ARTICLES 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 9508 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 40% of all survival for patients with a single unresectable brain patients with systemic cancer. We aimed to assess whether metastasis. WBRT and stereotactic radiosurgery should, stereotactic radiosurgery provided any therapeutic benefit therefore, be standard treatment for patients with a single in a randomised multi-institutional trial directed by the unresectable brain metastasis and considered for patients Radiation Therapy Oncology Group (RTOG). with two or three brain metastases. Methods Patients with one to three newly diagnosed brain Lancet 2004; 363: 1665–72 metastases were randomly allocated either whole brain radiation therapy (WBRT) or WBRT followed by stereotactic Introduction radiosurgery boost. Patients were stratified by number of Brain metastases occur in 20–40% of patients with metastases and status of extracranial disease. Primary systemic cancer;1 30–40% present with a single metastasis.2 outcome was survival; secondary outcomes were tumour Outlook for patients is poor with a median survival time of response and local rates, overall intracranial recurrence rates, 1–2 months with corticosteroids,3 which can be extended cause of death, and performance measurements. to 6 months with whole brain radiation therapy (WBRT),4,5 and some investigators6,7 report that survival can be further Findings From January, 1996, to June, 2001, we enrolled lengthened when WBRT is preceded by surgical resection. 333 patients from 55 participating RTOG institutions—167 Originally developed by the Swedish neurosurgeon Lars were assigned WBRT and stereotactic radiosurgery and 164 Leksell,8 radiosurgery is a technique that involves single were allocated WBRT alone. Univariate analysis showed that treatment radiation precisely focused at intracranial there was a survival advantage in the WBRT and stereotactic targets. Radiosurgery is frequently used to treat brain radiosurgery group for patients with a single brain metastasis metastases, sometimes preferred to surgery as a less (median survival time 6·5 vs 4·9 months, p=0·0393). invasive alternative. We report results of the first multi- Patients in the stereotactic surgery group were more likely to institutional prospective randomised comparison of have a stable or improved Karnofsky Performance Status WBRT with or without stereotactic radiosurgery for (KPS) score at 6 months’ follow-up than were patients patients with one to three brain metastases. allocated WBRT alone (43% vs 27%, respectively; p=0·03). By multivariate analysis, survival improved in patients with an Methods RPA class 1 (p<0·0001) or a favourable histological status Participants (p=0·0121). The study population included patients with confirmed systemic malignant disease. All patients were aged 18 Interpretation WBRT and stereotactic boost treatment years or older with no previous cranial radiation. Entry improved functional autonomy (KPS) for all patients and criteria included a contrast-enhanced MRI scan showing one to three brain metastases with a maximum diameter Departments of Neurosurgery (D W Andrews MD), Radiology of 4 cm for the largest lesion and additional lesions not (A E Flanders MD), and Radiation Oncology (M Werner-Wasik MD, exceeding 3 cm in diameter.9 Metastases were deemed W J Curran Jr MD), Thomas Jefferson University Hospital, unresectable if they were located in deep grey matter or in Philadelphia, PA, USA; American College of Radiology, eloquent cortex. Postoperative patients with either Philadelphia, PA, USA (C Scott PhD); Methodist Hospital Cancer residual or distal brain metastases were eligible if the total Center, Minneapolis, MN, USA (P W Sperduto MD); Department of Radiation Oncology, University of Rochester, Rochester, NY number of metastases remained three or fewer. We M C Schell PhD); Akron City Hospital, Summa Health System, Akron, excluded patients who had Karnofsky Performance Status OH (W Demas MD); UC Davis Medical Center, Sacramento CA (KPS) score of less than 70, haemoglobin concentration (J Ryu MD); University of Colorado Cancer Center, Denver CO less than 80 g/L, absolute neutrophil count of less than (L E Gaspar MD); Notre Dame Hospital, University of Montreal, Montreal, Canada (J P Bahary MD); Department of Oncology, McGill Recursive partitioning analysis classes for brain University Health Center, Montreal (L Souhami MD); SUNY Health metastases11 Science Center, Brooklyn, NY (M Rotman MD); and University of Class 1 Class 2 Class 3 Wisconsin Comprehensive Cancer Center, Madison, WI KPS у70 у70 <70 (M P Mehta MD) Primary status Controlled Uncontrolled Correspondence to: Professor David W Andrews, Thomas Jefferson Age (years) <65 у65 University, 909 Walnut Street, 2nd Floor, Philadelphia, PA 19107, Extracranial Brain only Brain plus other USA disease status sites (e-mail: [email protected]) Table 1: RPA class definitions THE LANCET • Vol 363 • May 22, 2004 • www.thelancet.com 1665 For personal use. Only reproduce with permission from The Lancet publishing Group. ARTICLES Grade 1 Grade 2 Grade 3 Grade 4 WBRT+stereotactic WBRT alone surgery (n=164) (n=167) Motor None or no Subjective Mild objective Objective change weakness/ weakness weakness with Age (mean [range]) (years) 58·8 (19–82) 59·9 (24–90) no objective without impairment of <65 109 (66%) 101 (60%) findings significant function у65 55 (34%) 66 (40%) impairment Largest metastasis of function <2 cm 83 (50·5%) 98 (59%) Sensory None or no Mild Mild or Severe objective >2 cm to р3 cm 57 (35%) 45 (27%) change paraesthesias/ moderate sensory loss or >3 cm to р4 cm 24 (14·5%) 24 (14%) loss of deep objective paraesthesias tendon reflexes sensory loss/ that interfere Men 86 (52%) 89 (53%) paraesthesias with function Histological status For other neurological signs and symptoms, see http://www.rtog.org/ Squamous 19 (12%) 19 (11%) members/toxicity/tox.html. Adenocarcinoma 84 (51%) 78 (47%) Table 2: RTOG CNS toxicity criteria Large cell 27 (16%) 25 (15%) Small cell 14 (9%) 10 (6%) ␮ Melanoma 7 (4%) 7 (4%) 1000 cells/ L, or platelet count less than 50 000 cells per Renal 5 (3%) 5 (3%) ␮L. Patients with metastases in the brain stem, or within 1 Other 5 (8%) 11 (7%) cm of the optic apparatus were excluded since no safety Information missing 0 1 (<1) data for these sites were available from the antecedent Primary tumour site phase I study, RTOG 9005.10 Patients who had received Breast 15 (9%) 19 (11%) treatment for systemic cancer within 1 month of Lung 105 (64%) 106 (63%) enrolment were judged to have active disease and were Skin/melanoma 7 (4%) 9 (5%) excluded. Patients with newly diagnosed cancer Other 23 (14%) 17 (10%) Kidney 2 (1%) 2 (1%) presenting with brain metastases or patients with Bladder 0 3 (2%) unknown primaries were both considered to have Colon 4 (2%) 2 (1%) unknown disease control and were included in the study. Ovarian 1 (1%) 2 (1%) The Cancer Therapy Evaluation Program (CTEP) at Unknown primary 7 (4%) 0 the National Cancer Institute and the ethics review boards Neurological function at each RTOG participating institution reviewed and No symptoms 54 (33%) 67 (40%) approved the trial protocol. Patients gave written Minor symptoms 81 (50%) 72 (43%) Moderate symptoms 27 (17%) 28 (17%) informed consent. Information missing 2 (1%) 0 Interventions RPA class 1 46 (28%) 45 (27%) Patients were randomly allocated either WBRT alone or 2 118 (72%) 122 (73%) WBRT with stereotactic radiosurgery boost. All patients received WBRT in daily 2·5 Gy fractions to a total of 37·5 KPS 90–100 93 (57%) 105 (63%) Gy over 3 weeks. 70–80 71 (43%) 62 (37%) Patients allocated stereotactic radiosurgery boost Primary site received this treatment within 1 week of completing Controlled/absent 126 (77%) 125 (75%) WBRT. We chose this schedule in anticipation of tumour Unknown control 38 (23%) 42 (25%) shrinkage that would minimise radiosurgery treatment Metastases volume. If patients were registered at RTOG centres not Brain alone 52 (32%) 52 (31%) Brain and one other 61 (37%) 59 (35%) 333 patients eligible for extracranial site Brain and two others 35 (21%) 35 (21%) RTOG 95-08 trial extracranial sites Brain and >2 16 (10%) 21 (13%) 2 patients additional sites excluded Number of brain metastases 1 92 (56%) 94 (56%) 331 patients randomised 2 39 (24%) 46 (28%) to treatment 3 33 (20%) 27 (16%) MMSE 15–24 16 (10%) 10 ( 6%) 164 patients allocated to 167 patients allocated to 25–30 138 (84%) 142 (85%) WBRT and stereo- WBRT alone Information missing 10 (6%) 15 (9%) tactic surgery 167 patients completed MMSE=mini-mental state examination. Data are n (%) unless otherwise stated. 133 patients completed treatment Table 3: Patients’ baseline characteristics treatment 31 patients did not performing radiosurgery, this also streamlined referrals receive stereotactic surgery during WBRT to RTOG institutions with established radiosurgery programmes including both Gamma Knife and LINAC-based systems.10 0 lost to follow-up 0 lost to follow-up We assigned radiosurgery doses in accordance with prescriptions from an earlier dose-escalation RTOG 164 patients included in 167 patients included in radiosurgery trial (90–05).10 We treated metastases up to main analysis main analysis 2·0 cm in broadest diameter with a surface isodose prescription of 24·0 Gy; metastases larger than 2 cm but equal to or smaller than 3 cm with 18·0 Gy; and Figure 1: Trial profile metastases larger than 3 cm and less than or equal to 4 cm 1666 THE LANCET • Vol 363 • May 22, 2004 • www.thelancet.com For personal use.