Int. J. Radiation Oncology Biol. Phys., Vol. 62, No. 5, pp.

1371–1378, 2005
Copyright © 2005 Elsevier Inc.
Printed in the USA. All rights reserved
0360-3016/05/$–see front matter

doi:10.1016/j.ijrobp.2005.01.002

CLINICAL INVESTIGATION Liver

A PHASE I TRIAL OF STEREOTACTIC BODY RADIATION THERAPY

(SBRT) FOR LIVER METASTASES

TRACEY E. SCHEFTER, M.D.,* BRIAN D. KAVANAGH, M.D., M.P.H.,* ROBERT D. TIMMERMAN, M.D.,†
HIGINIA R. CARDENES, M.D.,‡ ANNA BARON, PH.D.,§ AND LAURIE E. GASPAR, M.D., M.B.A.*
*Department of Radiation Oncology, University of Colorado Health Sciences Center, Aurora, CO; †Department of Radiation
Oncology, University of Texas-Southwestern, Dallas, TX; ‡Department of Radiation Oncology, Indiana University School of
Medicine, Indianapolis, IN; §Department of Biostatics, University of Colorado Comprehensive Cancer Center, Aurora, CO

Purpose: To determine the maximum tolerated dose (MTD) of stereotactic body radiation therapy (SBRT) for
liver metastases.
Methods and Materials: A multicenter Phase I clinical trial was conducted. Eligible patients had one to three liver
metastases, tumor diameter <6 cm, and adequate liver function. The first cohort received 36 Gy to the planning
target volume (PTV) in three fractions (F). Subsequent cohorts received higher doses up to a chosen maximum
of 60 Gy/3F. At least 700 mL of normal liver had to receive a total dose <15 Gy. Dose-limiting toxicity (DLT)
included acute Grade 3 liver or intestinal toxicity or any acute Grade 4 toxicity. The MTD was exceeded if 2/6
patients in a cohort experienced DLT.
Results: Eighteen patients were enrolled (10 male, 8 female): median age, 55 years (range, 26 – 83 years); most
common primary site, colorectal (6 patients); median aggregate gross tumor volume, 18 ml (range, 3–98 ml). Four
patients had multiple tumors. No patient experienced a DLT, and dose was escalated to 60 Gy/3F without
reaching MTD.
Conclusions: Biologically potent doses of SBRT are well tolerated in patients with limited liver metastases.
Results of this study form the basis for an ongoing Phase II SBRT study of 60 Gy over three fractions for liver
metastases. © 2005 Elsevier Inc.

Stereotactic body radiation therapy (SBRT), Liver metastases, Oligometastases, Phase I trial, Hepatic irradiation.

INTRODUCTION noninvasive and also deliverable on an outpatient basis,

Stereotactic body radiation therapy (SBRT) is an emerging
treatment paradigm defined in recently published American
Society for Therapeutic Radiology and Oncology (ASTRO)
and American College of Radiology guidelines as a “treat-
ment method to deliver a high dose of radiation to the target,
utilizing either a single dose or a small number of fractions
with a high degree of precision within the body” (1). SBRT
has previously been labeled with an assortment of monikers
such as extracranial radiosurgery and extracranial stereotac-
tic radioablation. Potential indications for SBRT include a
broad spectrum of tumor types and locations (2).
Liver metastases provide a logical opportunity for inves-
tigating the application of SBRT. Surgical resection of
limited metastatic disease in the liver is known to be asso-
ciated with favorable outcome in well-selected patients (3–
7), suggesting a clinical benefit from metastectomy in some
patients. SBRT, if demonstrated safe and similarly effec-
tive, would be advantageous over surgery, being entirely
with no requirement for anesthesia.
The few reported studies of SBRT for liver tumors have
included both single-fraction and multiple fraction regi-
mens. Herfarth and colleagues at Heidelberg University
applied single-fraction SBRT to primary and metastatic
liver lesions and safely escalated the dose from 14 to 26 Gy
(8). Blomgren and colleagues at the Karolinska Institute
administered 20 – 45 Gy in two to four fractions to a group
of 17 patients with liver metastases, observing only one
instance of serious toxicity possibly attributable to SBRT
(9). Wulf and colleagues at the University of Wurzburg used
fractionated SBRT, typically 30 Gy in three fractions, in 23
patients with solitary liver lesions and observed no Grade 3
or higher acute or late toxicity from treatment (10).
Our protocol design involves the use of multiple fractions
rather than a single-fraction regimen and is similar to the
strategy employed in the Indiana University Phase I trial of
SBRT for medically inoperable lung cancer (11). The ra-

Reprint requests to: Tracey E. Schefter, M.D., Department of
Radiation Oncology, University of Colorado Health Sciences Cen-
ter, Campus Mailstop F-706, P.O. Box 6510, Denver, CO 80045-
0510. Tel: (720) 848-0116; Fax: (720) 848-0222; E-mail:
Tracey.Schefter@uchsc.edu
Supported (in part) by a grant from the American Cancer Soci-
ety.
Received Dec 1, 2004, and in revised form Jan 2, 2005. Ac-
cepted for publication Jan 3, 2005.

1371
1372 I. J. Radiation Oncology ● Biology ● Physics
tionale for a multiple fraction regimen is based on several
factors including the well-described putative advantages of
fractionation including reoxygenation of otherwise radiore-
sistant hypoxic tumor and redistribution of tumor clonogens
into sensitive phase. This Phase I study was designed to
establish the maximum tolerated dose (MTD) of a three-
fraction regimen of liver SBRT for patients with limited
liver metastases from solid tumors in anticipation of a
subsequent Phase II study to evaluate the efficacy of SBRT
in that setting.
METHODS AND MATERIALS
Eligibility
The protocol was approved by the Institutional Review Boards
of the participating institutions—the University of Colorado and
Indiana University. Patients who had surgically or medically un-
resectable liver metastases or who declined surgery for resectable
liver metastases were eligible if they met the criteria listed in
Appendix A.
Further restrictions were imposed by constraints of the normal
tissue cumulative dose distribution noted in the following section.
All patients signed a study-specific Institutional Review Board–
approved consent form before enrollment.
Dose escalation
Patients received three fractions of SBRT starting at 12 Gy/
fraction (total, 36 Gy), increased by 2 Gy/fraction for each subse-
quent dose group according to a standard Phase I design. Any
Grade 3 liver, gastric, small bowel, or spinal cord toxicity or any
Grade 4 toxicity from SBRT was considered a dose-limiting tox-
icity (DLT). Each cohort consisted of 3 patients, unless 1 of the
patients experienced a DLT, in which case the cohort was ex-
panded to 6 patients. The maximum tolerated dose (MTD) was
defined as the dose level below that which results in DLT in 2 or
more of the 6 patients in each cohort. An upper limit of 20
Gy/fraction (total dose, 60 Gy in three fractions) was preselected
at the time of study design as the highest dose level to be evalu-
ated. It was determined that at least 5 patients would be enrolled in
this cohort even if none of the first 3 experienced DLT, as a means
of added verification of dose tolerance.
SBRT technique and dose specifications
Patients were immobilized during computed tomography (CT)
simulation and treatment using a Stereotactic Body Frame (Elekta,
Inc., Crawley, UK) or equivalent customized external vacuum-
type or synthetic body mold. Respiratory control was achieved
using an Active Breathing Coordinator (Elekta, Inc.) or abdominal
compression whenever possible during both simulation and treat-
ment. In some cases, a set of planning CT images through the liver
only were obtained using rapid acquisition after intravenous ra-
diographic contrast material infusion to highlight the tumor; an-
other set of images covering the liver plus a generous margin
above and below were obtained using the respiratory control
device. These two sets of images were then fused, often with
additional pre-SBRT diagnostic CT images, magnetic resonance
images. or positron emission tomography-CT scan, to allow accu-
rate identification of the location of the gross tumor volume (GTV)
during treatment.
The GTV was considered to be identical to the clinical target
Volume 62, Number 5, 2005
volume and was expanded by a minimum 5-mm radial margin and
10 mm craniocaudal margin to create the planning target volume
(PTV) for patients who were treated using respiratory control. Two
patients were unable to tolerate any type of respiratory control
system, and the PTV was expanded additionally to account for the
respiratory motion observed at the time of simulation. Extent of
diaphragmatic excursion was evaluated in each patient under flu-
oroscopy.
Stereotactic body radiation therapy was planned and adminis-
tered using dynamic conformal arcs or multiple noncoplanar static
beams generated by a linear accelerator with energies 6 –15 MV.
The nominal prescription dose was prescribed to the isodose line
covering the PTV (generally 80 –90% isodose line). Although
there were no restrictions on the maximum dose delivered within
the PTV itself, normal tissue dose constraints were strictly applied.
Patients were ineligible for enrollment in the SBRT protocol in the
current dose cohort if the normal tissue dose limits defined below
were exceeded.
Stereotactic patient repositioning and tumor relocalization was
accomplished by referencing fiducial markers on the body immo-
bilization device or reflective markers on the patient surface (Ex-
acTrac, BrainLab, Inc., Westchester, IL). Accurate patient reposi-
tioning and tumor relocalization were verified with either a repeat
verification CT scan of the patient in the treatment position or with
the combined application of external fiducial skin markers and
orthogonal X-ray images. Most patients were given prophylactic
antiemetic therapy (generally consisting of a single dose of 5-HT3
inhibitor with or without 4 mg dexamethasone, orally) before daily
SBRT.
It was considered highly desirable to keep daily treatment times
(total time during which the patient was lying on the treatment
table) to less than 45 min. The rationale was to minimize any
patient inconvenience or discomfort associated with prolonged
immobilization and to avoid the potentially detrimental effects of
intrafraction radiation repair that can occur during excessively
lengthy individual treatments (12, 13). To comply with this guide-
line, some patients with multiple lesions were treated with two
separate three-fraction treatment courses. The three fractions of
SBRT administered to any given lesion could be given on consec-
utive days or could be separated with intervening days, according
to the preference of the treating radiation oncologist and practical
clinic scheduling considerations; the total course of SBRT was to
be completed within 14 days.
Normal tissue dose constraints
To establish specified limitations on the dose to normal liver, we
applied a strategy concordant with the so-called “critical volume
model” for normal tissue injury originally proposed by Yaes and
Kalend (14). Published reports have indicated that up to 80% of the
liver can be safely removed in a patient with adequate liver
function (15). To exercise an even greater level of caution in terms
of the volume of normal liver tissue that must be preserved,
estimating that a typical normal liver volume is approximately
2000 mL, we specified that a minimum volume of 700 mL or 35%
of normal liver should remain uninjured by SBRT. The tolerance
dose when the entire liver is irradiated has been demonstrated to be
at least 33 Gy in 22 fractions (16). For a generic alpha/beta ratio
estimate of 3 Gy and the assumption of no tumor proliferation
during treatment, the biologically equivalent dose of this schedule
of 33 Gy in 22 fractions is 49.5 Gy3 according to standard
linear-quadratic modeling, ignoring any proliferation correction
(17). An SBRT regimen of 15 Gy in three fractions would have a
 A Phase I trial of SBRT
normal tissue biologically equivalent dose of 40 Gy3, safely below
the maximum tolerable level. We therefore mandated that at least
700 mL of normal liver (entire liver minus cumulative GTV) had
to receive at total dose less than 15 Gy.
Furthermore, at least 67% of the right kidney had to receive a
total dose of less than 15 Gy in three fractions (5 Gy per fraction).
The percent of total kidney volume (defined as the sum of the left
and right kidney volumes) receiving 15 Gy total in three fractions
(5 Gy per fraction) was required to be less than 35% of the total
kidney volume. The maximum dose to any point within the spinal
cord could not exceed 18 Gy total in three fractions (6 Gy per
fraction), and the maximum point dose to the stomach or small
intestine could not exceed 30 Gy total in three fractions (10 Gy per
fraction).
Follow-up
Patients were evaluated at least once during the treatment course
for detailed account of new symptoms. Any observed toxicity at
this time and at all other times was documented in the case report
form. Additional follow-up visits were planned at 4 – 6 weeks after
treatment completion and at 3-month intervals for the first 2 years
after treatment completion. Serum liver enzymes were obtained
4 – 6 weeks after SBRT and at 3-month intervals. Physical exam-
ination, including abdominal inspection and palpation, was per-
formed at each follow-up visit. Documentation at each visit in-
cluded performance status, fatigue and general malaise, skin
toxicity, pain, anorexia, nausea, vomiting, dyspepsia, and any
other symptoms reported by the subject. Liver imaging was ob-
tained at 3-month intervals.
All data were stored and managed using Research Data Man-
agement Framework (www.RDMF.net, Aurora, CO). System con-
sulting and data management were provided by Whitedragonfly
Systems, LLC, Aurora, CO.
RESULTS
Patient population
A total of 18 patients were enrolled in the protocol: 10
men and 8 women. The median age at the time of enroll-
ment was 54 years (range, 26 – 83 years). The median time
from initial cancer diagnosis to SBRT study enrollment was
19 months (range, 6 –232). Fourteen patients had a solitary
lesion, 2 had two lesions, and 2 patients had three individual
discrete lesions. In some instances in which multiple GTVs
Table 1. Primary site of malignancy for patients treated on the
Phase I SBRT protocol
Primary site
Bladder
Breast
Colorectal
Esophageal
Liver*
Head and neck
Lung
Ovary
Pancreas
* See text for explanation.
● T. E. SCHEFTER et al. 1373
were in close proximity, more than one GTV was included
within the same PTV. The median aggregate total gross tumor
volume (sum of all GTVs) was 17.8 mL (range, 3–98 mL).
PTVs ranged in magnitude from 8 –210 mL (median, 41 mL).
The primary sites of disease are listed in Table 1. Two patients
with primary hepatocellular carcinoma were treated. The
first was treated in the 36-Gy cohort as definitive therapy for
a patient with medically inoperable disease. Subsequently,
the investigators elected to write a separate Phase I protocol
for patients treated with SBRT as primary therapy for hep-
atocellular carcinoma. The second hepatocellular carcinoma
patient on the current protocol was treated for a focus of
hepatic metastasis separate from his previously resected
primary cancer.
Sixteen patients had received at least one type of systemic
therapy before liver SBRT; 8 patients had received three or
more types of chemotherapeutic agent. The most common
agents were a platinum derivative (10 patients), a taxane (6
patients), and 5-fluorouracil (4 patients). One patient had
gefitinib alone before SBRT. The patient with ovarian can-
cer had had prior radiofrequency ablation to a different liver
metastasis. Twelve patients remained alive at the time of
analysis, a median of 7.1 months after enrollment in the
protocol (range, 3.8 –12.3 months). Six patients died within
3.1–18.9 months after enrollment. One patient died most
likely as a result of progressive liver metastases, 4 patients
died of complications from progressive extrahepatic metas-
tases, and 1 patient died from preexisting medical comor-
bities unrelated to SBRT.
Toxicity
The patient groups, number of patients per dose group,
and all toxicity are listed in Table 2. No patient experienced
dose-limiting toxicity. A fourth patient was enrolled in the
fourth group, total dose 54 Gy, because he was unwilling to
wait until the mandated 30-day observation time after treat-
ment of the third patient in the same group before dose
escalation. It was reasoned that if the third patient had
experienced a DLT, the group would have expanded, anyway;
if the fourth patient had experienced DLT, the group would
have been expanded to 6 patients. Because the 60-Gy total
dose level was the highest planned dose escalation, 5 patients
were enrolled. There were no observed cases of DLT; there-
fore, it was concluded that the MTD had not been exceeded.
Prophylactic antiemetic therapy was allowed at the dis-
n cretion of the treating radiation oncologist. Twelve patients
were premedicated: 8 received granisetron, 1 of whom also
1 received dexamethasone; 3 received ondansetron, 1 of
1
6
whom also received dexamethasone; and 1 patient received
1 dexamethasone alone. No patient complained of nausea
2 after liver SBRT. Serial evaluation of liver function tests
1 revealed no significant changes in bilirubin or alkaline phos-
4 phatase levels (data not shown). Among patients not known
1
1
to have disease progression within the liver, there was a
trend toward modest elevation of alanine aminotransferase
and aspartate aminotransferase, as shown in Fig. 1.
1374 I. J. Radiation Oncology ● Biology ● Physics Volume 62, Number 5, 2005

Table 2. Patient groups and number of patients per group (n)

Dose per Total dose

Group n fraction (Gy) (Gy) DLTs Non-DLT toxicity

1 3 12 36 None
2 3 14 42 None
3 3 16 48 None Grade 1 dermatitis *(1)
4 4 18 54 None Grade 1 pain (1)
5 5 20 60 None Grade 1 fatigue (1), grade 1
dermatitis* (1), grade 1 pain (1)

There were no dose-limiting toxicities (DLTs) observed in any patient. See text for explanation of group size.
* Dermatitis was limited to localized erythema and hyperpigmentation with minimal dry desquamation, as previously described (18).

Normal tissue dosimetry After SBRT, it was typical to observe radiographic

In 11 patients, the maximum dose per fraction at any
point in the spinal cord was less than 2 Gy and was not
further analyzed; in the remaining 7 patients, the maximum
dose at any point within the spinal cord ranged from 3.3– 6.0
Gy per fraction (9.9 –18 Gy total dose). In all of these cases,
the volume of spinal cord receiving a cumulative total dose
above 15 Gy was less than 1 mL.
In 12 patients, the maximum cumulative dose to any
point in the right kidney was less than 15 Gy, ranging from
0.1–12 Gy. In the 6 patients in whom a portion of the right
kidney received a cumulative dose greater than 15 Gy
through the three fractions administered, the median percent
of the right kidney that received more than 15 Gy was 16%
(range, 2–36). Doses administered to the left kidneys were
even lower, as expected, and are not further analyzed since
there were no clinical consequences from dose to the kidneys.
The median volume of uninvolved liver (normal liver
minus GTV) was 1783 mL (range, 875–2806 mL). The
median volume of uninvolved liver that received a cumu-
lative dose of less than 15 Gy in three fractions was 1362
mL (range, 700 –2662 mL). The dose–volume histograms
for uninvolved liver for all patients are shown in Fig. 2.
changes in the liver of the nature and appearance described
by Herfarth and colleagues (19), namely well-circumscribed
hypodense regions recapitulating the dose distribution. Fig-
ures 3 and 4 illustrate the isodose distributions from two
representative cases and changes observed on follow-up
imaging. The post-treatment hypodense region corre-
sponded roughly to the volume of uninvolved liver that
received 30 Gy or more in three fractions.
Prescription isodose, target coverage, and equivalent
uniform dose analysis
The isodose distribution applied during SBRT typically
includes planned heterogeneity within the tumor intended to
intensify the dose within the tumor (20). In this protocol, the
median isodose line prescribed to cover the PTV was 80%
of the maximum point dose within the PTV (range, 72–
88%). The median percent of the PTV covered by the
prescription isodose line was 98% (range, 91–100%).
To evaluate the effect of dose inhomogeneity within the
target volumes on the equivalent uniform dose (EUD) ad-
3000

60 2500 Group 1
Group 2
2000 Group 3
uninvolved liver, cc

45
Group 4
1500
Group 5
Units/Liter

30 1000

500
15
AST
ALT 0
0 15 30 45 60
0 dose, Gy
Baseline 1-1.5 mos 2-3 mos
Fig. 2. Absolute dose (Gy) vs. absolute volume of uninvolved liver
Fig. 1. Changes in Alanine aminotransferase (ALT) and aspartate (mL). Patients in different dose cohorts are represented with the
aminotransferase (AST) after stereotactic body radiation therapy. different line styles shown in the figure. Group 1 patients received
The normal range is 0 – 47 U/L. The positive error bars (standard a nominal dose of 36 Gy in three fractions to the planning target
deviation) are shown for ALT, and negative error bars are shown volume; Group 2, 42 Gy in three fractions; Group 3, 48 Gy in three
for AST. The upward trend at the first follow-up evaluation did not fractions; Group 4, 54 Gy in three fractions; Group 5, 60 Gy in
reach statistical significance. three fractions.
 A Phase I trial of SBRT ● T. E. SCHEFTER et al. 1375

ministered, we calculated the EUD according to methods

previously described (21), using the following formula:

EUD ⫽ 2Gy
1n 冋兺
1 N

V i⫽1
Di
Vi共SF2兲 2Gy 册
1n共SF2兲

SF2 is the surviving fraction after 2 Gy (here estimated to be

0.5) and Di is the dose given to the ith subvolume Vi within
the total volume, V. The results are shown in Fig. 5, where
the nominal prescription dose is plotted against the EUD
given to the GTVs and PTVs. It may be seen that an
approximately similar ratio between nominal dose and EUD
was maintained throughout all dose levels within the study.

DISCUSSION
Tolerance of liver SBRT
Results of the present Phase I study indicate that a ste-
reotactic body radiation therapy (SBRT) dose of at least 60
Gy in three fractions may be safely administered to patients
with one to three discrete liver metastases, as long as an
adequate volume of normal liver tissue is spared from the
high-dose region. Doses were escalated according to stan-
dard Phase I design, from 36 Gy to 60 Gy (in three frac-
tions) in increments of 6 Gy per cohort. There was no Grade
3 or 4 toxicity; therefore, the MTD was not reached up to
the predefined upper limit of 60 Gy.
In the liver SBRT experience reported from the Karo-
linska Institute, the single instance of serious toxicity
occurred in a patient with a history of gastritis who
experienced an exacerbation after SBRT that might have
been prompted by the treatment (9). We did not observe
any Grade 2 or higher bowel toxicity in the present study,
but it should be emphasized that strict normal tissue dose
limits were applied. It is conceivable that for some le-
sions on the medial surface of the liver, it might not be
possible to restrict the maximum point dose to the stom-
ach or intestinal tissue to 10 Gy or less. We would urge
extreme caution in this setting, and we would not extend
the observations from the present study to imply an
understanding of the stomach or intestinal MTD with
SBRT, because few patients had lesions that closely
approached the gastrointestinal tract.
The critical volume model applied to the normal liver
dose constraint in the present study of liver SBRT differs
fundamentally from the Lyman normal tissue complication
probability model that has been employed by others in dose
selection for partial liver irradiation using conventional
fractionation (23). Observations from the University of
Michigan group have demonstrated that the Lyman normal
tissue complication probability model is a good predictor of
radiation-induced liver disease. Among a large series of
patients treated with chemotherapy and partial liver irradi-
ation, 19 of 203 (9%) suffered Grade 3 or higher radiation-
induced liver disease (RILD), consistent with the Lyman
Fig. 3. (a) Color wash isodose (total dose) distribution for a
representative case. The patient was treated in dose Group 4 (54
Gy in three fractions to the planning target volume). The gross
tumor volume is outlined in purple and planning target volume in
pink. A single dynamic conformal arc technique was used. Note
the very small volume of total liver that received more than 15 Gy
in three fractions. (b) Left, 6 weeks post-stereotactic body radia-
tion therapy contrast-enhanced computed tomography scan ob-
tained in the early portal-venous phase. Right, super-positioning of
the 30 Gy isodose volume after fusion of the follow-up image with
the planning computed tomography image. Note that the hypo-
dense region corresponds approximately to the 30 Gy total dose
volume.
model’s predictions. The mean dose to the liver was a robust
predictor of RILD: no patient who received a mean total
liver dose below 31 Gy suffered RILD, supporting a concept
of liver tissue architecture as a parallel arrangement of
functional subunits (24).
The lack of any RILD in the present series does not
contradict these prior predictions and observations from
series of conventionally fractionated liver irradiation in any
way. We would attribute the lack of RILD after SBRT with
a generally low mean dose to the uninvolved liver, as is
apparent in Fig. 2. The mean dose to uninvolved liver
remained acceptably low even in the highest dose group (60
Gy in three fractions to the PTV), ranging from 3.3 to 23.9
1376 I. J. Radiation Oncology ● Biology ● Physics Volume 62, Number 5, 2005

Gy (median, 15.3 Gy)—all below the threshold expected to

induce RILD.

Normal tissue effects: radiobiologic and

clinical implications
Stereotactic body radiation therapy induced characteristic
hypodense radiographic changes in regions of uninvolved
liver, as originally described by Herfarth after single-frac-
tion SBRT (19). The radiographic change did not correlate
with any clinical endpoint, and there was no distortion of
normal liver anatomy otherwise seen (i.e., no swelling of the
liver and no displacement of liver vessels or bile ducts).
Nevertheless, it is interesting to consider the effect in terms
of the radiobiologic features, which might give a hint of the
underlying etiology. In their analysis, Herfarth and col-
leagues identified a median threshold dose for the observed
normal tissue reaction of 14 Gy at an interval of 2–3 months
after SBRT. The approximate isoeffective dose in three
fractions from our observations was 30 Gy in the cases
analyzed in the present study.
If we consider, then, the possibility that the phenomenon
results from a radiobiologic process that follows conven-
tional linear-quadratic modeling, we can estimate an ␣/␤
ratio for the effect by considering the biologically equiva-
lent dose equation:

BED ⫽ nd 1 ⫹冉 d
␣⁄␤ 冊
where n ⫽ number of fractions, and d ⫽ dose per fraction.
Setting the isoeffective doses from the Herfarth study and
the present study equal to each other and substituting values

Fig. 4. Planning and follow-up images for another patient treated

in the fourth dose group (54 Gy in three fractions to the planning
target volume). (a) Upper left, three-dimensional rendering of the
liver (pink), kidneys (purple), spinal cord (green), and planning
target volume (brown), with blue and yellow line segments indi-
cating the orientation of the three noncoplanar dynamic conformal
arcs used for treatment. Other panels indicate axial, coronal, and
sagittal views of the gross tumor volume (outlined in green) and
planning target volume (outlined in brown) with surrounding nor-
mal anatomic structures. (b) Upper left, schematic representation
of the start and stop positions of the noncoplanar arcs, here as blue
and yellow fans. Other panels are identical to the corresponding
panels in Fig. 3a, except that the isodose (total dose) distribution is
superimposed as a color wash. (c) Upper panel, pretreatment
portal-venous phase computed tomography showing the large me-
tastasis in the right posterior lobe, with annotated diameter mea-
surement in the slice shown on the left. Center panel, pre–ster-
eotactic body radiation therapy (SBRT) planning image with the
30 Gy isodose contour shown in yellow color wash (left side), with
arrow pointing to the corresponding hypodense region seen at the
3-month post-SBRT follow-up image (right side). Again, the hy-
podense region corresponds to the approximate contours of the 30
Gy isodose volume. Lower panel, 6-month post-SBRT images
showing resolution of the larger hypodense region and minimal
residual abnormality at the site of the treated lesion.
 A Phase I trial of SBRT
80
70
EUD, GTV
EUD, PTV
60
EUD, Gy
50
40
30
30 36 42 48 54 60
Nominal prescription dose, Gy
Fig. 5. Nominal prescription dose (Gy) vs. equivalent uniform dose
(EUD), Gy. Note that a line of identity is also depicted on the
graph. In all except one case, the EUD exceeded the nominal
prescription dose. The average ratio of gross tumor volume (GTV)
EUD/prescription dose was 1.2 (range 1.1–1.3). In some cases,
multiple GTVs were encompassed in a single PTV.
into the previous equation yields the following expression:
冉 冊 冉 冊
14 10
14 1 ⫹ ⫽ 30 1 ⫹
␣⁄␤ ␣⁄␤
Solving the equation yields an estimate for ␣/␤ of 0.25 Gy.
Although this very low value would not be expected for
either malignant or normal epithelial tissue, it is not unusual
for lymphoid cells (22). It is tempting to speculate, then, that
the hypodensity in some way directly or indirectly reflects
local lymphocyte depletion or other local immunomodula-
tory effect.
Further study would be necessary to establish the mech-
anistic effect of the observed hypodensity with a higher
level of confidence. However, regardless of the true etiol-
ogy, it is important to be aware of the expected normal
tissue reactions that occur in the few months after SBRT,
because evaluation of local tumor control is more difficult
during that time frame. For fully aggressive liver SBRT to
a dose of 60 Gy in three fractions, it is probably necessary
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in three fractions, was chosen because it is predicted to
provide a very high rate of tumor control. Fowler and
colleagues considered the question of how much dose is
necessary to achieve a very high tumor control probability
(TCP) with SBRT, primarily analyzing the use of SBRT for
lung cancer, and calculated that a total dose of 60 – 69 Gy in
66 three fractions (20 –23 Gy per fraction) is necessary if there
is even a small amount of hypoxia present (25). Predictive
models are, of course, only as good as the baseline assump-
tions applied. For example, in the present series the mean
total equivalent uniform dose given to the GTV in the 60
Gy-dose cohort was actually 72 Gy in three fractions, or 24
Gy per fraction, and the median GTV was 17 mL. If we
apply the same assumptions for estimating TCP that we
have previously employed, namely an estimated clonogen
density of 107/mL and a Gaussian distribution of radiosen-
sitivity across the tumor cell population (21), varying the
estimated surviving fraction after 2 Gy from 0.4 to 0.5 will
alter the predicted TCP for a 17-mL tumor from greater than
99% down to approximately 75%. It will only be through
careful future observations of the actual control rates
achieved with aggressive SBRT that we will be able to
refine our estimates of the true radiosensitivity parameters
in vivo and possibly also understand the influence of tumor
hypoxia in this setting.
CONCLUSION
Our results show that it is safe to deliver 60 Gy in three
fractions of 20 Gy using SBRT techniques for patients with
one to three discrete liver metastases and adequate pre-
SBRT hepatic function, as long as 700 mL of uninvolved
normal liver receives less than 15 Gy total dose. This dose
regimen is predicted to yield a high rate of tumor control. A
Phase II trial is ongoing to evaluate the rate of local tumor
control achieved at an SBRT dose of 60 Gy in three frac-
tions.
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APPENDIX
ELIGIBILITY CRITERIA
● 1–3 liver metastases from any solid tumor except a germ
cell tumor or lymphoma
● Maximum tumor diameter ⬍6 cm
● Karnofsky performance status ⬎60%
● Life expectancy ⬎3 months
● No prior radiotherapy to the liver
● Adequate liver function, defined as total bilirubin ⬍3
mg/dL, serum albumin ⬎2.5 g/dL, serum levels of liver
enzymes ⬍3 times the upper limit of normal, and
normal prothrombin time and partial thromboplastin
Volume 62, Number 5, 2005
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21. Kavanagh BD, Timmerman RD, Benedict SH, et al. How
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25. Fowler JF, Tome WA, Welsh JS. Estimation of required doses
in stereotactic body radiation therapy. In: Kavanagh BD, Tim-
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time unless the patient was receiving anticoagulant
medication
● No chemotherapy within 14 days before or after stereo-
tactic body radiation therapy
● Age ⱖ18 years
● No evidence of progressive or untreated gross disease
outside of the liver
● No active liver infection
● Adequate kidney function (serum creatinine ⬍1.8 mg/
dL)