Stereotactic body radiation therapy for patients with heavily pretreated liver metastases and liver tumors.

Abstract

We present our initial experience with CyberKnife stereotactic body radiation therapy (SBRT) in a heavily pretreated group of patients with liver metastases and primary liver tumors. From October 2007 to June 2009, 48 patients were treated at the Philadelphia CyberKnife Center for liver metastases or primary liver tumors. We report on 30 patients with 41 discrete lesions (1-4 tumors per patient) who received an ablative radiation dose (BED ≥ 79.2 Gy10 = 66 Gy EQD2). The treatment goal was to achieve a high SBRT dose to the liver tumor while sparing at least 700 cc of liver from radiation doses above 15 Gy. Twenty-three patients were treated with SBRT for metastatic cancer to the liver; the remainder (n = 7) were primary liver tumors. Eighty-seven percent of patients had prior systemic chemotherapy with a median 24 months from diagnosis to SBRT; 37% had prior liver directed therapy. Local control was assessed for 28 patients (39 tumors) with 4 months or more follow-up. At a median follow-up of 22 months (range, 10-40 months), 14/39 (36%) tumors had documented local failure. A decrease in local failure was found with higher doses of SBRT (p = 0.0237); 55% of tumors receiving a BED ≤ 100 Gy10 (10/18) had local failure compared with 19% receiving a BED > 100 Gy10 (4/21). The 2-year actuarial rate of local control for tumors treated with BED > 100 Gy10 was 75% compared to 38% for those patients treated with BED ≤ 100 Gy10 (p = 0.04). At last follow-up, 22/30 patients (73%) had distant progression of disease. Overall, seven patients remain alive with a median survival of 20 months from treatment and 57 months from diagnosis. To date, no patient experienced persistent or severe adverse effects. Despite the heavy pretreatment of these patients, SBRT was well tolerated with excellent local control rates when adequate doses (BED > 100 Gy10) were used. Median survival was limited secondary to development of further metastatic disease in the majority of patients.

Full text

Page 1

ORIGINAL RESEARCH ARTICLE
published: 09 March 2012
doi: 10.3389/fonc.2012.00023
Stereotactic body radiation therapy for patients with
heavily pretreated liver metastases and liver tumors
Rachelle Lanciano*, John Lamond, JunYang, Jing Feng, SteveArrigo, Michael Good and Luther Brady
Philadelphia CyberKnife, Drexel University, Havertown, PA, USA
Edited by:
Sean Collins, Georgetown University
Hospital, USA
Reviewed by:
Dalong Pang, Georgetown University
Hospital, USA
Keith Unger, Georgetown University,
USA
*Correspondence:
Rachelle Lanciano, Philadelphia
CyberKnife, Drexel University, 2010
West Chester Pike, Suite 115,
Havertown, PA, USA.
e-mail: rlancmd@gmail.com
We present our initial experience with CyberKnife stereotactic body radiation therapy
(SBRT) in a heavily pretreated group of patients with liver metastases and primary liver
tumors. From October 2007 to June 2009, 48 patients were treated at the Philadelphia
CyberKnife Center for liver metastases or primary liver tumors. We report on 30 patients
with 41 discrete lesions (1–4 tumors per patient) who received an ablative radiation dose
(BED≥79.2Gy10=66Gy EQD2). The treatment goal was to achieve a high SBRT dose
to the liver tumor while sparing at least 700cc of liver from radiation doses above 15Gy.
Twenty-threepatientsweretreatedwithSBRTformetastaticcancertotheliver;theremain-
der (n=7) were primary liver tumors. Eighty-seven percent of patients had prior systemic
chemotherapy with a median 24months from diagnosis to SBRT; 37% had prior liver
directed therapy. Local control was assessed for 28 patients (39 tumors) with 4months or
more follow-up. At a median follow-up of 22months (range, 10–40months), 14/39 (36%)
tumors had documented local failure. A decrease in local failure was found with higher
doses of SBRT (p=0.0237); 55% of tumors receiving a BED≤100Gy10 (10/18) had local
failure compared with 19% receiving a BED>100Gy10 (4/21).The 2-year actuarial rate of
local control for tumors treated with BED>100Gy10 was 75% compared to 38% for those
patientstreatedwithBED≤100Gy10(p=0.04).Atlastfollow-up,22/30patients(73%)had
distant progression of disease. Overall, seven patients remain alive with a median survival
of 20months from treatment and 57months from diagnosis. To date, no patient expe-
rienced persistent or severe adverse effects. Despite the heavy pretreatment of these
patients, SBRT was well tolerated with excellent local control rates when adequate doses
(BED>100Gy10) were used. Median survival was limited secondary to development of
further metastatic disease in the majority of patients.
Keywords:livermetastases,stereotacticbodyradiationtherapy,hepatocellularcarcinomaandcholangiocarcinoma
INTRODUCTION
The treatment of liver metastases and primary liver tumors has
evolved with surgery as the current standard of care for local-
ized lesions in medically operable patients (Robertson et al.,
2009). Some patients with extensive liver metastasis at presen-
tation can become surgical candidates following chemotherapy,
as improved drugs with better response rates have been devel-
oped (Adam et al., 2009). However, only a limited proportion of
liver metastases patients (10–20%) can ultimately undergo sur-
gical resection because of associated comorbidities, age, disease
extent, and patient wishes.
Alternativeliverdirectedtreatmentapproachesforunresectable
liver metastases and primary liver tumors include radiofrequency
ablation, cryotherapy, and chemoembolization. These techniques
have selection criteria which limit eligibility such as size,location,
and number of tumors (Kemeny, 2006). Stereotactic body radia-
tion therapy (SBRT) is used to deliver ablative doses of radiation
toanextracranialtargetwithhighprecisionandrapidfall-off that
spares surrounding tissues. Early SBRT results revealed excellent
tolerance and local control rates for liver metastases and primary
livertumors(Hoyeretal.,2006;MendezRomeroetal.,2006;Wulf
etal.,2006;Leeetal.,2009;Rusthovenetal.,2009).TheCyberKnife
system (Accuray Inc., Sunnyvale, CA, USA) has several features
that make it well suited for liver SBRT. Radiation delivery is per-
formed by a linear accelerator mounted on a robotic arm that
accuratelyalignsanddeliverstheradiationintheformofhundreds
of “beamlets”which allows optimization of the tumor dose while
sparing surrounding normal tissue. In addition, the CyberKnife’s
Synchrony motion tracking system, which uses real-time imaging
and fiducial tracking, improves targeting accuracy because of the
ability to track the tumor, and adjust the beam during respira-
tion (Kilby et al.,2010).With better accuracy,tighter margins and
higher doses are possible. Initial reports on CyberKnife SBRT for
liver tumors have shown promising local control with minimal
toxicity for select patients with hepatocellular carcinoma (HCC;
Choi et al.,2008; Louis et al.,2010),metastases (Ambrosino et al.,
2009; Stintzing et al., 2010), and mixed populations of both HCC
and metastases (Goodman et al.,2010).
In this report we describe our initial experience with
CyberKnife SBRT in a heavily pretreated group of patients with
liver metastases and primary liver tumors with regard to SBRT
technique and outcome.
www.frontiersin.org
March 2012 | Volume 2 | Article 23 | 1

Page 2

Lanciano et al.SBRT for liver metastases/tumors
MATERIALS AND METHODS
PATIENTS
From October 2007 to June 2009, 48 patients were treated at the
Philadelphia CyberKnife Center for liver metastases or primary
livertumors.Patientsweredividedintoablative(BED≥79.2Gy10
equivalent to 2Gy×33, 12Gy×3, or 8.5Gy×5) and non-
ablative (BED<79.2Gy10) populations. The BED was calculated
asBED=D∗(1+d/α/β)whereD isthetotaldose,d isthedoseper
fraction and the α/β ratio for the tumor was 10Gy. The total bio-
logicallyequivalentdosein2Gyfractions,EQD2,wascalculatedas
EQD2=D∗[(d +α/β)/(2Gy+α/β)]. An ablative dose regimen
was defined as at least 66Gy in 2Gy per fraction (EQD2=66Gy)
based on conventional fractionation. For this IRB approved retro-
spective study,only those patients treated with an ablative dose of
radiation (BED≥79.2Gy10) were further studied and reported.
No patient had impaired liver function or more than four discrete
lesions.
TREATMENT
Stereotactic body radiation therapy was delivered using the
CyberKnife system (Accuray Incorporated, Sunnyvale, CA, USA)
with 6mV photons. Multiplan software was used for treatment
planning. All patients had one to three gold fiducial markers
placed under CT guidance within each tumor for tracking during
treatment. Triple phase contrast enhanced CT was obtained for
treatment planning 7–10days following fiducial placement. Liver
windows with contrast were usually used for contouring the clini-
caltargetvolume(CTV),however,onoccasionthelivermetastases
were more visible on liver windows without contrast so both were
obtainedineachpatient.Inadditiontothelivertumor/metastases
(CTV), normal tissues in proximity to the tumor were contoured
including the bowel, heart, rib, and kidney. Normal tissue dose
constraints were applied as defined by Timmerman (2008). The
entire liver was contoured in all patients and the tumor volume
subtracted for dose volume histogram analysis. The gross target
volume (GTV) equaled the CTV. The planning target volume was
defined by a uniform 5mm CTV expansion. If necessary, due to
normal tissue proximity, margins were reduced to 3mm or less.
Dose was generally prescribed to the 60–80% isodose line to cover
95%ofthePTVwiththeprescribeddose.Bothisocentricandnon-
isocentrictreatmentplanswereuseddependingonpatientspecific
variables (liver size and tumor shape). However, non-isocentric
treatment plans were used in the majority of patients. Treatment
was delivered using between 80 and 150 beams. Synchrony track-
ingwasutilizedinallpatientstoaccountforrespiratorymovement
of the tumor by tracking the fiducials throughout the respiratory
cycle. During treatment, tracking images were taken every three
beams.
FOLLOW-UP AND STATISTICAL ANALYSIS
Patients were generally seen at 1 and 3months after treatment
and every 6months thereafter. Acute toxicities were defined as
those occurring within 3months of treatment. All toxicities were
graded using the Radiation Therapy Oncology Group (RTOG)
scoring system (Cox et al., 1995). PET/CT, CT, or MRI imaging
was obtained at 3–6months follow-up to assess local control. For
HCC CT or MRI was preferred. The RECIST 1.1 (Therasse et al.,
2000) and PERCIST 1.0 (Wahl et al., 2009) criteria were used to
define local failure depending on the availability of PET/CT. In
either case, each lesion was evaluated independently if more than
one lesion was treated per patient. In the absence of PET/CT,local
failure was defined as ≥5mm net increase in the target lesion’s
longestdiameter(Therasseetal.,2000);otherwise(preferred)local
failure was defined as a persistently metabolically active mass or
recurrenceof metabolicactivitywithamaximumSUVaboveliver
background activity. Pretreatment PET/CT with a metabolically
active target lesion was required for PET/CT evaluation (Wahl
et al., 2009). Unpaired t-tests and chi-squared analysis were used
to assess statistical significance. Kaplan–Meier local control and
survival analysis was performed.
RESULTS
PATIENTS
The
(BED≥79.2Gy10) had 41 discrete lesions (range 1–4 tumors per
patient). The majority of patients were treated for liver metas-
tases (n =23) with the rest either cholangiocarcinoma (n =4) or
HCC (n =3). Median age of all patients was 64years (range 47–
89). The patients were heavily pretreated. Eighty-seven percent
of patients (n =26) had prior systemic chemotherapy for treat-
ment of liver metastases or liver tumor. Thirty-seven percent of
patients (n =11) had prior liver directed therapy which included
surgical resection, chemoembolization, radiofrequency ablation,
photodynamic therapy, or previous external beam radiation with
four patients having more than one prior liver directed treat-
ment. The median time from diagnosis to SBRT for all patients
was 26months (range, 1–95months). Patient characteristics are
summarized in Table 1.
30patients treatedwith anablativeSBRTdose
TREATMENT FACTORS
The treatment planning goal was to spare at least 700cc of
uninvolved liver from doses of radiation greater than 15Gy
to maintain hepatic function (Schefter et al., 2005). Thus, the
pretreatment liver and tumor volumes were important factors
determining prescribed dose as detailed in Table 1. Median pre-
treatment liver volume was 1464cc (range 907–2450cc). Median
volume of liver receiving ≤15Gy was 1142.5cc (range 662.2–
2000.1cc) Patients with previous liver directed therapy had a
lower median pretreatment liver volume and median volume
of liver receiving ≤15Gy compared to those patients with no
previous liver directed therapy. Radiation doses ranged from
12Gy×3 fx (BED=79.2Gy10, EQD2=66Gy) to 20Gy×3 fx
(BED=180Gy10, EQD2=150Gy) with the most common frac-
tionation being 12.5Gy×3 fx (BED=84.4 Gy10,EQD2=70Gy)
prescribed to the 60–80% isodose line to cover 95% of the PTV.
Over half of the patients had PET/CT for local control assess-
mentwith79%of localfailuresdocumentedbyPET/CT(Table2).
Figure 1 shows the SBRT dose distribution and correspond-
ing response as assessed by PET/CT of a patient who received
sequential courses of CyberKnife SBRT to two hepatic metastases.
CLINICAL OUTCOMES
At 22months (range,10–40months) median follow-up,14 (36%)
of the 39 tumors in the 28 patients with more than 4months
Frontiers in Oncology | Radiation Oncology
March 2012 | Volume 2 | Article 23 | 2

Page 3

Lanciano et al.SBRT for liver metastases/tumors
Table 1 | Patient characteristics and treatment parameters.
Patients
Lesions
Age
Median
Range
Liver lesions per patient
1
2
3
4
Primary liver malignancy (n =7)
Cholangiocarcinoma
Hepatocellular carcinoma
Metastatic disease (n =23)
Colorectal cancer
Breast cancer
Esophageal cancer
Gastrointestinal stromal tumor
Pancreatic cancer
Non-small cell lung cancer
Previous systemic therapy
Yes
No
Unknown
Previous liver directed therapy
Yes
No
Surgical resection
Chemoembolization (CE)
Surgical resection, RFA
Radiofrequency ablation (RFA)
Radiation therapy
CE, RFA
Surgical resection, CE, RFA
Photodynamic therapy (PDT)
Pretreatment liver volume (cc)
All patients
Previous liver directed therapy
No previous liver directed therapy
Pretreatment tumor volume (cc)
All tumors
Largest per patient
Pretreatment median total per patient
tumor volume (cc)
All patients
Previous liver directed therapy
No previous liver directed therapy
Volume of liver receiving ≤15Gy (cc)
All patients
Previous liver directed therapy
No previous liver directed therapy
Prescribed Dose (BED)
12Gy×3 (79.2Gy10, EQD2=66Gy)
12.5Gy×3(84.38Gy10, EQD2=70Gy)
30
41
64
47–89
Number
22
6
1
1
Percent
73
20
3.33
3.33
4
3
13.33
10.00
15
3
1
1
1
2
50.00
10.00
3.33
3.33
3.33
6.67
26
1
3
86.67
3.33
10.00
11
19
2
2
2
1
1
1
1
1
Median
1464
1346.4
1638.4
36.67
63.33
6.67
6.67
6.67
3.33
3.33
3.33
3.33
3.33
Range
907 .8–2450
1118–2253
907 .8–2450
25.33
46.85
0.534–316
1.77–316
60.9
60.7
61.2
2.29–316
10.3–201.7
2.29–316
1142.5
1041.4
1215.3
Number
2
17
662.2–2000.1
662.2–1901.9
689.0–2000.1
Percent
6.67
56.67
(Continued)
10Gy×5 (100Gy10, EQD2=84Gy)
14Gy×3 (100.8Gy10, EQD2=84Gy)
15Gy×3 (112.5Gy10, EQD2=94Gy)
17 .5Gy×3(144.4Gy10, EQD2=120Gy)
20Gy×3 (180Gy10, EQD2=150Gy)
Treatment planning
Isocentric
Non-isocentric
1
3
10
4
4
3.33
10.00
30.00
13.33
13.33
13
28
31.70
68.30
Table 2 | Summary of the follow-up imaging performed denoting the
imaging modality used in the assessment of the 14 local failures.
Number of tumors Percent
FOLLOW-UP IMAGING
PET/CT
CT
MRI
PET/CT, MRI
Surgery
LOCAL FAILURE EVALUATION
PET/CT
CT
22
13
3
2
1
54
32
7
5
2
11
3
79
21
follow-up had local failure. Median time to local failure from
SBRT was 13months (range, 6–21months). One- and two-year
actuarial local control rates are 92 and 56%, from time of SBRT
(Figure 2A). The 2-year actuarial rate of local control for tumors
with a CTV of ≤25.3cc was 57% compared to 52% for those
patients with a CTV of >25.3cc (Figure 2B). A decrease in local
failure was found with higher SBRT dose (p=0.0237);55% of the
tumorsreceivingaBED≤100Gy10(10/18)hadlocalfailurecom-
paredwith19%treatedwithaBED>100Gy10(4/21).The2-year
actuarial rate of local control for tumors treated with BED>100
Gy10 was 75% compared to 38% for those patients treated with
BED≤100Gy10 (Figure 2C, p=0.04). Distant disease progres-
sion included all failures outside the treatment volume including
distant liver sites. Twenty-two of 30 patients (73%) had distant
disease progression at last follow-up,with distant failure the most
common pattern of failure.
Seven (23%) patients remain alive with a median 20months
survival from SBRT and 57months from diagnosis. One-, two-,
and three-year actuarial survival rates are 73, 31, and 17%
from SBRT (Figure 3A). Given the heavily pretreated popula-
tion, actuarial survival from diagnosis is also presented. Three-,
five-, and seven-year actuarial survival rates are 73, 44, and 25%
from diagnosis (Figure 3B). The 1-year actuarial rate of over-
all survival for those patients with a largest CTV ≤46.85cc was
86% compared to 60% for those with a largest CTV >46.85cc
(Figure 3C). At 2years this difference was less (35 vs 26%,
p =0.0899). The 2-year actuarial rate of overall survival for those
patients treated with a BED≤100 Gy10 was 21% compared
to 42% for those treated with a BED>100 Gy10, not statisti-
cally significant (Figure 3D). At 3years this difference was less
(14 vs. 16%).
www.frontiersin.org
March 2012 | Volume 2 | Article 23 | 3

Page 4

Lanciano et al.SBRT for liver metastases/tumors
FIGURE 1 | Example of complete response to SBRT assessed by
PET/CT. A 63-year-old African American male with two metachronous liver
metastases 4years after colon resection (T3N0 adenocarcinoma). He
received 2years of chemotherapy for the liver metastases with progression
and was referred for SBRT. (A)Tumor 1 and (B) tumor 2. Shown in each
panel are the (a) axial and (b) coronal views of the pretreatment PET/CT; the
(c) axial and (d) coronal views of the post-treatment PET/CT and the (e) axial
and coronal treatment planning CT denoting the SBRT dose distribution.
Treatment was well tolerated by all patients with no observed
acute toxicities and minimal late toxicities observed. One patient
with a solitary liver metastasis (CTV 141cc) developed a grade
3 small bowel obstruction 5months after SBRT. Following resec-
tion, pathology revealed poorly differentiated metastatic adeno-
carcinoma involving the small bowel mesentery and abdominal
wall along with separate specimens from the abdominal wall and
umbilical hernia. One patient with a large gastrointestinal stro-
mal tumor (CTV 123cc) developed a grade 2 liver abscess in the
treatment volume 16months after receiving SBRT of 37.5Gy in 3
fractions. Hospitalization, drainage catheter and antibiotics were
required. This patient’s most recent CT demonstrated progres-
sion of disease outside the treated mass with continued abscess
within the treated mass and was coded as a local failure by size
criteria. Both patients had local/regional failure that could have
accounted for the presumed complications. One patient with a
solitary liver metastasis adjacent to ribs (CTV 10cc) experienced
painwithagrade4ribfracture19monthsaftertreatmentwithno
evidenceoflocalfailure.Retrospectivedosecalculationtoadjacent
ribs revealed 9.5cc of total rib volume received over 30Gy.
One patient received treatment for a new liver metastasis
9months after initial SBRT and one patient was retreated for local
failure 22months after initial SBRT; both patients’second courses
FIGURE 2 | Local control analysis (A) from time of SBRT.
(B) Comparison of local control for tumors with a CTV ≤25.3cc to those
with a CTV >25.3cc. (C) Comparison of local control for those tumors
receiving a BED10 of ≤100Gy10 to those receiving a BED10>100Gy10.
Frontiers in Oncology | Radiation Oncology
March 2012 | Volume 2 | Article 23 | 4

Page 5

Lanciano et al.SBRT for liver metastases/tumors
FIGURE 3 | Survival analysis (A) from time of SBRT and (B)
from time of diagnosis. (C) Comparison of overall survival for
patients with a largest CTV ≤46.85cc to those with a largest CTV
>46.85cc. (D) Comparison of overall survival for those patients
receiving a BED10 of ≤100Gy10 to those receiving a
BED10>100Gy10.
of treatment are included in this analysis. The patient retreated
for local failure received two courses of SBRT, each 45Gy×3 fx.
At last follow-up by PET/CT, this patient has local control in the
treated lesion, but new distant liver metastases. Five months after
retreatment,he had grade 2 toxicity consisting of abdominal pain,
inflammation of the second portion of the duodenum and pelvic
fluidbyCTscan,buttheseSBRTrelatedsymptomsresolvedwithin
7months of retreatment.
DISCUSSION
While SBRT for liver metastases and primary tumors is a rel-
atively new concept, a large body of retrospective literature is
available describing early treatment results (Hoyer et al., 2006;
Mendez Romero et al., 2006; Wulf et al., 2006; Lee et al., 2009;
Rusthoven et al., 2009; van der Pool et al., 2010; Chang et al.,
2011; Vautravers-Dewas et al., 2011) including four prospective
Phase I studies (Schefter et al., 2005; Lee et al., 2009; Goodman
et al.,2010; Rule et al.,2011). The earliest phase I trial reported by
Schefteretal.(2005)establishedthebenefitandsafetyof SBRTfor
liver metastases with eligible patients having 1–3 lesions, tumor
diameters <6cm, and adequate liver function. Dose limiting tox-
icity was not found despite escalation to 60Gy in 3 fractions.
Dose volume constraints ensured at least 700cc of uninvolved
liver received <15Gy. When we began SBRT this was the only
published prospective study, however, early retrospective series
(Hoyer et al., 2006; Mendez Romero et al., 2006; Wulf et al.,
2006; Lee et al., 2009) were available which helped to initiate
our program in 2007. Based on these studies, our initial dose
fractionation schema was 12.5Gy×3 fractions. As our experi-
ence and the literature matured, we progressively increased dose.
Because of the dose prescription variability in this series, a dose
response analysis was possible which documented increased local
control for a BED>100 Gy10. McCammon et al. (2009) reviewed
their lung and liver experience with stereotactic radiation and
found a dose response with increased nominal dose of 54Gy or
greater in 3 fractions. Their 3-year actuarial local control rate was
89.3% for a dose >54Gy compared to 59 and 8.1% for those
treated to 36–53.9Gy and <36Gy, respectively. Rule et al. (2011)
revealed improved local control of 100% at 2years in a phase I
trial with dose escalation to 60Gy in 5 fractions for liver metas-
tases compared to 56% local control with 30Gy in 3 fractions. A
pooled analysis of patients treated with SBRT for colorectal liver
metastases from Stanford University, Princess Margaret Hospital
and University of Colorado revealed total dose, dose per fraction
and BED to be significant for local control by lesion in multi-
variate analysis. They estimated a dose of 46–54Gy in 3 fractions
or a BED of 117 Gy10 (EQD2=98Gy) would be required for
1-year local control rates >90% (Chang et al., 2011). Vautravers-
Dewas et al. (2011) did not demonstrate a dose response in 42
patients with 62 metastases, however, their dose prescription was
limited to 40Gy in 4 fractions and 45Gy in 3 fractions (BED
80–113Gy10, EQD2=66–94Gy). The current series is consis-
tent with the above literature which confirms adequate dose is
requiredforlocalcontrolwithaBED>100Gy10(EQD2=90Gy)
suggested. However, given the mixed population of primary and
metastatic tumors combined with a range of primary tissue types,
www.frontiersin.org
March 2012 | Volume 2 | Article 23 | 5