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CLINICAL INVESTIGATION Liver

STEREOTACTIC BODY RADIOTHERAPY FOR PRIMARY HEPATOCELLULARCARCINOMA

DAVID L. ANDOLINO, M.D.,* CYNTHIA S. JOHNSON, M.S.,y MARY MALUCCIO, M.D.,z PAUL KWO, M.D.,x

A. JOSEPH TECTOR, M.D.,z JENNIFER ZOOK, M.D.,* PETER A. S. JOHNSTONE, M.D.,*

AND HIGINIA R. CARDENES, M.D., PH.D.*

Departments of*Radiation Oncology, yBiostatistics, zSurgery, and xMedicine, Indiana University School of Medicine, Indianapolis, IN

Purpose: To evaluate the safety and efficacy of stereotactic body radiotherapy (SBRT) for the treatment of primaryhepatocellular carcinoma (HCC).Methods and Materials: From 2005 to 2009, 60 patients with liver-confined HCC were treated with SBRT at the In-

diana University Simon Cancer Center: 36 Child-Turcotte-Pugh(CTP) Class A and 24 CTPClass B. The median num-ber of fractions, dose per fraction, and total dose, was 3, 14 Gy, and 44 Gy, respectively, for those with CTP Class Acirrhosis and 5, 8 Gy, and 40 Gy, respectively, for those with CTP Class B. Treatment was delivered via 6 to 12 beamsand in nearly all cases was prescribed to the 80% isodose line. The records of all patients were reviewed, and treatmentresponse was scored according to Response Evaluation Criteria in Solid Tumors v1.1. Toxicity was graded according totheCommonTerminologyCriteria forAdverse Events v4.0. Local control(LC),timeto progression (TTP), progression-free survival (PFS), and overall survival (OS) were calculated according to the method of Kaplan and Meier.Results: The median follow-up time was 27 months, and the median tumor diameter was 3.2 cm. The 2-year LC,PFS, and OS were 90%, 48%, and 67%, respectively, with median TTP of 47.8 months. Subsequently, 23 patientsunderwent transplant, with a median time to transplant of 7 months. There were no $Grade 3 nonhematologictoxicities. Thirteen percent of patients experienced an increase in hematologic/hepatic dysfunction greater than1 grade, and 20% experienced progression in CTP class within 3 months of treatment.Conclusions: SBRT is a safe, effective, noninvasive option for patients withHCC#6 cm. As such, SBRT should be con-sidered when bridging to transplant or as definitive therapy for those ineligible for transplant. 2011 Elsevier Inc.

Hepatocellular carcinoma, Stereotactic body radiotherapy.

INTRODUCTION

Hepatocellular carcinoma (HCC) is the fourth most common

cancer in theworld, responsible for 19,000 deaths annually in

the United States alone (1, 2). The disease often presents in

the setting of advanced cirrhosis, and orthotopic liver

transplant (OLT) provides the greatest chance for both cure

and long-term survival (3, 4). Surgical resection and

percutaneous ablation can provide comparable rates of

long-term overall survival, but preexisting hepatic dysfunc-

tion and lesion size can significantly limit both modalitieswith regard to patient eligibility and treatment efficacy (58).

Stereotactic body radiotherapy (SBRT), the precise deliv-

ery of highly conformal external-beam radiation in two to

five fractions, may provide an effective, noninvasive, alter-

native option and has the potential to improve outcomes in

nonsurgical candidates with tumors up to 6 cm. SBRT has

been shown to be both safe and extremely effective for the

treatment of metastatic lesions in noncirrhotic livers, and

Phase I investigations now suggest that SBRT can also be

safely used to treat HCC in patients with Child-Turcotte-

Pugh (CTP) Class A or B liver cirrhosis (912). In 2005,

a prospective Phase I/II study was initiated at the Indiana

University Simon Cancer Center (IUSCC) investigating

SBRT for the treatment of HCC. The results of an interim

analysis including all patients enrolled thus far, and those

treated off the study but according to the protocol, are

presented below.

METHODS AND MATERIALS

The records of all patients with HCC treated with SBRT from

2005 to 2009 were reviewed. Only those patients with disease con-

fined to the liver at the time of treatment were included in the

Reprint requests to: David L. Andolino, M.D., Department ofRadiation Oncology, Indiana University School of Medicine, 535Barnhill Dr, RT 041, Indianapolis, IN 46202. Tel: (317) 944-1186; Fax: (317) 944-2486; E-mail: dandolin@iupui.edu

Data presented orally at the Annual Meeting of the AmericanSociety for Radiation Oncology, San Diego, October 31 - Novem-ber 4, 2010.

Conflict of interest: none.Received Jan 9, 2011, and in revised form March 29, 2011.

Accepted for publication April 4, 2011.

e447

Int. J. Radiation Oncology Biol. Phys., Vol. 81, No. 4, pp. e447e453, 2011Copyright 2011 Elsevier Inc.

Printed in the USA. All rights reserved0360-3016/$ - see front matter

doi:10.1016/j.ijrobp.2011.04.011

http://dx.doi.org/10.1016/j.ijrobp.2011.04.011http://dx.doi.org/10.1016/j.ijrobp.2011.04.011http://dx.doi.org/10.1016/j.ijrobp.2011.04.011http://dx.doi.org/10.1016/j.ijrobp.2011.04.011

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analysis. Pathologic confirmation of HCC was not required as long

as established radiographic criteria were satisfied (13). Prior liver-

directed therapy was allowed.

All patients were immobilized in the stereotactic body frame

(Elekta Oncology, Norcross, GA), which included a rigid three-

sided frame with vacuum pillow and abdominal compression for

control of respiratory motion of the target. Immediately before

dual-phase computed tomography (CT) simulation, abdominal

compression was adjusted under fluoroscopy to limit diaphragmaticexcursion to less than 0.5 cm. Six to 12 fields were designed to treat

the CT-defined (arterial-phase) gross tumor volume, with a radial

expansion of 0.5 cm and superiorinferior expansion of 1.0 cm to

define the planning target volume (PTV).

Based on our prior Phase I feasibility trial, the majority of

patients with CTPA cirrhosis received a total dose of 48 Gy in three

fractions, and those with CTP B cirrhosis received a total dose of 40

Gy in five fractions (12). No patient received more than two frac-

tions per week. Virtually all treatments were prescribed to the

80% isodose line covering the surface of the PTV. For patients

with CTP A cirrhosis, one third of the uninvolved liver was re-

stricted to #10 Gy, and $500 cc of uninvolved liver received

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third of the left kidney was allowed to receive >15 Gy. The maxi-

mum allowed dose to 0.5 cm of small bowel was 12 Gy.

A physician evaluation and routine blood work, including com-

plete blood count and liver function tests, were performed before

each fraction. If at the time of this pretreatment evaluation a pa-

tients liver function seemed to be worsening, based on the results

of either physical examination or laboratory tests, treatment was

postponed and the interfraction interval was extended. All patients

returned to clinic 1 month after the completion of treatment, at3-month intervals for the first 2 years, and at 6-month intervals

thereafter. Surveillance imaging, either contrast-enhanced dual-

phase CT or magnetic resonance imaging, and the above-listed

blood tests were obtained at the time of each visit. Acute and

long-term toxicities were graded according to the Common Termi-

nology Criteria for Adverse Events v4.0. Radiographic tumor

response was scored according to the Response Evaluation Criteria

in Solid Tumors (RECIST) v1.1.

The Kaplan-Meier method was used to determine the median

follow-up time from first treatment date, and the duration of

follow-up time was compared via log-rank test (14). Follow-up

was censored at death. Demographic and treatment characteristics

were compared between patients who did and did not undergo OLT,using the Mann-Whitney or two-sample ttests and Fishers exact or

chi-square tests for continuous and categoric variables, respec-

tively. Univariate log-rank tests and Cox proportional hazards

models were used to investigate the association of categoric and

continuous variables, respectively, with local control (LC),

progression-free survival (PFS), time to progression (TTP), and

overall survival (OS). All times were calculated as months from

date of first treatment. C was censored at the date of OLT or the

date of last follow-up, whichever occurred first, and local failure

was defined as recurrence within the treated PTV. Regional failure

was defined as intrahepatic recurrence, in a region of the liver com-

pletely distinct from the treated PTV, and distant failure was defined

as any extrahepatic disease recurrence.

RESULTS

Sixty patients with liver-confined HCC were treated with

SBRT, with a median follow-up time of 27 months. Six

patients received prior treatment for HCC, all in the form

of transarterial chemoembolization. Twenty-three patients

proceeded to OLT, with a median time to transplant of 7

months. The median number of fractions, dose per fraction,

and total dose were 3, 14 Gy, and 44 Gy, respectively, for

patients with CTP A cirrhosis, compared with 5, 8 Gy, and

40 Gy, respectively, for patients with CTP B cirrhosis. The

median interfraction interval and total duration of treatment

was 3 days and 13 days, respectively, for those with CTP Acirrhosis, and 4 days and 20 days, respectively, for those with

CTP B cirrhosis. Patient demographics and treatment spe-

cifics for the entire cohort, including a comparison of non-

transplant and transplant populations, are detailed in Table 1.

Entire cohort (+/ transplant)

As scored per RECIST v1.1, the rates of complete and par-

tial treatment response were 30% and 40%, respectively,

with another 25% of patients having stable disease. The

median PFS and OS were 20.4 months and 44.4 months,

respectively (Fig. 1). Median LC has yet to be achieved at

the time of this writing. Actuarial 2-year LC, PFS, and OSwere 90%, 48%, and 67%, respectively. The median TTP

was 47.8 months, with a median survival from date of pro-

gression of 23 months. Regional failure was the most fre-

quent route of initial disease progression (Table 2).

Larger tumor volume, CTP Class B (Fig. 2), and absence

of OLT were associated with worse PFS (p = 0.029, 0.013,

and 0.018, respectively) and OS (p = < 0.001, 0.018, and 3 cm, for which the rates of

LC achieved with radiofrequency ablation fell to

approximately 80% or less, our results seem even more

encouraging (21, 22). Equally notable, and perhaps more

clinically relevant, is the median TTP of 4 years for the

entire cohort and 3 years for the nontransplantedpopulation. These rates are comparable to those obtained

with percutaneous ablation and surgical resection, and they

exceed the quoted rate of 10 to 27 months after

transarterial chemoembolization or radioembolization for

similarly sized lesions (19, 23, 24).

The impact on overall survival relative to other liver-

directed therapies remains to be determined. The heteroge-

neity of the population, especially with regard to the severity

of liver cirrhosis and the presence or absence of extensive

comorbidities, precludes an accurate comparison of overall

survival, and formal Phase II/III investigations are required

before comparisons can be made.Comparing our experience with SBRT for primary HCC

with those mentioned above, several differences become

apparent that are worthy of further exploration. For in-

stance, the rate of LC reported in our series, 90% at 2

years, exceeds the rate of 65% LC at 1 year as reported

by Tse et al. (11). Although the higher median dose per

fraction and total dose used in our series may have played

a role in producing more durable LC, the most likely expla-

nation lies in the fact that the median tumor volume treated

by Tse et al. was nearly six times larger than that in our

series: 173 cc vs. 27 cc. With regard to differences in tox-

icity, approximately one third of our population had docu-mented Grade 3 hematologic or hepatic dysfunction after

treatment, whereas Choi et al. reported not a single inci-

dence of Grade 3 toxicity (16). However, we have shown

a relationship between pretreatment CTP score and the de-

velopment of subsequent toxicity. As such, we are inclined

to attribute at least some of this difference in toxicity to

differences in pretreatment hepatic function. Although all

patients in our series had some degree of liver cirrho-

sis40% with CTP Class Bonly 80% of the patients

treated by Choi et al. were considered to have cirrhosis,

with only 25% qualifying as CTP Class B (16).

In conclusion, SBRT is a noninvasive, safe, and effec-tive modality for the treatment of HCC #6 cm, and as

such warrants greater recognition as a viable option in

the management of this malignancy. At IUSCC, SBRT

is now considered to be the primary option for bridging

to transplant, provided the patient meets eligibility crite-

ria, and is also strongly considered for first-line definitive

therapy when transplant is not an option.

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Table 4. Hematologic and hepatic toxicity

Change in Common ToxicityCriteria grade, pre-SBRT

grade/ post-SBRT grade n (60)

Liver enzymesNo change 460/ 1 8

1/ 2 31/ 3 12/ 3 2

AlbuminNo change 430/ 1 21/ 2 82/ 3 7

PlateletsNo change 400/ 1 41/ 2 61/ 3 22/ 3 7

3/

4 1INRNo change 500/ 1 41/ 2 41/ 3 12/ 3 1

Alkaline phosphataseNo change 530/ 1 7

BilirubinNo change 310/ 1 70/ 2 41/ 2 10

2/ 3 71/ 4 1

Abbreviation: SBRT = stereotactic body radiation therapy.

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