VOLUME

26

NUMBER

FEBRUARY

2008

JOURNAL OF CLINICAL ONCOLOGY

O R I G I N A L

R E P O R T

Phase I Study of Individualized Stereotactic Body Radiotherapy for Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma
Regina 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 Biostatistics, 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 development award (L.A.D.). Presented in part at the American Society for Therapeutic Radiology and Oncology 47th Annual Meeting, November 5-9, 2006, Denver, CO; the European Society for Therapeutic Radiology and Oncology, October 8-12, 2006, Leipzig, Germany; and the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL. Authors disclosures of potential conicts of interest and author contributions are found at the end of this article. Corresponding author: Laura Dawson, MD, Department of Radiation Oncology, 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

Purpose To report outcomes of a phase I study of individualized stereotactic body radiotherapy treatment (SBRT) for unresectable hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (IHC). Patients and Methods Patients with unresectable HCC or IHC, and who are not suitable for standard therapies, were eligible for six-fraction SBRT during 2 weeks. Radiation dose was dependent on the volume of liver irradiated 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. Results Forty-one patients with unresectable Child-Pugh A HCC (n 31) or IHC (n 10) completed six-fraction SBRT. Five patients (12%) had grade 3 liver enzymes at baseline. The median tumor size was 173 mL (9 to 1,913 mL). The median dose was 36.0 Gy (24.0 to 54.0 Gy). No radiation-induced liver disease or treatment-related grade 4/5 toxicity was seen within 3 months after SBRT. Grade 3 liver enzymes were seen in ve patients (12%). Two patients (5%) with IHC developed transient biliary obstruction after the rst few fractions. Seven patients (ve HCC, two IHC) had decline in liver function from Child-Pugh class A to B within 3 months after SBRT. Median survival 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. Conclusion Individualized 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 less than 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 common in tumors larger than 4 cm and tumors adjacent to large vessels.4,5 Transarterial chemoembolization 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 associated with cure in the absence of local therapies. Historically, the role of radiotherapy for liver tumors has been limited by the risk of radiationinduced liver disease (RILD), consisting of anicteric hepatomegaly, ascites, and elevated alkaline phosphatase, that can occur within 3 months after lowdose 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, reducing 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
657

Information 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. 134.96.155.211

Tse et al

liver irradiated.15 Stereotactic body radiation therapy (SBRT), referring 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 individualized dose allocation would allow small and large HCCs and IHCs to be treated, with the potential to improve outcomes. We report the results of a phase I trial of individualized six-fraction SBRT for unresectable HCC and IHC.
PATIENTS AND METHODS
Patients Patients with unresectable HCC or IHC were eligible for this phase I trial, which was approved by the Research Ethics Board. Patients had to be older than 18 years, with a life expectancy more than 12 weeks, Child-Pugh A liver function, more than 800 cm3 of uninvolved liver, Karnofsky performance score 60. Extrahepatic disease was not an exclusion criterion, as long as the greatest burden of disease was within the liver. Ineligibility criteria included bilirubin 3 upper limit of normal, AST or ALT 6 upper limit of normal, creatinine less than 200 mol/L, international normalized ratio 1.3 (after correction with vitamin K or allowable if patient required anticoagulants), hemoglobin less than 90 g/L, platelets less than 80,000/L, clinical ascites, and previous irradiation to the right upper abdomen. A biopsy was not required for HCC patients if the tumors enhanced typically on two imaging modalities and the -fetoprotein (AFP) level was increased on a known background of liver disease. Histologic diagnosis was required for IHC patients. No chemotherapy 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 1.0 represents whole organ irradiation. After the rst year, patients with elevated creatinine and those who had received prior irradiation were eligible, as long as the cumulative doses did not exceed dened normal tissue limits. Radiation Treatment Each patients treatment was individualized with respect to immobilization, radiation planning, and prescription dose to minimize the uninvolved liver volume required to be irradiated, and to maintain normal tissue dose limits. Simulation took place during 2 days to include an education session, kilovoltage uoroscopy, computed tomography (CT) planning, and magnetic resonance imaging (MRI). Kilovolt uoroscopy and cine MRI18 were used to measure liver breathing motion and reproducibility of liver position with repeated exhale breath holds, using the active breathing control device (Elekta Oncology Systems, Crawley, United Kingdom). Abdominal compression was used to reduce breathing motion for patients not suitable for breath hold. Respiratory sorted CT scans were obtained for patients treated in free breathing with and without abdominal compression.19 Tumors imaged on the planning triphasic CT and/or MRI and enhancing large vessel thromboses were included within the gross target volume (gross tumor volume [GTV]). An 8-mm margin around the GTV within liver and nonenhancing thromboses was included within the clinical target volume. The planning target volume (PTV) margins were individualized, as described previously18 (minimum 5 mm). The PTV around the GTV was the primary target (PTVPrimary), whereas the PTV around the clinical target volume (PTVSecondary) was a secondary target. Conformal planning was used, with three to 10 coplanar or noncoplanar beams of 6 to 18 MV, with up to three segments within each eld. The dose volume histogram (DVH) for the liver minus the GTV (referred to as liver) was used to estimate the risk of RILD and to allocate dose to PTVPrimary. The dose to PTVPrimary was allocated depending on the Veff (Appendix, online only) and the uninvolved liver volume with a maximum dose of 60 Gy. The target dose to PTVSecondary, containing possible microscopic disease, was 24 Gy. SBRT was delivered in six fractions during 2 weeks, usually on alternate days (eg, Monday, Wednesday, and Friday) although variations were permitted (eg, Tuesday, Wednesday, and Friday) for logistic reasons (eg,
658

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 27 Gy, and the maximal dose to the heart was 40 Gy (Appendix Table A1, online only). Efforts were made to minimize the dose to all normal tissues. Treatment verication was performed using orthogonal megavolt image guidance (using the dome of the diaphragm and vertebral body for guidance)20 or, when available, kilovoltage cone beam CT imaging and kilovoltage orthogonal uoroscopy, as described previously.21 Escalation Strategy The radiation dose was escalated in three predened liver Veff strata (low, 0.2; mid, 0.2 to 0.5; and high, 0.5 to 0.8; Fig 1A. Within each strata, there were three escalation levels, based on the risk of estimated liver toxicity (5%, 10%, and 20%). For the low Veff strata, the dose per fraction was planned to be escalated (from 9 to 9.5 to 10 Gy for six fractions). For mid and high Veff strata, the doses could be modied by up to 3 Gy as long as the nominal risk level was not exceeded. Doses were reduced if necessary to maintain nonhepatic normal tissue limits. Three patients had to be treated in each stratum with no doselimiting toxicity within 3 months after SBRT before escalation to the next level was permitted. If toxicity occurred, a minimum of six patients were treated at that level. While waiting until 3 months after SBRT, at which time the presence

A
Total Prescribed Dose in 6 Fractions (Gy)
60 50 40 30 20 10 Low Veff 0 0.2 Mid Veff 0.4 High Veff 0.6 0.8 1.0
Level 1 (5%) Level 2 (10%) Level 3 (20%)

Veff

B
Total Prescribed Dose in 6 Fractions (Gy)
60 50 40 30 20 10
HCC patients IHC patients

0.2

0.4

0.6

0.8

1.0

Veff
Fig 1. (A) Prescribed dose per fraction and effective liver volume irradiated (Veff). (B) Relationship between Veff and prescribed dose to tumor. HCC, hepatocellular carcinoma; IHC, intrahepatic cholangiocarcinoma.
JOURNAL OF CLINICAL ONCOLOGY

Information 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. 134.96.155.211

Stereotactic Radiotherapy for Primary Liver Cancer

or absence of toxicity was determined, patients could be treated at the predened dose level. Evaluation Patients were assessed weekly during SBRT and after completion of treatment at 1 month, every 3 months for the rst 12 months, and every 6 months to 36 months (or more frequently if clinically indicated). Liver triphasic CT or MRI was performed at each follow-up. Chest CT was performed at 12 months (or more frequently if preexisting lung metastases were present). Toxicity was graded using the National Cancer Institute Common Toxicity Criteria for Adverse Events version 3.0. Dose-limiting toxicity was any Common Toxicity Criteria grade 4 or 5 hepatic, thrombocytopenia, or GI toxicity occurring within 1 month of SBRT, or RILD requiring treatment in the absence of disease progression13 within 3 months of SBRT. For Child-Pugh liver function determination, the international normalized ratio was assumed to be stable in patients requiring warfarin. Tumor response was assessed using Response Evaluation and Criteria in Solid Tumors (RECIST). Local in-eld recurrence was dened as recurrence within the high-dose region ( 80% isodose volume), demonstrated by new enhancement or RECIST progressive disease. Actuarial survival and local control rates were evaluated by the Kaplan-Meier method.

RESULTS

was seen in one patient. Three patients developed transient asymptomatic right-sided pleural effusions (HCC) 3 months after SBRT (Table 3). Seven patients (23%) experienced progression from Child-Pugh A classication to B within 3 months after SBRT (ve HCC, two IHC). Two HCC patients had baseline Child-Pugh A6 classication. 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 function had lower median prescription doses (29.1 v 36.9 Gy; P .03), higher median liver Veff (0.44 v 0.56; P .04), and higher mean liver doses (16.0 v 18.0 Gy; P .05), and were more likely to have larger tumors (P .08). Two patients (6%) experienced late toxicity. One patient with HCC developed a tumor-duodenal connection on imaging 15 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 progression, 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), with 1-year survival rate of 51% (95% CI, 34% to 65%). For HCC, the median survival was 11.7 months (95% CI, 9.2 to 21.6 months) and the 1-year survival rate was 48% (95% CI, 30% to 64%). The median survival of HCC patients with preexisting large vessel thrombosis was 11.6 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-eld local control rate was 65% (95% CI, 44% to 79%) for all patients. The overall RECIST response rate was 49% (complete response [CR], 5%; partial response, 44%), with a stable disease rate of 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 rst 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%) had a reduction in AFP levels after SBRT (median, 472 g/L; range, 16 to 10,400 g/L; Appendix Fig A1, online only).
DISCUSSION

Patients From August 2003 to March 2006, 49 patients with HCC or IHC consented for treatment. Seven patients found to 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) completed SBRT 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 Italian Program score 1 (39%) or 2 (32%). All IHC patients had vascular involvement or extrahepatic disease at baseline. Other patient characteristics are listed in Table 1. All risk levels were investigated for mid and high Veff strata, with 19 and 18 patients treated in the mid and high Veff strata, 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 Veff was 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 rst 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
www.jco.org

This study demonstrated that six-fraction SBRT (24 to 54 Gy) is a feasible treatment for unresectable HCC and IHC. The treatment was well tolerated and there were no occurrences of dose-limiting toxicity. A maximum tolerated dose using this dose allocation approach was not determined. The most clinically signicant change after SBRT was a decline in Child-Pugh classication from A to B observed in seven patients (17%). Compared with other patients, the majority of these
659

Information 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. 134.96.155.211

Tse et al

Table 1. Patient, Disease, and Previous Treatment Characteristics Total Characteristic No. of patients Sex Male Female Age, years Median Range Race/ethnicity White Asian/Indian Karnofsky performance score 100 90 80 70 Unknown Liver disease Hepatitis B Hepatitis C Hepatitis B/C/D Alcoholic cirrhosis Unknown Tumor marker: AFP, g/L Median Range 400 400 Child-Pugh classication, HCC patients A5 A6 CLIP score, HCC patients 0 1 2 3 4 5 Barcelona Clinic liver cancer stage A1-A3 A4 B C D AJCC TNM stage T1N0 T2N0 T3N0 T3N1 T4N0 T2N1M1 T3N1M1 Extrahepatic/metastatic disease Locoregional lymphadenopathy only Periportal and mediastinal nodes Periportal and peripancreatic nodes Metastases Liver only Liver and locoregional lymphadenopathy Liver and mesenteric/pancreatic metastases Liver and abdominal wall metastases No. 41 31 10 62 41-85 15 16 9 12 11 5 4 24 32 29 14 10 13 12 1 4 1 1,049 5-714,500 13 (%) 18 (%) 28 3 1 12 10 5 3 0 0 3 10 18 0 3 5 19 1 1 1 1 3 1 1 1 42 39 3 13 3 % No. 31 24 7 66 41-85 48 52 HCC % 76 No. 10 7 3 57 49-79 IHC % 24

42 58 90 10 3 39 32 16 10

10 32 58

10 16 61 3 3 3 3 10 3 3 3

10 6

100 60

4 1 1 1 1 (continued on following page)

40 10 10 10 10

660

JOURNAL OF CLINICAL ONCOLOGY

Information 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. 134.96.155.211

Stereotactic Radiotherapy for Primary Liver Cancer

Table 1. Patient, Disease, and Previous Treatment Characteristics (continued) Total Characteristic Vascular involvement PV alone Hepatic vein and IVC PV, splenic vein and SMV Cardiac atrium and IVC PV and hepatic vein Previous treatments (%) No prior therapy RFA only TACE only Alcohol ablation only Chemotherapy only Transplantation and alcohol ablation Resection Resection, chemotherapy Resection, RFA, TACE, alcohol ablation Resection, alcohol ablation Resection, TACE RFA and TACE RFA and alcohol ablation No. 20 % 49 No. 16 12 2 1 1 HCC % 52 42 6 3 3 No. 4 3 IHC % 40 30

1 17 41 12 4 2 3 1 (doxorubicin) 1 5 2 1 1 1 1 2 39 13 6 10 3 3 16 6 3 3 3 3 6 5

10 50

4* 1

40 10

Abbreviations: HCC, hepatocellular carcinoma; IHC, intrahepatic cholangiocarcinoma; AFP, -fetoprotein; CLIP, Cancer of Liver Italian Program; AJCC, American Joint Committee on Cancer; PV, portal vein; IVC, inferior vena cava; SMV, superior mesenteric vein; RFA, radiofrequency ablation; TACE, transarterial chemoembolization; IV, intravenously; FU, uorouracil. *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 FU and gemcitabine at a different institution.

patients had HCC and were treated with lower doses without response. Hepatic disease progression may have contributed to the decline 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 transient biliary obstruction. A unique feature of this study is the combination of hypofractionated 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 rst established the safety of an individualized dose allocation approach for liver cancer, using hyperfractionation.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 the 128 patients, ve patients (4%) developed RILD. In a French phase II trial of 27 patients with small HCCs of Child-Pugh class A or B, the in-eld local control was 78% after 36 to 66 Gy in 2 Gy per fraction.22 Three (27%) of the Child-Pugh class B patients developed acute 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 2. Volumes and Doses Delivered (in six fractions) All Parameter Tumor volume, cm3 Liver Veff Prescription dose, Gy Dose to 95% of tumor, Gy Mean liver dose, Gy Uninvolved liver volume, cm3 Maximum stomach dose, Gy Median 173 0.48 36.0 30.4 17.5 1,680 18.3 Range 9-1,913 0.16-0.80 24.0-54.0 17.6-54.7 5.2-25.2 892-3,264 5.4-30.8 Median 173 0.46 36.0 32.0 17.8 1577 18.3 HCC Range 9-1,913 0.16-0.80 24.0-54.0 21.2-54.7 8.8-25.2 892-3,264 5.4-30 Median 172 0.50 32.5 29.8 16.3 1,831 22.5 IHC Range 10-465 0.18-0.63 28.2-48.0 17.6-48.9 5.2-22.7 1,461-2,431 7.5-30.8

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

www.jco.org

661

Information 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. 134.96.155.211

Tse et al

Table 3. Acute ( 3 months after SBRT) Biochemical Changes and Toxicity CTC Toxicity Liver enzymes, grade 0 1 2 3 4-5 Bilirubin, grade 0 1 2 3 4-5 Albumin, grade 0 1 2 3 4-5 Platelets, grade 0 1 2 3 4-5 Lethargy, grade 1 2 3 4-5 Nausea, grade 1 2 3 4-5 Pleural effusion, grade 1 2-5 HCC (total 31) 1 9 12 8 0 19 6 3 2 0 13 15 2 0 0 7 21 2 1 0 common* 4 1 0 uncommon* 6 3 0 3 0 IHC (total 10)

1.0

Hepatocellular carcinoma (n = 31) Intrahepatic cholangiocarcinoma (n = 10)

Probability of Survival

0.8

1 3 4 2 0 7 0 2 1 0 6 4 0 0 0 8 2 0 0 0 common* 3 0 0 uncommon* 1 0 0 0 0

0.6

0.4

0.2

12

18

24

30

Time of Follow-Up (months)

Fig 2. Overall survival by disease type.

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

patients (Child-Pugh A or B) with maximum tumor size of 7 cm, with 25 Gy in ve 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 recurrence at 4 months and 7 months, respectively, after initial treatment. 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 cirrhosis.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 toxicity 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.

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 experience reported 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 ve 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 (ve with HCC), with no serious toxicity. No local recurrence was observed in the HCC patients; however, three patients died with out-of-eld tumor progression at 2, 7, and 17 months, respectively. Mendez Romero et al16 treated 11 HCC
662

Hepa tic in

D ld P -fie
5 (12%) 4 (10%) 2 (5%) 0

Hepat ic o u
PD ield t-f
14 (34%)

7 (17%)

5 (12%)

D is

t a n t m e t a s t a si

Fig 3. Site of rst disease recurrence. PD, progressive disease; in-eld, within the high-dose irradiated volume; out-eld, outside the high-dose irradiated volume.
JOURNAL OF CLINICAL ONCOLOGY

Information 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. 134.96.155.211

Stereotactic Radiotherapy for Primary Liver Cancer

The individualized dose allocation approach used here facilitated the treatment of large tumors that are not amenable to other treatments. A disadvantage of this approach is that patients with largevolume disease are more likely to receive lower doses. Combining radiation therapy with radiation sensitizers may improve outcomes 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 majority of patients with HCC and IHC. Despite a spectrum of 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 rationale for phase II and III studies of six-fraction SBRT in this setting.3,33,34
AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following author(s) indicated a nancial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a U are those for which no compensation was received; those

relationships marked with a C were compensated. For a detailed description of the disclosure categories, or for more information about ASCOs conict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: Laura A. Dawson, Elekta Oncology Systems Expert Testimony: None Other Remuneration: None

AUTHOR CONTRIBUTIONS
Conception and design: Gina Lockwood, John J. Kim, Laura A. Dawson Financial support: Laura A. Dawson Administrative support: Gina Lockwood, Laura A. Dawson Provision of study materials or patients: Regina V. Tse, Maria Hawkins, John J. Kim, Bernard Cummings, Jennifer Knox, Morris Sherman, Laura A. Dawson Collection and assembly of data: Regina V. Tse, Maria Hawkins, Gina Lockwood, John J. Kim, Laura A. Dawson Data analysis and interpretation: Regina V. Tse, Maria Hawkins, Gina Lockwood, Laura A. Dawson Manuscript writing: Regina V. Tse, Maria Hawkins, Gina Lockwood, John J. Kim, Bernard Cummings, Morris Sherman, Laura A. Dawson Final approval of manuscript: Regina V. Tse, Maria Hawkins, Gina Lockwood, John J. Kim, Bernard Cummings, Jennifer Knox, Morris Sherman, Laura A. Dawson
ated liver radiotherapy with active breathing control. Int J Radiat Oncol Biol Phys 62:1247-1252, 2005 21. Hawkins MA, Brock KK, Eccles C, et al: Assessment of residual error in liver position using kV cone-beam computed tomography for liver cancer high-precision radiation therapy. Int J Radiat Oncol Biol Phys 66:610-619, 2006 22. Mornex F, Girard N, Beziat C, et al: Feasibility and efcacy of high-dose three-dimensional radiotherapy in cirrhotic patients with small-size hepatocellular carcinoma non-eligible for curative therapies: Mature results of the French phase II RTF-1 trial. Int J Radiat Oncol Biol Phys 66:11521158, 2006 23. Liu MT, Li SH, Chu TC, et al: Threedimensional conformal radiation therapy for unresectable hepatocellular carcinoma patients who had failed with or were unsuited for transcatheter arterial chemoembolization. Jpn J Clin Oncol 34:532539, 2004 24. Seong J, Park HC, Han KH, et al: Clinical results and prognostic factors in radiotherapy for unresectable hepatocellular carcinoma: A retrospective study of 158 patients. Int J Radiat Oncol Biol Phys 55:329-336, 2003 25. Park HC, Seong J, Han KH, et al: Doseresponse relationship in local radiotherapy for hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 54:150-155, 2002 26. Park W, Lim DH, Paik SW, et al: Local radiotherapy for patients with unresectable hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 61:11431150, 2005 27. Ben-Josef E, Normolle D, Ensminger WD, et al: Phase II trial of high-dose conformal radiation therapy with concurrent hepatic artery oxuridine for unresectable intrahepatic malignancies. J Clin Oncol 23:8739-8747, 2005 663

REFERENCES
1. Parkin DM, Bray F, Ferlay J, et al: Global cancer statistics, 2002. CA Cancer J Clin 55:74-108, 2005 2. El-Serag HB, Mason AC: Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 340:745-750, 1999 3. Chou FF, Sheen-Chen SM, Chen YS, et al: Surgical treatment of cholangiocarcinoma. HepatoGastroenterology 44:760-765, 1997 4. Kuvshinoff BW, Ota DM: Radiofrequency ablation of liver tumors: Inuence of technique and tumor size. Surgery 132:605-611, 2002 5. Solbiati L, Livraghi T, Goldberg SN, et al: Percutaneous radio-frequency ablation of hepatic metastases from colorectal cancer: Long-term results in 117 patients. Radiology 221:159-166, 2001 6. Camma ` C, Schepis F, Orlando A, et al: Transarterial chemoembolization for unresectable hepatocellular carcinoma: Meta-analysis of randomized controlled trials. Radiology 224:47-54, 2002 7. Yeo W, Mok TS, Zee B, et al: A randomized phase III study of doxorubicin versus cisplatin/ interferon alpha-2b/doxorubicin/uorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma. J Natl Cancer Inst 97:15321538, 2005 8. Leung TW, Patt YZ, Lau WY, et al: Complete pathological remission is possible with systemic combination chemotherapy for inoperable hepatocellular carcinoma. Clin Cancer Res 5:1676-1681, 1999 9. Knox JJ, Hedley D, Oza A, et al: Combining gemcitabine and capecitabine in patients with advanced biliary cancer: A phase II trial. J Clin Oncol 23:2332-2338, 2005 www.jco.org

10. Abou-Alfa GK, Schwartz L, Ricci S, et al: Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 24: 4293-4300, 2006 11. Philip PA, Mahoney MR, Allmer C, et al: Phase II study of Erlotinib (OSI-774) in patients with advanced hepatocellular cancer. J Clin Oncol 23:66576663, 2005 12. Philip PA, Mahoney MR, Allmer C, et al: Phase II study of erlotinib in patients with advanced biliary cancer. J Clin Oncol 24:3069-3074, 2006 13. Lawrence TS, Robertson JM, Anscher MS, et al: Hepatic toxicity resulting from cancer treatment. Int J Radiat Oncol Biol Phys 31:1237-1248, 1995 14. Eccles C, Brock KK, Bissonnette JP, et al: Reproducibility of liver position using active breathing coordinator for liver cancer radiotherapy. Int J Radiat Oncol Biol Phys 64:751-759, 2006 15. Ten Haken RK, Martel MK, Kessler ML, et al: Use of Veff and iso-NTCP in the implementation of dose escalation protocols. Int J Radiat Oncol Biol Phys 27:689-695, 1993 16. Me ndez Romero A, Wunderink W, Hussain SM, et al: Stereotactic body radiation therapy for primary and metastatic liver tumors: A single institution phase I-II study. Acta Oncol 45:831837, 2006 17. Wulf J, Guckenberger M, Haedinger U, et al: Stereotactic radiotherapy of primary liver cancer and hepatic metastases. Acta Oncol 45:838-847, 2006 18. Dawson LA, Eccles C, Craig T: Individualized image guided iso-NTCP based liver cancer SBRT. Acta Oncol 45:856-864, 2006 19. Rietzel E, Pan T, Chen GT: Four-dimensional computed tomography: Image formation and clinical protocol. Med Phys 32:874-889, 2005 20. Dawson LA, Eccles C, Bissonnette JP, et al: Accuracy of daily image guidance for hypofraction-

Information 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. 134.96.155.211

Tse et al

28. McGinn CJ, Ten Haken RK, Ensminger WD, et al: Treatment of intrahepatic cancers with radiation doses based on a normal tissue complication probability model. J Clin Oncol 16:2246-2252, 1998 29. Dawson LA, McGinn CJ, Normolle D, et al: Escalated focal liver radiation and concurrent hepatic artery uorodeoxyuridine for unresectable intrahepatic malignancies. J Clin Oncol 18:22102218, 2000

30. Chiba T, Tokuuye K, Matsuzaki Y, et al: Proton beam therapy for hepatocellular carcinoma: A retrospective review of 162 patients. Clin Cancer Res 11:3799-3805, 2005 31. Blomgren H, Lax I, Goranson H, et al: Radiosurgery for tumors in the body: Clinical experience using a new method. J Radiosurg 1:63-74, 1998 32. Herfarth KK, Debus J, Lohr F, et al: Stereotactic single-dose radiation therapy of liver tumors:

Results of a phase I/II trial. J Clin Oncol 19:164-170, 2001 33. Scho niger-Hekele M, Hanel S, Wrba F, et al: Hepatocellular carcinomasurvival and clinical characteristics in relation to various histologic molecular markers in Western patients. Liver Int 25:62-69, 2005 34. Fujii T, Takayasu K, Muramatsu Y, et al: Hepatocellular carcinoma with portal tumor thrombus: Analysis of factors determining prognosis. Jpn J Clin Oncol 23:105-109, 1993

Acknowledgment We thank all members of the Princess Margaret Hospital Hepatocellular Carcinoma Multidisciplinary Tumor Board for their input regarding treatment 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).

664

JOURNAL OF CLINICAL ONCOLOGY

Information 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. 134.96.155.211

ERRATUM
The February 1, 2008, article by Tse et al entitled, Phase I Study of Individualized Stereotactic Body Radiotherapy for Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma (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.

Table 3. Acute ( 3 months after SBRT) Biochemical Changes and Toxicity CTC Toxicity Liver enzymes, grade 0 1 2 3 4-5 Bilirubin, grade 0 1 2 3 4-5 Albumin, grade 0 1 2 3 4-5 Platelets, grade 0 1 2 3 4-5 Lethargy, grade 1 2 3 4-5 Nausea, grade 1 2 3 4-5 Pleural effusion, grade 1 2-5 HCC (total 31) 1 9 12 8 0 19 6 3 2 0 13 15 2 0 0 7 21 2 1 0 Common* 4 1 0 Uncommon* 6 3 0 3 0 IHC (total 10) 1 3 4 2 0 7 0 2 1 0 6 4 0 0 0 8 2 0 0 0 Common* 3 0 0 Uncommon* 1 0 0 0 0

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

In the Discussion section, the last sentence of the last paragraph, the median survival rates 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:

2008 by American Society of Clinical Oncology

3911

Information 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. 134.96.155.211

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

Information 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. 134.96.155.211