Rationale
Methods
Search strategy
Eligibility criteria
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Published in English with a publication date of 1990 forward.
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Patients with newly diagnosed single brain metastases.
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Fully published peer-reviewed primary comparative studies (all comparative study designs for primary data collection included; e.g., randomized controlled trials (RCTs), non-randomized trials, cohort studies or case–control studies)
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Study comparisons include: WBRT versus surgery + WBRT
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Number of participants with newly diagnosed brain metastases >5 per study arm
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Baseline information on study participants is provided by treatment group in studies evaluating interventions exclusively in patients with newly diagnosed brain metastases. For studies with mixed populations (i.e., includes participants with conditions other than newly diagnosed brain metastases), baseline information is provided for the intervention sub-groups of participants with newly diagnosed brain metastases.
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Published in English.
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Patients with newly diagnosed brain metastases.
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Fully published peer-reviewed primary comparative studies (all comparative study designs for primary data collection included; e.g., RCT, non-randomized trials, cohort studies or case–control studies) for studies published 1990 forward; RCTs published 1970 forward.
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Study comparisons include: WBRT dose/fractionation schedule 1 versus WBRT dose/fractionation schedule 2
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Number of participants with newly diagnosed brain metastases >5 per study arm.
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Baseline information on study participants is provided by treatment group in studies evaluating interventions exclusively in patients with newly diagnosed brain metastases. For studies with mixed populations (i.e., includes participants with conditions other than newly diagnosed brain metastases), baseline information is provided for the intervention sub-groups of participants with newly diagnosed brain metastases.
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Published in English with a publication date of 1990 forward.
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Patients with newly diagnosed brain metastases.
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Fully published peer-reviewed primary studies (all study designs for primary data collection included; e.g., RCT, non-randomized trials, cohort studies, case–control studies or case series).
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Any study evaluating the outcome(s) of WBRT by tumor histopathology (or primary tumor type).
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Number of participants with newly diagnosed brain metastases >5 per study arm for comparative studies and >5 overall for non-comparative studies.
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For studies evaluating the outcome(s) of WBRT by histopathology (or primary tumor type) exclusively in patients with newly diagnosed brain metastases, baseline characteristics are presented and stratified by histologic/primary tumor group. For studies with mixed populations (i.e., includes participants with conditions other than newly diagnosed brain metastases), baseline characteristics are presented and stratified by histologic/primary tumor group for the sub-group of participants with newly diagnosed brain metastases.
Study selection and quality assessment
Meta-analyses
Evidence classification and recommendation levels
Guideline development process
Scientific foundation
Surgical Resection plus WBRT versus WBRT alone
First author (year) | Study design/evidence class | Interventions | Population | Median survival | # Pts with recurrence/progressiona
| Median time to recurrence/progression |
---|---|---|---|---|---|---|
Randomized trials | ||||||
Patchell (1990) [6] | RCT Evidence class I | G1: WBRT (n = 23) G2: WBRT + surgery (n = 25) | Single BM | G1: 15 weeks G2: 40 weeks (Survival curves: log-rank; P < 0.01) | At original site: G1: 12/23 (52%) G2: 5/25 (20%) (P < 0.02) | At original site: G1: 21 weeks G2: >59 weeks (LR curves: log-rank; P < 0.0001) |
At distant or leptomeningeal sites: G1: 3/23 (13%) G2: 5/25 (20%) (P = NS) | ||||||
Mintz (1996) [7] | RCT Evidence class I | G1: WBRT (n = 43) G2: WBRT + surgery (n = 41) | Single BM | G1: 6.3 months G2: 5.6 months (Survival curves: log-rank; P = NS) | NR | NR |
Vecht (1993) [8] | RCT Evidence class I | G1: WBRT (n = 31) G2: WBRT + surgery (n = 32) | Single BM | G1: 6 months G2: 10 months (Survival curves: log-rank; P = 0.04) | NR | NR |
Other study designs | ||||||
Ampil (1996) [9] | Retrospective cohort study Evidence class II | G1: WBRT (n = 34) G2: WBRT + surgery (n = 11) | Cerebellum BM | G1: 3 months G2: 15 months (Wilcox on rank sum; P = 0.005) | NR | NR |
Rades (2008) [10] | Retrospective cohort study Evidence class II | G1: WBRT (n = 96) G2: Surgery + WBRT (n = 99) | Single BM | G1: 6 months G2: 11.5 months (Survival curves: log-rank; p < 0.001) | NR | At original site: NR (LR curves: log-rank; P < 0.001) |
At distant site: NR (DR curves: log-rank; P = NS) | ||||||
At any site: NR (BR curves: log-rank; P < 0.001) | ||||||
Sause (1990) [11] | Prospective non-randomized trial Evidence class II | G1: WBRT (n = 55) G2: WBRT + surgery (n = 25) | Single BM | G1: 6.7 months G2: 15.5 months (Survival curves: log-rank; P = 0.004) | NR | NR |
WBRT dosing/fractionation schedule
First author (year) | Study design/evidence class | WBRT total dose/fractionation | Population | Median survival | # Pts with recurrence/progressiona
| Median time to recurrence/progression |
---|---|---|---|---|---|---|
Randomized trials | ||||||
Borgelt (1981) [12] | RCT Evidence class I | First RCT: G1: 10 Gy/1 fraction (n = 26) G2: 30–40 Gy over 2–4 weeks (n = 112) | BM | First RCT: G1: 15 weeks G2: 21 weeks (Survival curves: log-rank; P = NS) | NR | Median time to progression (measured by deterioration in neurologic function): First RCT: Initial NF 1: G1: 9 weeks; G2: 14 weeks Initial NF 2: G1: 9 weeks; G2: 10 weeks Initial NF 3: G1: 7 weeks; G2: 12 weeks (Cox’s model; P = 0.07) |
Second RCT: G3: 12 Gy/2 fractions (n = 33) G4: 20 Gy over 1 week (n = 31) | Second RCT: G3: 13 weeks G4: 12 weeks (Survival curves: log-rank; P = NS) | Second RCT: Initial NF 1: G3: 9 weeks; G4: 10 weeks Initial NF 2: G3: 11 weeks; G4: 8 weeks Initial NF 3: G3: 3 weeks; G4: 3 weeks (Cox’s model; P = NS) | ||||
Chantani (1994) [13] | RCT Evidence class I | Normal LDH: G1: 30 Gy/10 fractions (n = 46) G2: 50 Gy/20 fractions (n = 46) | Lung cancer BM | G1: 5.4 months G2: 4.8 months (Survival curves G1 vs. G2: log-rank; P = NS) G3: 3.4 months G4: 2.4 months (Survival curves G3 vs. G4:log-rank; P = NS) | NR | NR |
High LDH: G3: 30 Gy/10 fractions (n = 35) G4: 20 Gy/5 fractions (n = 35) | ||||||
Chantani (1985) [14] | RCT Evidence class I | G1: 30 Gy/10 fractions (n = 35) G2: 50 Gy in 20 fractions (n = 34) | Lung cancer BM | G1: 4 months G2: 3 months (Survival curves: log-rank; P = NS) | NR | NR |
Davey (2008) [15] | RCT Evidence class I | G1: 20 Gy/5 daily fractions (n = 45) G2: 40 Gy/20 fractions/twice daily (n = 45) | BM | G1: 19.1 weeks G2: 19.1 weeks (Survival curves: log-rank; P = NS) | NR | NR |
Haie-Meder (1993) [16] | RCT Evidence class I | G1: 18 Gy/3 fractions (n = 110) G2: 18 Gy/3 fractions; 4 weeks later a second identical course or 25 Gy/10 fractions (n = 106) | BM from lung, breast, head and neck or unknown primaries | G1: 4.2 months G2: 5.3 months (Survival curves: log-rank; P = NS) | NR | NR |
Komarnicky (1991) [17] | RCT Evidence class I | G1: 30 Gy/10 fractions (n = 193) G2: 30 Gy/6 fractions (n = 200) G3: 30 Gy/6 fractions + MISO (n = 196) G4: 30 Gy/10 fractions + MISO (n = 190) | BM | G1: 4.5 months G2: 4.1 months G3: 3.1 months G4: 3.9 months (Survival curves: log-rank; P = NS) | # of pts retreated for BM after protocol therapy: G1: 54/179 (30%) G2: 54/180 (30%) G3: 33/173 (19%) G4: 54/163 (33%) (P = NS) | NR |
Kurtz [18] (1981) | RCT Evidence class I | G1: 30 Gy/10 fractions (n = 130) G2: 50 Gy/20 fractions (n = 125) | BM with no extra-cranial metastases | G1: 18.2 weeks G2: 16.9 weeks (Survival curves: log-rank; P = NS) | Overall in brain: G1: 109/124 (88%) G2: 105/118 (89%) (P value not reported) | Overall in brain: G1: 11 weeks G2: 10 weeks (P value not reported) |
Murray (1997) [19] | RCT Evidence class I | G1: 30 Gy/10 fractions/daily (n = 213) G2: 54.4 Gy/34 fractions/twice daily (n = 216) | BM | G1: 4.5 months G2: 4.5 months (Survival curves: Prentice modified Wilcox on; P = NS) | NR | NR |
Priestman (1996) [20] | RCT Evidence class I | G1: 12 Gy/2 fractions (n = 270) G2: 30 Gy/10 fractions (n = 263) | BM | G1: 77 days G2: 84 days (Survival curves: log-rank; P = 0.04) | NR | NR |
Sause [21] (1993) | Randomized phase I/II trial Evidence class I | G1: 32 Gy in 1.6 Gy fractions + boost to 48.0 Gy] (n = 62) G2: 32 Gy in 1.6 Gy fractions + boost to 54.4 Gy] (n = 115) G3: 32 Gy in 1.6 Gy fractions + boost to 64.0 Gy] (n = 104) G4: 32 Gy in 1.6 Gy fractions + boost to 70.4 Gy] (n = 53) Fractions administered twice daily | BM | G1: 4.2 months G2: 5.2 months G3: 4.8 months G4: 6.4 months (Survival curves: log-rank; P = NS) | NR | NR |
Other study designs | ||||||
Bach (1996) [22] | Retrospective cohort study Evidence class II | G1: 22 Gy/4 fractionsb (n = 57) G2: 50.4 Gy/28 fractionsb (n = 44) | BM from SCLC | G1: 88 days G2: 160 days (Survival curves: log-rank; P = 0.00001) | NR | NR |
Conill [23] (2006) | Retrospective cohort study Evidence class II | G1: 20 Gy/5 fractions + TMZ based chemotherapy (n = 11) G2: 30 Gy/10 fractions + TMZ based chemotherapy (n = 10) | BM from melanoma | G1: 4.0 months G2: 4.0 months (Survival curves: log-rank; P = NS) | Data not reported by group; no statistically significant difference between groups (P = NS) | NR |
Nieder (1995) [24] | Retrospective cohort study Evidence class II | G1: WBRT [40 Gy in 20 fractions ± local boost 10–20 Gy] (n = 39) G2: WBRT [30 Gy in 10 fractions] (n = 39) [matched to G1] | BM | G1: 3.5 months G2: 2.5 months (Survival curves: log-rank; P = NS) | # Pts with local CR/PR: G1: CR 5/39 (13%); PR 25/39 (64%) G2: CR 4/39 (10%); PR 15/39 (38%) (CR or PR G1: 77% vs. G2: 48%; P = 0.037) | Median time to BM progression: G1: 3.0 months G2: 2.5 months (Progression-free curves: log-rank; P = NS) |
Nieder (1997) [25] | Prospective cohort study with historical controls Evidence class III | G1: Surgery + WBRT [30 Gy/2.5 Gy fractions/twice daily] (n = 11) G2: WBRT [50.4 Gy/1.8 Gy fractions/twice daily] (n = 15) G3: WBRT [30 Gy/2.5 Gy fractions/twice daily] (n = 36) G4: Historical group WBRT [30 Gy/3 Gy fractions/daily] (n = 246) G5: Historical group surgery + WBRT [30 Gy/3 Gy fractions/daily] (n = 37) | BM | G1: 3.3 months G2: 2 months G3: 2 months G4: 2.5 months G5: 7.3 months (Survival curves G2, G3, G4: log-rank; P = NS) | # of pts with follow up CT with BM progression/recurrence anywhere in brain: G1: 3/9 (33%) G2: 4/11 (36%) G3: 11/25 (44%) G4: 29/202 (14%) G5: 5/35 (14%) | Median time to any recurrence in brain: Not reported BR curves G3 vs. G4: log-rank; P = 0.0001 BR curves G2 vs. G3: log-rank; P = NS BR curves G2 vs. G4: log-rank; P = NS |
Rades (2007) [26] | Retrospective cohort study Evidence class II | G1: 20 Gy/5 fractions (n = 140) G2: 30 Gy/10 fractions or 40 Gy/20 fractions (n = 264) | BM from NSCLC | Median survival: Not reported 6 month survival rate: G1: 40% G2: 30% (Survival curves: log-rank; P = NS) | NR | NR |
Rades (2007) [27] | Retrospective cohort study Evidence class II | G1: 30 Gy/10 fractions (n = 257) G2: 45 Gy/15 fractions or 40 Gy/20 fractions (n = 159) | ≥2 BM | Median survival:NR 6 month survival rate: G1: 33% G2: 29% (Survival curves: log-rank; P = NS) | 6 month local control rate: G1: 39% G2: 41% (LR curves: log-rank; P = NS) | NR |
Rades (2008) [28] | Retrospective cohort study Evidence class II | G1: 20 Gy/5 fractions (n = 387) G2: 30 Gy/10 fractions or 40 Gy/20 fractions (n = 698) | BM | Median survival: Not reported 1 year survival rate: G1: 20% G2: 18% (Survival curves: log-rank; P = NS) | NR | NR |
Author | Year | Total dose (Gy) | Fractions | BED (Gy; α/β = 10) |
n
| Median survival (weeks) |
---|---|---|---|---|---|---|
Borgelt | 1981 | 12 | 2 | 19.2 | 33 | 13 |
Priestman | 1996 | 12 | 2 | 19.2 | 270 | 11 |
Borgelt | 1981 | 10 | 1 | 20 | 26 | 15 |
Borgelt | 1981 | 20 | 5 | 28 | 31 | 12 |
Chatani | 1994 | 20 | 5 | 28 | 35 | 10.4 |
Davey | 2008 | 20 | 5 | 28 | 45 | 19.1 |
Haie-Meder | 1993 | 18 | 3 | 28.8 | 110 | 18.3 |
Chatani | 1994 | 30 | 10 | 39 | 46 | 23.5 |
Chatani | 1994 | 30 | 10 | 39 | 35 | 14.8 |
Chatani | 1985 | 30 | 10 | 39 | 35 | 17.4 |
Komarnicky | 1991 | 30 | 10 | 39 | 193 | 19.5 |
Komarnicky | 1991 | 30 | 10 | 39 | 190 | 16.9 |
Kurtz | 1981 | 30 | 10 | 39 | 130 | 18.2 |
Murray | 1997 | 30 | 10 | 39 | 213 | 19.6 |
Priestman | 1996 | 30 | 10 | 39 | 263 | 12 |
Komarnicky | 1991 | 30 | 6 | 45 | 200 | 17.8 |
Komarnicky | 1991 | 30 | 6 | 45 | 196 | 13.5 |
Davey | 2008 | 40 | 20a
| 48 | 45 | 19.1 |
Sause | 1993 | 48 | 30a
| 55.7 | 62 | 18.3 |
Haie-Meder | 1993 | – | – | 50.8 | 106 | 23 |
Chatani | 1994 | 50 | 20 | 62.5 | 46 | 20.9 |
Chatani | 1985 | 50 | 20 | 62.5 | 34 | 13 |
Kurtz | 1981 | 50 | 20 | 62.5 | 125 | 16.9 |
Murray | 1997 | 54.4 | 34a
| 63.1 | 216 | 19.6 |
Sause | 1993 | 54.4 | 34a
| 63.1 | 115 | 22.6 |
Sause | 1993 | 64 | 40a
| 74.2 | 104 | 20.9 |
Sause | 1993 | 70.4 | 44a
| 81.7 | 53 | 27.8 |
Borgelt | 1981 | 30–40 | 10–20 | 34.5–56 | 112 | 21 |
Impact of tumor histopathology on WBRT treatment outcomes
First author (year): Sundström (1998) [29] | ||
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Study characteristics | Study outcomes | Study quality |
Study design: case series | Primary outcome: survival | Quality assessment: N/A as non-comparative study |
Inclusion criteria: Pts treated with WBRT for BM diagnosed by CT or MRI Minimum midline dose to the whole brain of at least 25 Gy | Median survival by primary tumor type: Breast: 7 months (range 1–62 months) Lung: 4 months (range 1–21 months) Renal cell: 4 months (range 2–34 months) Melanoma: 3 months (range 1–6 months) Other primaries: 4 months (range 1–9 months) (Survival curves: P-value not reported) | AANS/CNS evidence classification: class III |
Interventions: WBRT [mean dose 30 Gy (range 25–40 Gy) in 1.8–3 Gy fractions] | Tumor control: not reported | |
Median follow-up: not reported # Male: Breast: 0/19, lung: 26/35, renal cell: 4/9, melanoma: 6/6, other: 6/6 | Median time to recurrence of brain metastases: not reported | |
Median age (range): Breast: 53 years (39–77 years) Lung: 64 years (43–78 years) Renal cell: 61 years (41–69 years) Melanoma: 61 years (39–62 years) Other: 61 years (50–71 years) | Functional performance: not reported by histology | |
Cause of death: not reported | ||
Adverse events: not reported by tumor type | ||
# Of brain metastases: Breast: 1 BM 9/19, 2 BM 4/19, >2 BM 6/19 Lung: 1 BM 15/35, 2 BM 5/35, >2 BM 15/35 Renal cell: 1 BM 3/9, 2 BM 2/9, >2 BM 4/9 Melanoma: 1 BM 3/6, 2 BM 0/6, >2 BM 3/6 Other: 1 BM 3/6, 2 BM 2/6, >2 BM 1/6 | ||
Extra-cranial disease: Extra-cranial metastases: Breast: 17/19 Lung: 6/35 Renal cell: 5/9 Melanoma: 4/6 Other: 5/6 | ||
Baseline functional performance: WHO classification (0 (best) to 4 (worst) Performance status (PS): Breast: PS 0–1 9/19, PS 2 5/19, PS 3 5/19 Lung: PS 0-1 10/35, PS 2 16/35, PS 3 9/35 Renal cell: PS 0–1 2/9, PS 2 5/9, PS 3 2/9 Melanoma: PS 0–1 6/6 Other: PS 0–1 3/6, PS 2 1/6, PS 3 2/6 |