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Phase I Study of Individualized Stereotactic BodyRadiotherapy for Hepatocellular Carcinoma andIntrahepatic CholangiocarcinomaRegina V. Tse, Maria Hawkins, Gina Lockwood, John J. Kim, Bernard Cummings, Jennifer Knox,Morris Sherman, and Laura A. Dawson

From the Radiation Medicine

Program, Departments of Biostatis-

tics, Medical Oncology, Princess

Margaret Hospital, University Health

Network, University of Toronto; and

Department of Medicine, University of

Toronto and University Health

Network, Toronto, Ontario, Canada.

Submitted September 15, 2007;accepted October 24, 2007; published

online ahead of print at www.jco.org on

January 2, 2008.

Supported in part by Elekta Oncology

Systems, and a 2002 American Society

of Clinical Oncology career develop-

ment award (L.A.D.).

Presented in part at the American Soci-

ety for Therapeutic Radiology and

Oncology 47th Annual Meeting,

November 5-9, 2006, Denver, CO; the

European Society for Therapeutic Radi-

ology and Oncology, October 8-12,

2006, Leipzig, Germany; and the 43rd

Annual Meeting of the American Soci-

ety of Clinical Oncology, June 1-5,

2007, Chicago, IL.

Authors disclosures of potential con-

flicts of interest and author contribu-

tions are found at the end of this

article.

Corresponding author: Laura Dawson,

MD, Department of Radiation Oncol-

ogy, Princess Margaret Hospital,

University of Toronto, 610 University

Ave, Toronto, Ontario M5G 2M9,

Canada; e-mail: laura.dawson@

rmp.uhn.on.ca.

2008 by American Society of Clinical

Oncology

0732-183X/08/2604-657/$20.00

DOI: 10.1200/JCO.2007.14.3529

A B S T R A C T

PurposeTo report outcomes of a phase I study of individualized stereotactic body radiotherapy treatment(SBRT) for unresectable hepatocellular carcinoma (HCC) and intrahepatic cholangiocarci-noma (IHC).

Patients and Methods

Patients with unresectable HCC or IHC, and who are not suitable for standard therapies, wereeligible for six-fraction SBRT during 2 weeks. Radiation dose was dependent on the volume of liverirradiated and the estimated risk of liver toxicity based on a normal tissue complication model.Toxicity risk was escalated from 5% to 10% and 20%, within three liver volumeirradiated strata,provided at least three patients were without toxicity at 3 months after SBRT.

ResultsForty-one patients with unresectable Child-Pugh A HCC (n 31) or IHC (n 10) completedsix-fraction SBRT. Five patients (12%) had grade 3 liver enzymes at baseline. The median tumorsize was 173 mL (9 to 1,913 mL). The median dose was 36.0 Gy (24.0 to 54.0 Gy). Noradiation-induced liver disease or treatment-related grade 4/5 toxicity was seen within 3 monthsafter SBRT. Grade 3 liver enzymes were seen in five patients (12%). Two patients (5%) with IHCdeveloped transient biliary obstruction after the first few fractions. Seven patients (five HCC, twoIHC) had decline in liver function from Child-Pugh class A to B within 3 months after SBRT. Mediansurvival of HCC and IHC patients was 11.7 months (95% CI, 9.2 to 21.6 months) and 15.0 months(95% CI, 6.5 to 29.0 months), respectively.

ConclusionIndividualized six-fraction SBRT is a safe treatment for unresectable HCC and IHC.

J Clin Oncol 26:657-664. 2008 by American Society of Clinical Oncology

INTRODUCTION

Hepatocellular carcinoma (HCC) is the third most

common cause of cancer death in the world,1 with

an increasing incidence in North America.2 Hepatic

resection and transplantation, resulting in 5-year

survival rates from 30% to 70%,1 are feasible in lessthan 20% of patients. Similarly, less than 30% of

patients with intrahepatic cholangiocarcinoma

(IHC) are candidates for surgery, which is the only

potentially curative option.3

For small HCC, radiofrequency ablation and

other ablative techniques achieve excellent local

control. However, local recurrences are more com-

mon in tumors larger than 4 cm and tumors

adjacent to large vessels.4,5 Transarterial chemoem-

bolization improves survival modestly compared

with supportive care in HCC.6 Chemotherapy is as-

sociated with low response rates (5% for HCC,7,8

30% for IHC9). Targeted agents are showing activity

in HCC10,11 and IHC,12 but are unlikely to be asso-

ciated with cure in the absence of local therapies.

Historically, the role of radiotherapy for liver

tumors has been limited by the risk of radiation-

induced liver disease (RILD), consisting of anicterichepatomegaly, ascites, and elevated alkaline phos-

phatase, that can occur within 3 months after low-

dose whole-liver irradiation.13

Technological advances in radiation planning,

breathing motion reduction strategies, and image

guidance14 have made it possible for radiation to be

delivered conformally to focal liver cancers, re-

ducing the risk of toxicity. At the University of

Michigan (Ann Arbor, MI), an individualized

dose allocation strategy was developed for liver

cancer treatment, dependent on the volume of

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134.96.155.211Information downloaded from jco.ascopubs.org and provided by at Saarlaendische Universitaets on June 26, 2013 from

Copyright 2008 American Society of Clinical Oncology. All rights reserved.

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liver irradiated.15 Stereotactic body radiation therapy (SBRT), re-

ferring to the delivery of potent radiation in few fractions, has also

been used safely, predominantly in small liver metastases that

require less than 25% of the liver to be irradiated.16,17

We hypothesized that the combination of SBRT and individual-

ized dose allocationwould allow smalland largeHCCs andIHCsto be

treated, with the potential to improveoutcomes. We report the results

of a phase I trial of individualized six-fraction SBRT for unresectable

HCC and IHC.

PATIENTS AND METHODS

PatientsPatients with unresectable HCC or IHC were eligible for this phase I trial,which was approved by the Research Ethics Board. Patients had to be olderthan 18 years, with a life expectancy more than 12 weeks, Child-Pugh A liverfunction, more than 800 cm3 of uninvolved liver, Karnofsky performancescore 60. Extrahepatic disease was not an exclusion criterion, as long as thegreatest burden of disease was within the liver. Ineligibility criteria includedbilirubin 3 upper limit of normal, AST or ALT 6 upper limit of

normal,creatinine lessthan200mol/L, international normalized ratio

1.3(after correction with vitamin K or allowable if patient required anticoagu-lants), hemoglobin less than 90 g/L, platelets less than 80,000/L, clinicalascites,and previousirradiationto theright upper abdomen.A biopsy wasnotrequired for HCC patients if the tumors enhanced typically on two imagingmodalities and the-fetoprotein (AFP) levelwas increased on a known back-ground of liver disease.Histologicdiagnosis wasrequired forIHC patients. Nochemotherapy was permitted at least 2 weeks before and 4 weeks after SBRT.The effective liver volume irradiated (Veff) had to be less than 0.8, where 1.0represents whole organ irradiation. After the first year, patients with elevatedcreatinine andthose whohad receivedpriorirradiationwere eligible,as longasthe cumulative doses did not exceed defined normal tissue limits.

Radiation TreatmentEach patients treatment was individualized with respect to immobilization,

radiation planning, and prescription dose to minimize the uninvolved livervolume required to be irradiated, and to maintain normal tissue dose limits.Simulation took placeduring 2 days to include an education session, kilovolt-age fluoroscopy, computed tomography (CT) planning, and magnetic reso-nance imaging (MRI). Kilovolt fluoroscopy and cine MRI18 were used tomeasure liver breathing motion and reproducibility of liver position withrepeatedexhale breath holds, using the active breathing control device (ElektaOncology Systems, Crawley,United Kingdom). Abdominal compression wasused to reduce breathing motion for patients not suitable for breath hold.Respiratory sorted CT scans were obtained for patients treated in free breath-ing with and without abdominal compression.19

Tumors imaged on the planning triphasic CT and/or MRI and enhanc-ing large vessel thromboses were included within the gross target volume(grosstumorvolume [GTV]). An 8-mm margin aroundthe GTVwithin liverandnonenhancingthromboseswas includedwithinthe clinicaltargetvolume.

The planning target volume (PTV) margins were individualized, as describedpreviously18 (minimum5 mm). ThePTV aroundthe GTVwas theprimarytarget (PTVPrimary), whereas the PTV around the clinical target volume(PTVSecondary) was a secondary target. Conformal planning was used, withthree to 10 coplanar or noncoplanar beams of6 to 18MV, with up to threesegments within each field.

The dose volume histogram (DVH) for the liver minus the GTV (re-ferred to as liver) was used to estimate the risk ofRILDand to allocate dose toPTVPrimary. The dose to PTVPrimarywas allocated depending on the Veff(Ap-pendix,onlineonly)andthe uninvolvedliver volumewith a maximumdoseof60 Gy. The target dose to PTVSecondary, containing possible microscopic dis-ease, was 24 Gy. SBRT was deliveredin sixfractions during 2 weeks,usually onalternate days (eg,Monday,Wednesday,andFriday) althoughvariations werepermitted (eg, Tuesday, Wednesday, and Friday) for logistic reasons (eg,

holidays). The maximal permitted dose to 0.5 mL of the esophagus, stomach,duodenum, or bowel was 30 Gy. The maximal dose to the spinal cord was 27Gy, and the maximal dose to the heart was 40Gy (Appendix Table A1, onlineonly). Efforts were made to minimize the dose to all normal tissues.

Treatment verificationwas performed using orthogonal megavoltimageguidance (using the dome of the diaphragm and vertebral body for guid-ance)20 or, whenavailable, kilovoltage conebeam CT imagingand kilovoltageorthogonal fluoroscopy, as described previously.21

Escalation StrategyThe radiation dose was escalated in three predefined liver Veffstrata (low,0.2; mid, 0.2 to 0.5; and high, 0.5 to 0.8; Fig 1A. Within each strata, therewere three escalation levels, based on the risk of estimated liver toxicity (5%,10%,and20%).Forthe low Veffstrata, thedoseper fraction wasplannedto beescalated (from9 to 9.5to 10Gy forsix fractions). Formidand high Veffstrata,the doses could bemodifiedby upto 3 Gyas longas the nominal risk level wasnot exceeded. Doses werereduced if necessaryto maintain nonhepatic normaltissue limits. Three patients had to be treated in each stratum with no dose-limiting toxicitywithin3 months after SBRTbeforeescalation to the nextlevelwas permitted. If toxicity occurred, a minimum of sixpatients were treated atthatlevel.While waitinguntil 3 months after SBRT, at which timethe presence

A

0

TotalPrescribed

Dose

in

6Fractions(Gy)

Veff

60

50

40

30

20

10

0.2 0.4 0.6 0.8 1.0

B

0

HCC patients

IHC patients

TotalPrescribed

Dos

e

in

6Fractions(Gy)

Veff

0.2 0.4 0.6 0.8 1.0

Low

Veff

Mid

Veff

High

Veff

60

50

40

30

20

10

Level 1 (5%)

Level 2 (10%)

Level 3 (20%)

Fig 1. (A) Prescribed dose per fraction and effective liver volume irradiated (V eff).

(B) Relationship between Veff and prescribed dose to tumor. HCC, hepatocellular

carcinoma; IHC, intrahepatic cholangiocarcinoma.

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or absence of toxicity was determined, patients could be treated at the pre-defined dose level.

EvaluationPatients wereassessed weekly during SBRTand after completion of treatmentat 1 month, every 3 months for the first 12 months, and every 6 months to 36months (or morefrequently if clinically indicated). Liver triphasic CT or MRIwas performed at each follow-up. Chest CT was performed at 12 months (ormore frequently if preexisting lung metastases were present). Toxicity was

graded using the National Cancer Institute Common Toxicity Criteria forAdverse Events version 3.0.Dose-limiting toxicity was any Common ToxicityCriteria grade 4 or 5 hepatic, thrombocytopenia, or GI toxicity occurringwithin1monthofSBRT,orRILDrequiringtreatmentintheabsenceofdiseaseprogression13 within 3 months of SBRT. For Child-Pugh liver function deter-mination, the international normalized ratio was assumed to be stable inpatients requiring warfarin.

Tumor responsewas assessed using Response Evaluation and CriteriainSolid Tumors (RECIST). Local in-field recurrence was defined as recurrencewithin the high-dose region ( 80% isodose volume), demonstrated by newenhancement or RECIST progressive disease. Actuarial survival and localcontrol rates were evaluated by the Kaplan-Meier method.

RESULTS

Patients

From August 2003 to March 2006, 49 patients with HCC or IHC

consented fortreatment. Seven patientsfoundto be ineligible,because

of changes in liver function (n 4), thrombocytopenia (n 1),

inadequate normal liver volume less than 800 mL (n 1), or tumor

progression (n 1), were taken off study before treatment. Another

patient with HCC was taken off study after one fraction (7.5 Gy); he

was found to have a variceal bleed that started before his SBRT. The

remaining 41 patients(31 HCC,10 IHC)completedSBRT as planned,

and are described here.

The majority of HCC patients were American Joint Committee

on Cancer TNM stage T3, N0 (61%), and Cancer of Liver ItalianProgram score 1 (39%) or 2 (32%). All IHC patients had vascular

involvement or extrahepaticdisease at baseline. Other patient charac-

teristics are listed in Table 1.

All risk levels were investigated for mid and high Veffstrata, with

19 and 18 patients treated in the mid and high Veffstrata, respectively.

For the low Veff strata, four patients were treated at level 1 and the

higher levels were not investigated because of poor accrual (potential

patients were often suitable for other therapies).

For all patients, the median tumor volume (of largest single

lesions) was 173 mL (9 to 1,913 mL). The median liver Veffwas 0.48

(0.16 to 0.80). The median prescription dose was 36.0 Gy in six

fractions (24.0 to 54.0 Gy; Fig 1B; Table 2).

Toxicity

The median follow-up time was 17.6 months (range, 10.8 to 39.2

months). Overall, treatment was well tolerated, with no dose-limiting

toxicity or RILD observed. During SBRT, two patients with IHC

developed transient biliary obstruction (prescription doses 30.6 Gy

and 28.8 Gy, respectively).

Three-month follow-up data was unavailable for one patient

with HCC who died as a result of a pulmonary embolus 2.3 months

after SBRT. Within the first 3 months, eight of the 31 HCC patients

and two of the 10 IHC patients developed grade 3 liver enzymes; no

grade 4 or 5 liver enzymes were observed. Grade 3 thrombocytopenia

was seen in one patient. Three patients developed transient asymp-

tomatic right-sided pleural effusions (HCC) 3 months after

SBRT (Table 3).

Seven patients(23%)experienced progression from Child-Pugh

A classificationto B within 3 monthsafter SBRT (five HCC, two IHC).

Two HCC patients had baseline Child-Pugh A6 classification. The

majority of these patients had progressive disease at 1 month after

SBRT. On Mann-Whitney testing, compared with patients without

Child-Pugh progression, the patients who had a decline in liver func-

tion had lower median prescription doses (29.1 v36.9 Gy; P .03),

higher median liver Veff(0.44 v0.56; P .04), and higher mean liver

doses (16.0 v18.0 Gy; P .05), and were more likely to have largertumors (P .08).

Two patients (6%) experienced late toxicity. One patient with

HCCdeveloped a tumor-duodenalconnectionon imaging15 months

after completion of SBRT. This patient died 22 months after SBRT as

a result of a GI bleed. Another patient with IHC developed a small

bowel obstruction 17 months after SBRT requiring bypass surgery, at

which time extrahepatic progressive disease was detected. Both late

toxicities were believed to be related to disease persistence or progres-

sion, with a possible contribution from the radiation treatment.

Survival

The median survival of all patients was 13.4 months (95% CI, 11.1 to

21.1 months),with1-year survivalrateof 51%(95% CI,34% to 65%).

For HCC, the median survival was 11.7 months (95% CI, 9.2 to 21.6

months) andthe 1-yearsurvival rate was48% (95% CI, 30%to 64%).

The median survival of HCC patients with preexisting large vessel

thrombosis was11.6 months (95% CI, 3.3 to 21.6 months) compared

with 17.2 months (95% CI, 9.0 to 22.5 months) for patients without

(P .19). The median survival and 1-year survival for IHC was

15.0 months (95% CI, 6.5 to 29.0 months) and 58% (95% CI, 23%

to 82%; Fig 2).

Response

The 1-year in-field local control rate was 65% (95% CI, 44% to 79%)

for all patients. The overall RECIST response rate was 49% (complete

response[CR], 5%; partialresponse, 44%),with a stable diseaserateof

42%. The responses of the large vessel thrombosis in patients with

HCC were CR, 6%; partial response, 19%; and stable disease, 38%.

One patient developed a CR of a portal vein and inferior vena cava

thrombosis 18 months after SBRT. The most frequent site of first

progression was outside the treated volume (Fig 3).

Of 21 HCC patients with elevated baseline AFP levels (median,

3,141 g/L; range, 19 to 714,500) and available follow-up levels, 16

patients (76%) hada reduction in AFPlevels after SBRT (median,472

g/L; range, 16 to 10,400g/L; Appendix Fig A1, online only).

DISCUSSION

This study demonstrated that six-fraction SBRT (24 to 54 Gy) is a

feasible treatment for unresectable HCC and IHC. The treatmentwas

welltolerated and there wereno occurrencesof dose-limiting toxicity.

A maximum tolerated dose using this dose allocation approach was

not determined. The mostclinicallysignificant change after SBRTwas

a decline in Child-Pugh classification from A to B observed in seven

patients (17%). Compared with other patients, the majority of these

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Table 1. Patient, Disease, and Previous Treatment Characteristics

Characteristic

Total HCC IHC

No. % No. % No. %

No. of patients 41 31 76 10 24

Sex

Male 31 24 7

Female 10 7 3

Age, yearsMedian 62 66 57

Range 41-85 41-85 49-79

Race/ethnicity

White 15 48

Asian/Indian 16 52

Karnofsky performance score

100 9 24

90 12 32

80 11 29

70 5 14

Unknown 4 10

Liver disease

Hepatitis B 13 42

Hepatitis C 12 39

Hepatitis B/C/D 1 3

Alcoholic cirrhosis 4 13

Unknown 1 3

Tumor marker: AFP, g/L

Median 1,049

Range 5-714,500

400 13 (%) 42

400 18 (%) 58

Child-Pugh classification, HCC patients

A5 28 90

A6 3 10

CLIP score, HCC patients

0 1 3

1 12 39

2 10 32

3 5 16

4 3 105 0

Barcelona Clinic liver cancer stage

A1-A3 0

A4 3 10

B 10 32

C 18 58

D 0

AJCC TNM stage

T1N0 3 10

T2N0 5 16

T3N0 19 61

T3N1 1 3

T4N0 1 3

T2N1M1 1 3

T3N1M1 1 3

Extrahepatic/metastatic disease 3 10 10 100

Locoregional lymphadenopathy only 1 3 6 60

Periportal and mediastinal nodes 1 3

Periportal and peripancreatic nodes 1 3

Metastases 4 40

Liver only 1 10

Liver and locoregional lymphadenopathy 1 10

Liver and mesenteric/pancreatic metastases 1 10

Liver and abdominal wall metastases 1 10

(continued on following page)

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patients had HCC and were treated with lower doses without re-

sponse. Hepatic disease progression may have contributed to the de-

cline in liver function in these patients.

An unexpected toxicity observed in two patients with IHC was

transient biliary obstruction likely due to radiation-induced edema.

Pretreatment dexamethasone was recommended for subsequent

patients with central tumors; no additional biliary obstruction was

observed. Biliary obstruction has not been reported previously

after conventional fractionation or hyperfractionation, and the

hypofractionated schedule used here likely contributed to tran-

sient biliary obstruction.

A unique feature of this study is the combination of hypofrac-

tionated radiotherapy with an individualized dose allocation. This

combination allows patients with small and large tumors unsuitable

for other therapies to be treated using short-course radiation therapy.

Most of the prior published reports of radiation therapy for primary

liver cancers use 1.8 to 3 Gy per day to total doses of 60 to 90 Gy. 22-27

The University of Michigan group first established the safety of an

individualized dose allocation approach for liver cancer, using hyper-

fractionation.28,29 Ben-Josef et al27 reported median survival rates of

15.2 and 13.3 months for HCC and IHC patients, respectively, with a

trend to improved survival in patients treated with higher doses. Of

the128 patients, fivepatients(4%) developed RILD. In a French phase

II trial of 27 patients with small HCCs of Child-Pugh class A or B, the

in-field local control was 78% after 36 to 66 Gy in 2 Gy per fraction.22

Three (27%) of theChild-PughclassB patientsdevelopedacute grade

4 toxicity. Another large series from Korea of 158 HCC patients of

Child-Pugh class A or B were treated with 25 to 60 Gy in 1.8 Gy daily

fractions. The median survival was 10 months, with no grade 4 or 5

toxicity reported.25 Others have also observed excellent outcomes

Table 1. Patient, Disease, and Previous Treatment Characteristics (continued)

Characteristic

Total HCC IHC

No. % No. % No. %

Vascular involvement 20 49 16 52 4 40

PV alone 12 42 3 30

Hepatic vein and IVC 2 6

PV, splenic vein and SMV 1 3

Cardiac atrium and IVC 1 3PV and hepatic vein 1 10

Previous treatments (%)

No prior therapy 17 41 12 39 5 50

RFA only 4 13

TACE only 2 6

Alcohol ablation only 3 10

Chemotherapy only 1 (doxorubicin) 3 4* 40

Transplantation and alcohol ablation 1 3

Resection 5 16 1 10

Resection, chemotherapy 2 6

Resection, RFA, TACE, alcohol ablation 1 3

Resection, alcohol ablation 1 3

Resection, TACE 1 3

RFA and TACE 1 3

RFA and alcohol ablation 2 6

Abbreviations: HCC, hepatocellular carcinoma; IHC, intrahepatic cholangiocarcinoma; AFP, -fetoprotein; CLIP, Cancer of Liver Italian Program; AJCC, AmericanJoint Committee on Cancer; PV, portal vein; IVC, inferior vena cava; SMV, superior mesenteric vein; RFA, radiofrequency ablation; TACE, transarterialchemoembolization; IV, intravenously; FU, fluorouracil.

*Three patients received gemcitabine (1,000 mg/m2 IV days 1 and 8) and capecitabine (650 mg/m2 orally twice a day for 14 days). The fourth patient received FUand gemcitabine at a different institution.

Table 2. Volumes and Doses Delivered (in six fractions)

Parameter

All HCC IHC

Median Range Median Range Median Range

Tumor volume, cm3 173 9-1,913 173 9-1,913 172 10-465

Liver Veff 0.48 0.16-0.80 0.46 0.16-0.80 0.50 0.18-0.63

Prescription dose, Gy 36.0 24.0-54.0 36.0 24.0-54.0 32.5 28.2-48.0

Dose to 95% of tumor, Gy 30.4 17.6-54.7 32.0 21.2-54.7 29.8 17.6-48.9

Mean liver dose, Gy 17.5 5.2-25.2 17.8 8.8-25.2 16.3 5.2-22.7

Uninvolved liver volume, cm3 1,680 892-3,264 1577 892-3,264 1,831 1,461-2,431

Maximum stomach dose, Gy 18.3 5.4-30.8 18.3 5.4-30 22.5 7.5-30.8

Abbreviations: HCC, hepatocellular carcinoma; IHC, intrahepatic cholangiocarcinoma; Veff, effective liver volume irradiated.


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following various photon, proton, or heavy ion fractionations

for HCC.26,30

There is less literature on hypofractionated radiotherapy for

HCC. Prior SBRT experience is predominantly from Asia, most

often in tumors less than 7 cm. The early liver SBRT experiencereported by Blomgren et al31 included nine HCCs and one IHC

within 20 liver tumors treated with one to three fractions of 5 to 15

Gy. Objective responses were seen in 14 tumors (70%), with stable

disease in five tumors (25%). Herfarth et al32 used 14 to 26 Gy in

one fraction that was well tolerated in 37 patients with 60 liver

tumors less than 6 cm (including three IHC and one HCC). More

recently, Wulf et al17 reported on 39 patients with liver cancer who

received SBRT (five with HCC), with no serious toxicity. No local

recurrence was observed in the HCC patients; however, three

patients died with out-of-field tumor progression at 2, 7, and 17

months, respectively. Mendez Romero et al16 treated 11 HCC

patients (Child-Pugh A or B) with maximum tumor size of 7 cm,

with 25 Gy in five fractions, 30 Gy in three fractions, or 37.5 Gy in

three fractions. Two of the patients who received 25 Gy were

re-treated with 24 Gy in three fractions as a result of local recur-rence at 4 months and 7 months, respectively, after initial treat-

ment. The overall 1-year HCC local control rate and survival was

82% and 75%, respectively. One patient (Child B) developed grade

4 hepatic toxicity, one patient developed classic RILD, and another

patient developed non-RILD liver decompensation, emphasizing

the potential for liver toxicity in patients with underlying cirrho-

sis.16 In one report from Japan, in which the dose per fraction was

greater than 4 Gy, late biliary toxicity was observed 29 and 38

months following irradiation.30 Although no RILD or biliary tox-

icity was observed in the present study, a decline in liver function

was seen in seven patients, and there is the potential for other

toxicities to occur as more patients are treated and observed for

longer periods. We strongly recommend a multidisciplinary team

approach and long-term follow-up of patients with hepatobiliary

cancer treated with SBRT.

Table 3. Acute ( 3 months after SBRT) Biochemical Changes and Toxicity

CTC Toxicity HCC (total 31) IHC (total 10)

Liver enzymes, grade

0 1 1

1 9 3

2 12 4

3 8 2

4-5 0 0Bilirubin, grade

0 19 7

1 6 0

2 3 2

3 2 1

4-5 0 0

Albumin, grade

0 13 6

1 15 4

2 2 0

3 0 0

4-5 0 0

Platelets, grade

0 7 8

1 21 22 2 0

3 1 0

4-5 0 0

Lethargy, grade

1 common* common*

2 4 3

3 1 0

4-5 0 0

Nausea, grade

1 uncommon* uncommon*

2 6 1

3 3 0

4-5 0 0

Pleural effusion, grade

1 3 0

2-5 0 0

Abbreviations: SBRT, stereotactic body radiotherapy treatment; CTC,Common Toxicity Criteria; HCC, hepatocellular carcinoma; IHC, intrahe-patic cholangiocarcinoma.*Grade 1 lethargy and nausea not collected prospectively.

0

Probab

ilityofSurvival

Time of Follow-Up (months)

1.0

0.8

0.6

0.4

0.2

6 12 18 24 30

Hepatocellular carcinoma (n = 31)

Intrahepatic cholangiocarcinoma (n = 10)

Fig 2. Overall survival by disease type.

5(12%)

2

(5%)

4 (10%) 14 (34%)

0 7 (17%)

5 (12%)

Distantmetastasis

Hepati

cin-fie

ldPD Hepaticout-fie

ldPD

Fig 3. Site of first disease recurrence. PD, progressive disease; in-field, within the

high-dose irradiated volume; out-field, outside the high-dose irradiated volume.

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The individualizeddose allocationapproachused herefacilitated

the treatment of large tumors that are not amenable to other treat-

ments. A disadvantage of this approach is that patients with large-

volume disease are more likely to receive lower doses. Combining

radiation therapy withradiation sensitizersmay improveoutcomes in

these patients. The patients with large-volume disease are also at

higher risk of developing a decline in their liver function after SBRT,

providing a rationale for radiation protectors as well.

In summary, individualized six-fraction SBRT is safe in the ma-

jority of patientswith HCC and IHC.Despitea spectrumof doses that

ranged from palliative (24 Gy in six fractions) to highly potent (54 Gy

in six fractions), the hepatic and large-vessel disease was controlled

in the majority of patients. Given the locally advanced nature of

disease in these patients, the median survival rates (15.0 and 11.7

months for IHC and HCC, respectively) are better than expected,

providing rationalefor phase II and IIIstudies of six-fraction SBRT

in this setting.3,33,34

AUTHORS DISCLOSURES OF POTENTIAL CONFLICTSOF INTEREST

Although all authors completed the disclosure declaration, the followingauthor(s) indicated a financial or other interest that is relevant to the subjectmatter under consideration in this article. Certain relationships markedwith a U are those for which no compensation was received; those

relationships marked with a C were compensated. For a detaileddescription of the disclosure categories, or for more information about

ASCOs conflict of interest policy, please refer to the Author DisclosureDeclaration and the Disclosures of Potential Conflicts of Interest section inInformation for Contributors.Employment or Leadership Position: None Consultant or AdvisoryRole: None Stock Ownership: None Honoraria: None ResearchFunding: Laura A. Dawson, Elekta Oncology Systems Expert Testimony:None Other Remuneration: None

AUTHOR CONTRIBUTIONS

Conception and design: Gina Lockwood, John J. Kim, Laura A. DawsonFinancial support: Laura A. DawsonAdministrative support: Gina Lockwood, Laura A. DawsonProvision of study materials or patients: Regina V. Tse, Maria Hawkins,John J. Kim, Bernard Cummings, Jennifer Knox, Morris Sherman,Laura A. DawsonCollection and assembly of data: Regina V. Tse, Maria Hawkins, GinaLockwood, John J. Kim, Laura A. DawsonData analysis and interpretation: Regina V. Tse, Maria Hawkins, GinaLockwood, Laura A. Dawson

Manuscript writing: Regina V. Tse, Maria Hawkins, Gina Lockwood,John J. Kim, Bernard Cummings, Morris Sherman, Laura A. DawsonFinal approval of manuscript: Regina V. Tse, Maria Hawkins, GinaLockwood, John J. Kim, Bernard Cummings, Jennifer Knox, MorrisSherman, Laura A. Dawson

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Acknowledgment

We thank all members of the Princess Margaret Hospital Hepatocellular Carcinoma Multidisciplinary Tumor Board for their input regardingtreatment decisions for patients included in this study.

Appendix

The Appendix is included in the full-text version of this article, available online at www.jco.org. It is not included in the PDF version

(via Adobe Reader).

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ERRATUM

The February 1, 2008, article by Tse et al entitled, Phase I Study of Individualized

Stereotactic Body Radiotherapy for Hepatocellular Carcinoma and Intrahepatic Cholan-

giocarcinoma (J Clin Oncol 26:657-664, 2008) contained errors.In Table 3, the data for grades 1 and 2 lethargy and nausea were incorrect. The

corrected table is reprinted below in its entirety.

In the Discussion section, the last sentence of the last paragraph, the median survivalrates were given as 11.7 months for IHC and 15.0 months for HCC, and should have been

15.0 months for IHC and 11.7 months for HCC, as follows:

Table 3. Acute ( 3 months after SBRT) Biochemical Changes and Toxicity

CTC Toxicity HCC (total 31) IHC (total 10)

Liver enzymes, grade

0 1 1

1 9 3

2 12 4

3 8 2

4-5 0 0

Bilirubin, grade

0 19 7

1 6 0

2 3 2

3 2 1

4-5 0 0

Albumin, grade

0 13 6

1 15 4

2 2 0

3 0 0

4-5 0 0

Platelets, grade

0 7 8

1 21 2

2 2 0

3 1 0

4-5 0 0

Lethargy, grade

1 Common* Common*

2 4 3

3 1 0

4-5 0 0

Nausea, grade

1 Uncommon* Uncommon*

2 6 1

3 3 0

4-5 0 0

Pleural effusion, grade

1 3 02-5 0 0

Abbreviations: SBRT, stereotactic body radiotherapy treatment; CTC,Common Toxicity Criteria; HCC, hepatocellular carcinoma; IHC, intrahe-patic cholangiocarcinoma.*Grade 1 lethargy and nausea not collected prospectively.

2008 by American Society of Clinical Oncology 3911



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Given the locally advanced nature of disease in these patients, the median survival

rates (15.0 and 11.7 months for IHC and HCC, respectively) are better than expected,providing rationale for phase II and III studies of six-fraction SBRT in this setting.3,33,34

The online version has been corrected in departure from the print.

DOI: 10.1200/JCO.2008.18.7153

3912 2008 by American Society of Clinical Oncology



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