of brain metastases and indications for treatment alone or in combination with WBRT have been well established. The first trial by randomized patients with two to four brain metastases treated with WBRT to radiosurgery boost or observation. WBRT consisted of 30 Gy delivered in 12 fractions. Radiosurgery was delivered at any time within 1 month before or after WBRT and consisted of a single dose of 16 Gy. The radiosurgery arm had a significantly improved time to local failure (median 36 months vs 6 months, p =0.0005) and time to any brain failure (median 34 months vs 5 months, p =0.002). Survival, however, was similar as several patients who failed WBRT alone underwent salvage radiosurgery. The second trial by RTOG randomized 333 patients with one to three brain metastases treated with WBRT (37.5 Gy in 15 fractions daily) to radiosurgery boost versus observation. Radiosurgery doses were based on tumor size according to RTOG 9005 toxicity information ( ). No survival benefit was seen in patients with multiple metastases. Univariate analysis demonstrated a significant survival advantage in the WBRT plus SRS group for the following patients: single brain metastases (median survival 6.5 vs 4.9 months, p =0.039), patients with tumor size greater than 2 cm (median survival 6.5 vs 5.3 months, p =0.045), and RPA class 1 patients (median survival 11.6 vs 9.6 months, p =0.045). No differences were noted for time to intracranial tumor progression, neurologic death rate, or mental status, although the risk of developing local recurrence was 43% greater in the WBRT alone arm. The authors concluded that WBRT plus radiosurgery improved functional status for patients with one to three metastases and survival for patients with a single unresectable brain metastasis ( ).

Three randomized trials have evaluated the role of WBRT in addition to SRS in patients with less than three or four metastases. randomized 132 patients with one to four brain metastases, each less than 3 cm to WBRT and radiosurgery or radiosurgery alone. The primary endpoint was overall survival, and secondary endpoints included brain tumor recurrence, salvage brain treatment, functional preservation, toxicity, and cause of death. The median survival times were similar at 7.5 months in the WBRT plus SRS group and 8 months for SRS alone group ( p =0.42). The 1-year brain tumor recurrence rate was 46.8% in the WBRT plus SRS group and 76.4% for SRS alone group ( p <0.0001). Salvage brain treatment was less frequently required in the WBRT plus SRS group. Death from neurologic causes was similar between the groups.

conducted a randomized trial on patients (stopped early by the data monitoring committee) with one to three brain metastases and used neurocognition assessed through the validated Hopkins Verbal Learning Test (HVLT) as the primary endpoint. After 58 patients were recruited, the trial was stopped by the data monitoring committee as significant differences in learning and memory at 4 months were observed favoring the SRS alone arm. An absolute difference of 18% at 4 months was reported in the probability of neurocognitive decline favoring SRS alone. One-year local control (67% vs 100%) and 1-year distant brain control (45% vs 73%) favored the SRS and WBRT arm. Substantially more salvage procedures in the group treated with SRS alone (83% vs 7%) were observed. Although, this study was not powered to detect differences in overall survival (OS), median OS was 15 months vs 6 months favoring SRS alone. This apparent difference in OS favoring SRS alone, despite higher rates of recurrence, was likely at least in part due to imbalances in the two arms. More patients in the SRS and WBRT arm had liver or adrenal metastases and larger intracranial volume of disease.

The EORTC ( ) randomized 199 patients with one to three brain metastases who underwent SRS to observation ( n =100) vs WBRT ( n =99). The primary endpoint evaluated functional independence by measuring time to WHO performance status (PS) deterioration to more than 2. WBRT reduced the 2-year relapse rate both at initial sites from 31% to 19% ( p =0.04) and at new sites from 48% to 33% ( p =0.023). Salvage therapies were used more frequently in the observation arm. The median time to WHO PS more than 2 was 10.0 months in the observation arm and 9.5 months in the WBRT arm ( p =0.71). From these trials and a Cochrane systematic review ( ), there is evidence that the addition of WBRT to radiosurgery in patients with a limited number of brain metastases reduces intracranial relapses (local and distant) but fails to improve the duration of functional independence, likely has no impact on overall survival and is detrimental to neurocognitive function.

Whole Brain Radiation Therapy and Radiosensitizers

Radiosensitizers have been administered with RT to try to improve the efficacy of WBRT. A number of cytotoxic chemotherapeutic drugs (such as cisplatin and vinorelbine) and non-cytotoxic agents (such as temozolomide, metronidazole, misonidazole, bromodeoxyuridine, motexafin gadolinium and efaproxiral) have been used for their radiosensitizing properties, but have shown limited benefit when added to WBRT in clinical practice ( ).

One of the drugs studied is an analog of the magnetic resonance imaging (MRI) contrast agent thought to potentiate the effect of radiation. A phase III trial of WBRT with or without motexafin gadolinium was conducted on 401 patients. No significant differences were seen in median survival (5.2 months in the sensitizer arm compared to 4.9 months in the control arm) or median time to neurologic progression (9.5 months compared to 8.3 months). However, among 251 NSCLC patients, motexafin gadolinium was found to improve median time to neurologic progression (not reached compared to 7.4 months, p =0.048) and overall neurologic function ( ). A follow-up randomized study of WBRT with or without motexafin gadolinium in NSCLC patients only, revealed a trend to improved time to neurologic progression (15 months in the motexafin gadolinium arm vs 10 months in the WBRT alone arm, p =0.12) ( ). A similar selective benefit of the addition of efaproxiral (RSR13, Efraproxyn), a compound with radiosensitizing properties in hypoxic tissues, with WBRT was observed in the subgroup of patients with brain metastases from a breast cancer primary ( ). A confirmatory trial in only breast cancer patients with brain metastases, however, failed to demonstrate improved survival (8.5 months in the efaproxiral arm compared to 7.5 months in the control arm, p =0.233) ( ).

Clinical trials with WBRT adding drugs that are known to cross the blood–brain barrier and have documented activity in different malignanices have been disappointing. The RTOG 0320 published in abstract form only after premature closure due to slow accrual, the results of a three-arm phase III trial in patients with one to three brain metastases from NSCLC. Patients received WBRT plus radiosurgery ( n =126) and were randomized to one of three arms; no further treatment in arm 1, combined with temozolomide (75 mg/m ² /day) in arm 2, or combined with erlotnib (150 mg/day) in arm 3. Temozolomide is an oral alkylating agent with activity in gliomas and malignant melanoma and readily crosses the blood–brain barrier (BBB) achieving significant concentrations in the central nervous system. Erlotinib is an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase pathway, and also readily crosses the BBB and is active against some NSCLCs. Neither the addition of temozolomide or erlotinib resulted in an improvement in OS, nor time to CNS progression compared to WBRT and SRS alone. In fact, median survival favored WBRT and SRS alone (13.4 months in arm 1, 6.3 months in arm 2, 6.1 months in arm 3). This surprising result was not related to excess toxicity ( ).

In contrast to radiosensitizers, some studies have attempted to use drugs that may have neuroprotective properties. RTOG 0641 has recently presented in abstract form the results of a study on 508 eligible patients treated with WBRT of 37.5 Gy in 15 daily fractions, randomized to memantine 20 mg daily for 28 weeks versus placebo. Memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist, and is approved for the treatment of moderate to severe Alzheimer’s disease. The primary objective was assessment of memory on the Hopkins Verbal Learning Test-Revised (HVLT-R) at 24 weeks. The secondary endpoints were time to cognitive decline, overall survival and progression-free survival. Memantine resulted in less decline in delayed recognition at 24 weeks ( p =0.015), cognitive function failure at 24 weeks ( p =0.01) and increased the time to cognitive decline (HR 0.78, p =0.015). Memantine also resulted in fewer declines in executive and global function. There were no differences in overall or progression-free survival ( ).