Stereotact ic Body Radiat ion Therapy forHepatoce l lu lar Carcinoma

By Laura A. Dawson, MD, Sameh Hashem, MD, and Alexis Bujold, MD

Overview: Stereotactic body radiotherapy (SBRT), in whichhighly conformal potent radiation doses are delivered in fewerfractions than traditional radiation therapy (RT), is an increas-ingly popular treatment for hepatocellular carcinoma (HCC).The great majority of HCCs smaller than 6 cm and withChild-Pugh A liver function are controlled with SBRT withlimited toxicity. Long-term local control is reduced in larger

tumors, and toxicity is increased in patients with Child-Pugh Bor C liver function. SBRT is an effective treatment for tumorvascular thrombi and can lead to sustained vascular recana-lization. The first site of recurrence following SBRT is mostoften within the liver, away from the high dose volume,providing rationale for combining SBRT with regional or sys-temic therapies. Randomized trials of SBRT are warranted.

GLOBALLY, HCC IS THE sixth most common cancerand the fourth most common cause of cancer-related

death. The overall 5-year survival is poor (approximately5%), and its incidence is increasing.1 While resection andtransplant can cure HCC, only a minority of patients aresuitable for surgery because of multifocal or extrahepaticcancer, inadequate liver function, and/or involvement oflarge vessels. Radiofrequency ablation and percutaneousethanol injection are associated with excellent local controlin small HCCs, but outcomes are reduced in HCCs largerthan 4 cm or adjacent to large vessels.

RT is an effective local therapy that has the potential tobenefit patients unsuitable for and/or at high risk of compli-cations following standard local-regional therapies. All ofthe following have facilitated the safe delivery of tumorcidaldoses to focal HCCs using conformal RT: advances in imag-ing, RT planning techniques (to produce three-dimensionalconformal RT plans minimizing dose to surrounding tis-sues), image-guided radiotherapy (IGRT; to localize thetumor at time of treatment), tumor immobilization (to ac-count for breathing-related organ motion), and improvedknowledge of what volume of liver is required to be sparedfrom radiation to preserve function. Protons and carbonions—available at specialized centers—have the ability tospare more liver parenchyma than photons.

SBRT—which is shorter radiotherapy schedules (hypo-fractionation), with higher very conformal doses delivered ateach radiation fraction—has more recently been used totreat focal HCC. This has been used when the majority of theliver can be spared from irradiation. Initially stereotacticimmobilization body frames were used to aid in patientSBRT positioning, but with recent advancements in IGRT,the requirement for such frames has disappeared, as theliver can be directly visualized before or during RT deliverly.SBRT is widely available (unlike protons or carbon ions) andmore convenient for patients than conventionally fraction-ated RT, as it is delivered in far fewer fractions (typically 10or less) than standard fractionated RT. This article willfocus primarily on SBRT for HCC.

Liver Tolerance of RT

Just as a portion of the liver may be resected with surgeryor ablated with radiofrequency ablation, portions of the livercan tolerate high doses of radiation, without liver toxicity.With long-term follow-up, atrophy of the irradiated portionof the liver and hypertrophy of the spared portions of theliver are commonly seen. Objective response assessment ischallenging within 4 months following RT because ofchanges in the irradiated liver volume during that time.

The classical described toxicity following RT for livercancer is a clinical syndrome of anicteric hepatomegaly,ascites, and elevated liver enzymes (particularly serumalkaline phosphatase) occurring within three months afterRT, referred to as classic radiation-induced liver disease(RILD).2 For the most part, this toxicity is preventable, aslong as a sufficient fraction of liver can be spared from RT.For example, the risk of classic RILD is less than 5% whenthe mean liver doses are kept less than 14 Gy (in 6 fractions)and 28 Gy (in 1.5 Gy fractions).

Other hepatic toxicities, referred to as “nonclassic RILD”are more challenging to prevent. Such toxicities includereactivation of viral hepatitis, elevation of liver enzymes,and a general decline in liver function. The partial volumetolerance of the liver following RT is less clearly defined fornonclassic RILD, with different dose-volume tolerances andrisk factors observed for different types of liver toxicity. InTaiwan, 17 of 89 patients with HCC treated with up to 66 Gy(in 1.8–3 Gy per fraction) developed liver toxicity. The riskwas increased in hepatitis B carriers and in Child-Pugh Bliver function.3 Treatment of viral hepatitis B is importantbefore initiating RT. Other studies have shown that the riskof toxicity is increased if the spared volume of liver is toosmall. For example, in a study of 48 patients with HCCtreated with three-fraction SBRT (30–39 Gy), 11% of pa-tients had a decline in Child-Pugh class, and this was morelikely if less than 800 mL of liver could be spared from 18 Gyor more.4

Outcomes: Non-SBRT RT

The first experience in RT for HCC was with hyper- orconventional fractionation, using conformal RT. The mediansurvival of patients with locally advanced HCC treated withconventional fractionation ranges from 6 to 19 months.5-9 Amajority of series demonstrated that patients treated withhigher RT doses had better local control and survival thanthose treated with lower doses.

Protons or carbon ions produced from highly specializedtreatment units not widely available have also been used totreat HCC. An advantage of protons is that they are associ-

From the Department of Radiation Oncology, Princess Margaret Hospital, University ofToronto, Toronto, Ontario, Canada, and the Departement de Radio-oncologie Clinique-Enseignement-Recherche, Hopital Maisonneuve-Rosemont, Montreal, Quebec, Canada.

Authors’ disclosures of potential conflicts of interest are found at the end of this article.Address reprint requests to Laura Dawson, MD, 610 University Ave., Toronto, ON, M5G

2M9, Canada; email: laura.dawson@rmp.uhn.on.ca.© 2012 by American Society of Clinical Oncology.1092-9118/10/1-10

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ated with unique dose distributions that allow rapid falloffin dose and substantial sparing of dose to tissues adjacent totumors. Proton or carbon RT has the best reported outcomespostradiation in patients with HCC.10,11 In one prospectivestudy, patients with Child-Pugh A liver disease and poten-tially resectable single HCCs, had a 5-year survival of 56%following proton therapy.10 In another series, in six patientswith HCC who went on to have liver transplantation 6 to18 months after proton therapy (63 Gy equivalent in 15fractions), two complete pathologic responses were observed,demonstrating proof that high-dose RT may ablate HCC.12

Proton and photon therapy have been used to success-fully treat HCC with portal vein or inferior vena cavathrombosis.11

Outcomes: SBRT

More recently, SBRT has been used to treat patients withHCC, with a summary of outcomes shown in Table 1.Blomgren et al first reported on the use of SBRT on extracra-nial sites in 1995 and 1998.13,14 In this series that includedpatients with HCC, 15 to 45 Gy was delivered over one tofive fractions. The majority of patients had objective re-sponses. Subsequently, Herfarth et al treated 60 liver tu-mors (which included 3 primary HCCs) in 37 patients with

14 to 26 Gy SBRT in one fraction. The treatment was welltolerated.15 Wulf et al then reported on 39 patients treatedwith three-fraction SBRT to the liver, five of whom hadHCC. No more than 50% of the total functional liver tissuecould receive more than 5 Gy, and no more than 30% couldreceive more than 7 Gy. The doses delivered ranged from 30Gy to 37.5 Gy in three fractions. No local failures were seenin two HCC patients after 15 and 48 months. Three of theHCC patients died of disease progression in the liver outsidethe RT field at 2, 7, and 17 months. No acute or late serioustoxicity was reported in any patient.16

Mendez Romero et al treated eight patients with 11 HCCsof Child-Pugh A or B (in addition to 17 patients with livermetastases) with 25 Gy in five fractions, 30 Gy in threefractions, or 37.5 Gy in three fractions over 5 to 10 days. Themaximum tumor size was 7 cm. Two of the patients withHCC who received 25 Gy in five fractions failed locally at 4and 7 months and were retreated with 24 Gy in threefractions. The local control rate of the patients with HCCwas reported as 82%, and the 1- and 2-year actuarialsurvival rates were 75% and 40%, respectively. One patientin the HCC group with Child-Pugh B liver function devel-oped grade 5 toxicity because of liver failure and infection.17

In Toronto, a prospective dose-escalation study of six-fraction SBRT was conducted in 31 patients with locallyadvanced HCC unsuitable for standard therapies. A typicalplan is shown in Fig. 1. The dose per fraction was deter-mined based on the effective volume of normal liver irradi-ated (Veff). When the effective liver volume irradiated waslow (Veff � 25%), doses of 54 Gy (9 Gy � 6) were deliveredsafely to HCCs, with excellent local control. For patientsrequiring moderate volume liver irradiation (Veff 25% to80%), doses from 24 to 54 Gy (4 to 9 Gy � 6) were deliveredsafely. All patients had Child-Pugh liver function A, and themajority of patients had portal vein thrombosis. No classicRILD was seen. Five patients had a decline in their Child-Pugh class at 3 months. These patients had extensivetumors, and three had tumor progression that likely contrib-uted to the decline in liver function. The median survivalwas 11.7 months (95% CI, 9.2–21.6 months).18 One hundredand two eligible patients were included in an update of theToronto phase I study and a subsequent phase II study,using the same dose-allocation approach. Underlying liver

KEY POINTS

● Stereotactic body radiation therapy (SBRT)—highlyconformal, potent-dose radiation therapy delivered infewer fractions than usual (usually � 10)—is beingused more commonly in hepatocellular carcinoma(HCC).

● SBRT is most effective in HCC smaller than 6 cm,with local control rates from 70% to 95% at 2 years.

● SBRT can also lead to sustained control of HCCslarger than 6 cm and the recanalization of vasculartumor thrombi from HCC.

● Toxicity risks are increased in patients with Child-Pugh B and C baseline liver function.

● Randomized trials of SBRT for HCC are required.

Table 1. Selected Outcomes from HCC SBRT Series

Number of Patients Dose/FractionMedian Follow-up

(Months) Tumor SizeOverall

Response Rate Survival

Blomgren, 199814 9 pts HCC, 1 pt IHC 5–15 Gy/1–3 # NR NR 70% NRChoi, 200623 20 pts HCC 50 Gy/5–10 # 23 3.8 cm (2–6.5 cm) 80% overall OS 1 yr: 70%

20% CR/60% PR OS 2 yr: 43.1%Mendez Romero, 200617 11 pts HCC 25 Gy/5 # NR � 7 cm 1-yr LC: 82% OS 1 yr: 75%

CP A and B 30 �37.5 Gy/3 #Tse, 200818 31 pts HCC 36 Gy (median)/6 # 18 Median: 173 cm3 1-yr infield LC: 65% OS 1 yr: 48%

All CP A Range 24–54 GyLouis, 201026 25 pts HCC 45 Gy/3 # 13 Median: 150 cm3 86% overall OS 1 yr: 79%

CP A and B OS 2 yr: 52%Kwon, 201024 42 pts HCC 30–39 Gy/3# 29 15.4 cm3 (3–82 cm3) Overall: 86% OS 3 yr: 59%

CP A 90% 3-yr LC: 68%Facciuto, 201122 27 pts HCC 24–36/2–4 # 22 2.0 cm � 0.8 cm Overall: 37% OS 2 yr: 82%

All CP AAndolino, 201120 60 pts HCC 44 Gy (median)/3 # CP A 27 Median: 3 cm Overall: 90% OS 2 yr: 67%

CP A/B: 36/24 40 Gy (median)/5 # CP B

Abbreviations: HCC, hepatocellular carcinoma; SBRT, stereotactic body radiotherapy; Pts, patients; IHC, immunohistochemical; #, fractions; NR, not reported; OS,overall survival; CR, complete response; PR, partial response; LC, local control; CP, Child-Pugh.

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disease included hepatitis B, 39%; hepatitis C, 40%; andalcohol, 25%. Prior therapies were delivered in 50% ofpatients. Baseline Barcelona Clinic Liver Cancer stage wasclass C in 66%. Multiple lesions were present in 59% ofpatients, and the median sum of liver lesion diameters was10 cm (1.8–43 cm). Tumor vascular thrombosis was presentin 55% and extrahepatic disease in 14%. At one year, thelocal control of irradiated HCC was 79% (CI 95%, 66–87%).Median overall survival was 17.0 months (CI 95%, 10.6–21.8months).19

The Indiana University School of Medicine has also con-ducted prospective studies of HCC SBRT.20,21 In a phase Istudy by Cardenes et al, in 17 patients with HCC with 25lesions (median diameter 3.2 cm), dose was escalated inpatients with Child-Pugh A from 36 Gy in three fractions to48 Gy in three fractions, without dose-limiting toxicity. Inpatients with Child-Pugh B, two developed grade 3 hepatictoxicity at 42 Gy in three fractions. Subsequently, fivepatients with Child-Pugh B were treated with 40 Gy in fivefractions, and one patient developed liver failure.21 Overall,20% of patients experienced an increase in Child-Pugh class:seven of 36 patients with Child-Pugh A experienced progres-sion to Child-Pugh B, and five of 24 patients with Child-Pugh B progressed to Child-Pugh C, demonstrating anincreased risk of any toxicity in patients with worse Child-Pugh class at baseline. After a median follow-up of 27months, 2-year local control was 90%, progression-free sur-vival was 48%, and overall survival was 67%.

Retrospective series of SBRT have also been pub-lished.22,23 Kwon et al treated 42 patients with HCC with 30to 39 Gy in three fractions. With a median follow-up of 29months, the response rate was 86% (60% complete responseand 26% partial response).24 Seo et al treated 38 patientswith HCC with 33 to 57 Gy in three to four fractions, with a61% 2-year survival and 79% local control rate.25 Doses ofmore than 42 Gy in three fractions were associated withimproved local control. Twenty-five European patients withHCC have also been treated with SBRT (45 Gy in 3 frac-tions), with a 1-year local control rate of 95%.26

SBRT has been used to effectively treat HCC tumor

thrombi and has been used as a bridge to liver trans-plant.21,27,28 In most series, following SBRT, the first site ofrecurrence is in the liver outside the irradiated volume,providing rationale for studies combining regional or sys-temic therapies with SBRT.

Toxicity: SBRT

In addition to the potential for liver toxicity (includingclassic and nonclassic RILD), as previously described, SBRTis associated with the possibility for other late toxicity.Gastric, duodenum, and small and large bowel late toxicity(e.g., ulcer, fistula, bleed) are more likely to occur followingSBRT potent doses than conventional radiation fraction-ations. Therefore, HCC tumors best suited for SBRT arelocated at least 1 cm away from luminal gastrointestinalstructures. Proton pump inhibitors may reduce the risk ofluminal gastrointestinal toxicity, and strategies to movegastrointestinal structures away from the tumor itself maybe beneficial to patients.

A potential toxicity that is unique to SBRT is chest painand rib fracture. This has not commonly been reported but isa possible late sequelae from therapy for peripherally lo-cated HCCs. The risk of toxicities can be reduced by ensur-ing that radiation “hot spots” are within the target volumeand not near adjacent critical normal tissues.

Another potential toxicity is biliary. For caudate lesionsand HCC invading the biliary track, edema may occurfollowing SBRT, so care is required to stent the patientbefore therapy and/or to premedicate patients with steroidsto reduce this risk. In the long term, there is a risk of latebiliary stenosis, which has been rarely reported followingproton therapy and not yet reported following SBRT. None-theless, being cautious to reduce the dose per fraction and/oroverall maximal dose is reasonable for caudate lesions toreduce the risk of this potential late toxicity.

Conclusion

Technical advances in radiation oncology have made itpossible for SBRT to be used safely for the treatment of

Fig. 1. Axial slice of HCC SBRT plan showing aconformal isodose distribution. The red and bluesolid lines represent the gross target volume (GTV)and planning target volume (PTV) to be irradiated,to account for uncertainties, respectively. The HCCwas treated with 42 Gy in six fractions (pink line),which tightly surrounds the PTV, with a rapidfalloff in dose.

Abbreviations: HCC, hepatocellular carcinoma;SBRT, stereotactic body radiotherapy.

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HCC, with encouraging outcomes in early and locallyadvanced HCC. The risk of liver toxicity is increasedin patients with Child-Pugh B or C cirrhosis, hepatitis Bcarrier status, and large tumor size relative to theliver. Improved tumor control and survival are seen inpatients who can be treated with higher doses. Randomized

trials are required to better understand the benefitsand toxicities of SBRT. An international phase III study(RTOG 1112, in development) of sorafenib versus SBRTfollowed by sorafenib in locally advanced HCC shouldprovide some insight into the benefits of SBRT in thissetting.

Authors’ Disclosures of Potential Conflicts of Interest

Author

Employment orLeadershipPositions

Consultant orAdvisory Role

StockOwnership Honoraria

ResearchFunding

ExpertTestimony

OtherRemuneration

Laura A. Dawson Bayer

Sameh Hashem*

Alexis Bujold*

*No relevant relationships to disclose.

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