3.3 SRS / neurochirurgische resectie met of zonder WBRT I Study ID II Method III Patient

Transcription

1 1. Andrews DW et al, 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, The Lancet, RCT 2. Supported by grant number (RTOG U10 CA21661, CCOP U10CA37422, Stat U10 CA32115) from the National Cancer Institute RTOG >331Patients 5. October December Inclusion 18 yrs or older with no previous cranial radiation. A contrast enhanced MRI scan showing one to three brain metastases with a maximum diameter of 4cm for the largest lesion and additional lesions not exceeding 3 cm in diameter. Metastases were deemed unresectable if they were located in deep gray 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, patients with newly diagnosed cancer presenting with brain metastases, patients with unknown primaries Exclusion KPS < 70, haemoglobin concentration < 80g/L, absolute neutrophil count of less than 1000 cellsµl, platelet count less than cells/µl, metastases in the brain stem, or within 1 cm of the optic apparatus, patients who had received treatment for systemic cancer within one month of enrolment 2. Age, gender, size of metastasis, RPA class, KPS score, primary site, histology status, metastases (incl number), MMSE 1. WBRT with stereotactic radiosurgery boost. All WBRT was given daily 2,5 Gy fractions to a total of 37,5 GY over 3 weeks 2. WBRT allone. All WBRT was given daily 2,5 Gy fractions to a total of 37,5 GY over 3 weeks 1. Mean survival did not differ much between groups. No survival benifit between groups in patients with mulitple metastases. Patients with single metastasis in the stereotactic radiosurgery group had significantly better survival than those who were not allocated with boost treatment and other 1+2. No significant 1. A2. differences between treatment groups with 3. Multicentre study but respect to overall time to relative small sample size. intracranial tumour Description of progression or randomisation available neuroplogical death rates. There was a statistical sign improvement in KPS and decreased steroid use at 6 months in the stereotacticradiosurgery boost treatment group, but no difference in mental status was noted between groups

2 1. Aoyama H et al,stereotactic Radiosurgery Plus Whole- Brain Radiation Therapy vs Stereotactic Radiosurgery Alone for Treatment of Brain Metastases A Randomized Controlled Trial, JAMA, RCT Hospitals in Japan Patients 5. October December WBRT+stereotact surg: mean age=58,8 (19-82) 52% male, KPS 70-80= 43%.. WBRT allone. mean age=59,9% (24-90), 53% male, KPS 70-80= 37% 1. 18yr Old or older with 1-4 brain metastases, each with a maximum diameter of no more than 3 cm on contrastenhanced MRI scans, derived from a histologically confirmed systemic cancer. Patients had a Karnofski score of 70 or higher. 2. Age, sex, primary tumor site, primary tumor status, RPA, KPS score, Chemotherapy after brain treatment. 3. SRS allone; age mean(range) 62,5 (36-78), men 71%, KPS score = 52% SRS+WBRT; age mean(range) 62,1 (33-86), men 79%, KPS score = 53% 1.WBRT with SRS. WBRT dosage schedule was 30 Gy in 10 fractions over 2 to 2,5 weeks.srs dosage was prescribed to tumor margin. Metastases with a maximum diameter of up to 2 cm were treated with doses of 22 to 25 Gy and those larger than 2 cm were treated with doses of 18 to 20 Gy. 2. SRS allone. SRS dosage was prescribed to tumor margin. Metastases with a maximum diameter of up to 2 cm were treated with doses of 22 to 25 Gy and those larger than 2 cm were treated with doses of 18 to 20 Gy. 1. The median survival time and the 1-year actuarial survival rate were 7.5 months and 38.5% (95% confidence interval, 26.7%-50.3%) in the WBRT_SRS group. And 8.0 months and 28.4% (95% confidence interval, 17.6%-39.2%) for SRS alone (P=.42). and other 1+2. The 12-month brain tumor recurrence rate was 46.8% in the WBRT_SRS group and 76.4%for SRS alone group (P_.001). Salvage brain treatment was less frequently required in the WBRT_SRS group (n = 10) than with SRS alone (n = 29) (P_.001) 1. A2. 3. Not blinded, description of randomisation process, relative small sample size. Multicenter study

3 1. Chang et al, Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial, The Lancet Oncology, Do L et al, Resection followed by stereotactic radiosurgery to resection cavity for intracranial metastases, International Journal of Radiation Oncology Biology Physics, RCT 2. No external funding was received 3. Departments of Radation Oncology and Neurosurgery and the Brain and Spine Center, MD Anderson Cancer Centre, Houston Texas USA >58 5. Jan 2, Sept 14, Retrospective review 3. City Hope Nation Cancer Centre December December Inclusion age 18 years or greater; RPA class one or two, KPS 70; 1 to 3 newly diagnosed brain metastases eligible for SRS; brain MRI within 1 month of enrolment; and signed written informed consent. Exclusion undergone prior brain surgery, SRS, or WBRT; diagnosed with leukaemia, lymphoma, germ-cell tumour, smallcell lung cancer, leptomeningeal disease, or unknown primary tumour; if they were RPA class three (KPS <70); and if they were pregnant. 2. Gender, ethnic origin, Number of BM, Recursive partitioning analysis class, Graded prognostic assessment, Primary Site, Liver metastasis, Bone metastasis, Adrenal metastasis. 1. Newly diagnosed BM treated with resection followed by SRS/SRT to resection cavity. 2. Gender, Age, RPA class, KPS, Primary tumor site, Lesions, SRS/SRT dose 3. Not described 1. SRS dose was prescribed in accordance to the RTOG guidelines. WBRT was prescribed to a total dose of 30 Gy given in 12 daily fractions of 2*5Gy per day. 2. WBRT was prescribed to a total dose of 30 Gy given in 12 daily fractions of 2*5Gy per day. 1. SRS dose range was Gy. For the larger lesions, SRT to Gy in four to six equal fractions of Gy/fraction were given. For lesions that were not resected, SRS/SRT was used alone to the 80 90% isodose lines, with the dose prescription dependent on the size and site of the brain metastases. and other 1. SRS plus WBRT were % Of patients in 1. A2. signifi cantly more likely to the SRS plus WBRT 2. 1 Lost to FU. show a decline in learning group were free from CNS 3. The trial was stopped and memory function recurrence at 1 year, according to early (mean posterior compared with 27% of stopping rules on the probability of decline 52%) patients who received basis that there was a at 4 months than patients SRS alone (p=0 0003) high probability that assigned to receive SRS At month 4 there were 4 patients randomly alone (mean posterior deaths (13%) in the group assigned to receive probability of decline that received SRS allone, SRS+WBRT were sign. 24%). and 8 deaths (29%) in the More likely to show a In the SRS plus WBRT group that received decline in learning and group, 1 case of grade 3 SRS+WBRT memory function at 4 toxicity was attributed to months that the other radiation treatment. In the group. SRS group, one case of Investigators remained grade 3 toxicity was blinded tot the trial except attributed to radiation for treatment assignment, treatment. Two cases of which was monitored on grade 4 toxicity in the an annual basis by the group that received SRS data monitoring alone were diagnosed as committee radiation necrosis. 1. Of the 33 lesions treated by resection followed by SRS/SRT 12% developed local recurrence. Of the 20 leasions treated by SRS/SRT alone 20% had local recurrence. Overall 70% had brain tumor recurrences. Recurrence in lesions treated with SRS/SRT only occurred in 63%. Recurrence was symptomatic in 23% and was associated with neurologic deficit in 30%. Symptomes were: 1+2. At the last follow up visit, 14 of the 30 patients had died. The 12 month overall survival rate was 51%. 23% of the patients had died of progressive neurologic disease or with severe intercurrent central nervous system symptoms. The 12 monthly neurologic specific survival rate was 75% 1. C. 3. Small sample size, descriptive.

4 1. Fahrig A et al, Hypofractionated stereotactic radiotherapy for brain metastases-- results from three different dose concepts, Strahlenther Onkologie, Fuentes R et al, Surgery versus radiosurgery for patients with a solitary brain metastasis from non-small cell lung cancer, Cochrane Database of Systematic Reviews, Prospective Clinical Trial 3. Two German Novalis, BrainLAB AG, Heimstetten, Germany > June June Cochrane systematic review CENTRAL/MEDLINE/EM BASE/CINAHL 5. Randomized or controled trials, prospective or retrospective cohort studies >47finally used 1. Exclusion Location in the brainstem, mesencephalon, basal ganglia, capsula interna, total volume of one or more metastases > 3 cm3, patients with more than 4 metastases were admitted to WBRT, small cell lung cancer patients. 2. Age, Gender, RPA class, Number of metastases, PTV, Primary tumour, Localization 3. Not described 1. Histologically proven NSCLC, adults of more than 18 yrs old and have their primary tumour in complete remission when the diagnosis of a solitary brain metastasis was made. Also mandatory that the included patients had a MRI or a contrast enhanced CT scan as part of their initial evaluation different dose concepts for stereotactic radiosurgery: 1. (n=72) 5x 6-7Gy 2. (n=59) 10x4Gy 3. (n=97) 7x5Gy 1. Surgery (megavoltage stereotactic radiotherapy) with of without whole brain irradiation. 2. all types of radiosurgery with or withou whole brain irradiation for solitary brain metastasis from NSCLC, independently of the chemotherapy treatment that has been administered. headaches, nausea/vomiting and dizziness 1. 6 Months and 12 months were 83% and 66% respectively. Median survival of all patients was 16 months. This was significantly better in patients treated with 10x4Gy and 7x5Gy vs the 5x6-7 Gy group 17 vs 11 months respectively. The only sign influence factor on tumor specific and brain specific survival was RPA class in 42% patients. No early toxicity during treatment, requiring the increase of steroid medication, occurred. 10% of all patients experienced toxicity. side effects occured significantly more often after 5x6-7 Gy and 7x5Gy. None of the patients treated with 10x4Gy as affected by adverse effects. 1. No article was relavant for the review and other B. 3. There is a possible conflict of interest as it is not clear how Novartis is involved with this research. No patient characteristics for the different groups. no randomisation and blinding No article was relavant for the review 1. A1 2. No studies that matched the inclusion creteria. No RCT's that compared chirurgy and radiochirurgy for patients with a single brain MT resulting out of NSCLC

5 1. Gaspar L et al, Recursive partitioning analyses (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials, International Journal of Radiation Oncology Biology Physics, Hart MG et al, Surgical resection and whole brain radiation therapy versus whole brain radiation therapy alone for single brain metastases, Cochrane Database of Systematic Reviews, Kocher et al, Adjuvant Whole-Brain Radiotherapy Versus Observation after Radiosurgery or Surgical Resection of one to three Cerebral Metastases: 1. Review 3. RTOG 79-16, and >1200 out of 3 RTOG consecutive databases Cochrane systematic review 2. Internal source. Dr. Hart was the repient of a Cochrane Geneacological Cancer Review group Grant 3. Updated till CENTRAL, Medline, Embase, Cancerlit, Biosis and the Science Citation Index. 5. RCT's with low risk for bias studies with 3 RCT's 1. RCT 2. Supported by grant No. 2U10 CA through 5U10 CA from the NCI (Bethesda, MD) and by 1. Eligitibility criteria: study 1) KPS was 40 or more study 2) KPS was more than 60 study 3) KPS was 70 or more. 2. Age, KPS, tumor related characteristics 1. Patients with systemic cancer (primary site confirmed by histology) and a suspected single brain metastasis were included. 2. Age, sex, KPS 1. Inclusion criteria Age 18 years, WHO performance status 2, 1-3 brain metastases, Radiosurgery: single metastasis 3.5 cm, 1. See protocols RTOG RTOG 79-16; 30 Gy 10/6 fractions in 2/3 weeks and RTOG 85-28; 1,6Gy 2x a day seperated 4-8hrs 5x a week, boost 16Gy to 38,4Gy. RTOG 89-05; 37,5Gy in 15 daily fractions with or withour BUdR continuous 96hrs in the weeks prior and during radiation. 1. Surgical resection plus WBRT 2. WBRT allone. 1. Patients treated with complete surgery or radiosurgery and adjuvant WBRT (30 Gy in 10 fractions), five fractions per week. 1. The results indicates a survival difference according to KPS, age, number of BM, status and site of origin of primary lesion and the time of interval between presentation of primary and BM. The only treatment related variable associated with better survival was a delivered dose of 52 Gy or more. 1. The analysis did not demonstrate a statistically significant difference in survival between the two treatments. 1 trial had enough data and fount that those treated by surgery and WBRT maintained their functional independence longer that those by WBRT allone. There was a trend that those treated by surgery were less likely to die from neurological causes. No statistical heterogeneity was found between the trials. 1. Duration of functional indepence: no difference in median time till first report of deterioration to WHO PS of more than 2 (Observation = 10 months and other 1+2. The median survival 1. B. time (MST) of the entire group was 4,4 months. 3. Very old data over a The MST for the patiens long period, difference in with a KPS > 70 was 4,9 patient characteristics not months. The MST for the transparant, therefore patients with a KPS < 70 unable to see the balance was 2,3 months. The MST between the different for patients with controlled groups after using the primary lesion was 5,5 decision tree, large months and 3,9 for sample size patients with uncontrolled primary lesion. Patients <65 years was 6.1 months and 4,0 months for patients >65 years. The MST was 4,8 and 7,1 months for the patients with and without other systemic metastases, respectively 1+2. The results do not 1. A1 demonstrate that either 2. Included studies where treatment was more likely critically reviewed using to to cause adverse the inclusion criteria. Only events studies with a low risk for bias were included. Blinding was not always possible in case of surgery 1+2. Overall intracranial progression was sign more frequent in the OBS arm (78%) than the WBRT arm (48%). Median progress free survival was 1. A patients ineligible 3. Unknown if study is performed in single centre or multiple centres. No explanation about the

6 Results of the EORTC Study, Journal of clinical Oncology, 2011 donation from Deutsche Krebshilfe from Germany through the EORTC Charitable Trust 3. Not described Patients were included between November 1996 to November 2007 multiple metastases 2.5 cm diameter, Surgery: complete surgical resection, Radiosurgery; histologic confirmation of primary tumor or other metastases 4 years ago, stereotactic biopsy of the brain metastasis otherwise, Stable systemic cancer for 3 months and/or asymptomatic synchronous primary tumor without metastases outside the CNS or unknown primary tumor. Exclusion criteria Brain metastasis of small-cell lung cancer, lymphoma, leukemia, myeloma, germ cell tumors, Brain stem metastases, Leptomeningeal metastases, Recurrent brain metastases after surgery and/or radiosurgery and/or brain irradiation, Inability to interrupt chemotherapy during whole-brain radiotherapy. 2. Age, Sex, WHO performance status, Neurologic status, Localization of primary tumor, Macroscopic tumor outside the brain. 3. WBRT (180) versus Observation (179): patient and lesion characteristics were well ballanced. 2. Patients treated with complete surgery or radiosurgery and observation. versus WBRT = 9,5 months). and other slightly longer in patients reason for differentiating receiving WBRT(4.6 in assigning moments for months) to OBS(3.4 the different treatment months). No difference groups. was found between the two arms in overall survival.13 late toxicity events were reported in the WBRT arm and 3 in the OBS arm. Progression-free survival Median progression-free survival slightly longer in patients receiving WBRT (4,6 months) versus observation group (3,4 months) Overall survival no difference between WBRT and observation group (10,7 vs. 10,9 months) Late toxicities in WBRT group 1 patient probably died of toxicity, neurologic death was more frequent in the observational arm (44%) than in WBRT arm (28%) Quality of life acute toxicity of WBRT was mild.

7 1. Kondziolka D et al, Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases, International Journal of Radiation Oncology Biology Physics, RCT 2. Dr. Kondziolka is supported by NIH Grant K09-NS Not reported Not reported 1. Eligible criteria: histologic confirmation of the tumor type either at the primary site or at a site of metastatic disease; All BM were 25 mm in mean diameter and more than 5 mm from the optic chiasm; patients had only 2, 3, or 4 tumors on contrast-enhanced MRI scan prior to randomization; patients had a KPS of 70. Histologic tumor types could include lung, breast, colon, renal cell, melanoma, bladder, ovarian, and uterine carcinomas. Patients considered ineligible either did not meet one or more of the above criteria or could not undergo MR scanning. 2. Age, gender. Tumor histology, Systemic disease, number of tumors 3. Not described 1. WBRT: megavoltage beams with a source axis distance no less than 80 cm. Fraction sizes of 2.5 Gy. Midplane dose 30 Gy in 12 fractions Radiosurgery: performed within the time course of WBRT. Time interval between WBRT and radiosurgery in patients randomized to radiosurgery, was 1 month. Patients randomized to undergo radiosurgery had Gamma Knife radiosurgery administered using stereotactic MR guidance. Patients received a tumour margin dose of 16 Gy. Patients with symptomatic cerebral edema were got dexamethasone 24 mg per day in divided doses or less. All patients received a single 40 mg intravenous dose of methylprednisolone. 1. Local failure at 1 year was 100% after WBRT alone but only 8% in patients who had boost radiosurgery. The medain time to local failure was 6 months after WBRT alone in comparison to 36 months after WBRT plus radiosurgery. Patients who received WBRT alone lived a median of 7,5 months, while those who received WBRT plus radiosurgery liver 11 months. and other 1+2. There was no neurologic or systemic morbidity related to steriotactic radiosurgery. Survival did not depend on histology or number of tumours, but was related to extent of extracranial disease 1. B. 3. The study was randomized but had a very small sample size (the trial was stopped at 60% accrual mark due to benefit in stereotactic radiosurgery group). Methods are well described. There is a possible conflict of interest

8 1. Lagerwaard FJ et al, Identification of prognostic factors in patients with brain metastases: a review of 1292, International Journal of Radiation Oncology Biology Physics patients, Retrospective cohort study 3. Department of Radiation Oncology, Daniel den Hoed Cancer Center, Rotterdam > January December Documented brain metastases from solid tumors. Only patients with CT diagnoses of BM. Patients with mere clinical suspicion or isotop scanning of the brain were excluded. 2. Sex, Age, Site of primary, ECOG, Systemic tumor activity, Number of brain metastases 3. Not described 1. All patients were treated with high doses of steroids dexamethasone (dose range 4 16 mg/day, mean 14.6 mg/day). The majority of patients were treated with steroids and WBRT, using lateral opposed fields with a 4 MV or 6 MV linear accelerator, fractionation schedules (76%) 30 Gy in 10 fractions or 20 Gy in 5 fractions (dose range 8 56 Gy, mean 31.5 Gy; SD Gy). One hundred and forty-eight patients with single brain metastasis received an additional boost dose (range 5 20 Gy; mean 11.5 Gy; SD Gy). In 95 patients with single brain metastasis were treated with surgery followed by radiotherapy (dose range Gy; mean 38.7 Gy; SD Gy), started within 6 weeks after operation. 118 (9.1%) were treated with steroids only after diagnosis of brain metastases. 2. Brain tumour management with WBRT alone and other 1. The overall survival Analysis within months, with 6 months, primary tumour groups and 2 year survival showed interval between percentages of 36%, 12%, primary tumour and BM, and 4 respectively. measured at 2 years, to Survival was statistically be a prognostic factor in sign, different between patients with breast patients treated with primaries (p=0,03). In steroids only (1.3 pulmonary and renal months), patients treated primaries no statistical with radiotherapy (3,6 sign could be found months)and patients according to interval. treated with radiosurgery Primary tumours other followed by radiotherapy than breast, renal and (8,9 months) unknown primaries showed no significant difference with respect to survival, tested against lung primaries. Within the subgroup of patiens treated with radiotherapy only, three prognostic subgroups could be constructed: 1: Good prognosis: ECOG 0 or 1 and no or limited systemic tumor activity and good response to steroids. 2: Poor prognosis: ECOG 2 or 3 and systemic tumor activity limited or extensive and little response to steroids. 3: Moderate prognosis: All other patients treated with radiotherapy 1. B Patients lost to FU 3. Old data, big sample size, retrospective

9 1. Le Pechoux CD et al, Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC , RTOG 0212, and IFCT 99-01): a randomised clinical trial, The Lancet Oncology, Lester JFM et al, Prophylactic cranial irradiation for preventing brain metastases in patients undergoing radical treatment for nonsmall-cell lung cancer: A Cochrane review, Cochrane Database of Systematic Reviews, RCT 2. Unrestricted grants from Institut Gustave- Roussy, Association pour la Recherche sur le Cancer (2001), Programme Hospitalier de Recherche Clinique (2007). The EORTC contribution to this trial was supported by grants 5U10 CA through 5U10 CA from the National Cancer Institute Centres in 22 countries, Mostly EU and North USA / 4 Patients lost to FU 5. 1 September December Cochrane systematic review 3. Between 1966 and December MEDLINE, EMBASE, LILACS, Cancerlit 5. RCT's 6. 4 RCT's 1. Histologically proven limited stage SCLC in complete remission after initial treatment were eligible for inclusion in the trial. Patients had to have a WHO performance status of less or equal to 2 2. Sex, Age 3. Standard dose; age yrs= 60 (38-83), sex= 234 males. Higher dose, age yrs= 60 (34-78), sex= 226 males. 1. Patients with histologically or cytologically confirmed NSCLC treated with radical intent and no radiological evidence of brain metastasis prior to randomisation patients adenocarcinoma or largecell carcinoma confined to the chest 254 patients Stage III inoperable NSCLC and 97 patients NSCL 13% Stage I/II, 87% stage III and 281 male patients inoperable NSCLC 1. PCI at higher dose (36 Gy in 18 daily fractions of 2 Gy (conventional fractioning) or 24 twice daily fractions of 1,5 Gy (hyperfractionated accelerated radiotherapy)) 2. PCI at standard dose (25Gy in 10 daily fractions of 2,5 Gy) 1. Using PCI 2. Not using PCI 1. 2 Year incidence of total brain metastases are 29% (95%CI 24-35) in the standard group and 23% (95%CI 18-29) in the higher dose group. 1. Incidence of brain metastases: PCI did significantly reduce the incidence of brain metastases in three trials. The incidence of brain metastases was sign lower in the PCI arm compared to the control arm. Time to brain metastases: The VALG trial, median time to development of brainmetastases was 34 weeks in the PCI group and 29 weeks in the control group, not sign. The Umsawasdi trial, PCI was also reported to significantly prolong the median time to CNS metastases (50.5 weeks vs 23 weeks, P=0.002, and other 1+2. There was a lower overall survival in the higher dose group 1+2. Toxicity: Two trials reported no late complication of PCI. One trial reported no excexxive neurological toxicity with PCI compared to the control arm. Quality of life: Quality of life measures were not carried uit in any of the studies 1. B Lost to follow up 3. Multicentre and multicountry study. Relative big sample size. Lost to follow up described. No description of randomisation 1. A2 2. Small population and no meta-analyses done. Rondimizing method unclear for two included studies.

10 1. Li J et al, Regression after whole-brain radiation therapy for brain metastases correlates with survival and improved neurocognitive function, Journal of Clinical Oncology, Mintz AHK et al, A randomized trial to assess the efficacy of surgery in addition to radiotherapy in patients with a single cerebral metastasis, Cancer, Prospective study 3. Multicenter study > Not reported 1. Randomized trial 2. Funded by the NCI of Canada and Ontario Oncology groep 3. Not reported > September March Adult patients were eligible to participate if they had radiologically demonstrated BM from histologically proven solid tumor, required WBRT, and had a KPS of 70 or more. 3. Not described 1. Patients younger than 80 yrs and had a lesion consistent with a single brain metastasis on CT and pathologic confirmation of cancer within the previous 5 years. KPS over Age, sex, KPS, location primary, extend of disease 3. Radiation allone; Mean age yrs/sd = 58 (9.86) Sex (M/F)= 22/21 Surgery and Radiation; Mean age yrs/sd = 58,9 (8,98) Sex (M/F)= 24/17 1. All patients received 10 daily fractions of 3Gy WBRT 1. Surgergy + radiation craniotomy under general asesthesia to achive gross total removal of the metastases or lobectomy. (300 cgy x10 fractions of radiation over 2 weeks) 2.Radiation alone (300 cgy x10 fractions of radiation over 2 weeks) Cox s regression model). The prevalence of brain metastases at 12 and 24 months for PCI versus observation in RTOG was not significant (15% vs 17% and 15% vs 31%). Survival: No trial reported a survival advantage with PCI over observation. 1. Patients with greater tumour shrinkage after WBRT survive longer. The one year survival in the good responding patients was 28% aginst 16% in the poor responding patients 1. Median survival for radio ther allone= 6,28 mnths (95% CI 3-11,4) Median survival for radio ther + surg= 5,62 mnths (95% CI 3,9-7,2) and other 1+2. Tumor shrinkage is associated with better preservation of specific NCF functions, especially executive function and fine motor coordination Quality of life not significant different for both diff. KPS 70 (mean 0,32 SD=0.30 P=0.98) 1. B.. 3. Scans were reviewed blinded, relative big sample size, multicentre but there is a conflict of interest. The two groups do have almost the same number of participants. However the group differences are not showed and makes it difficult to interpret the results. 1. B Blinded multicentre study, relative small sample size. Relative low KPS to still be included. Heterogenous group of patient group when primary malignancy is considered

11 1. Muacevic A et al, Microsurgery plus whole brain irradiation versus Gamma Knife surgery alone for treatment of single metastases to the brain: a randomized controlled multicentre phase III trial, Journal of Neuro-Oncology, Randomized trial 2. This study was granted by Elekta Research Foundation 3. Multicentre >64 5. October October Single untreated brain metastasis with a diameter of similar or more than 3cm in an operable site, were aged between 18 and 80 years, had a historically proven cancer at a site ouside the CNS, presented with a KPS greater or equal to 70 and were thought to have a stable systemicdisease with a life expectancy of at least 4 months. For patients with an unknown primary tumor, a confirmatory stereotactic biopsy was required 2. Sex, age, KPS, RPA 3. - Surgery only; Sex (male/female)= 15/18, Age year Mean/median/range= 58,3/59/32-75 KPS(mean/median/range) = 76,4/80/ WBRT and surgery; Sex (male/female)= 12/19, Age year Mean/median/range= 54,3/55/35-78 KPS(mean/median/range) = 79,4/80/ WBRT and Surgery WBRT: dose of 40Gy over 4 weeks (2Gy x 20 fractions). Gamma knife surgery was administered using stereotactic MRI guidance. The treatment was performed on an outpatient basis. The mean dose applied to the tumor margin (prescribed tumor dose) was 21 Gy (range: Gy). The prescribed tumor dose was in the range of Gy for radio-resistant tumors (such as melanoma, hypernephroma) and in the range of Gy for more radio-sensitive tumors (such as breast cancer). The mean maximum dose was 41 Gy (range: Gy), and on average, the 50% isodose (range: 35 85%) was used to irradiate the tumor margin. Conformal multiple isocenter Gamma Knife surgery (mean number of isocenters per patient: 7) was performed in all patients 2.WBRT 40Gy over 4 weeks (2Gy x 20 fractions). 1. Length of survival did not differ between the treatment groups, median survival was 9.5 months after surgery plus WBRT and 10.3months after radiosurgery allone and other 1+2. The 1-year 1. B. neurological death rate 2. 0 was higher in the surgery 3. Multicentre study not group than in the finished due to losing radiosurgery group (29% patients. Small sample vs 11%); the difference, size, no blinding however, was statistically not significant (P = 0.3). The 1-year systemic death rate was in the range of 53% in both treatment groups (P = 0.8). Early and late Grade 1 or 2 complications occurred significantly more often after surgery plus WBRT than after radiosurgery alone (P\0.01), whereas no significant differences could be detected for early or late grade 3 or grade 4 toxicities HRQL scores and disease status was assessed 6 weeks and 6 months after treatment. Generally, HRQL scores were maintained at baseline levels prior to tumor progression and significantly decreased thereafter mostly due to systemic disease progression. Improved scores for the domains role functioning and QOL were seen 6 weeks after radiosurgery (P\0.05). However, this difference was lost 6 months after treatment

12 1. Nieder CA et al, The role of postoperative radiotherapy after resection of a single brain metastasis: Combined analysis of 643 patients, Strahlentherapie und Onkologie, Slotman B et al, Prophylactic cranial irradiation in extensive small-cell lung cancer, New England Journal of Medicine, Systematic literature review 3. Up to June Medline 5. Up to June Randomized trial 2. Supported by grants (5U10-CA through 5U10- CA ) from the National Cancer Institute and by funds from the Dutch Cancer Society for local data management. Dr. Postmus reports receiving consulting fees from Astra-Zeneca, GlaxoSmithKline, Transgene, and Transave; lecture fees from Roche, GlaxoSmithKline, Eli Lilly, and Abraxis; and grant support from Actelion, Roche, and GlaxoSmithKline. No other potential conflict of interest relevant to this article was reported. 3. Multicentre patients 5. February 2001-March Key words: "resection or neurosurgery", "brain metastases, cerebral metastases or secondary brain tumo(u)r", reference list of all articles --> all publications reporting on patient groups with single brain metastases + clearly defined radiation doses and evaluation of the brain relapse pattern. 2. Median age (range), median time after diagnose, sex, WHO performance scale. 1. Cytologically or histologically confirmed, extensive small-cell lung cancer, defined as disease beyond the hemithorax and supraclavicular nodes or pleural effusion containing tumor cells. All patients had to have had a response to systemic chemotherapy, as judged by the standard treatment policy of each participating center. 2. Median age (range), median time after diagnose, sex, WHO performance scale. 3. Prophylactic Cranial Irradiation; median age= 62 (range 37-75), Median time after diagnose = 4,2 mo, Sex = 67,8% (n=97) male. WHO perf scale = 0; 36,4%, 1; 55,9% 2; 7,7%. Control; median age= 63 (range 39-75), Median 1. WBRT and different types of local partialbrain radiotherapy 1. Prophylactic Cranial Irradiation Radiation to the intracranial content was administered with the use of two opposed lateral fields with a linear accelerator (4 to 18 MV) or cobalt unit. Each field was treated daily on a schedule of four to five fractions per week. The dose was specified to the midline. The following schedules for cranial irradiation could be used: 20 Gy in 5 or 8 fractions, 24 Gy in 12 fractions, 25 Gy in 10 fractions, or 30 Gy in 10 or 12 fractions. The biologically equivalent doses for these schedules range from 25 to 39 Gy.Radiotherapy had to start 4 to 6 weeks after chemotherapy. 2. No further therapy 1.after surgery alone (n=94) 38 patients developed a local relapse at the original site. After additional radiotherapy (n=224) 28 patients developed a local relapse at the original site. 18% ofwas the total local relapse rate. Postoperative radiotherapy at least doubles the local control rate compared to surgery alone 1. Symptomatic brain metastases were observed in 24 of the 143 patients in the irradiation group (16,8%) and 59 of the 143 in the control group (41,3%). The cummulative risk of symptomatic brain metastases at 6 and 12 months were 4,4% and 14,6% in the irradiation group and 32,0% and 40,4% in the control group. and other B 2. A small amount of studies included for results. The included studies are difficult to compare as they are testing and measuring different subjects. No clear insight view into the results of the different studies as all results are combined while this seems not possible Survival without disease progression was sign. Longer in the irradiation group than the control group with a median of 14,7 weeks vs 12,0 weeks.. At six months the surv. Rate without disease progr. Was 23,4% (95%CI, 16.6 to 30.9) in the irradiation group and 15,5% (95% CI, 10,1 to 22,0) in the control group. The irradiation group had also 1+2 sign longer overall survival than the control group 6.7 mocompared to 5,4mo. The rate of compliance with the quality of life assessment was 93,7% at baseline but decreased to 46,3% at 9 mo. From baseline to month 9, there was no statistical or clinically significant difference in global health status between the study groups 1. B. 3. Multicentre study with relative big sample size

13 1. Stafinski T et al, Effectiveness of stereotactic radiosurgery alone or in combination with whole brain radiotherapy compared to conventional surgery and/or whole brain radiotherapy for the treatment of one or more brain metastases: a systematic review and meta-analysis, Cancer Treatment Reviews, Systematic review 3. Not reported 4. Not reported 5. Randomised or controlled (e.g., pseudorandomised or quasirandomised in which allocation was not truly randomised) trials and prospective or retrospective cohort studies with concurrent comparison groups time after diagnose = 4,2 mo, Sex = 57,3% (n=82) male. WHO perf scale = 0; 36,4%, 1; 53,1% 2; 10,5% yrs of age or older who had been diagnosed through CT, MRI or PET with more one or more brain metastases less than 4 cm in diameter and had not received prior cranial irradiation, regardless of primary tumour histology and status or the presence of extracranial metastases. 1. SRS allone or in combination with WBRT 2. conventional surgery and / or WBRT 1. -Based on the trend observed across studies it appears that the addition of WBRT to SRS does not improve survival. -None of the reviewed studies assessed health related quality of life. -Only one trial compared the functional independence following treatment between patients who received WBRT+SRS and those who received WBRT only. At 6 mo the WBRT+SRS was faring better and other 1+2. WBRT + SRS versus WBRT: In two trials, a statistically significant difference in local tumour control at 24 months was found (pooled HR (95% CI): 0.49 ( ) p < 0.005)). Specifically, patients who received. One trial reported about the number of patients within each treatment arm whose cause of death was related to uncontrolled metastatic brain disease. The relative risk of neurologic death was indicating that there was no difference in the risk of neurologic death between treatment arms. Information on adverse events was collected in two trials. Andrews: no statistically significant difference in the incidence of acute or late toxicities between treatment arms. Kondziolka: concluded that there was no neurologic or systemic morbidity related to SRS. WBRT + SRS were 51% less likely to have lost local tumour control 24 months after treatment. WBRT + SRS and SRS alone were 91% and 62%, respectively. WBRT + SRS versus SRS: Local 1. B 2. No blinding used in the included studies

14 1. Tsao MN et al, Whole brain radiotherapy for the treatment of multiple brain metastases, Cochrane Database of Systematic Reviews, Varlotto et al, Analysis of tumor control and toxicity in patients who have survived at least on year after radiosurgery for brain metastases, International Journal of 1. Cochrane systematic review CENTRAL,,MEDLINE, EMBASE, CANCERLIT, CINAHL 5. Trials Retrospective study 3. University of Pittsburgh Medical Center > Adult participants receiving whole brain radiotherapy for multiple metastases to the brain from any primary cancer. 2. Patient characteristics were extracted based on age, KPS and status of extracranial disease from the trials. Treatment characteristics were also extracted. If patient populations or treatment characteristics were deemed to be heterogeneous, we did not pool data for metaanalysis. 1. Patients were eligible for radiosurgery if they had a KPS of 50 or more and if the metastasis had an avarage tumor diameter of 3,5cm or more. 1. Altered whole brain radiotherapy dose fractioned schedules vs conventional WBRT fractioned schedules (3000cGy in 10 frac OR 2000 cgy in 5 frac) WBRT and systemic therapy WBRT plus radiosensitizers vs brain radiotherapy WBRT plus radiosurgery vs WBRT Radiosurgery alone or radiosurgery and WBRT Steroids alone vs Whole brain radiotherapy 2. for all groups except the first group of interventions the last named therapy is used as the control arm 1. Radiosurgery was performed with a gamma knife in all patients. The mean, peripheral, radiosurgical tumor dose was 16 Gy (range 12 25). The maximal doses varied 1. No difference in survival at 6 mo was found. No significant difference was found in response rate between patients receiving only WBRT and those receiving treatment with WBRT and radiosensitizers. No sign. difference in tumor progression of brain specific quality of life was found. A higher proportion of participants in the efaproxiral arm had stable or improving quality of life scores and KPS as compared to participants treated with whole brain radiotherapy alone 1. The actuarial rate of distal failure was 23% and 67,1% at one and 5 years respectively. The longest interval between radiosurgery and distal failure was 50 months. and other tumour control was not considered in the cohort study. The statistical significant difference in 12 month local tumour control between treatment arms in the trial led by Chougule et al. was not provided. Neurologic death. Neither Chougule et al. nor the cohort study reported the incidence of neurologic death All six studies that assessed the addition of radiosensitizers to whole brain radiotherapy reported serious adverse effects 1+2. Overall, local failure developed in 37 of the 208 tumours. Of the 137 patients, 17 experienced local failure alone, 48 experienceddistal intracranial recurrence 1. A1 2. SWOT analysis done. Large sample size. 1. C.. 3. Long inclusion period started a long time ago, small sample size as the total has been split up in the different subgroups.

15 Radiation Oncology Biology Physics, Weltman E et al, Radiosurgery for brain metastases: a score index for predicting prognosis, International Journal of Radiation Oncology Biology Physics, Retrospective study 3. Hospital Isrealita Albert Einstein, Sao Paulo, Brazil July December Age, KPS, Gender 3. Not described 1. Exclusion more than 5 lesions, any lesion larger than 30cm3, KPS less than 50, clinical evidence requiring urgent neurological intervention, or a very poor overall prognosis due to progressive systemic disease. 2. Sex, Primary tumours, KPS, age, Systemic disease status. 3. Not described 3.3 SRS / neurochirurgische resectie met of zonder WBRT I Study ID II Method III Patient characteristics between 24 and 50 Gy (mean maximal dose 32). Of the lesions, 151 were treated with the 50% isodose and 1, 2, 19, 1, 20, 13, and 1 were treated with the 45%, 55%, 60%, 65%, 70%, 80%, and 90% isodose line, respectively. 1. WBI was a 3000cGy total dose administred over 2 weeks (300 cgy/day, 5 days/week) for patients with KPS<70 and 4000cGy adminstred over 4 weeks (200cGy/day, 5days/week). The radiosurgery procedures followed the F. L. Fisher stereotactic treatment planning systemversions 2.21 and 3.1X, and were performed with a 6 MV linear accelerator (36, 38). One to 5 lesions were treated per patient, per treatment. The median prescribed dose was 18 Gy, calculated at 80% of the maximum dose in the grid calculation Age, NSCLC and concomitant WBRT and SRS were factors correlated with distant intecranial relapse. The actuarial incidence of adverse events at 1 and 5 years was 2,8% and 11,4%. 1. Survival ranged from less than 1 month to more than 65 months. Overall actuarial median survival was 6.8 months, with two living patients living 30 and 65 months after radiosurgery. Survival curves for WBI, metastatic brain lesion site, age, prim tumour histology did not demonstrate sign difference among subsets by log rank test. However the number of lesions and the largest brain lesion volume subset curves differed signif. Actuarial median survival was months for patiens with KPS 80 and 3.46 months for those with KPS 70 and other alone and 3 experienced both local and distal failure. At 1 and 5 years, the actuarial local control rate was 89,6% and 62.8% respectively. No local recurrences developed after 37 months RPA Kaplan Meier survival curve showed significant a difference between the three classes with the expected median survival for class 1 which is months, 7.75 months for class 2 and 3.38 months for class 3. The actuarial median survival for the low SIR group is 2,91 months, 7 months for the intermediate SIR group and 31,38 months for the high SIR group and other (s) 1. C. 3. Small sample size, old data but not too long period, People were not per definition seperated in homogenous classes. The influences of other possible prognostic facors is not tested of study quality

16 1. Fife KM et al, Determinants of in melanoma patients with cerebral metastases. Journal of Clinical Oncology, Fowler A et al, Survival of patients following neurosurgical treatment of colorectal adenocarcinoma metastasis in the Northern Sydney-Central Coast area. Journal of Clinical Neuroscience, Retrospective 3. Multi-centre patients (follow-up until 2003) 1. Retrospective 2. The authors acknowledge the support of Sydney Neuro- Oncology group in preparation of this study 3. Northern Sydney / Central Coast Area Health Service Patients (follow-up until first of May, 2007) 1. Presence of cerebral metastases, treated at the Sydney Melanoma Unit from 1952 to Age, sex, date of primary melanoma diagnosis, Breslow thickness, presence of extracranial metastases, number of cerebral metastases, radiotherapy dose, details of surgery 3. Cohort vs. cohort Patients with diagnosis of craniotomy for metastasis from colorectal adenocarcinoma (histopathological diagnosis) from 1999 onwards; either admitted by a neurosurgeon or had an inpatient referral and care of a neurosurgeon with a therapeutic intent; patients who were admitted to the neurosurgical unit with an established diagnosis or a likely diagnosis of CNS colorectal metastasis on clinical grounds and not specifically undergoing resective surgery; patients undergoing cerebrospinal fluid (CSF) diversion or tumor cyst drainage 2. Age, sex, location primary tumor, KPS, multiplicity, diameter of lesion, neurosurgical intervention, WBRT 3. Treated with WBRT vs. untreated with WBRT 1. Surgery (craniotomy with macroscopically complete excision, subtotal resection or biopsy), postoperative radiotherapy, (palliative) WBRT --> dose range = 4-60 Gy in 5 or 10 daily fractions 1. Not reported 1. Cohort Pts (3%) had surgery and radiotherapy; - Median survival = 11.5 months; Cohort Pts (24%) had surgery and radiotherapy; - median survival = 8.9 months Patients received radiotherapy after surgical intervention --> 13 pts had WBRT only, 1 pt WBRT combined with stereotactic radiosurgery and 2 pts WBRT combined with localised field radiotherapy; median survival of pts who had WBRT = 10.6 months as compared to pts without adjunct radiotherapy (5.2 months) and other 1+2. Treatment modality, systemic disease activity, performance status 1. B 3. Retrospective, small sample size pts concerning group who received radiotherapy in cohort , did dosage radiotherapy varied over time? C 2. 16/32 Patients received WBRT after surgery 3. Small sample size, treatment primary tumors (and/or stage) in other institutions (no correction possible), no description about the dosage of WBRT (reproducibility?)

17 1. Korinth MC et al, Prognostic Factors for Patients with Microsurgically Resected Brain Metastases. Onkologie, Nieder C et al, The Role of Postoperative Radiotherapy after Resection of a Single Brain Metastasis; combined Analysis of 643 Patients. Stahlentherapie und Onkologie, Paek SH et al, Reevaluation of surgery for the treatment of brain metastases: review of 208 patients with single or multiple brain metastases treated at one institution with modern neurosurgical techniques. Neurosurgery, Patchell RA et al, Postoperative Radiotherapy in the Treatment of Single Metastases to the Brain: A Randomized Trial. JAMA, Retrospective 3. Department of neurosurgery of the University Hospital Aachen Patients 5. July September 1996 (duration follow-up 3 months to 7 years after inclusion) 1. Systematic review 3. Multi-centre Publications, 643 pooled patients (follow-up until June 1, 2007) 1. Retrospective 3. Department of Neurosurgery at Thomas Jefferson University Hospital, Philadelphia Patients 5. March December 2002 (duration follow-up until May 2003) 1. Prospective randomised trial 3. Multi-centre, universityaffiliated cancer treatment facilities Eligible patients of whom 51 were not randomised due to refusal and physician preference 1. Surgical resection of brain metastasis 2. Sex, age, localisation primary tumor, duration neurological symptoms, preoperative KPS, extracerebral tumor progression 3. Not reported 1. Key words: "resection or neurosurgery", "brain metastases, cerebral metastases or secondary brain tumo(u)r", reference list of all articles --> all publications reporting on patient groups with single brain metastases + clearly defined radiation doses and evaluation of the brain relapse pattern 1. Single or multiple brain metastases, underwent craniotomies 2. Age, sex, location primary cancer, systemic disease, symptoms (presenting), preoperative treatments, KPS, RTOG 9508-eligibility, brain tumor location, tumor size 3. Not reported 1. Inclusion at least 18 years old who had a tissue-proven diagnosis of metastatic brain tumor obtained from a complete resection of a single brain metastasis exclusion patients with incomplete removed brain metastases by surgery, 1. Mean total dose = 32 (16-61) Gy, administered in single doses of 2 (1.3-3) Gy 1. Relapse after (in)complete resection with WBRT vs. relapse after (in)complete resection without WBRT 1. Surgery 1. RT was started within 28 days after surgery; 50.4 Gy / 5.5 weeks (1.8 Gy x 28 fractions) 2. No RT /187 Pts = postoperative WBRT; - Actuarial survival = 11.2 months (compared to 5.6 months (no postoperative WBRT) and 11.8 months (unknown whether postoperative WBRT 1. After additional radiotherapy (224 patients from 3 studies, all had complete resection) = 28 pts developed local relapse Pts / 208 pts were treated with radiation therapy (WBRT and/or stereotactic radiosurgery (SRS)) 1. Recurrence rate of tumor anywhere in the brain in radiation group = 18% vs 70% in observation group; recurrence rate at original BM was lower in radiation group than in observation group (10% vs. 46%); - Time to any brain and other 1+2. Localisation metastasis, primary tumor, KPS, absence extracerebral tumor progression, stable disease 1+2. No significant doseresponse relationship Median survival time of surgery = 8 months; - Treatment with postoperative radiotherapy =survival time of 9.1 months versus no postoperative radiotherapy (0.8 months) Survival times were not significantly different between both groups - Time between diagnosis of primary tumor and development of BM was increased with increased survival - Postoperative radiotherapy prevented 1. C 2. No loss to follow up reported 3. Retrospective, old data 1. B 2. No information about patient characteristics (can patients be pooled?), quality assessment separate studies not described, most studies included are observational 1. B 2. No lost to follow up reported 3. Moderate sample size, no blinding at assessment 1. A2 2. None were lost to follow-up 3. Old dataset, high quality study design, reproducibility study high, small sample size