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Articles Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 958 randomised trial David W Andrews,
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Articles Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 958 randomised trial David W Andrews, Charles B Scott, Paul W Sperduto, Adam E Flanders, Laurie E Gaspar, Michael C Schell, Maria Werner-Wasik, William Demas, Janice Ryu, Jean-Paul Bahary, Luis Souhami, Marvin Rotman, Minesh P Mehta, Walter J Curran Jr Background Brain metastases occur in up to % of all patients with systemic cancer. We aimed to assess whether stereotactic radiosurgery provided any therapeutic benefit in a randomised multi-institutional trial directed by the Radiation Therapy Oncology Group (RTOG). Methods Patients with one to three newly diagnosed brain metastases were randomly allocated either whole brain radiation therapy (WBRT) or WBRT followed by stereotactic radiosurgery boost. Patients were stratified by number of metastases and status of extracranial disease. Primary outcome was survival; secondary outcomes were tumour response and local rates, overall intracranial recurrence rates, cause of death, and performance measurements. Findings From January, 1996, to June, 21, we enrolled 333 patients from 55 participating RTOG institutions 167 were assigned WBRT and stereotactic radiosurgery and 164 were allocated WBRT alone. Univariate analysis showed that there was a survival advantage in the WBRT and stereotactic radiosurgery group for patients with a single brain metastasis (median survival time 6 5 vs 4 9 months, p= 393). Patients in the stereotactic surgery group were more likely to have a stable or improved Karnofsky Performance Status (KPS) score at 6 months follow-up than were patients allocated WBRT alone (43% vs 27%, respectively; p= 3). By multivariate analysis, survival improved in patients with an RPA class 1 (p 1) or a favourable histological status (p= 121). Interpretation WBRT and stereotactic boost treatment improved functional autonomy (KPS) for all patients and Departments of Neurosurgery (D W Andrews MD), Radiology (A E Flanders MD), and Radiation Oncology (M Werner-Wasik MD, W J Curran Jr MD), Thomas Jefferson University Hospital, Philadelphia, PA, USA; American College of Radiology, Philadelphia, PA, USA (C Scott PhD); Methodist Hospital Cancer Center, Minneapolis, MN, USA (P W Sperduto MD); Department of Radiation Oncology, University of Rochester, Rochester, NY M C Schell PhD); Akron City Hospital, Summa Health System, Akron, OH (W Demas MD); UC Davis Medical Center, Sacramento CA (J Ryu MD); University of Colorado Cancer Center, Denver CO (L E Gaspar MD); Notre Dame Hospital, University of Montreal, Montreal, Canada (J P Bahary MD); Department of Oncology, McGill University Health Center, Montreal (L Souhami MD); SUNY Health Science Center, Brooklyn, NY (M Rotman MD); and University of Wisconsin Comprehensive Cancer Center, Madison, WI (M P Mehta MD) Correspondence to: Professor David W Andrews, Thomas Jefferson University, 99 Walnut Street, 2nd Floor, Philadelphia, PA 1917, USA ( survival for patients with a single unresectable brain metastasis. WBRT and stereotactic radiosurgery should, therefore, be standard treatment for patients with a single unresectable brain metastasis and considered for patients with two or three brain metastases. Lancet 24; 363: Introduction Brain metastases occur in 2 % of patients with systemic cancer; 1 3 % present with a single metastasis. 2 Outlook for patients is poor with a median survival time of 1 2 months with corticosteroids, 3 which can be extended to 6 months with whole brain radiation therapy (WBRT), 4,5 and some investigators 6,7 report that survival can be further lengthened when WBRT is preceded by surgical resection. Originally developed by the Swedish neurosurgeon Lars Leksell, 8 radiosurgery is a technique that involves single treatment radiation precisely focused at intracranial targets. Radiosurgery is frequently used to treat brain metastases, sometimes preferred to surgery as a less invasive alternative. We report results of the first multiinstitutional prospective randomised comparison of WBRT with or without stereotactic radiosurgery for patients with one to three brain metastases. Methods Participants The study population included patients with confirmed systemic malignant disease. All patients were aged 18 years or older with no previous cranial radiation. Entry criteria included a contrast-enhanced MRI scan showing one to three brain metastases with a maximum diameter of 4 cm for the largest lesion and additional lesions not exceeding 3 cm in diameter. 9 Metastases were deemed unresectable if they were located in deep grey matter or in eloquent cortex. Postoperative patients with either residual or distal brain metastases were eligible if the total number of metastases remained three or fewer. We excluded patients who had Karnofsky Performance Status (KPS) score of less than 7, haemoglobin concentration less than g/l, absolute neutrophil count of less than Recursive partitioning analysis classes for brain metastases 11 Class 1 Class 2 Class 3 KPS 7 7 7 Primary status Controlled Uncontrolled Age (years) 65 65 Extracranial Brain only Brain plus other disease status sites Table 1: RPA class definitions THE LANCET Vol 363 May 22, Grade 1 Grade 2 Grade 3 Grade 4 Motor None or no Subjective Mild objective Objective change weakness/ weakness weakness with no objective without impairment of findings significant function impairment of function Sensory None or no Mild Mild or Severe objective change paraesthesias/ moderate sensory loss or loss of deep objective paraesthesias tendon reflexes sensory loss/ that interfere paraesthesias with function For other neurological signs and symptoms, see members/toxicity/tox.html. Table 2: RTOG CNS toxicity criteria cells/ L, or platelet count less than 5 cells per L. Patients with metastases in the brain stem, or within 1 cm of the optic apparatus were excluded since no safety data for these sites were available from the antecedent phase I study, RTOG Patients who had received treatment for systemic cancer within 1 month of enrolment were judged to have active disease and were excluded. Patients with newly diagnosed cancer presenting with brain metastases or patients with unknown primaries were both considered to have unknown disease control and were included in the study. The Cancer Therapy Evaluation Program (CTEP) at the National Cancer Institute and the ethics review boards at each RTOG participating institution reviewed and approved the trial protocol. Patients gave written informed consent. Interventions Patients were randomly allocated either WBRT alone or WBRT with stereotactic radiosurgery boost. All patients received WBRT in daily 2 5 Gy fractions to a total of 37 5 Gy over 3 weeks. Patients allocated stereotactic radiosurgery boost received this treatment within 1 week of completing WBRT. We chose this schedule in anticipation of tumour shrinkage that would minimise radiosurgery treatment volume. If patients were registered at RTOG centres not 164 patients allocated to WBRT and stereotactic surgery 133 patients completed treatment 31 patients did not receive stereotactic surgery lost to follow-up 164 patients included in main analysis Figure 1: Trial profile 333 patients eligible for RTOG 95-8 trial 331 patients randomised to treatment 2 patients excluded 167 patients allocated to WBRT alone 167 patients completed treatment lost to follow-up 167 patients included in main analysis WBRT+stereotactic WBRT alone surgery (n=164) (n=167) Age (mean [range]) (years) 58 8 (19 82) 59 9 (24 9) 65 19 (66%) 11 (%) (34%) 66 (%) Largest metastasis 2 cm 83 (5 5%) 98 (59%) 2 cm to 3 cm 57 (35%) 45 (27%) 3 cm to 4 cm 24 (14 5%) 24 (14%) Men 86 (52%) 89 (53%) Histological status Squamous 19 (12%) 19 (11%) Adenocarcinoma 84 (51%) 78 (47%) Large cell 27 (16%) 25 (15%) Small cell 14 (9%) 1 (6%) Melanoma 7 (4%) 7 (4%) Renal 5 (3%) 5 (3%) Other 5 (8%) 11 (7%) Information missing 1 ( 1) Primary tumour site Breast 15 (9%) 19 (11%) Lung 15 (64%) 16 (63%) Skin/melanoma 7 (4%) 9 (5%) Other 23 (14%) 17 (1%) Kidney 2 (1%) 2 (1%) Bladder 3 (2%) Colon 4 (2%) 2 (1%) Ovarian 1 (1%) 2 (1%) Unknown primary 7 (4%) Neurological function No symptoms 54 (33%) 67 (%) Minor symptoms 81 (5%) 72 (43%) Moderate symptoms 27 (17%) 28 (17%) Information missing 2 (1%) RPA class 1 46 (28%) 45 (27%) (72%) 122 (73%) KPS 9 93 (57%) 15 (63%) 7 71 (43%) 62 (37%) Primary site Controlled/absent 126 (77%) 125 (75%) Unknown control 38 (23%) 42 (25%) Metastases Brain alone 52 (32%) 52 (31%) Brain and one other 61 (37%) 59 (35%) extracranial site Brain and two others 35 (21%) 35 (21%) extracranial sites Brain and 2 16 (1%) 21 (13%) additional sites Number of brain metastases 1 92 (56%) 94 (56%) 2 39 (24%) 46 (28%) 3 33 (2%) 27 (16%) MMSE (1%) 1 ( 6%) (84%) 142 (85%) Information missing 1 (6%) 15 (9%) MMSE=mini-mental state examination. Data are n (%) unless otherwise stated. Table 3: Patients baseline characteristics performing radiosurgery, this also streamlined referrals during WBRT to RTOG institutions with established radiosurgery programmes including both Gamma Knife and LINAC-based systems. 1 We assigned radiosurgery doses in accordance with prescriptions from an earlier dose-escalation RTOG radiosurgery trial (9 5). 1 We treated metastases up to 2 cm in broadest diameter with a surface isodose prescription of 24 Gy; metastases larger than 2 cm but equal to or smaller than 3 cm with 18 Gy; and metastases larger than 3 cm and less than or equal to 4 cm 1666 THE LANCET Vol 363 May 22, 24 Single metastasis (n=14) Multiple metastases (n=17) Physician refusal 1 (7%) 2 (12%) Patient refusal 5 (36%) 4 (24%) No tumour 1 (7%) 4 (24%) Disease progression 4 (29%) 5 (29%) Death 1 (7%) 2 (12%) Other 2 (14%) Table 4: Reasons for not receiving stereotactic radiosurgery with 15 Gy. The protocol stipulated isodose prescriptions within ratios of prescription isodose/tumor volume (PITV) and maximum dose/prescribed dose (MDPD) previously set by the RTOG. 1 Treatment plans could use either MRI or CT imaging sets. Primary outcome was overall survival in patients with solitary or multiple brain metastases. Secondary outcomes were tumour response and local control rates, overall intracranial recurrence rates, cause of death, and performance measurements. Sample size The study was designed to detect a 5% improvement in median survival time for all patients receiving stereotactic radiosurgery boost from 7 1 months to 1 6 months after treatment with % statistical power. Based on this assumption, we estimated that a sample size of 124 patients per group would be needed. We assumed that 5% of patients would be ineligible or unassessable, and thus calculated that we should have a total sample size of 262 patients. Additionally, the study included a predefined hypothesis in the single brain metastasis patients with % statistical power to detect a 75% improvement in median survival time. On the assumption that 5% of patients had a single brain metastasis, the original projection of 62 patients was modified after two interim analyses by the RTOG Data Monitoring Committee. Because 15% of people allocated to stereotactic radiosurgery did not receive this treatment, the number of patients with a single metastasis was increased to 94 patients per group for a final adjusted target sample size of 326 patients. Randomisation Patients were stratified by number of brain metastases (single vs 2 3) and extent of extracranial disease (none vs present). Randomisation within strata by permutated blocks was done by use of computerised techniques at RTOG headquarters when member institutions telephoned to enrol eligible patients. We compared pretreatment characteristics between treatment groups using the Wilcoxon rank-sum test or Fisher s exact test to assess balance. Our analysis included assignments of patients to RTOG recursive partitioning analysis (RPA) classes for brain metastases in accordance with methods described by Gaspar and colleages, 11 to ensure intergroup homogeneity and also to assess outcomes according to RPA class (table 1). Post-treatment surveillance We did clinical evaluations and MRI scans at 3 month intervals up to 1 year. 12 Acute toxicities were identified as events that arose within 9 days of the start of radiotherapy and late toxicities as events that occurred thereafter according to RTOG CNS toxicity criteria (table 2). 1 Treatment responses and local control rates were reported by institution over the course of the study. Local control was defined as unchanged or improved serial post-treatment MRI scans judged initially as either a complete response, partial response, or stable disease. Complete response was defined as total radiographic disappearance of all lesions with stabilisation of the neurological examination after glucocoriticoids had been stopped. Partial response was defined as greater than a 5% decrease in size of all lesions with improvement or stabilisation of the neurological examination with stable glucocorticoid dose. Stable disease was defined as a 5% decrease in size of all lesions with improving or stable neurological examination. Progressive disease was WBRT+stereotactic surgery (n=1) WBRT alone (n=166) Grade Grade Acute toxicities* Nausea/vomiting Hearing loss Skin (acute) Skin (subacute) Neurological (central) Neurological (peripheral) Other Worst reported toxicity grade per patient 69 (43%) 28 (18%) 3 (2%) 1 (1%) 59 (36%) 43 (26%) WBRT+stereotactic surgery (n=113) WBRT alone (n=112) Late toxicities Nausea/vomiting Hearing loss Skin (chronic) Neurological (central) Neurological (peripheral) 3 1 Other Worst reported toxicity grade per patient 16 (14%) 7 (6%) 3 (3%) 3 (3%) 16 (14%) 8 (7%) 2 (2%) 1 (1%) Age 7 years (n=128) (n=129) Worst reported acute toxicity grade per patient 56 (44%) 24 (19%) 1 (1%) 47 (36%) 32 (25%) Age 7 years (n=32) (n=37) Worst reported acute toxicity grade per patient 13 (41%) 4 (13%) 3 (9%) 12 (32%) 11 (3%) Worst reported acute toxicity grade by stereotactic surgery dose in patients with single metastasis 15 Gy (n=2) 4 (2%) 4 (2%) 18 Gy (n=29) 11 (38%) 7 (24%) 1 (3%) 24 Gy (n=33) 17 (52%) 1 (3%) 1 (3%) *Events occurring within 9 days of radiation treatment. Events occurring at or beyond 9 days. Table 5: Treatment-related toxicities THE LANCET Vol 363 May 22, Single brain metastasis 2 brain metastases Total WBRT and SRS WBRT alone WBRT and SRS WBRT alone WBRT and SRS WBRT alone (n=73) (n=82) (n=64) (n=67) (n=137) (n=149) Brain metastases 19 (26%) 22 (27%) 2 (31%) 24 (36%) 39 (28%) 46 (31%) Cancer at other Site 38 (52%) 44 (54%) 31 (48%) 36 (54%) 69 (5%) (54%) Complications of radiotherapy 1 (2%) 1 (1%) Pneumonia 3 (4%) 2 (2%) 1 (2%) 4 (3%) 2 (1%) Pulmonary embolism 3 (4%) 1 (1%) 4 (3%) Myocardial infarction 1 (1%) 1 (2%) 1 (1%) 1 (1%) Other 5 (7%) 6 (7%) 6 (9%) 2 (3%) 11 (8%) 8 (5%) Unknown 8 (11%) 4 (5%) 4 (6%) 4 (6%) 12 (9%) 8 (5%) SRS=stereotactic surgery. Table 6: Causes of death defined as an increase in the size of any lesion, the development of new intracranial lesions or stable disease with deterioration of the neurological examination. The reappearance of tumour in the brain MRI scan constituted recurrent disease. If a patient developed a recurrence or one or more new brain metastases, further treatment was allowed as clinically indicated. Cause of death was judged as either systemic or neurological failure by the reporting institution. Patients were ascribed a neurological death if they had stable systemic disease but succumbed to intracranial disease progression associated with progressive neurological dysfunction. Post-treatment MRI scans were also sent to RTOG headquarters for central review by a neuroradiologist (AEF). At central review, treatment responses were assessed at 3 months and local control rates at 1 year. 13 Variations in slice thickness, field strength, or imaging planes were accepted. We excluded patients for any of five reasons: mixing modalities (eg, MRI and CT); same modalities but missing a key pulse sequence (eg, a T2/FLAIR or post contrast T1); missing films of a sequence that reportedly was done; no follow-up study of any kind; or uninterpretable copies. This protocol did not stipulate steroid management, but steroid dose prescriptions were recorded at each visit. Dosimetry, radiosurgery isosurface prescriptions, dose conformality and homogeneity calculations were all centrally reviewed by two physicians (DWA and PWS) and a medical physicist (MS). 1 Proportion alive (%) 2 2 Overall survival estimated with the Kaplan-Meier method and groups were compared via the log-rank statistic. To assess the effect of prognostic variables, we did univariate and multivariate Cox proportional hazards analyses 15 for variables including age, KPS, known extracranial metastases (yes vs no), and RPA class. Univariate tests were not adjusted for multiple comparisons. Multivariate analyses were done to estimate the effect of treatment group on outcome, adjusting for RPA class. Role of the funding source The sponsor had no role in study design, data collection, data analysis, data interpretation, or the writing of the report. WBRT+SRS MST 6 5 months WBRT alone MST 5 7 months p= 1356 Survival in patients with single metastasis WBRT+SRS MST 6 5 months WBRT alone MST 4 9 months p= 393 Survival in patients with multiple metastases WBRT+SRS MST 5 8 months WBRT alone MST 6 7 months p= 9776 Survival by tumour size WBRT+SRS; metastasis 2 cm WBRT alone; metastasis 2 cm WBRT+SRS; metastasis 2 cm* WBRT alone; metastasis 2 cm *p= 449 vs WBRT alone Statistical analyses Analysis was by intention to treat. We treated all outcomes as independent hypotheses, and we did not adjust for multiple comparisons. 14 Subsequent exploratory subsets within these hypotheses were subject to inflation of the type I error. There were nine subsequent subsets of survival for an adjusted significance level of 56. This significance level was applied when assessing the p for survival subsets other than single metastasis patients. Survival was measured from the date of randomisation until death or last follow-up. Survival was 2 Survival by highest tumour surface isodose prescription 15 Gy 18 Gy 24 Gy p= 3956 Survival by treatment unit LINAC Gamma knife p= Months MST=mean survival time. Figure 2: Intention-to-treat outcomes by tumour size, extent of intracranial disease, radiation dose, and treatment technique 1668 THE LANCET Vol 363 May 22, 24 Number Mean p Better prognosis survival association time Univariate analysis Overall WBRT alone WBRT plus SRS Not significant Single metastasis WBRT alone Boost SRS, single WBRT plus SRS metastasis Other subgroups Largest tumour 2 cm WBRT alone Not significant at WBRT plus SRS level RPA class 1 WBRT alone Not significant at WBRT plus SRS level Squamous/non-small cell lung carcinoma WBRT alone Not significant WBRT plus SRS Karnofsky 9 WBRT alone Not significant WBRT plus SRS Brain alone WBRT alone Not significant WBRT plus SRS Brain plus one extracranial site WBRT alone Not significant WBRT plus SRS 61 8 Brain plus two extracranial sites WBRT alone Not significant WBRT plus SRS Multivariate analysis Overall* 327 RPA class 1 vs class 1 Class 1 Histology Lung primary WBRT vs WBRT+SRS NC 1249 Not significant Single metastasis 184 RPA class 1 vs class 1 Class 1 WBRT vs WBRT+SRS NC 533 Not significant SRS=Stereotactic surgery. NC=not calculated; *Data not complete in four patients; Data not complete in two patients. Table 7: Univariate and multivariate survival analyses Results Between January 31, 1996, and June 15, 21, 333 patients were recruited to the study. Follow-up data were reported to January, 22. Patients were from 55 RTOG member institutions, with 2 institutions enrolling one or two patients. We excluded two patients (in one case, no confirmation of eligibilty was provided; in the other, the WBRT+stereotact
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