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Research Article
PURPOSE: To evaluate early outcomes of hepatic tumors treated with robotic SBRT (cyberknife).
MATERIALS AND METHODS: Between March 2007 and December 2012; 59 patients: 48 Hepatic
Metastases (HM), 8 Hepatocellular Carcinoma (HCC), 3 Cholangiocarcinoma (CC).
CTV margin for HCC and CC was 5 mm, PTV margin: 3 mm. no margin for HM.
Median dose: 47.61 Gy in 3 fractions prescribed to 80 % isodose line.
RESULTS: we report 1 grade 3 toxicity.
HCC; overall survival (OS): 41.7% at 1 year, local control (LC): 75% at 1 year.
At 1 and 2 years we report, respectively.
HM; OS: 83.6% and 57%, disease free survival (DFS): 69.5% and 46.1%, LC: 76.3% and 57.9%.
CC; OS: 100% and 50%, DFS and LC: 50% and 0%.
Factors influencing better OS; type of lesion, age < 65 years (p= 0.033), small PTV volume
(p= 0.002), for DFS; dose of 45 Gy (p= 0.001), dose per fraction of 15 Gy (p= 0.001), coverage > 95%
for PTV (p= 0.001), For LC; type of lesion, dose to PTV (p= 0.037), coverage > 95% for PTV (p=
0.001).
CONCLUSION: Age, volume of tumor, dose, coverage of target volume are prognostic factors for
survival and LC.
Keywords: Cyberknife, Hepatocellular carcinoma, hepatic metastases, Cholangiocarcinoma, Local Control, Survival.
INTRODUCTION
Liver cancer is the sixth most commonly diagnosed cancer Stereotactic body radiotherapy (SBRT) offers a treatment
and third leading cause of death worldwide, with 749,700 option for hepatocellular carcinoma (HCC) and hepatic
new cases and 696,000 deaths during 2008, its Incidence metastases (HM) patients who are not eligible for other
in France is about 6 per 100,000 (Parkin DM, 2001; Ferlay modalities especially with use of CyberKnife; an image-
J, 2010). guided robotic radiosurgery system capable of detecting
and correcting intrafraction tumor motion and adapting to
While surgical resection offers 5-year survival rates of 30- patient’s breathing and moving linear accelerator in
60%, only 10-30% of liver tumors are eligible for surgery, concert with it. SBRT for HM and HCC has shown
due to advanced stage of local disease or comorbid encouraging rates of local control (LC) and low toxicity
medical conditions (Lau WY, 2017; Fuss M, 2004). Other (Ambrosino G, 2009; van der Pool AE, 2010).
therapeutic options are liver transplantation, percutaneous
alcohol ablation, transarterial chemoembolization (TACE) *Corresponding Author: Dr. EMAN ELALFY: MBBCh,
and radiofrequency ablation (RFA); most of these MSc, MD. Lecturer in Cancer Management and, Research
approaches have limitations depending on size, location, Department, Medical Research Institute, Alexandria
number and distribution of lesions (Orlando A, 1997; University. Egypt
Horigome H, 2001). E-mail: eman.elalfy@alexu.edu.eg
Results of Stereotactic Body Radiotherapy (SBRT) for Management of Hepatic Tumors: Analysis of Local Control and Survival Outcomes
ElAlfy and Bondiau 49
Preliminary results in HCC have shown the efficacy of 34 HM were from gastointestinal tract (oesophagus, colon,
using SBRT as a locally ablative modality for HCC, rectum, stomach, anal canal and, pancreas) 2 ovary, 6
specifically in those unfit for other local therapies (Choi BO, breast, 1 lung, 2 choroidal melanoma, 1 kidney, 1 thyroid
2008; Méndez Romero A, 2006; Tse RV, 2008). and, 1 carcinoma of unknown origin.
Nevertheless, its effect on survival is seldom reported. We Performance status (PS) measured according to ECOG
will present our results for 76 primary or secondary HM mostly it was 2.Median volume of PTV was 23.726 cm³,
treated with SBRT (Cyberknife) and factors associated mean PTV volume was 46.574 cm³ (range, 2.030 -
with their early outcomes such as overall survival (OS), 215.398 cm³).
disease free survival (DFS) and local control (LC).
Table (1): Patients and Treatment characteristics:
We will present our results for 76 lesions in 59 patients Total N
diagnosed with either primary hepatic malignancies or (%)
Hepato- Hepatic Cholangio-
metastases to the liver treated with SBRT (Cyberknife) and Or
carcinoma Metastases carcinoma
factors associated with their early outcomes such as Median
overall survival (OS), disease free survival (DFS) and LC. (range)
Sex:
Male 33
MATERIALS AND METHODS 8 (100%) 25 (52.1%) 0 (0%)
(55.9%)
Female 26
Patients: Between March 2007 and December 2012, 0 (0%) 23 (47.9%) 3 (100%)
(44.1%)
Medical records were retrospectively reviewed of 59 Age:
patients underwent SBRT with real-time tracking for < 65 26
primary or secondary HM. 2 (25%) 23 (47.9%) 1 (33.3%)
years (44.1%)
The ethics committee has already approved that ≥ 65 33
retrospective analysis of the liver cancer cases treated by 6 (75%) 25 (52.1%) 2 (66.7%)
years (55.9%)
SBRT. P.S.:
0 11
The selected patients shoould met the inclusion criteria 0 (0%) 11 (22.9%) 0 (0%)
(18.6%)
that were as follows: 1 21
1) ECOG performance status ≥2; (35.6%)
3 (37.5%) 17 (35.4%) 1 (33.3%)
2) all the treated lesion were confined to the liver with the
2 27
chossen residual normal liver volume to be ≥700 cc; 5 (62.5%) 20 (41.7%) 2 (66.7%)
(45.8%)
3) those unfit for other standard local therapy according
Total 45 (25- 45 (40-45) 44 (25-45) 42 (40-45)
to the liver tumor board or refusing to undergo other
Dose 45) Gy Gy Gy Gy
local treatment;
No. of
4) the selected patients have accepted and signed 3 (3-5) 3 (3-4) 3 (3-5) 3 (3-4)
fraction
informed consent to be treated with SBRT using the
CyberKnife real-time tracking system. ISO-
80% 80%
Dose 80% 80.0%
(70%- (70%-
While the Exclusion criteria were as follows : line for (77%-84%) (80%-84%)
119%) 119%)
1) patients with more than 3 liver lesions; PTV
2) those who recieved atypical dose and fractionations No. of 136 141 143 130
that not applied in our standard etracrainal SBRT beams (27-281) (97-181) (27 -281) (118-133)
protocal of treatment which is median dose of 47.61 Dose / 15 (5-15) 15 (10-15) 15 (5-15) 14 (10-15)
Gy in 3 fractions prescribed to 80 % isodose line. fraction Gy/f Gy/f Gy/f Gy/f
Results of Stereotactic Body Radiotherapy (SBRT) for Management of Hepatic Tumors: Analysis of Local Control and Survival Outcomes
J. Cancer. Clin. Oncol. 50
Gross Tumor Volume (GTV) was based on MRI image All time to event endpoints were calculated from the
fused on the dosimetric CT scan helped by PET scan when initiation of SBRT treatment. OS: included death from any
needed. For HM cases; we do not use margin (clinical cause. DFS: counted events as appearance of new lesions
target volume (CTV) = GTV + 0 mm), as according to our within liver or distant relapse. LC: included events
center protocol that follows the logistic explanation involving pre-existing treated lesions only.
presumed by the Radiation Therapy Oncology Group
(RTOG) used by (Timmerman RD et al, 2018) in the Rates were estimated using Kaplan-Meier method.
protocol of lung SBRT that did not apply margin for the Differences among survival curves were compared using
presumed microscopic extension. log-rank test. Univariate analyses of LC and survival were
performed using the Cox regression model. Fisher exact
For HCC and CC cases margins were 5 mm (CTV= GTV test and Pearson chi-squares methods were used to study
+ 5 mm) to treat any microscopic disease extension. the association between categorical variables and
Planning Target Volume (PTV) contained the CTV and 3- Kruskal-Wallis test for continuous variables. Pearson
mm geometric margin to account for the uncertainty. correlation coefficient was used to assess association
Time was Less than one week between dosimetric CT and between two quantitative variables. A p value ≤ 0.05 was
start of treatment. chosen as the significance threshold.
Results of Stereotactic Body Radiotherapy (SBRT) for Management of Hepatic Tumors: Analysis of Local Control and Survival Outcomes
ElAlfy and Bondiau 51
Clinical outcomes:
Results of Stereotactic Body Radiotherapy (SBRT) for Management of Hepatic Tumors: Analysis of Local Control and Survival Outcomes
J. Cancer. Clin. Oncol. 52
Cholangiocarcinoma:
found nineteen (9.4%) of 203 patients had developed
radiation induced liver disease RILD and reported factors
OS affected by: Max dose> 55 Gy for GTV (P = 0.033),
predicting RILD to be mean liver dose, primary liver cancer
CTV (P= 0.024), PTV (P= 0.041); No factor influencing
and male, therefore our results of low rate of toxicity can
DFS or LC.
be explained by the use of a new technology with tracking
Toxicity: capabilities.
Results of Stereotactic Body Radiotherapy (SBRT) for Management of Hepatic Tumors: Analysis of Local Control and Survival Outcomes
ElAlfy and Bondiau 53
Because of dose variability in these retrospective series In our study OS was 83.6% and 57% at1 and 2 years. Also,
Hoyer et al. (2006); Mendez Romero et al. (2006) and Lee Katz et al. (2007) reported Survival was 78% and 37% at
et al. (2009) a dose response analysis documented 10 and 20 months, respectively, Hoyer et al. (2006)
increased LC for a biological equivalent dose (BED) > 100 demonstrated 5-year survival for liver / lung metastases
Gy that support what we found that dose >35 Gy for PTV from colorectal cancer to be 13%.
is influencing LC.
As dose influencing LC we found logically that coverage > We observed patients with age < 65 years experienced
95% of target volume also influencing LC; moreover higher OS than older age group which explained by lower
number of beams influencing coverage factor. comorbidity, also males had higher OS as most of primary
was from colorectal so they may be received previous 5-
Hepatocellular carcinoma; Flurouracil chemotherapy.
We found that tumor size influenced the OS which is
We found OS was 41.7% at 1 and 2 years while Choi et al discussed in other studies as Rusthoven KE, et al. (2009)
[9] found OS was 70% and 43.1%, Cardenes et al. (2010) and, Wada H, et al. (2004) demonstrated that lesions less
OS was 75% and 60% at 1 and 2 years and, Tse et al. than 3 cm have better LC, Dewas S, et al. (2012) identified
(2008); OS was 51% at 1-year, the difference for OS at 1 diameter and volume of GTV and PTV as prognostic
year between previous studies and our results can be factors of LC.
explained by our low number of HCC cases.
We found LC at 1 and 2 years to be 75% which is In other series, stratification by size revealed no significant
consistent with other series as Choi et al. (2008) found LC difference in LC, Vautravers-Dewas C, et al. (2011) and
was 71.9% at median follow-up 10.5 months van der Pool Chang BK, et al. (2007) found tumor size did not predict
et al. (2010) reported LC of 74% at 2 years. Ambrosino et the LC.
al. (2009) obtained disease control in 74.1% of cases,
While in Dewas S, et al. (2012) observed LC at 1 and 2 We found DFS was 69.5% at one year and 46.1% at two
years of 90.5%. years; LC was 76.3% and 57.9% at 1 and 2 years;
respectively. Quite similar to our study, Katz et al. (2007)
There is dose–response relationship for HCC with non- reported progression-free survival was 24% at 12 months;
stereotactic conformal hepatic irradiation with an LC was 76% and 57% at 10 and 20 months; respectively.
increased response rate as the dose increases [Park HC, Many studies discussed the issue of dose response
et al. (2002). The same relationship holds when relationship as McCammon R, et al. (2009) found a dose
reproduced using the millimetric tracking accuracy of response with increased dose of 54 Gy or greater in 3
Cyberknife, in our study we found that dose superior than fractions, Chang et al. [29] demonstrated that total dose,
35 Gy for the PTV is influencing LC. dose per fraction and BED correlated with LC, Dewas S,
et al. (2012) found that; the only prognostic factor for LC is
As dose influencing LC we found coverage > 95% of target the dose, also we found that a dose > 35 Gy for the PTV
volume influencing LC. is influencing LC, while Vautravers-Dewas C, et al. (2011)
did not demonstrate any dose response.
Hepatic Metastases;
Cholangiocarcinoma;
Metastatic disease to liver remains difficult management
problem, diffuse involvement throughout the liver with or We found OS was 100% at one year and 50% at two years.
without extra-hepatic sites of disease, carries a poor Both DFS and LC were 50% at one year and 0% at two
prognosis with median survival of only 6 months, Scheele years, and Kopek N, et al. (2010) reported median
J, et al. (1990). progression-free survival was 6.7 months and OS was
10.6 months for unresectable CC.
Regarding metastatic hepatic lesions in the literature, the
median follow-up ranges from six to 54 months and our All are summarized in TABLE (4).
median follow up was10 months (range; 1-68 months).
Results of Stereotactic Body Radiotherapy (SBRT) for Management of Hepatic Tumors: Analysis of Local Control and Survival Outcomes
J. Cancer. Clin. Oncol. 54
Table (4): Overview of studies of stereotactic body radiation therapy for liver lesions:
Study No. of No. RT No. of Tumor Follow up Local control Design
lesions of dose fractions volume/ period (outcome)
Pts. (Gy) (Fx) Lesion size median at 1 and 2
(medians) in months years
Ambrosino et al. HM (n = 27) 27 25-60 3 69 cc/- 13 (6-16) 85.2% Retrospective
2009 overall control CyberKnife
Van der Pool et HM CRC 20 37.5 3 -/23 mm 26 (6-57) -/74 -
al. 2010 (n = 31)
Choi et al. 2008 HCC 31 30-39 3 25 cc/- 10.5 71.9% Retrospective
(n = 32. (2 – 18.5) at the median CyberKnife
including of 10.5 months
9 PT)
Mendez et al. HCC 25 25– 3-5 22 cc/32 mm 12.9 94/82 Phase I/II
2006 (n = 11) 37.5 (1.1–322) 75/75 (HCC) Body Frame
HM (n = 34) 100/86 (HM)
Katz et al. 2007 HM (n = 174) 69 30-55 7-20 9.9 cc/27 mm 14.5 76/57 Retrospective
Exac Trac
Hoyer et al. 2006 HM CRC 64 45 3 -/35 4.5 years -/79 Phase II
(n = 44) Body Frame
Liu et al 2013 106 62 60-50 3-5 88 mm 18 93/82 Retrospective
study
Herfarth etal. HCC + CC 37 14-26 1 10 cc/- - 67/- Phase I/II
2001 (n = 4)
HM (n = 56)
Lee et al. 2009 HM (n = 68) 68 27-60 6 75.2 cc/- 10.8 71/- Phase I
Respiration
control
Cardenes et al HCC(n=25) 17 36-48 3 34 cc/40 mm 24(10-42) 100% Phase I
2010 Cyberknife
Dewas et al . 153 120 27-48 2-4 73 cc/48 mm 15(12-18) 80.4/72.5 Retrospective
2012 HCC (n=48) Cyberknife
HM(n=99)
CC(n=6)
Rusthoven et al. HM (n = 63) 47 60 3 15 cc/27 mm 16 95/92 Phase I/II
2009
Wada et al. 2004 HM 5 45 3 NR 71.2(2y) Retrospective
Vautravers- 62 HM 42 40-45 4-3 34 mm 14.3 86(2y) -
Dewas et al. 2011
Chang et al. 2007 102 65 22-60 30.1 mm 14.4 62/45 Retrospective
McCammon et al. 246 141 >54-36 - - - 89.3(3y) Retrospective
2009
Kopek et al. 2010 - 27 45 3 - 5.4 ys 81.5 -
ACKNOWLEDGEMENT CONCLUSIONS
The authors acknowledge Mrs. Laurence Milan; Our results demonstrate that robotic SBRT (Cyberknife) is
Cyberknife/Cyclotron, Department of Radiotherapy, an effective modality with good LC and low morbidity for
Centre Antoine-Lacassagne (CAL), Nice, France; for her primary and secondary HM.
valuable contribution during and beyond the conduct of Factors influencing the survival and LC in our study are:
this study. age < 65 years, sex, P.S., volume of tumor and PTV,
coverage of target volume, total dose and dose per
fraction.
Results of Stereotactic Body Radiotherapy (SBRT) for Management of Hepatic Tumors: Analysis of Local Control and Survival Outcomes
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Results of Stereotactic Body Radiotherapy (SBRT) for Management of Hepatic Tumors: Analysis of Local Control and Survival Outcomes
J. Cancer. Clin. Oncol. 56
Results of Stereotactic Body Radiotherapy (SBRT) for Management of Hepatic Tumors: Analysis of Local Control and Survival Outcomes