Radiotherapy for Brain Metastases

Transcription

1 Radiotherapy for Brain Metastases Robert B. Den, MD a, David W. Andrews, MD b, * KEYWORDS Brain metastases Treatment approaches SRS WBRT The optimal treatment of brain metastases remains controversial. There are several patientand treatment-related factors that must be considered to determine the optimal management for a given patient. At present, there is randomized control evidence supporting multiple treatment strategies incorporating radiotherapy. INCIDENCE Brain metastases affect 20% to 40% of patients with cancer 1 and are the most common intracranial tumor in adults. The incidence of metastases is thought to be increasing because of better detection and treatment of systemic malignancy. When considering various treatment approaches for brain metastases it is crucial to distinguish between single metastasis, only one lesion in the brain, regardless of extracranial status, and solitary metastasis, central nervous system (CNS) metastasis as the only site of disease, because this has disparate prognostic significance. PROGNOSIS In 1997, the Radiation Therapy Oncology Group (RTOG) analyzed their database of 1200 patients with brain metastases from 3 consecutive RTOG trials conducted between 1979 and 1993 to determine the patient factors that affected overall survival (OS). 2 This report defined 3 groups by recursive partitioning analysis (RPA): group 1, patients with Karnofsky performance score (KPS) of 70 or more, age less than 65 years, primary controlled metastasis, and no other extracranial metastases; group 2, patients with KPS of 70 or more, age of 65 years or greater, primary uncontrolled metastasis, other extracranial metastases; and group 3, patients with KPS less than 70. The median OS for these 3 cohorts was 7.1 months, 4.2 months, and 2.3 months, respectively. Since the publication of the report, there have been 2 updates to the RTOG RPA classification. Sperduto and colleagues 3 devised a new classification called the graded prognostic assessment (GPA) based on the RPA classification. The advantage of the GPA over the RPA classification is its ease of use and objectivity. The GPA classification is developed based on a point system and uses the following criteria: age, KPS, and cranial and extracranial metastases. Patient age is scored (0, 0.5, 1) stratified by age greater than 60 years, 50 to 59 years, or less than 50 years. KPS is scored (0, 0.5, 1) for age less than 70 years, 70 to 80 years, and 90 to 100 years. Cranial metastases are scored (0, 0.5, 1) for 3 brain metastases, 2 to 3 brain metastases, and 1 brain metastasis. Extracranial metastases are scored (0 or 1) if present or absent. The scores are summed, and OS correlates with higher score. Median OS is 2.6 months, 3.8 months, 6.9 months, and 11.0 months for a GPA score of 0 to 1, 1.5 to 2.5, 3, and 3.5 to 4, respectively. In addition, the RTOG recently defined diseasespecific GPA 4 based on more than 4000 patients with newly diagnosed brain metastases. This study defined various prognostic factors, which were scored to categorize patients based on OS. For patients with lung cancer (both small cell lung cancer [SCLC] and non-sclc [NSCLC]), 4 prognostic factors were included (age, KPS, extracranial metastases, and number of brain metastases). For a Department of Radiation Oncology, Thomas Jefferson University, 111 South 11th Street, Bodine Cancer Center, Philadelphia, PA 19107, USA b Department of Neurosurgery, Thomas Jefferson University, 909 Walnut Street, 3rd Floor, Philadelphia, PA 19107, USA * Corresponding author. address: david.andrews@jefferson.edu Neurosurg Clin N Am 22 (2011) doi: /j.nec /11/$ e see front matter. Published by Elsevier Inc. neurosurgery.theclinics.com

2 38 Den & Andrews patients with renal cell carcinoma or melanoma, 2 prognostic factors were used (KPS and number of brain metastases). For brain metastases from either a mammillary or gastrointestinal source, only KPS was required for prognostic significance. Based on these patient factors, median OS was determined (Tables 1 and 2). NATURAL HISTORY The natural history of symptomatic brain metastases is severe without surgical or radiotherapeutic intervention. The median OS without any treatment is 1 month 5 and with glucocorticosteroids alone reaches 2 months. 6 Thus, it is critical to determine a patient s expected survival before initiation of therapy; if it seems to be less than 30 days, intervention may not be warranted. TREATMENT APPROACHES There are several different treatment approaches for patients with brain metastases. Herein, the randomized evidence supporting various algorithms is presented. There is at present much controversy between the standard of care and the current National Comprehensive Cancer Network (NCCN) guidelines. The 2010 NCCN guidelines recommend either whole brain radiotherapy (WBRT) or chemotherapy for patients with 1 to 3 brain metastases, disseminated systemic disease, and poor treatment options. For patients with stable or newly diagnosed systemic disease with 1 to 3 brain metastases, options include surgery followed by WBRT or stereotactic radiosurgery (SRS), SRS plus WBRT, or SRS alone. For patients with greater than 3 metastases, WBRT alone is recommended. WBRT Alone WBRT as a monotherapy for brain metastases generally consists of opposed lateral beams covering the entire cranium with margin and treatment with a dose of 30 Gy in 10 fractions (fxns). This dose and fractionation scheme was tested in 2 RTOG trials, 7 RTOG 6901 and RTOG RTOG 6901 randomized 910 patients to 4 radiation schemes (30 Gy in 10 fxns, 30 Gy in 15 fxns, 40 Gy in 15 fxns, and 40 Gy in 20 fxns) with a median survival of 4.8, 4.1, 4.1, and 3.6 months, respectively, whereas RTOG 7361 analyzed 3 different radiation dose fractionation approaches (20 Gy in 5 fxns, 30 Gy in 10 fxns, and 40 Gy in 15 fxns) and found no difference in the median OS of 3.4, 3.6, and 3.6 months, respectively. Numerous other randomized controlled trials 8e20 compared various fractionation schemes, and none have been shown to be superior. However, RTOG 85e28 13 that delivered 32 Gy twice a day (1.6 Gy/fxn) plus an escalating boost for a total dose of 48 to 70.4 Gy showed increased survival for doses greater than 54 Gy, but these results were not validated in the subsequent RTOG 9104 trial. 9 WBRT with or without Surgery Having established the benefit of WBRT over steroids or no treatment in terms of OS, the role of surgical management was analyzed in 3 randomized controlled trials 21e23 and 1 trial originally randomized but changed to a registry trial because of poor accrual. 24 Patchell and colleagues 21 randomized 48 patients with suspected single brain metastasis to biopsy and then to WBRT versus surgery plus WBRT. Surgery was performed within 72 hours of randomization, and WBRT was administered within 14 days of surgery; for those patients Table 1 GPA criteria for brain metastases Points NSCLC/SCLC Age (y) >60 59e50 <50 KPS <70 70e80 90e100 No. of Cranial Metastases >3 2e3 1 Extracranial Metastases Present Absent Renal Cell Carcinoma/Melanoma KPS <70 70e80 90e100 No. of Cranial Metastases >3 2e3 1 Breast/Gastrointestinal Tract KPS <

3 Radiotherapy for Brain Metastases 39 Table 2 Median OS (in months) GPA Score NSCLC SCLC Melanoma Renal Cell Carcinoma Breast Gastrointestinal Tract 0e e e Overall randomized to WBRT alone, treatment began within 48 hours of randomization or biopsy. The dose and fractionation was 36 Gy in 12 fxns. The results revealed an increase in median OS (9 months vs 3 months, P<.05), decrease in neurologic death (14 months vs 6 months, P<.05), decrease in local recurrence (20% vs 52%, P<.05), time to recurrence (>14 months vs 5 months, P<.05), and quality of life for patients with KPS greater than 70 (9 months vs 2 months, P<.05) for surgery plus WBRT compared with WBRT alone. There was lower distant brain recurrence, 20% versus 13% (P 5.52), and no difference in systemic death. Thus, this trial demonstrated that for patients with single metastasis, the addition of surgery to WBRT results in patients living longer, having fewer recurrences, and having improved quality of life in comparison to patients receiving WBRT alone. The second published study by Vecht and colleagues 22 randomized 63 patients with suspected single brain metastasis to resection plus WBRT versus WBRT alone. The WBRT dosage was 2 Gy twice a day for 40 Gy over 2 weeks. None of the patients underwent magnetic resonance imaging (MRI) staging. This study showed that the median OS improved with WBRT plus surgery compared with WBRT alone (10 months vs 6 months, P<.05). For patients with stable extracranial disease, the median OS improved with surgery from 7 months to 12 months. However, in patients with progressive extracranial disease, there was no difference in the median OS between the 2 groups (median OS was 5 months for both the groups). In terms of functional independence, patients with stable extracranial disease had longer independence with surgery (4 months vs 9 months), but no difference was noted in those with progressive extracranial disease (2.5 months for both the groups). This trial demonstrated an improvement in OS for all patients; however, further analysis revealed that most deaths were caused by systemic disease and surgery benefited those with stable extracranial disease. The third randomized trial by Mintz and colleagues 23 randomized 84 patients with suspected single brain metastasis and KPS greater than 50 to WBRT (30 Gy in 10 fxns) versus WBRT plus surgery. All patients underwent computed tomographic staging. This trial failed to demonstrate an improvement in median OS for the addition of surgery to WBRT (6 months vs 6 months), and in addition, there was no difference in quality of life. However, this trial allowed patients with worse baseline KPS to be enrolled, and this population was shown to have minimal to no benefit with the addition of surgery to WBRT. Thus, the 3 randomized trials reveal a benefit to OS in patients with KPS greater than 70 with the addition of surgery to WBRT. Surgery with or without WBRT Having demonstrated the benefit of adding surgery to WBRT, the reverse question was explored in one randomized controlled trial. Patchell and colleagues 25 randomized 95 patients with single brain metastasis to complete resection (verified by MRI) followed by observation or postoperative WBRT (50.4 Gy over 5.5 weeks). Patients were eligible if their KPS was greater than 70, despite other sites of metastases. Randomization was stratified by the extent of extracranial disease and primary tumor type. The primary outcome was tumor recurrence anywhere in the brain. Postoperative WBRT was associated with less recurrence anywhere in the brain (18% vs 70%, P<.05), at the site of resection (10% vs 46%, P<.05), and in other areas of the brain (14% vs 37%, P<.05). In addition, there was decreased neurologic death (14% vs 44%, P<.05). There was no difference in OS or length of time for which the patient remained independent. This study was not powered to demonstrate a difference in overall time. Also, it should be noted that this study used a nonstandard WBRT dose. However, this study demonstrated a benefit in terms of neurologic death and local control to the addition of WBRT to surgery. A second randomized controlled trial conducted by the European Organization for Research and Treatment of Cancer (EORTC) randomized

4 40 Den & Andrews patients to surgery or SRS and to observation or WBRT. This work has been presented as an abstract at the 2009 American Society of Therapeutic Radiation Oncology annual meeting. EORTC randomized 359 patients with 1 to 3 brain metastases, with or without stable systemic disease or asymptomatic primary tumors, and KPS from 0 to 2 to surgery (160 patients) or SRS (185 patients) and to observation or WBRT (30 Gy in 10 fxns). Within the surgical arm, 96% of patients had solitary lesions, whereas in the SRS arm, 33% had multiple lesions. The median survival was 10 months (observation) versus 9.5 months (WBRT), which was not a statistically significant difference. Intracranial progression at 6 months and 24 months was 39.7% and 54.2% versus 15.2% and 31.2% for observation and WBRT, respectively. Statistically significant reduction was there in local failure (31.3% vs 16.4%) as well as distant intracranial failures (32.4% vs 17.6%) (P<.001). In addition, neurologic cause of death was 43% versus 25%. The results of this study are similar to the prior trials in that there is no improvement in OS with WBRT; however, it demonstrated improvement in local control, distant intracranial failure, and death from neurologic causes. Role of SRS SRS has been explored in the management of brain metastases alone or in conjunction with surgery and WBRT. There are no randomized trials of surgery with or without SRS or surgery versus SRS, and thus this topic is not discussed further. However, several trials have examined the benefit of the addition of SRS to WBRT and the converse case of addition of WBRT to SRS. WBRT with or without SRS WBRT with or without SRS has been studied in 2 randomized controlled trials. Andrews and colleagues 27 randomized 331 patients with 1 to 3 brain metastases with a maximum diameter of 4 cm to WBRT 37.5 Gy per 15 fxns versus WBRT plus radiosurgery (15e24 Gy, based on size) in the multicenter setting. Patients were stratified by the number of metastases and extent of extracranial disease. The primary end point was median survival. Secondary end points included tumor control at 1 year, KPS and mini-mental state examination (MMSE) at 6 months, and cause of death (neurologic vs nonneurologic). The median OS was 6.5 months versus 5.7 months for WBRT versus WBRT plus SRS, respectively (P 5.14); however, for patients with single metastasis, OS was 4.9 months versus 6.5 months (P<.05). In addition, there was a higher 3-month response rate and local control at 1 year (71% vs 82%) for the addition of SRS to WBRT. There was no difference in overall time to progression (any intracranial failure) and neurologic death. Local recurrence was 43% more likely with WBRT alone than with WBRT plus SRS. There was an improved KPS (4% vs 13%) and decreased steroid use at 6 months for WBRT plus SRS, but there was no difference in mental status. In summary, this trial demonstrated that WBRT plus SRS was beneficial for patients with single metastasis but did not improve median OS. A second single-institution randomized controlled trial from the University of Pittsburgh led by Kondziolka and colleagues 28 randomized adults with a KPS greater than 70 with 2 to 4 solid metastatic brain tumors, each 2.5 cm in mean diameter, to WBRT versus WBRT plus SRS. The primary end point of the study was imagingdefined local control. This trial was stopped early after a significant interim benefit in local control was demonstrated for the WBRT plus SRS arm. From the 27 patients randomized, the 1-year local failure was 100% versus 8% for WBRT versus WBRT plus SRS (P<.05) and the time to failure was 6 months versus 36 months for WBRT versus WBRT plus SRS (P<.05). The median OS was 7.5 months versus 11 months (P 5.22); however, because of early termination, the statistical power to assess differences in median survival was limited. However, patients in the WBRT arm who received salvage SRS had a median OS of 11 months (similar to WBRT with immediate SRS), whereas patients who received only WBRT had a median OS of 7 months (P<.05 to WBRT plus SRS). Thus, these data demonstrate a benefit to the addition of SRS to WBRT. SRS with or without WBRT There are 2 published, prospective, randomized trials comparing SRS alone with SRS plus WBRT, 29,30 and 1 prospective randomized trial has been presented as an abstract comparing surgery or SRS with either surgery or SRS with adjuvant WBRT. 26 The first published trial JROSG 99e1 randomized patients with 1 to 4 brain metastases, size less than 3 cm, and RPA class I to II to SRS alone (for <2 cm, 22e25 Gy; for 2e3 cm, 18e20 Gy) versus WBRT (30 Gy in 10 fxns) followed by SRS (with a dose reduction of 30%). The primary end point was OS, and the trial was terminated early (132 of expected 188 patients enrolled) because of low likelihood of showing a difference in primary end point. The trial demonstrated a median OS of 7.5 months versus 8.0

5 Radiotherapy for Brain Metastases 41 months (P 5.42), with a discordant 1-year OS of 38% versus 28% (P 5.42) for WBRT plus SRS versus SRS, respectively. Although neurologic death (23% vs 19% [P 5.64] for WBRT plus SRS versus SRS alone) was not significant, there was a statistically significant difference in the 12- month actuarial local tumor control rate of 88.7% in the WBRT plus SRS group versus 72.5% in the SRS-alone group (P 5.002), 12-month actuarial brain tumor recurrence rate of 46.8% in the WBRT plus SRS group versus 76.4% in the SRSalone group (P<.001), and 12-month actuarial rate of developing new brain metastases of 41.5% in the WBRT plus SRS group versus 63.7% in the SRS-alone group (P 5.003). Further, the addition of WBRT decreased the need for salvage brain treatment (10 patients vs 29 patients), and importantly, no statistically significant difference in neurotoxicity was reported. A more detailed review 31 of the trial s neurocognitive component as assessed by MMSE revealed that the average duration until deterioration of neurocognition was 16.5 months in the WBRT plus SRS group and 7.6 months in the SRS-alone group (P 5.05). Thus, indicating that control of the brain tumor is the most important factor for stabilizing neurocognitive function (NCF). The second randomized controlled study 30 was a single-institutional study that randomized patients with RPA class I to II (KPS70) and 1 to 3 brain metastases to SRS (median dose of 19 Gy) versus SRS (median dose, 20 Gy) plus WBRT (30 Gy in 12 fxns). The primary end point of this trial was NCF that is objectively measured as a significant deterioration (5-point drop compared with baseline) in Hopkins Verbal Learning Test-Revised (HVLT-R) total recall at 4 months. This trial was halted early (58 of expected 90 patients enrolled) because of significantly worse cognitive outcome in WBRT plus SRS arm. The results of the trial revealed that OS was compromised in the WBRT plus SRS arm. The median and 1-year survival were higher for the SRS-alone group than for patients in the SRS plus WBRT group (15.2 months vs 5.7 months, 63% vs 21%; P 5.003); however, 1-year local tumor control rate was 67% for patients in the SRS group and 100% for patients in the SRS plus WBRT group (P 5.012), the 1-year distant brain tumor control rate was 45% for patients in the SRS group and 73% for patients in the SRS plus WBRT group (P 5.02), and the 1-year freedom from CNS metastasis recurrence was 27% (95% confidence interval [CI], 14e51) for the SRS group and 73% (95% CI, 46e100) for the SRS plus WBRT (P<.001) group. Thus, in case of neurologic control, SRS plus WBRT was superior. However, death from neurologic causes was not statistically significant (7 deaths vs 8 deaths, P 5.15). In the SRS-alone arm, 1 patient received salvage WBRT and 7 patients underwent salvage craniotomy compared with none in the SRS plus WBRT arm. NCF had a statistically significant decline (52% vs 24%) in the SRS plus WBRT arm versus SRS-alone arm. Thus, this trial demonstrated that the addition of WBRT improved local neurologic control, distant brain disease, and freedom from CNS metastasis recurrence but failed to show an improvement in death from neurologic cause, and in fact, this trial demonstrated worse NCF and OS. This is the first trial to show a decline in OS for the addition of WBRT. However, there are several criticisms to this trial that should be noted. A prior prospective study 32 revealed that for patients treated with WBRT a biphasic pattern of post-wbrt NCF is noted. With multiple time points measured, NCF of longterm survivors typically declines at about the 2- to 4-month point but subsequently rebounds. Given the complexity of NCF, a battery of tests over time is required to assess neurocognition adequately. 33 Another concern is the balance of the study groups. Several findings point to patients in the combined group having a disproportionately worse prognosis at outset. The SRS-alone group comprised a majority of women, patients with single metastasis, RPA class I patients, and an absence of patients with lung and abdominal metastases. In fact, the OS of the SRS-alone arm was 7 months longer than that of the Japanese study 29 (15.2 months vs 8.0 months). Furthermore, the combined therapy group had a greater burden in disease volume. Baseline NCF is highly correlated with the volume of indicator lesions but not with the number of metastases. 34 In addition, there was a trend for worse baseline function in the SRS plus WBRT arm versus SRS-alone arm. Also, the investigators did not account for possible bias due to medications, which could have adversely affected neurocognition. 35 There was a high rate of salvage in the SRS-alone arm. This finding suggests that treatment assignment led to bias in the subsequent aggressive approach to salvage therapy in the SRS-alone group. In the SRSalone group, chemotherapy was administered to more patients and for a longer duration. Given the proximity of death to the primary end point (1-month difference), it is unclear if the decline in NCF was caused by irradiation or progressive decline. Several studies revealed a decline in mental function before death. 36 There is currently 1 open trial examining the question of SRS with or without WBRT and it is being conducted by the North Central Cancer

6 42 Den & Andrews Group and American College of Surgeons Oncology Group. This trial is randomizing patients with 1 to 3 cerebral metastases to SRS versus SRS plus WBRT. The primary end point is OS, and secondary end points include time to CNS (brain) failure, quality of life, duration of functional independence, long-term neurocognitive status, and posttreatment toxicity. Can WBRT Be Improved with the Addition of Chemotherapy? There have been several randomized controlled trials examining the addition of various chemotherapeutic agents to WBRT. None of the trials demonstrated a statistically significant improvement in OS. Phillips and colleagues 11 conducted the RTOG 8905 trial that randomized 72 patients with a KPS of 70 or more and no other metastases to WBRT (37.5 Gy/15 fxns) with or without bromodeoxyuridine. The median OS was 6.1 months versus 4.3 months (P 5.904) for the WBRT versus WBRT plus bromodeoxyuridine groups. Mehta and colleagues 37 randomized 401 patients to 30- Gy WBRT versus WBRT with concurrent motexafin gadolinium. There was no difference in survival (4.9 months vs 5.2 months, P 5.48) or time to neurologic progression (9.5 months vs 8.3 months, P 5.95). However, there was an improvement in neurologic progression in patients with NSCLC. Guerrieri and colleagues 38 randomized 42 patients with brain metastases from NSCLC to WBRT with or without carboplatin. OS was 4.4 months versus 3.7 months (P 5.64), but this trial was stopped early because of poor accrual. Ushio and colleagues 39 randomized patients with lung cancer to 3 arms, WBRT, WBRT plus chloroethylnitrosureas, and WBRT plus chloroethylnitrosoureas plus tegafur. There was no difference in survival among the 3 arms. Neuhaus and colleagues 40 randomized 96 of a planned 320 patients with SCLC or NSCLC and with brain metastases to WBRT (40 Gy in 20 fxns) versus WBRT plus topotecan. This trial was closed early because of poor accrual, and there was no difference in local recurrence or disease-free survival. Knisely and colleagues 41 randomized patients in the multicenter arena on RTOG 0118 to WBRT (37.5 Gy in 15 fxns) with or without thalidomide. This trial, which was stopped early because of nonsuperiority, accrued 183 patients with multiple (>3), large (>4 cm), or midbrain metastases from extracranial disease. The median OS in both cohorts was 3.9 months; however, 48% of patients had to discontinue use of thalidomide due to toxicity. Thus, these collective studies failed to demonstrate a benefit to the addition of chemotherapy to WBRT. Can WBRT Be Improved? Improvement to traditional WBRT is currently being examined in the RTOG trial. Given the concern for neurocognitive decline after WBRT, an intensity-modulated hippocampal sparing approach is being pursued. RTOG 0933 is a phase 2 clinical trial that aims to test the hypothesis that for patients with brain metastases, avoiding the hippocampus during WBRT may delay or reduce the onset, frequency, and/or severity of NCF decline, without compromising intracranial disease control. Numerous studies have examined the incidence of brain metastasis within 5 mm of the hippocampal regions. Gondi and colleagues 42 found that of the more than 1000 brain metastases evaluated, 34 (3%) were within 5 mm of the hippocampus and none were in the hippocampus. Thus, the feasibility of improving memory decline without compromising function is possible. Another approach to reduce neurocognitive decline being pursued in the prospective setting is the addition of memantine, an N-methyl-Daspartate receptor antagonist that has proven to be effective in the treatment of vascular dementia, to WBRT in RTOG This trial randomizes patients to WBRT (37.5 Gy in 15 fxns) versus placebo or memantine. The planned accrual is 536 patients, and the primary outcome is to determine whether the addition of memantine to WBRT preserves NCF, specifically memory as measured by the HVLT-R for delayed recall, compared with placebo and WBRT in patients with brain metastases at 24 weeks from the beginning of drug treatment. SUMMARY There is a clear benefit to the addition of radiotherapy in the management of brain metastases. WBRT has been shown to be beneficial when added to surgery, and surgery has been demonstrated to be beneficial to WBRT in patients with good KPS and controlled extracranial disease. The role of WBRT followed by SRS has been demonstrated to provide benefit including improvement of OS, but SRS followed by WBRT continues to remain controversial. There are several trials that examine improving the neurotoxicity associated with WBRT. However, there is no role to the addition of chemotherapy to WBRT at present.

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