Stereotactic Body Radiation Therapy to Liver

Fig. 9.1

Barcelona Clinic Liver Cancer Staging System (From Klein et al. [7] based on Dawson [102]) This figure describes potential treatment options, and suggestions for the incorporation of radiotherapy treatment, and trials. CLT cadaver liver transplant, LDLT live donor liver transplant, PST performance status (ECOG), RT radiotherapy, RF radiofrequency ablation

RFA achieves excellent control rates of >90 % for HCC and IHC if lesions are less than 3–3.4 cm in diameter, but local recurrences are more common if tumours are adjacent to large vessels which exert a cooling effect, or are larger than 4 cm diameter [8, 9]. In addition tumours close to the biliary tract or near the diaphragm can be technically demanding to ablate, making the procedure highly operator dependent.

Palliative TACE offers only a modest gain in overall survival compared with best supportive care in advanced HCC and IHC, but can also be used as a bridge to transplant in conjunction with other local ablative options [10, 11].

Systemic chemotherapy with agents such as doxorubicin, cisplatin, gemcitabine, and oxaliplatin for HCC has disappointing response rates (5–20 %), and does not prolong survival [12–14]. Newer targeted agents such as Sorafenib (SHARP trial), Sunitinib and Erlotinib are showing promise [15, 16], but are unlikely to be associated with cure in the absence of local ablative therapies. A phase 3 trial comparing sorafenib with sunitinib was stopped early due to safety concerns over sunitinib [17].

Systemic chemotherapy for IHC with Gemcitabine & Cisplatin has a response rate of 30 % [18]. Sorafenib had a response rate of 0 % in a SWOG study [19]. Studies of newer Tyrosine Kinase Inhibitors are ongoing.

Historically, the role of radiotherapy for liver tumours has been limited by the risk of radiation-induced liver disease (RILD). RILD is characterised by anicteric hepatomegaly, ascites, and elevated alkaline phosphatase occurring within 3 months of liver irradiation [20]. Recently, however, advances in radiotherapy technique (including radiotherapy planning, motion management strategies, and image guidance) have made it possible for radiation to be delivered conformally to partial liver volumes. Dawson et al. analysed over 180 patients and demonstrated that the liver exhibits a large volume effect with a low volume threshold for RILD [21]. Emami et al. have shown that when two-thirds of the liver is irradiated, doses up to 35 Gy are permissible and when only one-third is irradiated, permissible dose increases to 50 Gy [22].

Awareness of this important dose-volume effect, in conjunction with advances in radiotherapy technique, has allowed the development of SBRT techniques for hepatic malignancy.

Radiation therapy has a particularly important role for HCC unsuitable for, or resistant to other locoregional liver directed therapies. Radiotherapy does not feature in many consensus guidelines or documents largely due to a relative lack of Level 1 randomised trial data. However it is also clear that non radiation oncologists currently have a poor understanding of the potential of this rapidly advancing field.

SBRT is a form of high-precision radiotherapy characterised by: reproducible immobilisation; measures to account for tumour motion during treatment planning and delivery; dose distributions tightly covering the tumour, with rapid dose fall off in surrounding normal tissues; and most importantly, the use of relatively few, high dose fractions of radiation (extreme hypofractionation), usually delivered in 1–8 treatments [23].

9.2.1 Summary of Evidence for SBRT in Inoperable HCC

The evidence for SBRT for HCC is largely confined to retrospective series, and prospective phase 1 trials (Table 9.1). SBRT has comparable efficacy with other local therapies and should be considered for early stage HCC unsuitable or refractory to, other liver directed therapies. Use of SBRT to slow progression of HCC whilst awaiting transplantation is growing in popularity although generally has been investigated in patients not suitable or refractory to, other bridging therapies [38, 43]. Pathological complete responses seen after SBRT bridging to transplant demonstrate that SBRT is an effective treatment however Level 1 evidence is urgently required. SBRT can also be considered for Child Pugh B patients unsuitable for standard locoregional therapy, however the risk of radiation induced liver disease (RILD) is higher.

Table 9.1

Trials of SBRT in unresectable HCC

Author [ref]	Year	Number of patients	Dose (Gy), no. fractions	Median volume (cm³)	Median follow up (months)	LC 1 year (%)	LC 2 years (%)	OS 1 year (%)	OS 2 years (%)	Comments
Blomgren et al. [24]	1998	11	15–45 in 1 or 3			100
Choi et al. [25]	2006	20	50 Gy in 5 or 10	25	23			81	43	Retrospective
Mendez Romero et al. [26]	2006	11	25 in 5, 30 in 3 or 37.5 in 3	22	12.9	94	82	75	40	Phase I/II
Tse et al. [27]	2008	41	24–54 in 6	173	17.6	65		48		Phase 1
Choi et al. [28]	2008	32	30–39 in 3	25	17.3	72		81		Retrospective +/− TACE
Seong et al. [29]	2009	37							28	Survey
Cardenes et al. [30]	2010	17	36–48 in 3, 40 in 5 (CP B)	34	24	100		75	60	Phase 1
Loius et al. [31]	2010	25	45 in 3	73	15	91	90	79	52	Retrospective
Seo et al. [32]	2010	38	33–57 in 3 or 4	40					61	Retrospective, prior TACE
Kwon et al. [33]	2010	42	30–39 in 3	15.4	28.7	72		93	58 (3 years)
Chan et al. [34]	2011	16	45 in 10	134	24	91		62	28 (3 years)
Andolino et al. [6]	2011	60	40 in 5 (CP-B), 42 in 3 (CP-A)		27		90		67	Retrospective
Bujold et al. [35]	2011	102	24–54 in 6		15	79
Ibarra et al. [36]	2012	21	21–45 in 3	334	7.8	63 %		87	55	Retrospective
Huang et al. [37]	2012	36	25–48 in 4 or 5		14	88	75		64	Retrospective
Katz et al. [38]	2012	18	50 in 10	63	19.6			100		Bridging
Sanuki et al. [39]	2013	185	35–40 in 5		24		91 (3 years)		70 (3 years)	Retrospective
Takeda et al. [40]	2013	63	35–40 in 5		31	100	95	100	87
Bujold et al. [41]	2013	102	24–54 in 6	283 (PTV)	17	87
Kang et al. [42]	2012	47	42–60 in 3 (median 57 Gy)				95		69	Prospective salvage therapy following TACE
Ibarra et al. [36]	2012	32 (21 HCC)	21–45 in 3		13			87	55	Retrospective

LC local control, OS overall survival, CP Child Pugh score

9.3 Liver Metastases

The annual incidence of colorectal cancer (CRC) in the US is over 150,000 cases. There are over 50,000 annual deaths. Approximately 80 % of patients with stage IV CRC have liver disease considered unresectable at presentation [44].

Autopsy studies show that 40 % of colorectal cancer patients relapse with liver only metastases [45–47]. Oligometastatic liver disease (that is up to 5 metastases) may be amenable to aggressive local therapy with the potential for long term disease control [48, 49], or even cure [50, 51]. The evidence to support the local ablation of oligometastases is largely single institution retrospective case series, and some small prospective phase 2 trials. There are currently no prospective trials comparing aggressive local therapy with best supportive care.

Surgery has been the gold standard treatment for colorectal liver metastases, with retrospective series reporting 5 year survivals of 25–47 %, [50–54]. However, up to 80 % of patients are not suitable for resection due to the location, size and distribution of metastases, or poor patient performance status, or significant medical co-morbidities. Chemotherapy can downstage inoperable to operable disease in only around 10–20 % of cases [55]. Newer chemotherapy combinations such as FOLFOXIRI, or FOLFOX/FOLFIRI in combination with the biological agents Bevacizumab or Cetuximab can downstage a significantly higher proportion, but at the cost of considerable toxicity. Response rates can be as high as 70 % with triplet combinations. These chemotherapy combinations have also extended median survival in metastatic CRC to 24 months [56].

Thermal destruction by radiofrequency ablation (RFA) or microwave for CRC liver metastases gives 3 year survival rates of 30–46 % [57–60]. There are data to suggest that local control of CRC liver metastases is related to survival—Aloia et report a sevenfold increase in the risk of local failure and a threefold increase in the risk of death, in patients treated with RFA rather than surgical resection, despite similar rates of distant intrahepatic and extrahepatic failure in both groups [61]. Chang et al. report also a strong correlation between local control and survival in patients treated with SBRT for liver metastases [62].

Surgical data for resection of non-CRC liver metastases are more limited. However, a large (n = 1,452) retrospective, multi-institutional series has reported a 5 year survival of 36 % and 10 year survival of 23 % for carefully selected non-CRC, with metastases from breast cancer having the best and melanoma and squamous cell cancers the poorest survival [63]. There are some reports of non-CRC having better local control and survival than CRC when treated with SBRT [64, 65].

9.3.1 Evidence Supporting SBRT to Liver Metastases

Currently, the evidence for SBRT for liver metastases is predominantly retrospective case series (Table 9.2), with some prospective phase 1 and 2 trials (Table 9.3). Within the studies there is significant heterogeneity in patient selection, size and number of lesions treated, dose-fractionation, prescription points and dosimetric criteria.

Table 9.2

Retrospective studies of SBRT for liver metastases

Study	n	Vol/number of mets	Histology	Immobilisation/resp motion	Dose	Prescription point	Toxicity	Outcome
Blomgren et al. (1995) [66]	14	3–260 mL	CRC (11); anal canal (1); kidney (1); ovarian (1)	SBF/AC	7.7–45 Gy (1–4 frx)	Periphery of PTV	2 cases of haemorrhagic gastritis	50 % response rate
Wada et al. (2004) [67]	5	NR	NR	VM/AC	45 Gy (3 frx)	90–100 % isodose	No serious toxicity	2 year LC 71.2 %
Wada et al. (2004) [67]	5	NR	NR	VM/AC	45 Gy (3 frx)	90–100 % isodose	No RILD	2 year LC 71.2 %
Wulf et al. (2006) [68]	44	9–355 mL	CRC (23); breast (11); ovarian (4); other (13)	SBF/AC	30–37.5 Gy (3 frx)	30 Gy: 65 % isodose; others—80 % isodose (covering 95 % of PTV)	No grade 2–4 toxicity	1 year LC 92 %;2 year LC 66 %
Wulf et al. (2006) [68]	44	9–355 mL	CRC (23); breast (11); ovarian (4); other (13)	SBF/AC	26 Gy 1 frx		No grade 2–4 toxicity	1 year OS 72 %;2 year OS 32 % (LC for 37.5 Gy: 1 year 100 %; 2 year: 82 %)
Katz et al. (2007) [69]	69	0.6–12.5 cm; (median 2.7 cm)	CRC (20); breast (16); pancreas (9)	VM/Resp. gating	30–55 Gy (5–15 frx)	100 % isodose with 80 % covering PTV	No grade 3–4 toxicity	10 months LC 76 %
			Lung (5); other (19)		50 Gy/5frx preferred			20 month LC 57 %
			Lung (5); other (19)		50 Gy/5frx preferred			Median OS 14.5 months
Van der Pool et al. (2010) [70]	20	0.7–6.2 cm (median 2.3 cm)	CRC (20)	SBF/AC	37.5–45 Gy (3 frx)	95 % of PTV received prescribed dose	2 grade 3 late liver enzyme changes; 1 grade 2 rib fracture	1 year LC 100 %
								2 year LC 74 %
								Median survival 34 months
Habermehl et al. (2013) [71]	90	62 (11–333)	50 % colorectal	VM, AC	17–30 Gy median 24 Gy single		Grade 1 fatigue, fever, loss appetite, raised transaminases	Median OS 24 months
Habermehl et al. (2013) [71]	90	62 (11–333)	50 % colorectal	VM, AC	17–30 Gy median 24 Gy single		Grade 1 fatigue, fever, loss appetite, raised transaminases	1 year PFS 70 %
Berber et al. (2013) [72]	153	363 mets, GTV of 138.5 ± 126.8 cm³	50 % GI		37.5 ± 8.2 Gy in 5 ± 3 fractions			1 year LC = 62 %
Berber et al. (2013) [72]	153	363 mets, GTV of 138.5 ± 126.8 cm³	50 % GI		37.5 ± 8.2 Gy in 5 ± 3 fractions			1 year OS = 51 %
Fumagalli et al. (2012) [73]	90	113 liver mets	70 % GI	Cyberknife	45 Gy in 3	80 %	G1–3	LC 1 year 84 %, 2 years 66 %
Fumagalli et al. (2012) [73]	90	113 liver mets	70 % GI	Cyberknife	45 Gy in 3	80 %	G1–3	2 years OS = 70 %
Lanciano et al. (2012) [74]	30	41 lesions.	23 mets, 7 HCC	Cyberknife	Varying		G1/2 toxicities	Median FU 22 months
Lanciano et al. (2012) [74]	30	41 lesions.	23 mets, 7 HCC	Cyberknife	Varying		G1/2 toxicities	2 years LC 75 % (if BED > 100)

Abbreviations: SBRT stereotactic body radiotherapy, Mets metastases, RT radiotherapy, CRC colorectal cancer, SBF stereotactic body frame, VM vacuum mould, AC abdominal compression, ABC active breath control, NR not reported, LC local control, OS overall survival, frx fractions

Table 9.3

Prospective studies of SBRT for liver metastases

Study	Design	n	Volume/number of mets	Histology	Immobilisation/resp motion	Dose	Prescript. point	Toxicity	Outcome
Herfath et al. (2004) [64]	Ph 1–2	35	1–132 mL (median 10 ml)	CRC (18); breast (10); other (7)	SBF and VM/AC	Dose escalation: 14–26 Gy (1 frx)	Isocentre, with 80 % covering PTV	No significant toxicity reported	1 year LC 71 %; 18 month LC 67 % (18 month LC 81 % for Ph2)
Herfath et al. (2004) [64]	Ph 1–2	35	1–132 mL (median 10 ml)	CRC (18); breast (10); other (7)	SBF and VM/AC	Dose escalation: 14–26 Gy (1 frx)	Isocentre, with 80 % covering PTV	No significant toxicity reported	1 year OS 72 %; Med 25 months
Mendez Romero et al. (2006) [26]	Ph 1–2	25 (17 liver mets)	1.1–322 mL (median 22.2 mL)	CRC (14); lung (1); breast (1); carcinoid (1);	SBF/AC	37.5 Gy (3 frx)	65 % Isodose	2 grade 3 gammaGT elevations;	2 year LC 86 %
						30 Gy (3 frx) in 3 patients to spare OAR		1 grade 3 asthenia	2 year OS 62 %
						30 Gy (3 frx) in 3 patients to spare OAR		1 late portal hypertension	2 year OS 62 %
Hoyer et al. (2006) [75]	Ph 2	64 (44 liver)	1–8.8 cm (median 3.5 cm)	CRC only	SBF or VM/AC	45 Gy (3 frx)	ICRU ref-95 % to CTV and 67 % PTV	1 liver failure; 2 severe late GI toxicities	2 year LC 79 % (by tumour)
Hoyer et al. (2006) [75]	Ph 2	64 (44 liver)	1–8.8 cm (median 3.5 cm)	CRC only	SBF or VM/AC	45 Gy (3 frx)	ICRU ref-95 % to CTV and 67 % PTV	1 liver failure; 2 severe late GI toxicities	2 year LC 64 % (by patient)
Rusthoven et al. (2009) [76]	Ph 1–2	47	0.75–98 mL (median 14.93 mL)	CRC (15); lung (10); breast (4); ovarian (3); Oes (3); HCC (2); other (10):	VM/ABC or AC	Dose escalation: 36–60 Gy (3 frx) Ph2 60 Gy (3 frx)—36 pts	Isodose covering PTV (80–90 %)	No RILD	1 year LC 95 %; 2 year LC 92 %; median survival 20.5 months (32 months for breast and CRC p < 0.001). 2 year OS 30 %
Rusthoven et al. (2009) [76]	Ph 1–2	47	0.75–98 mL (median 14.93 mL)		VM/ABC or AC	Dose escalation: 36–60 Gy (3 frx) Ph2 60 Gy (3 frx)—36 pts	Isodose covering PTV (80–90 %)	Late grade 3/4 < 2 %
Lee et al. (2009) [65]	Ph 1–2	68	1.2—3,090 ml (med. 75.9 mL)	CRC (40); breast (12); gallbladder (4); lung (2); anal (2); melanoma (2); other (6)	VM/ABC or AC (AC if resp excursion >5 mm)	Individualised Dose 27.7–60 Gy (6 frx)	Isodose covering PTV (max 140 % in PTV)	No RILD	1 year LC 71 %
								10 % grade 3/4 acute toxicity	Median survival 17.6 months
								No grade 3/4 late toxicity	Median survival 17.6 months
Ambrosino et al. (2009) [77]	Prospect cohort	27	20–165 mL (median 69 mL)	CRC (11); pancreas (10); breast (2); 1 each of gallbladder, gastric, ovary, lung	Cyberknife™ (with synchrony™ to track US-placed gold fiducials)	25–60 Gy (3 frx)	80 % of prescribed dose covered PTV	No serious toxicity	Crude LC rate 74 %
Ambrosino et al. (2009) [77]	Prospect cohort	27	20–165 mL (median 69 mL)			25–60 Gy (3 frx)	80 % of prescribed dose covered PTV	36.2 % CRC cases—mild-moderate transient hepatic dysfunction. 3.7 % GI bleed; 3.7 % portal vein thrombosis	Crude LC rate 74 %
Goodman et al. (2010) [78]	Ph 1 (HCC and liver mets)	26 (19 liver mets)	0.8–146.6 mL (median 32.6 mL)	CRC (6); pancreas (3); gastric (2); ovarian (2); other (6)	Alpha-cradle.	18–30 Gy (1 frx)	Isodose that covered PTV (65–90 %)	4 cases grade 2 late toxicity (2 GI, 2 soft tissue/rib)	1 year local failure 23 %
					Cyberknife™ (with synchrony™ to track US-placed gold fiducials)				Median survival 28.6 months
									2 year survival 49 % (mets only)
Rule et al. (2011) [79]	Ph 1	27	0.75–135	Colorectal (12)		30 Gy (3 F)			24-month LC rates for the 30-, 50-, and 60-Gy cohorts were 56, 89, and 100 %
	Liver mets					50 Gy (5 F)
	Liver mets					60 Gy (5 F)
Scorsetti et al. (2013) [80]	Ph 2	61	76 mets	Colorectal 48 %	Rapidarc VMAT, VM	60–75 Gy (3 F)		65 % fatigue	Median FU 12 months (2–26)
	Liver mets		7.7–209	Breast 18 %				26 % transaminase rise (settle in 3 months)	CR + PR + SD = 95 %
				Gynae 12 %					LC at 6, 12, 22 months = 100, 94, 91 %
				Other 22 %					1 year OS = 84 %, median OS = 19 months

Patients were often heavily pre-treated with chemotherapy, surgery, or other local ablative therapies [70, 75]. SBRT has historically been used when the liver metastases were no longer amenable to other treatments (i.e. last resort, until recently).

Local control rates are 70–100 % at 1 year, and 60–90 % at 2 years [2] Several factors predicting local control (LC) may be identified, which may help in patient selection for treatment. The most consistently observed correlation with local control is baseline tumour volume [81–85]. Rusthoven et al. report a superior LC rate for tumours less than 3 cm (100 % vs 77 % at 2 years, p = 0.015) [76]. Number of tumours <3 and size <6 cm predicts for better outcome. Also, delivered BED >117 Gy₁₀ is associated with improved local control at 1 year [62]. Metachronous CRC liver metastases has a better prognosis than synchronous [75] Median overall survival is 10–34 months, and 2 year survival ranges from 30 to 83 % [2]. For CRC specifically, Hoyer et al. report a median survival of 1.6 years from SBRT [75]. Out-of-field progression of disease occurs in a substantial proportion of patients, although this is also reported after hepatic resection [48].

There are a number of predictors of overall survival, and long term survival is seen after treatment. Factors associated with increased survival are:

The absence of extra-hepatic disease (35.8 months vs 11.3 months [64, 75]).
Primary histology. Favourable primary histology includes breast, CRC, renal, carcinoid and GIST. Unfavourable primary sites include lung, ovary and non-CRC gastro-intestinal. Rusthoven et al. report median survival for favourable primary sites as 32 months vs 12 months for unfavourable primaries (p < 0.001) [76]. Lee et al. report superior 1 year survival for CRC (63 %) and breast cancers (79 %) compared to other primary sites (38 %) [65].
Tumours <3 cm diameter are associated with improved overall survival [65, 70].

Liver SBRT is very well tolerated, both in terms of acute and late toxicity, and may be used safely after other liver directed therapy (surgery or RFA). The means by which liver SBRT has been delivered in published series is variable, but with generally good outcomes. No particular SBRT technique has superior outcomes in terms of tumor control or toxicity. Patient Selection Criteria

For HCC, enhancement typically in the arterial phase on two imaging modalities and α-fetoprotein (AFP) increased on a background of liver disease
Biopsy-confirmed IHC
Unresectable tumour or inappropriate for other treatment modalities, or as a bridge to transplant for HCC
Patients should be discussed in Multi-Disciplinary Tumour Board meetings
Karnofsky Performance Status (KPS) ≥60
Life expectancy >3 months

Child-Pugh score: A, or B7/8 (Table 9.4)

Table 9.4

Child-Pugh liver score

Measure	1 point	2 points	3 points
Total bilirubin (μmol/l) (mg/dl)	<34 (<2)	34–50 (2–3)	>50 (>3)
Serum albumin (g/l)	>35	28–35	<28
INR	<1.7	1.71–2.20	<2.20
Ascites	None	Mild	Severe
Hepatic encephalopathy	None	Grade 1–2 (or suppressed with medication)	Grade 3 or 4

Points	Class	One year survival (%)	Two year survival (%)
5–6	A	100	85
7–9	B	81	57
10–15	C	45	35

>700 cc of uninvolved liver
No chemotherapy within 2 weeks prior, and 4 weeks after, SABR
No, or limited and potentially treatable, extra-hepatic disease.
Recovered from any previous therapy (such as surgery, chemotherapy or radiotherapy to other areas) with a minimum of 2 weeks break (for HCC, anthracycline based chemotherapy should be completed 4 weeks before SBRT)
Up to three metastases, with no limitation on actual size of a given tumour provided functional residual volume, and organ at risk (OAR) dose constraints can be met
Adequate organ function, defined as: Hemoglobin 90 g/L, absolute neutrophil count 1.5, platelets 80, bilirubin <3.0 times upper limit of normal, INR <1.3 or correctable with vitamin K and unless the patient is taking warfarin/coumarin, AST or ALT <5.0 times upper limit of normal. Creatinine less than 200 umol/L (if creatinine is above the normal range consideration should be given to dynamic renal scintigraphy (renography)) if there is anticipated to be any appreciable renal dose from the delivery of treatment.

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