Stereotactic body radiation therapy for colorectal liver metastases

Figures & data

Table 1. Characteristics of included studies.

Author/year	Design	N: pts.	N: liver lesions	Lesion’s size (range) cm/ml	Primary site/previous CT (%)	Dose: range Gy/n fxs (BED10 Gy)	Median follow-up (months)
Herfath/2004 [12]	Phase 1–2	18	1–3	≤6 cm/10 (1 to 132) ml	Colorectal (53%)/NR	14–26Gy/1fr (33.6–93.6Gy)	5.7
Mendez Romero/2006 [36]	Phase 1–2	14	1–4	3.2(0.5–7.2) cm/22.2(1.1–322) ml	Colorectal (82.3%)/NR	30–37.5Gy/3fr (60–84.4Gy)
Hoyer/2006 [13]	Phase 2	44	1–6	3.5(1–8.8) cm	Colon (59%), rectum (41%)/ (52%)	45Gy/3 fr (112.5 Gy)	52
Rusthoven/2009 [16]	Phase 1––2	15	1–3	2.7(0.4 to 5.8) cm/14.9(0.75–98) ml	Colorectal (31.9%)/≥1 (85%)	36–60 Gy/3fr (79.2–180 Gy)	16
Lee/2009 [14]	Phase 1	40	1–8	134.8(6.7–3,090) ml	Colorectal (58.8%)/≥1 (85%)	27.7–60 Gy/5–6 fr (40.44–120 Gy)	10.8
Kim/2009 [31]	Prospective	10	1–4	3.4–271 ml	Colon (60%), rectum (40)/≥1 line 100%	36–51 Gy/3 fr (79.2–137.7 Gy)	12
van der Pool/2010 [18]	Prospective	20	1–3	0.7–6.2 cm	Colon (75%), rectum (25%)/NR	37.5–45 Gy/3fr (93.6–112.5 Gy)	26
Chang/2011 [11]	Retrospective	65	1–4	30.1(0.6–3088) ml	Colorectal/≥1 (72%)	22–60 Gy/1–6 fr (40.5–180 Gy)	14
Vautravers–Dewas/ 2011 [40]	Retrospective	30	1–4	0.7–10 cm	–	40 Gy/4 fr (80 Gy) 45 Gy/3 fr (112.5 Gy)	14.3
Stintzing/2013 [38	Prospective	30	1	0.7–5.3 cm	Colorectal/67%	24–26 Gy/1fr (81.6–93.6 Gy)	23.3
Liu/2013 [32]	Retrospective	24	1–4	8.8(0.2–222.4) ml	Colorectal (23%)/NR	24–60 Gy/1–5 fr (81.6–132 Gy)	18
Berber/2013 [26]	Retrospective	53	1.6 (median)	182(60–581) ml	Colorectal/NR	41 Gy/3 fr (96.76 Gy)	17
Scorsetti/2015, 2018 [10,37]	Phase 2	42	1–3	1.1–5.4 cm/(1.8–134.3) ml	Colon (71%), rectum (29%)/(100 %)	75 Gy/3fr (262.5 Gy)	24
van de Voorde/2015 [39[	Retrospective	17	1–3	–	Colorectal (51.5%)/NR	EQD2 62–150 Gy /3–10fr	21
Goodman/2015 [29]	Retrospective	54	1–3	2.7(0.9–10.2) cm/29.7(3.4–149.8) ml	Colorectal (67%)/NR	32–60 Gy/3–5 fr (52.48–180 Gy)	33
Mendez Romero/ 2017 [34]	Retrospective	40	1–3	2.5(0.7–6.2) cm	Colorectal/NR	50.25 Gy/3 fr (134.42 Gy) 37.5 Gy/3 fr (84.38 Gy)	25 & 26
Ahmed/2016 [24]	Retrospective	22	1–5	2(0.6–6.7) cm	Colorectal (67%)/NR	50–60 Gy/5 fr (100–132 Gy)	20.5
Doi/2017 [28]	Retrospective	24	1–3	3.5(7–11.6) cm/8.7 (0.4–134.7) ml	Colon (75%), rectum (25%)/(87.5)	45–72 Gy/8 fr (71.7–115.5 Gy)	16.5
McPartlin/2016 [33]	Phase 1 & 2	60	1–6	40.8(0.6–3089) ml	Colorectal/≥1 (82%)	22.7–62.1/5–6 fr (31.28–126.37 Gy)	28.1
Joo/2017 [30]	Retrospective	70	1–3	41% ≥3 cm	Colorectal/3≥ (31%)	45–60 Gy/3–4 fr (58–180 Gy)	34.2
Andratschke/2018 [25]	Retrospective	213	1–4	0.6–699 ml	Colorectal (48.1%)/NR	Several doses/1–13 fr (102.5–134.3 Gy)	15
Vernaleone/2019 [19]	Retrospective	38	1–4	1–5 cm	Colon (71%), rectum (29%)/NR	25–45 Gy/3–5 fr (37.5–112.5 Gy)	11.8
Clerici/2019 [27]	Retrospective	104	1–3	–	Colorectal (51.5%)/NR	75 Gy/3fr (262.5 Gy)	33
Palma/2020[41]	Phase 2	9	1–5	–	Colorectal (14%)/NR	35–54 Gy/3–5fr (59.5–151.2)	51
Mendez Romero/ 2020 [35]	Prospective	359	1–2	27(8–88) ml	Colorectal (80.4%)/NR	11–12 Gy/5 fr (115.5–132 Gy) 18–20 Gy/3fr (151.2–180 Gy) 7.5 Gy/8 fr (105 Gy)	13.2

BED: biologic equivalent dose; NR: not reported.

Table 2. Outcomes with SBRT for colorectal liver metastases.

Author/year	Median OS (months)	1y OS (%)	2y OS (%)	3–5y OS (%)	1y LC (%)	2y LC (%)	3–5y LC (%)	Median PFS (months)	Liver or GI toxicity (%)
Herfath/2004 [12]	25	72	NR	–	71	–	–	–	No significant toxicity
Mendez Romero/2006 [36]	–	85	62	–	100	86	–	–	G3 elevation of gamma glutamyl transferase (8) and asthenia (4)
Hoyer/2006 [13]	19.2	67	38	–	–	78	–	6.5 (TTP)	G3 intestinal toxicity (5), liver failure (2), nausea & diarrhea G1–2 (34 & 23), G3 (3); death n = 1
Rusthoven/2009 [16]	32	–	30	–	95	92	–	6.1	No RILD
Lee/2009 [14]	17.6	63	–	–	71	–	–	3.9	G3 gastritis (2), nausea (2), lethargy, and thrombocytopenia), G4 thrombocytopenia (1), G I nontraumatic rib fractures (3)
Kim/2009 [31]	25	53	40	–	80	60	–	–	G1 nausea and musculoskeletal discomfort (40)
van der Pool/2010 [18]	34	100	83	–	100	74	–	11	Liver toxicity: G3 (10), G2 (90)
Chang/2011 [11]	–	72	38	–	62	45	–	–	GI–G2 & G3 acute GI toxicity 17 & 3
Vautravers–Dewas/ 2011 [40]	–	94	48	–	90	86	–	–	G1–2 nausea, vomiting, gastritis, gastric ulceration & hepatic pain (27 & 12.5, 12.5, 12.5 & 17.2)
Stintzing/2013 [38]	34.4	–	–	–	85	80	–	34.4 (DFS)	Bleeding and rising bilirubin (3)
Liu/2013 [32]	25.2	–	–	–	86	67	–	–	–
Berber/2013 [26]	–	56	–	–	60	–	–	–	G1 fatigue and nausea (21); death n = 1
Scorsetti/2015, 2018 [10,37]	29	65	65	18 at 5 years	95	91	78 at 5 years	12	G2 fatigue (55), transient hepatic transaminase increase (25) & nausea (12)
van de Voorde/2015 [39]	25	–	–		–	–		–	–
Goodman/2015 [29]	33.6	90	69	28% at 4 years	96	91	91% at 4 years	7.8	G1–2 fatigue (24.7), nonhepatic gastrointestinal toxicity (21.3), chest wall pain (9), and pleural effusion (2.5) & death n = 1
Mendez Romero/ 2017 [34]	43 & 35*	94 & 95*	81 & 69*	48% at 3 years	90 & 96*	90 & 74*	66 & 81* at 3 years	–	G1–2 liver toxicity (97.5), G3 liver toxicity (7.5), G 2 fat atrophy and skin induration (2.5), portal hypertension (2.5)
Ahmed/2016 [24]	–	100	73	–	79	59	–	–	–
Doi/2017 [28]	45	82.3	67.1	–	67.2	35.9	–	16	G1–2 liver toxicity (16), duodenal ulcer (4)
McPartlin/2017 [33]	16	63	26	26% at 4 years	50	32	9% at 4 years	–	G3 nausea (2)
Joo/2017 [30]	–	–	75	–	93	73	68% at 3 years	–	G1–2 nausea (34), G1–2
Andratschke/2018 [25]	24	–	–	–	–	–	–	–	G1–2 fatigue, nausea and diarrhea (23)
Vernaleone/2019 [19]	20.1	67	44	–	60	–	–	6.5	GI & G2 acute GI toxicity 4 & 3
Clerici/2019 [27]	21	87	–	–	88	–	–	–	G2 fatigue in (38) of patients, G2 transient transaminase increase (24)
Palma/2020 [41]	50	–	–	42% at 5 years	–	–	17.3% at 5 years	11	–
Mendez Romero/ 2020 [35]	–	84	63	44% at 3 years	87	75	68% at 3 years	–	G2 abdominal pain (0.005), bile duct stenosis (0.008), colecystitis (0.005), gallbladder perforation (0.002)

OS: overall survival; LC: local control; GI: gastrointestinal; G: grade; TTP: time to progression; DFS: disease free survival; RILD: radiation induced liver disease.

*It represents two different dose levels.

Table 3. Liver dose constraint recommendations for SBRT.

OAR	Single fraction constraints	Three fraction constraints	Five to six fraction constraints	Dose limiting toxicity
Liver	V12 < 30% (12)	V21 < 33% (36)	V22 < 50% (46)	RILD
	V7 < 50% (12)	V15 < 50% (36)	V22 < 50% (47)
	V9.1 < 700 cc (47)	V15 < 700 cc (16, 37, 29)	V21 < 700 cc (48)
	–	Mean < 15 Gy (23)	Mean < 20 (23)
Bowel	12 Gy point dose (12)	24 Gy point dose (47)	30 Gy point dose (14)	Chronic ulcer/fistula/perforation
	Duodenum: V11.2 < 5 cc (47)	Duodenum: V21 < 5 cc (47)	Duodenum: V33 < 0.5 cc (47)
	Small bowel: V11.9 < 5 cc (47)	Small bowel: V16.2 < 5 cc (47)	Small bowel: V34 < 0.5 cc (33)
	Large bowel: V14.3 < 20 cc (47)	Large bowel: V20.4 < 20 cc (47)	Large bowel: V36 < 0.5 cc (37)
Stomach	12 Gy point dose (12)	24 Gy point dose (47)	32 Gy point dose (47)	Chronic ulcer/fistula/perforation
	V11.2 < 10 cc (47)	V21 < 5 cc (37)	V32 < 0.5 cc (37)
Esophagus	14 Gy point dose (12)	25 Gy point dose (47)	20 Gy point dose (34)	Stenosis/fistula/perforation
	V12 < 5 cc (47)	V21 < 5cc (36)	V30 < 0.5 cc (47)
Kidney	V8.5 < 200 cc (47)	V16 < 200 cc (37)	V17.5 < 200 cc (37)	Renal dysfunction
	D75% <5 Gy (47)	D35% <15 Gy (13, 16)	combined: D66% <18 Gy (14)
Rib	30 Gy point dose (47)	76.4 Gy point dose (for 75 Gy/3 frs only) (47)	54 Gy point dose (47)	Chronic pain or fracture
	V22 < 1cc (47)	V30 < 30 cc (47)	V60 < 1.4 cc (47)
Spinal cord	12.4–14 Gy point dose (49)	18 Gy point dose (13, 16)	spinal cord plus 5 mm margin 27 Gy point dose (14)	Myelopathy
Heart/Pericardium	22 Gy point dose (48)	30 Gy point dose (48)	40 Gy point dose (48)	Pericarditis
	V16 < 15cc (48)	D30 < 1% (13, 26)	mean < 10 Gy (34)
Skin	26 Gy point dose (48)	30 Gy point dose (48)	36 Gy point dose (48)	Chronic ulceration
	V23 < 10 cc (48)	V30 < 10cc (48)	V40 < 10cc (48)

OAR: organ at risk; RILD: radiation induced liver disease.

Note: point dose <0.035 cc.

Shown dose constraints in Table 3 come from a wide variety of sources, arguably none of which are high level evidence supporting these constraints.

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