Table 1.
General characteristics and main outcomes of the studies.
| Studies | Study type and no. of BM | No. of patients | Treatments and comparison | Primary histology | Tumor control (months) | Survival (OS) (months) | Prognostic factors (OS) | ||
|---|---|---|---|---|---|---|---|---|---|
| Univariate | Multivariate | ||||||||
| Primary randomized controlled trials | Kondziolka et al. (3) | RCT 2–4 BMs |
27 13/14 |
WBRT vs. WBRT+SRS | Lung, Melanoma, RCC, Breast, Other | LC: 36 vs. 6 (p = 0.0005) |
MST: 7.5 vs. 11 (p = 0.22) breast 11 vs. lung 11 vs. melanoma 5.5 (p = 0.17) |
Extent of extracranial disease | – |
| Andrews et al. (4) | RCT 1–3 BMs |
331 167/164 |
WBRT vs. WBRT+SRS | Breast, Lung (Squamous, Adenocarcinoma, Large cell, Small cell), Melanoma, Renal, Other | LC: p = 0·0132 (Favors WBRT + SRS) |
MST: 5.7 vs. 6.5 (p = 0·1356) Single BM (6·5 vs. 4·9, p = 0·0393) Squamous NSCLC (5·9 vs. 3·9, p = 0·0508) (Favors WBRT + SRS) |
Single metastases, RPA class 1, largest metastasis was > 2 cm in diameter | RPA 1 and type of tumor (Lung primary) | |
| Aoyama et al. (5) | RCT 1–4 BMs |
132 67/65 |
WBRT+SRS vs. SRS | Breast, Lung, Colorectal Renal, Other |
12 month BTRR: 46.8% 76.4% (p < 0.001) |
MST: 8.0 (0.5-57.0) vs. 7.5 (0.8–58.7) (p = 0.42) |
Primary tumor status (stable), Extracranial metastases (stable), RPA 1, KPS (90–100) | Age (<65 y), Primary tumor status (stable), Extracranial metastases (stable), KPS score (90–100) | |
| El Gantery et al. (6) | RCT 1–3 BMs |
60 21/18/21 |
WBRT+SRS vs. SRS vs. WBRT | – | LC: 10 vs. 6 vs. 5 (p = 0.04) |
NS - Largest brain metastases = 3 cm in diameter: 15 vs. 8 vs. 5, p = 0.002 - Controlled primary: 12 vs. 8 vs. 5.5, p = 0.027 (Favors WBRT + SRS) |
Single brain metastasis | – | |
| Brown et al. (7) | RCT 1–3 BMs |
213 111/102 |
SRS vs. WBRT+SRS | Breast, Colorectal, Lung, Skin/melanoma, Bladder, Kidney, Gynecologic, Other | ICF: HR: 3.6; 95% CI, 2.2-5.9; (p < 0.001) | OS: HR: 1.02; 95% CI, 0.75–1.38; (p = 0.92) | – | – | |
| Chougule et al. (8) | RCT multiple |
109 36/37/31 |
SRS vs. WBRT vs. WBRT+SRS | Breast, Lung, colorectal | LC: 87 vs. 91 vs. 62% | MST: 7 vs. 5 vs. 9 p = NS - Breast 9.5 vs. Colorectal 7 vs. Lung 6 |
– | – | |
| Retrospective studies | Sanghavi et al. (9) | Retrospective | 1,702 502/1200 |
WBRT+SRS vs. WBRT | Lung, breast, melanoma and others | – | RPA I = 16.1 vs. 7.1 RPA II = 10.3 vs. 4.2 RPA III = 8.7 vs. 2.3 (p < 0.05) |
KPS, a controlled primary, absence of extracranial metastases, and RPA class | – |
| Sneed et al. (10) | Retrospective | 569 268/301 |
SRS vs. WBRT+SRS | Breast, Kidney, lung, melanoma and others | – | HR: 1.07 (0.89–1.27), p = 0.49 |
KPS, Extracranial metastases, Control of the primary, Number of metastases | – | |
| Frazier et al. (11) | Retrospective | 237 192/45 |
SRS vs. WBRT+SRS | Breast, Melanoma, NSCLC, Renal, Other | 5.9 (4.6–7.3) vs. 6.7 (4.0–12.1) (p = 0.22) |
14.6 (11.4–19.1) vs. 10.8 (6.2–18.0) (p = 0.31) |
KPS >70, histology of breast cancer, smaller tumor volume, and age <65 years | – | |
| Elaimy et al. (12) | Retrospective | 275 65/15/48/ 19/117/11 |
SRS/S+SRS/ WBRT+SRS/S +WBRT+SRS /WBRT/ S+WBRT |
NSCLC, SCLC, Breast, Melanoma, RCC, Other |
- | SRS vs. WBRT (HR:1.94; 95% CI: 1.37–2.73, p < 0.001) SRS vs. WBRT+SRS (HR:0.99; 95% CI: 0.93–1.05, p = 0.660) |
ECOG-PS, Primary histology - NSCLC vs. Melanoma & RCC (HR:1.17; 95% CI: 1.06-1.3, p < 0.001) - NSCLC vs. Breast (HR:0.87; 95% CI: 0.78-0.96, p < 0.001) |
– | |
| Lung cancer | Sperduto et al. (13) | Secondary analysis (RCT) | 252 126/126 |
WBRT+SRS vs. WBRT | Lung, gastrointestinal, renal cancers and melanoma | – | HR: 1.0; 95% CI: 0.8–1.4, p = 0.78) | MST: 21.0 vs. 10.3, (P = 0.05) (GPA 3.5–4.0) |
– |
| Aoyama et al. (14) | Secondary analysis (RCT) | 88 45/43 |
SRS vs. WBRT+SRS | NSCLC | HR: 5.01 (2.44–11.11, p < 0.001) |
HR: 1.33 (0.85–2.08, p = 0.20) |
HR: 1.92; 95% CI, 1.01–3.78, p = 0.04) DS GPA 2.5–4.0 group |
– | |
| Churilla et al. (15) | Secondary analysis (RCT) | 127 70/57 |
SRS vs. SRS+WBRT | NSCLC | HR: 4.11 (2.11–8.00), p < 0.001 | HR: 0.98 (0.66–1.46), p = 0.92 |
– | ||
| Li et al. (16) | Retrospective Single BMs | 70 29/23/18 |
WBRT/SRS vs. SRS+WBRT | Lung (SCLC, NSCLC) | - FFLP: 3.97 ± 0.33 vs. 6.85 ± 0.50 vs. 8.56 ± 1.36 (P < 0.0001) - FFNBM: 4.07 ± 0.32 vs. 6.74 ± 0.52 vs. 8.56 ± 1.36 (P < 0.0001) - SRS vs. SRS+WBRT (p = 0.0392) |
MST: 5.67 ± 0.38, 9.33 ± 0.59, and 10.64 ± 1.54, (P < 0.0001) SRS vs. SRS+WBRT (p = 0.7079) |
Tumor volume, the absence of active extra-cranial disease, treatment methods, and worst pattern of enhancement | – | |
| Sperduto et al. (17) | Prospective multiple |
1,888 815/396/342 |
WBRT vs. SRS/WBRT +SRS |
NSCLC | – | HR: 0.62;0.51–0.75, p < 0.0001 HR: 0.53;0.45–0.63, p < 0.0001 |
– | Age, KPS, ECM, No. of BMs | |
| Lin et al. (18) | Retrospective multiple | 20,396 20241/155 |
WBRT vs. WBRT+SRS | NSCLC | – | HR: 0.49 (0.36–0.66), p < 0.0001 |
– | – | |
| Minniti et al. (19) | Prospective 2–3 BMs |
122 66/66 |
WBRT vs. WBRT+SRS | NSCLC | - LC 6 month: 90 vs. 100% - 12 month: 47 vs. 93% - BC 6 month: 75 vs. 82% 12 month: 18 vs. 42% (p = 0.001) |
MST: 7.2 vs. 10.3, p = 0.005 |
Stable extracranial disease and KPS | – | |
| Marko et al. (20) | Prospective multiple |
162 26/121/15 |
SRS vs. WBRT vs. WBRT+SRS | NSCLC | – | MST: 12.32 vs. 12.25 vs. 12.74, (p = 0.98, 0.62, 0.91) | – | – | |
| Abacioglu et al. (21) | Prospective multiple |
100 (22/78) |
SRS vs. WBRT+SRS | NSCLC (Adenocarcinoma Squamous cell carcinoma Unclassified NSCLC) | – | MST: 8 vs. 9, p = 0.757 | Adenocarcinoma histology, KPS score ≥ 80, 1–3 metastases and tumor diameter < 2 cm | – | |
| Sun et al. (22) | Prospective multiple |
82 (33/49) |
WBRT+SRS vs. WBRT |
SCLC | – | MST: 13.4 vs. 8.5 months; p = 0.004 OS rate at 6 m: 84.5 vs. 59.8% 12 m: 62.7 vs. 29.9% 24 m: 21.5 vs. 9.6% (p = 0.004) |
Limited number (1 to 3) of BMs, KPS ≥ 70, asymptomatic BMs, controlled extracranial diseases, and maximum diameter of the largest tumor ≤ 2.0 cm | – | |
| Mansour and Shawky (23) | Prospective multiple |
36 | SRS+WBRT | SCLC | – | MST: 13.5 OS rate at 6m: 84.5% 12m: 62.7% 24m: 21.5% |
KPS, single BMs, controlled extracranial diseases, ≤ 2 cm maximum diameter of the largest BMs tumor and asymptomatic BMs | ≤ 2 cm maximum diameter of the largest BMs tumor | |
| Wegner et al. (24) | Prospective multiple |
44 (6/38) |
WBRT+SRS vs. SRS (prior WBRT or PCI = 30) |
SCLC | ALC at 6 m: 90%, 12 m: 86% |
MST: 14 vs. 6 (p = 0.04) | – | – | |
| Sperduto et al. (17) | Prospective multiple |
268 (247/21) |
WBRT vs. WBRT+SRS | SCLC | – | MST: 3.87 vs. 15.23, p = 0.003 |
– | KPS, age, ECM, No. of BMs | |
| Breast cancer | Caballero et al. (25) | Retrospective | 310 | SRS after prior WBRT | 90 breast, 113 NSCLC, 31 SCLC, 42 melanoma, and 34 miscellaneous | – | MST: 8.4 (11.4 vs. 8.1 vs. 7.2) | Breast; age <50 years, smaller total target volume, and longer interval from WBRT to SRS NSCLC; controlled primary tumor, and number of BM, melanoma; smaller total target volume |
Breast; age <50 years, smaller total target volume, and longer interval from WBRT to SRS NSCLC; number of BM, KPS, and controlled primary Melanoma; smaller total target volume |
| Firlik et al. (26) | Retrospective | SRS vs. WBRT+SRS | Breast cancer | 93% | P = 0.20 | Tumor volume and Solitary metastasis | – | ||
| Muacevic et al. (27) | Retrospective | SRS vs. WBRT+SRS | Breast cancer | 9.5 ± 1.4 vs. 11.4 ± 3.5, p = 0.7 |
KPS and RPA | – | |||
| Kased et al. (28) | Retrospective | SRS vs. WBRT+SRS | Breast cancer | MBFFP: 8.6 vs. 10.5, p = 0.75 | MST: 17.1 vs. 15.9, p = 0.20 |
Age <50 y KPS > 70 Primary controlled, ER positive Overexpression, Her2/neu overexpression. |
– | ||
| Sperduto et al. (17) | Retrospective multiple | 642 277/141/ 123 |
WBRT vs. SRS/WBRT +SRS |
Breast cancer | – | HR: 0.75;0.54–1.04, p = 0.088 HR: 0.72;0.53–0.98, p = 0.035 |
NA | KPS | |
| Jaboin et al. (29) | Retrospective | 100 26/25/37 |
SRS vs. SRS+WBRT vs. WBRT+ (salvage)SRS | Breast (luminal A, luminal B, HER2/neu, basal, unknown) | – | MST: 12.4 vs. 12.2 vs. 9.5, p = NS | Age, stage and number of lesions, CNS failure | – | |
| Perez et al. (30) | Retrospective | 231 66/165 |
SRS vs. SRS+WBRT | Breast cancer | – | HR: 1.78;1.06–2.99, p = 0.03 (multivariate) |
Controlled systemic disease, adjuvant chemotherapy, and RPA | – | |
| Sperduto et al. (31) | Retrospective | 383 | SRS/WBRT/ WBRT+SRS/ S+WBRT/S+ SRS+WBRT/ S+SRS |
Basal (TN) Luminal A (ER/PR(+)/HER2(–) HER2(+)/ER/PR(–) Luminal B (TP) |
– | MST: 7.3 (4.9–9.5) 10.0 (7.4–19.5) 17.9 (13.4–22.9) 22.9 (16.1–29.5) p < 0.01 |
– | – | |
| Cho et al. (32) | Retrospective | 131 79/43+4/5 |
SRS vs. WBRT+ salvage SRS vs. WBRT+SRS boost vs. S+SRS boost | ER(+)/HER2(–); 41(31%), ER(+)/HER2(+); 30 (23%), ER(–)/HER2(+); 23 (18%), and ER(–)/HER2(–); 28 (21%) (TNBC). | TNBC vs. ER(+)/HER2(–); HR:3.12 (p < 0.001) (retreatment or death) |
SRS vs. WBRT+SRS: HR = 1.18, p = 0.4 MST: 16 vs. 26 vs. 23, vs. 7 (p < 0.001) |
– | – | |
| Xu et al. (33) | Retrospective | 264 HER2known /unknown (172/92) |
SRS vs. S/WBRT 162/49+214 |
Breast cancer HER2+ vs. HER2–172 (82/90) |
– | SRS vs. S/WBRT: 96.6 vs. 106.5, p = 0.73 MST: OS:105.7 vs. 74.3, p < 0.01 Survival after SRS: 31.3 vs. 14.1, p < 0.01 |
HER2+; HR:0.66, p = 0.021 Age >45 y, Estrogen receptor positive, Progesterone receptor positive |
HER2+; HR:0.18, p < 0.001 | |
| Xu, et al. (34) | Retrospective | 103 (SRS = 27, WBRT+SRS = 59 S+SRS = 9, S+WBRT+ SRS = 8) |
SRS vs. WBRT+SRS | Breast cancer (Triple negative, Non–triple negative, ER+, PR+, HER2+) (TN = 24/Non–T N = 79 |
- OLC: 90/3% - ATC rate at 6 m: 96.5% - at 12 m: 92.2% - at 24 m:83.3% |
SRS vs. WBRT+SRS; p = 0.797 Non-TN vs. TN; MST: 43 (27.3–58.7) vs. 82 (66.3–97.7), p = 0.042 |
Non-TN vs. TN; HR:0.461 (0.279–0.763), p = 0.003 HER2+ vs. HER2–; HR:0.629 (0.405–0.975), p = 0.038 |
Non-TN status and lower recursive partitioning analysis class | |
| Radioresistant histology | Lwu et al. (35) | Retrospective | 103 34/56 |
SRS alone vs. SRS + prior WBRT | 41 RCC, 62 Melanoma | ALC at 6m: 89% 12 m: 84% 18: 76% 24 m:61% - LC at 12 m: 91% (RCC) and 75% (melanoma) |
HR: 0.98 (0.30–3.26), p = 0.98 - Melanoma vs. RCC; HR: 3.48 (1.08–11.23), p = 0.04) |
Tumor volume, Primary tumor | – |
| Brown et al. (36) | Retrospective | 41 | SRS vs. SRS+WBRT boost | 16 RCC, 23 melanoma, 2 sarcoma | LF; 12% DBF; 54% -SRS+WBRT vs. SRS: - ALC at 6 month; 100 vs. 85%, p = 0.018 - DBF rate at 6-m; 17 vs. 64%, p = 0.0027 |
MST: 14.2 - RCC vs. melanoma; 17.8 vs. 9.7, p = 0.12 |
Systemic disease status, RPA | RPA, histological diagnosis of primary tumor | |
| Manon et al. (37) | Retrospective | 31 | SRS | Melanoma 14, Sarcoma 3, RCC 14 | ICF at 3m; 25.8% - at 6 m; 48.3% |
8.3 months (95% CI, 7.4 to 12.2). | – | – | |
| Chang et al. (38) | Retrospective | 189 | SRS | 103 melanoma, 77 RCC, 9 sarcoma | 1-year AFFP: 64% RCC; 47% melanoma; 0% sarcoma (P < 0.001) |
MST: 7.5 1-year SR: 40% RCC; 25% melanoma; 22% sarcoma (P = 0.0354) |
– | – | |
| Renal cell carcinoma | Wronski, M., et al. (39) | Retrospective | 119 | WBRT | RCC | MST: 4.4 | – | single brain metastasis, lack of distant metastases at the time of diagnosis, and tumor diameter < or = 2 cm | |
| Takashi et al. (40) | Retrospective | 69 | SRS | RCC | 82.6% | MST: 9.5 | – | Number of lesions, KPS, RPA, and the interval from diagnosis of RCC to brain metastasis | |
| Jasonet al. (41) | Retrospective | 69 | SRS | RCC | ALC; 94% | MST: 6 | – | Age, preoperative KPS score, radiosurgical dose to the tumor margin, maximal radiosurgical dose, treatment iso-dose, time from diagnosis of renal cell cancer to the development of brain metastasis | |
| Goyal et al. (42) | Retrospective | 29 (13/16) | SRS vs. SRS+WBRT | RCC | -DBF: 33 vs. 25% - LC: 2/18 vs. 2/29, p = NS |
MST: 5.2 vs. 6.8, NS | – | – | |
| Mori et al. (43) | Retrospective multiple | 25 12/13 |
SRS vs. SRS+WBRT | RCC | MST: 11 SRS vs. SRS+WBRT; p = 0.35 |
Age, good KPS at the time of radiosurgery, nephrectomy prior to radiosurgery | Age, lack of active systemic disease, use of chemotherapy and/or immunotherapy after SR | ||
| Ippen et al. (44) | Retrospective multiple | 66 36/24/6 |
SRS vs. S+SRS vs. SRS+WBRT | RCC | −1-year LC: 84%, 94%, and 88%, p = 0.445 - DTC: Prior WBRT vs. others (p = 0.007) |
OS: 13.9, 21.9, 5.9 - Prior WBRT was associated with worst OS (uni/multivariate) |
Age, prior surgery, RPA, KPS, SIR, BSBM, number of brain metastases, initial tumor volume, and Ds-GPA | Age, RPA, KPS, and the initial number of brain metastases, prior surgery | |
| Fokas et al. (45) | Retrospective 1–3 (SRS/SRS+ WBRT) Multiple (WBRT) |
88 51/17/20 |
SRS vs. SRS+WBRT vs. WBRT | RCC | 1-, 2-, 3-year IC rates; 42%, 29%, 22% | MST: 12 vs. 16 vs. 2 -SRS/SRS+WBRT vs. WBRT; p < 0.001 |
Age, lack of extracranial metastases, RPA, SRS, SRS + WBRT | lack of extracerebral metastases, RPA, SRS, SRS + WBRT | |
| Bates et al. (46) | Retrospective multiple | 25 9/11/5 |
SRS vs. WBRT vs. SRS+WBRT | RCC | BPFS; 8.3 vs. 2.5 (p = 0.38) vs. 4.5 (p = 0.65). |
OS; 8.3 vs. 2.8 (p = 0.82) vs.8.5 (p = 0.65) | Age, sex, KPS, presence of extracranial metastases, history of smoking, alcohol consumption, DS-GPA, use of surgery, multiple intracranial metastases | DS-GPA score | |
| Melanoma | Hauswald et al. (47) | Retrospective | 87 | WBRT | Melanoma | – | MST: 3.5 OSR: - at 6 m: 29.2% - at 12 m: 16.5% |
DS-GPA, RPA | Total treatment dose, surgical resection, GPA |
| Noël et al. (48) | Retrospective | 25 | SRS | Melanoma | 3-, 6- and 12-m LC rates; 95 ± 3, 90 ± 5 and 84 ± 7% | MST: 8 months 3-, 6- and 12-m OS rates; 75 ± 9, 53 ± 10, and 29 ± 10% |
Extracranial controlled disease, SIR | - | |
| Seung et al. (49) | Retrospective | 55 11/28/16 |
WBRT+SRS, SRS, WBRT+SRS (salvage) | Melanoma | 6 month and 1-year actuarial freedom from progression rates of 89% and 77% | 35 wks | Total target volume treated | – | |
| Mathieu et al. (50) | Retrospective | 244 115/110/53 |
SRS (prior WBRT /prior surgery) | Melanoma | LC: 30.9% DC: 41.7% |
MST: 5.3 | Age, Extracranial disease status, RPA, KPS, Number of metastases, Single or multiple metastasis, WBRT at any time | Active extracranial disease, KPS, multiple metastases, tumor volume >8 cm3, cerebellar metastases | |
| Yu et al. (51) | Retrospective | 122 | SRS vs. SRS+WBRT 39 (32%) WBRT | Melanoma | – | MST: 7.0 | total intracranial tumor volume <3 cm3, inactive systemic disease | – | |
| Selek, U., et al. (52) | Retrospectiv3 | 103 61/12/30 |
RS, SRS+WBRT, WBRT+ SRS (salvage) | Melanoma | −1-year LC; 49% - 1-year DF; 14.7%. |
1-year OS: 25.2% | Score Index for Radiosurgery (SIR) | ||
| Dyer et al. (53) | Retrospective | 147 | SRS/SRS+ WBRT/salvage WBRT |
Melanoma | DICF: omission of up-front WBRT; HR: 2.24, p = 0.005 | MST: 7.3 Omission of up-front WBRT; HR: 2.56, p = 0.08 (multivariate) |
Extensive extracranial metastases, KPS, multiple brain metastases | Extensive extracranial metastases, KPS | |
| Bagshaw et al. (54) | Retrospective | 185 154/51/31 |
SRS/salvage WBRT /SRS+WBRT | Melanoma | MTTLF: 23.4 | MST: 7.8 | – | – | |
| Radbillet al. (55) | Retrospective | 51 32/8/8/2 |
SRS/SRS+ WBRT/SRS+S /SRS+WBRT +S |
Melanoma | ALC - at 26 wks: 66% -at 52 wks: 56% ADC - at 26 wks: 46% - at 52 wks: 25% |
OS rate - at 12 wks; 71% - at 26 wks;51%, - at 52 wks; 30% |
– | RPA I, Treatment of infratentorial lesion, Multiple lesions present (categoric) Initial WBRT with radiosurgery; HR:1.08 (0.39–2.98), p = 0.88 |
|
OS, overall survival; MST, median survival time; LC, local control; DF, distant failure; DC, distant control; ICF, intrcranial failure; MTTLF, median time to local failure; MTTDF, median time to distant failure; ALC, actuarial local control; DICF, distant intracranial failure; BPFS, brain progression free survival; IC, intracranial; DTC, distant tumor control; DBF, distant brain failure; AFFP, actuarial freedom from progression; FFNBM, free from new brain meatsases; RPA, recursive partitioning analysis; DS-GPA, Diagnosis-specific graded prognostic assessment; WBRT, whole brain radiotherapy; SRS, stereotactic radiosurgery; S, surgery; RCT, randomized controlled trial; NSCLC, non-small cell lung cancer, SCLC, small cell lung carcinoma; wks, weeks; m, months; NS, not significant; ER+, estrogen receptor positive; PR+, progesterone receptor positive; HER2+, human epidermal growth factor receptor 2; TN, triple negative; TNBC, triple negative breast cancer.