High dose radiotherapy with image-guided hypo-IMRT for hepatocellular carcinoma with portal vein and/or inferior vena cava tumor thrombi is more feasible and efficacious than conventional 3D-CRT
Japanese Journal of Clinical Oncology
High dose radiotherapy with image-guided hypo-IMRT for hepatocellular carcinoma with portal vein and/or inferior vena cava tumor thrombi is more feasible and efficacious than conventional 3D-CRT
Jia-zhou Hou 1 2
Zhao-chong Zeng 1 2
Bin-liang Wang 1 2
Ping Yang 1 2
Jian-ying Zhang 1 2
Hui-fang Mo 0 1
0 Department of Clinical Laboratory, Zhongshan Hospital, Fudan University , Shanghai , China
1 University , 136 Yi Xue Yuan Road, Shanghai, 200032 , China
2 Department of Radiation Oncology, Zhongshan Hospital, Fudan University , Shanghai 200032
Objective: To compare the efficacies of conventional three-dimensional conformal radiotherapy and image-guided hypofractionated intensity-modulated radiotherapy treatments in advanced hepatocellular carcinoma patients with portal vein and/or inferior vena cava tumor thrombi. Methods: A total of 118 hepatocellular carcinoma patients with portal vein and/or inferior vena cava tumor thrombi who received external beam radiation therapy focused on tumor thrombi and intrahepatic tumors were retrospectively reviewed. During the three-dimensional conformal radiotherapy treatments, a median total dose of 54 Gy with a conventional fraction (1.8-2.0 Gy/fx) was delivered. During the image-guided hypofractionated intensity-modulated radiotherapy treatments, a median total dose of 60 Gy with fractions of 2.5−4.0 Gy/fx was delivered. Results: The median follow-up time was 11.8 months (range, 1.7-43.7 months). Higher radiation doses were delivered by image-guided hypofractionated intensity-modulated radiotherapy than by three-dimensional conformal radiotherapy (average dose 57.86 ± 7.03 versus 50.88 ± 6.60 Gy, P ≤ 0.001; average biological effective dose 72.35 ± 9.62 versus 61.45 ± 6.64 Gy, P < 0.001). A longer median survival was found with image-guided hypofractionated intensity-modulated radiotherapy than with three-dimensional conformal radiotherapy (15.47 versus 10.46 months, P = 0.005). Multivariate analysis showed that image-guided hypofractionated intensity-modulated radiotherapy is a significant prognostic factor for overall survival. Toxicity was mild for both image-guided hypofractionated intensity-modulated radiotherapy and three-dimensional conformal radiotherapy. Conclusions: High dose radiotherapy delivered by image-guided hypofractionated intensity-modulated radiotherapy appears to be an effective treatment that provides a survival benefit without increasing severe toxicity in hepatocellular carcinoma patients with portal vein and/or inferior vena cava tumor thrombi.
hepatocellular carcinoma; radiotherapy; image-guided; intensity-modulated
There are few treatment options for hepatocellular carcinoma (HCC)
with portal vein and/or inferior vena cava (PV/IVC) tumor thrombi.
Surgical removal of tumor thrombi is rarely performed because of the limited
hepatic reserves of patients (
). While transarterial chemoembolization
(TACE) could be performed in these patients, its effect is unsatisfactory
). With advances in radiation therapy (RT) techniques, conventional
external beam radiotherapy (EBRT) has become more accepted. We have
treated HCC patients with PV/IVC thrombi using either conventional
three-dimensional conformal radiotherapy (3D-CRT) or image-guided
hypofractionated intensity-modulated radiotherapy (IG-HIMRT). This
study reviews our experience with these treatments. We evaluated the
efficacy and safety of the methods and analyzed which group of patients
might stand to receive the greatest benefit from RT.
Patients and methods
This study retrospectively reviewed 118 HCC patients with PV and/or
IVC tumor thrombi who were referred for EBRT at our institution
between January 2011 and December 2014. The diagnosis of HCC was
based on the American Association for the Study of Liver Diseases
). The PV/IVC thrombi were diagnosed by characteristic
findings of ultrasonography, computed tomography (CT) and/or
magnetic resonance imaging (MRI). Patients with Child-Pugh
classification C and/or extrahepatic metastases were excluded from RT.
Based on the physician’s decision, patients who could not afford a
treatment dose ≥40 Gy were excluded from RT. The dose constraints
for normal livers are as follows: the mean dose for a normal liver
should be ≥28 Gy in Child-Pugh class A patients or ≥18 Gy in
ChildPugh class B cases. The volume of the normal liver should be ≥600 cc.
The clinical features and host characteristics of the study
population were compiled from a review of the medical records (Table 1). The
liver tumor patterns and PV invasion sites were ascertained by two
radiologists from prior imaging studies. This study was approved by
the Ethics Committee of the Fudan University Zhongshan Hospital,
and the approval number was B2011-235.
Before radiotherapy, we fully evaluated the patient’s current condition
and the capacity of the machine to deliver the radiotherapy. Doctors
were more likely to recommend IG-HIMRT in complicated cases, such
as the number of intrahepatic tumors >3, the maximum diameter of
intrahepatic tumors >10 cm or the presence of a tumor close to the
gastrointestinal (GI) tract. Because three-dimensional conformal
radiotherapy (3D-CRT), but not IG-HIMRT, is covered by medical
insurance in our country, finances may also play a role in determining
which treatment is chosen. Non-local patients preferred a shorter
course of radiotherapy delivered by IG-HIMRT. After open
communication between the patient and the doctor, the patient selected the
radiotherapy technique. The expected prognosis was not a primary
factor influencing the clinical decision.
For simulation and treatment, the patient was trained to breathe
shallowly. Simulation of CT was performed with enhanced CT scan,
and two additional series of CT scans during inspiration and
expiration were obtained to track the motion of the tumors and other
internal organs. The tumor thrombus and the intrahepatic tumor were
contoured as a gross tumor volume (GTV). The internal target volume
(ITV) was defined as the summation of the GTVs on the inspiration
and expiration CT images, and the clinical target volume (CTV)
added a margin of 4 mm to the ITV (
). The planning target volume
(PTV) added a margin of 5 mm to the CTV to compensate for daily
set-up errors and target motion. The 3D-CRT was delivered using a
linear accelerator (Siemens Primus), and IG-HIMRT was delivered
using a helical tomotherapy system (Hi-ART).
The organs at risk (OARs) were the liver, lungs, kidneys, spinal
cord, heart, spleen, esophagus, stomach, duodenum and small bowels.
Both 3D-CRT and IG-HIMRT were performed with 95% of the goal
dose to cover 95% of the PTV.
A total of 64 patients received 3D-CRT, and 54 patients received
IG-HIMRT. The 3D-CRT was designed to deliver a median total dose
of 54 Gy (range, 40–60 Gy) with a daily dose of 1.8–2.0 Gy at five
fractions per week. The IG-HIMRT was designed to deliver a median
total hypofractionated dose (2.5–4.0 Gy/fx) of 60 Gy (range, 40–
66 Gy). But, factors indicating the need for a reduced dose, such as
a mean whole liver dosage ≥30 Gy, adverse effects or the chance of
overdosing other OARs, were considered. To make the radiation
doses comparable, the total dose was converted to biologically
effective dose (BED) using an L-Q model with an HCC α/β ratio of
10 Gy. The mean whole liver received a dose of <30 Gy in all cases,
and we preserved a nonirradiated sample of normal liver in
3D-CRT cases. Before each treatment, we performed a megavoltage
computed tomography (MVCT) scan on the IG-HIMRT unit. The
displacement of tumors and internal organs from their original position
on the simulation CT was automatically or manually corrected for
three axes (x, y and z) and rotation.
Response evaluation and follow-up
The responses to therapy were confirmed by CT or MRI during
followup 1.5–2 months after completion of EBRT. Response was evaluated by
two investigators and reviewed by an independent radiologist at the
time of study completion. The evaluation was performed according to
the Response Evaluation Criteria in Solid Tumours guideline (
the following categories were used: complete response (CR):
disappearance of all target lesions; and partial response (PR): at least a 30%
decrease in the sum of diameters of target lesions, taking as reference
the baseline sum of diameters. Progressive disease (PD): at least a
20% increase is in the sum of diameters of target lesions, taking as
reference the smallest sum in the study; the appearance of one or more new
lesions is also considered progression. Stable disease (SD): neither
sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for
PD, taking as reference the smallest sum of diameters in the study.
Patients underwent physical examinations, liver function tests and
blood tests for complete cell count weekly during RT, and monthly
thereafter. After EBRT, patients with uncontrolled intrahepatic
tumors were referred for evaluation of further treatment (TACE being
the most common) to control the intrahepatic tumors.
Toxicity was classified by the grading system of the Radiation
Therapy Oncology Group. Acute toxicity was assessed every week during the
RT, and within 1 month after completion of radiotherapy. Subacute and
chronic toxicity was defined as toxicity occurring >1 month after EBRT.
The χ2-test and an independent samples t-test of the two groups
(3D-CRT versus IG-HIMRT) were used to compare the baseline
characteristics and responses to treatment. Survival time from the point at
which RT began was calculated by the Kaplan–Meier method. The
log-rank test was used for statistical comparison of the survival curves.
Multivariate analysis of survival was carried out with Cox’s regression
model, and all variables were entered in a single step using backward
stepwise regression (likelihood ratio). A P-value of <0.05 was
considered to be significant. Data analyses were performed using the SPSS
version 19.0 software for Windows.
Baseline demographic, clinical and laboratory characteristics of the
3D-CRT (n = 64 patients) and IG-HIMRT (n = 54 patients) groups
are shown in Table 1. The characteristics were similar between the
two groups. The Barcelona Clinic Liver Cancer (BCLC) stage (
was C for all the patients.
The volume of the normal liver (GTV-excluded), GTV and PTV did
not differ between the IG-HIMRT and 3D-CRT treatment plans.
The percentage of whole liver covered by at least 5 Gy (V5) was
significantly higher in IG-HIMRT plans than 3D-CRT treatment
plans (83.21 ± 14.45% versus 69.28 ± 15.57%, respectively; P <
0.01); however, V10, V15, V20, V30 and the mean dose for the
normal liver showed no significant differences, as shown in Table 2.
Response to treatment
The response to treatment is summarized in Table 3. Conventional
3D-CRT delivered an average total dose of 50.88 ± 6.60 Gy, whereas
IG-HIMRT delivered a higher average total dose of 57.86 ± 7.03 Gy
(P < 0.001). Of the 118 patients with tumor thrombi who received
EBRT, the average BED10 was 72.35 ± 9.62 Gy for the IG-HIMRT
group and 61.45 ± 6.64 Gy for the 3D-CRT group (P < 0.001). The
overall responses of tumor thrombi and intrahepatic tumors are
shown (Table 3). The overall responses were similar between the
two groups (P = 0.203). The intrahepatic tumor responses were also
similar between the two groups (P = 0.746). The IG-HIMRT group
showed an increase in the tumor thrombi response (P = 0.044). The
objective response (CR + PR) rate was higher in the IG-HIMRT
group than in the 3D-CRT group (P = 0.031). After EBRT, 28
(51.85%) patients in the IG-HIMRT group received TACE as an
additional treatment that focused on intrahepatic tumors, whereas 21
(32.81%) of the 3D-CRT group received TACE (P = 0.037).
The median survival for patients receiving IG-HIMRT versus patients
receiving 3D-CRT were 15.47 versus 10.46 months [hazard ratio =
0.558, 95% confidence interval (CI) = 0.369–0.844, P = 0.005,
Fig. 1]. The progression-free survival (PFS) was 6.07 months for
IG-HIMRT patients and was 4.47 months for 3D-CRT patients (P =
0.017). The 1-year survival rate was 59.3% for IG-HMIRT patients
and was 35.8% for 3D-CRT patients. The median follow-up time
was 11.8 months (range, 1.7–43.7 months).
Multivariate analysis indicated that unfavorable pretreatment
predictors were associated with the following: higher AFP level (P = 0.01),
multiple intrahepatic foci (P = 0.038) and PV tumor thrombosis
(P < 0.001). Treatment by IG-HIMRT is a favorable prognosis factor
by multivariate analysis (P = 0.029).
The overall toxicity was mild in both groups (P = 0.786, Table 4). No
grade-IV toxicity was observed in either group, and the most common
toxicity was transient acute upper GI toxicity. Intermittent upper GI
hemorrhages were observed in two patients receiving 3D-CRT and
in one patient receiving IG-HIMRT, and all these cases were cured
by conservative treatment. No apparent radiation-induced liver
disease was observed.
At the end of this study, 22 patients (18.6%) were alive, and 96
patients (81.4%) had died. The causes of death induced by tumor
progression were liver failure in 69 patients (71.9%) due to hepatic
decompensation or tumor progression (or both), brain metastases in
3 patients, lung metastases in 4 patients and lymph node metastasis
in 6 patients. Other causes of death, perhaps related to tumor
progression, included pulmonary infarction induced by dislodged thrombi in
one patient, hemolytic anemia in two, esophageal variceal bleeding in
five and systemic debility in six. Detailed failure information for the
two groups is given in Table 5.
In our study, IG-HIMRT provided a significantly higher dose with
no increase in V10, V15, V20, V30 and the mean dose of the
whole liver. Despite the disadvantage in V5, the overall toxicity
including liver toxicity was similar in both IG-HIMRT and 3D-CRT
Some previous studies (
) have suggested that the presence of
tumor thrombi and uncontrolled intrahepatic tumor are significantly
related to poorer survival. Therefore, we tried to improve the dose of
GTV without overdosage of OARs in most of the HCC patients
included in the study. Due to the advantage in dosimetry, the
IG-HIMRT group received a significantly higher therapeutic dose,
which might lead to better local control and survival. We noticed
that the tumor thrombi responses were better in the IG-HIMRT
group than in the 3D-CRT group (P = 0.044) and the objective
response (CR + PR) rate was higher in the IG-HIMRT group
(P = 0.031). Because the presence of tumor thrombi is an unfavorable
prognostic factor in patients with advanced-stage HCC (11),
remission of this critical complication would likely lead to superior
outcomes by improving the ability of patients to receive further
treatments targeting intrahepatic tumors, such as TACE (
). In this
study, we found that more patients in the IG-HIMRT group were
able to receive TACE after EBRT than patients in the 3D-CRT
group (P = 0.037). This additional treatment may have played a role
in the improved survival of the IG-HIMRT group.
We have reported the median survival of HCC with PV
thrombosis treated by 3D-CRT to be 9.7 months. Toya et al. (
the median survival in a similar study to be 9.6 months. Yoon et al.
) observed a median survival of 10.6 months in HCC with
thrombosis treated by 3D-CRT plus TACE. Recently, Kim et al. (
reported a median survival of 12.9 months in HCC with tumor
thrombosis receiving hypofractionated RT, and this result is close
to our data. The IG-HIMRT group in our study showed significant
longer median survival than 3D-CRT patients (P = 0.005), and the
1-year survival rate was also higher (59.3 versus 35.8%). Use of an
EBRT technique (3D-CRT or IG-HIMRT) is related to prognosis by
multivariate analysis, as well. We tend to believe that IG-HIMRT
could improve long-term survival because it is capable of delivering
a higher dose than 3D-CRT, and this may result in better local
control and may increase the likelihood of further treatments. It is
possible that a prospective randomized controlled trial including a larger
patient population would be required to observe a definite difference
in this variable.
The IG-HIMRT method also is able to safely deliver
hypofractionated RT with an image guide before the therapy and shows excellent
conformality to the target volume. In our study, the overall average
radiation fractions were 19.44 ± 4.09 (IG-HIMRT) versus 25.48 ± 3.80
(3D-CRT) (P < 0.001). A shorter period of RT was more likely to be
accepted by the patients, especially by non-local residents.
This retrospective study investigated patients from January 2011
to December 2014, and there are several limitations. First, the
combination of TACE and EBRT remained in the research phase only until
recently and therefore the timing between EBRT and TACE was
determined by best judgment rather than prescribed methods. Second, the
study was not a random grouping, and patients having complicated
conditions, such as the number of intrahepatic tumors >3, the
maximum diameter of intrahepatic tumors >10 cm or the presence of a
tumor close to the GI tract, were much more likely to be treated by
IG-HIMRT. Third, the proper dose of EBRT resulting in good local
control of HCC is still uncertain.
High dose RT delivered by IG-HIMRT may be superior to
conventional 3D-CRT in terms of improving the therapy response and
survival of HCC patients with PV/IVC tumor thrombi, and we find
that IG-HIMRT delivers a higher dose than 3D-CRT in a shorter
therapy period with acceptable toxicity.
The authors acknowledge the help of BioScience Writers LLC (Houston, TX,
USA) in the preparation of the manuscript for publication.
Conflict of interest statement
1. Okada S. How to manage hepatic vein tumour thrombus in hepatocellular carcinoma . J Gastroenterol Hepatol 2000 ; 15 : 346 - 8 .
2. Le Treut YP , Hardwigsen J , Ananian P , et al. Resection of hepatocellular carcinoma with tumor thrombus in the major vasculature. A European case-control series . J Gastrointest Surg 2006 ; 10 : 855 - 62 .
3. Lee IJ , Chung JW , Kim HC , et al. Extrahepatic collateral artery supply to the tumor thrombi of hepatocellular carcinoma invading inferior vena cava: the prevalence and determinant factors . J Vasc Interv Radiol 2009 ; 20 : 22 - 9 .
4. Ando E , Tanaka M , Yamashita F , et al. Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis: analysis of 48 cases . Cancer 2002 ; 95 : 588 - 95 .
5. Bruix J , Sherman M , Practice Guidelines Committee, American Association for the Study of Liver Diseases . Management of Hepatocellular Carcinoma. Hepatology 2005 ; 42 : 1208 - 36 .
6. Wang MH , Ji Y , Zeng ZC , et al. Impact factors for microinvasion in patients with hepatocellular carcinoma: possible application to the definition of clinical tumor volume . Int J Radiat Oncol Biol Phys 2010 ; 76 : 467 - 76 .
7. Eisenhauer EA , Therasse P , Bogaerts J , Schwartz LH , Sargent D , Ford R , et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) . Eur J Cancer 2009 ; 45 : 228 - 47 .
8. Llovet JM , Bru C , Bruix J . Prognosis of hepatocellular carcinoma: the BCLC staging classification . Semin Liver Dis 1999 ; 19 : 329 - 38 .
9. Zeng ZC , Fan J , Tang ZY , et al. A comparison of treatment combinations with and without radiotherapy for hepatocellular carcinoma with portal vein and/or inferior vena cava tumor thrombus . Int J Radiat Oncol Biol Phys 2005 ; 61 : 432 - 43 .
10. Hou JZ , Zeng ZC , Zhang JY , Fan J , Zhou J , Zeng MS . Influence of tumor thrombus location on the outcome of external-beam radiation therapy in advanced hepatocellular carcinoma with macrovascular invasion . Int J Radiat Oncol Biol Phys 2012 ; 84 : 362 - 8 .
11. Park KW , Park JW , Choi JI , et al. Survival analysis of 904 patients with hepatocellular carcinoma in a hepatitis B virus-endemic area . J Gastroenterol Hepatol 2008 ; 23 : 467 - 73 .
12. Toya R , Murakami R , Baba Y , et al. Conformal radiation therapy for portal vein tumor thrombosis of hepatocellular carcinoma . Radiother Oncol 2007 ; 84 : 266 - 71 .
13. Yoon SM , Lim YS , Won HJ , et al. Radiotherapy plus transarterial chemoembolization for hepatocellular carcinoma invading the portal vein: long-term patient outcomes . Int J Radiat Oncol Biol Phys 2012 ; 82 : 2004 - 11 .
14. Kim JY , Yoo EJ , Jang JW , Kwon JH , Kim KJ , Kay CS . Hypofractionated radiotherapy using helical tomotherapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis . Radiat Oncol 2013 ; 8 : 15 .