Keywords HCC - hepatocellular carcinoma - iodine-131-lipiodol - neoplasm - transarterial radioembolization
Aakash Patel
Introduction
The purpose of this study is to present our experience regarding survival benefits
in inoperable intermediate stage hepatocellular carcinoma (HCC) and advanced stage
HCC treated with 131 I-lipiodol in 55 consecutive patients.
Materials and Methods
Approval was taken from the institutional ethics committee and written informed consent
was obtained from all patients. This is a retrospective study in HCC patients who
underwent transarterial radioembolization (TARE) between January 2014 and March 2017
at our institute. Patients with intermediate stage HCC (Barcelona Clinic Liver Cancer
[BCLC] stage B) not responding to prior treatment and/or advanced stage HCC (patients
with portal vein thrombosis [PVT]) (BCLC stage C) treated with 131 I-lipiodol were included in the study. For diagnosis of HCC the modified European
Association for Study of Liver (EASL) criteria was followed.[1 ] For all patients, baseline laboratory workup and imaging (computed tomography/positron
emission tomography [CT/PET]-CT/magnetic resonance imaging [MRI]) were performed.
The presence of PVT was recorded. The Child–Pugh and BCLC scores were calculated.
Patient selection : Intra-arterial 131 I-lipiodol therapy was given to BCLC stage B/C patients with Child–Pugh class A/B
cirrhosis having PVT evident on cross-sectional imaging (CT/PET-CT/MRI) or patients
without PVT not responding to prior treatment. Patients with Child–Pugh class A and
BCLC stage B, not suitable for curative procedure were considered for intra-arterial
131 I-lipiodol therapy. Patients with BCLC stage D, Child–Pugh class C cirrhosis, demonstrable
arteriovenous or arterioportal shunting on CT or digital subtraction angiography (DSA),
uncorrectable coagulopathy, and renal failure were excluded.
Technique : Intra-arterial 131 I-lipiodol therapy was performed under local anesthesia through transfemoral approach.
Introducer sheath (5F) (Terumo, Europe N.V.) was used to access the femoral artery.
Celiac artery and superior mesenteric artery were catheterized using 4F Yashiro catheter
(Terumo, Europe N.V.) or 4F Renal curve catheter (Terumo, Europe N.V.) and angiogram
obtained to delineate vascular anatomy and identify vessels supplying the tumor. Routine
DSA was performed in all patients and if there was arteriovenous or arterioportal
shunting the procedure was abandoned. The vessel supplying the tumor bed were super
selectively catheterized using 4F Yashiro catheter (Terumo, Europe N.V.) or 4F Renal
curve catheter (Terumo, Europe N.V.) or 2.7F microcatheter (Progreat, Terumo, Europe
N.V.) depending on the vascular anatomy. Doxorubicin (20 mg) was injected as a radiosensitizer
which was followed by slow injection of 7 to 10 mL 131 I-lipiodol (~50 mCi) under fluoroscopic control with adequate radiation protection.
In cases with extensive bilateral disease, infusion was started with catheter tip
in hepatic artery proper, distal to the gastroduodenal artery (GDA) origin to prevent
reflux into GDA. The injection was stopped when the lesion showed adequate lipiodol
fixation or if there was reflux into the normal branches. The puncture site was closed
using a closure device (Star closure device, Abbott Vascular, Illinois, United States)
and all radioactive lines were disposed as per radiation safety rules. Postprocedure,
the patient was isolated for 5 to 7 days and discharged after confirming the emitted
gamma radiation levels to be below 5 mR per hour. A scintigraphy scan was obtained
4 days after therapy to confirm tumor uptake of 131 I-lipiodol.
Patients did not receive any additional therapy after TARE for 6 to 8 weeks. All patients
underwent clinical, biochemical (serum alpha-fetoprotein [S.AFP]), and radiological
examination to evaluate tumor response after 4 weeks. Tumor response was graded according
to the EASL response criteria.[1 ]
Survival of patients was calculated up to either death or conclusion of the study.
Survival in patients who did not come for follow-up was calculated on the basis of
information provided by patient’s kin through telephonic calls.
Statistical analysis : Data were analyzed using a statistical analysis package (Social sciences, version
15.0 for Windows; SSPS Inc.). Survival data were plotted using Kaplan–Meier survival
curves.
Results
A total of 55 patients (52 males [94.5%], 3 females [5.4%]) were given intra-arterial
131 I-lipiodol therapy with a mean age of 63.9 ± 11.7 years (age range: 29–82 years).
Thirty-six patients (65.4%) belonged to Child–Pugh class A and 19 patients (34.5%)
belonged to class B. Nineteen patients (34.5%) belonged to BCLC stage B and 36 patients
(65.4%) belonged to BCLC stage C. Twenty-seven patients (49%) had PVT out of which
12 patients had branch PVT and 15 had main PVT. In 28 patients (50.9%) PVT was absent.
Twenty-four patients (43.6%) had extrahepatic spread on imaging (regional lymph node
enlargement) while 31 patients (56.3%) had a localized disease. Mean tumor size was
10.1 cm (range: 1.7–21.7 cm). For multifocal disease, the size of the largest lesion
was taken into consideration. Six patients (10.9%) had tumor of size < 5 cm, 20 patients
(36.3%) had tumor of size 5 to 10 cm, and 29 patients (52.7%) had tumor of size >
10 cm. Twenty patients (36.3%) had solitary lesion while 35 patients (63.6%) had multifocal
diseases at the time of treatment. Total 16 patients (29%) having a history of prior
treatment were treated with 131 I-lipiodol in our study. All patients with prior treatment had prior cycle/s of transarterial
chemoembolization (TACE). Out of these 16 patients, 5 had additional treatment with
tablet sorafenib, 2 patients had additional treatment with radiofrequency (RF) ablation,
and 2 patients had prior partial hepatectomy with recurrent disease. Twenty-nine patients
(52.7%) had elevated S.AFP values (> 300 ng/mL) and 26 patients (47.2%) had normal
S.AFP values at the time of treatment. Fifteen patients (27.2%) were hepatitis B positive
and 4 patients (7.2%) were hepatitis C positive.
Overall, the procedure was well tolerated by all our patients with mild intra-/postprocedural
toxicities ranging from pain, fever, nausea, vomiting, and loss of appetite occurring
in 43.6% of our patients. Only one patient in our study had severe postprocedural
complication in the form of hepatic abscess formation which was effectively managed
by parenteral antibiotics. This patient had a metallic biliary stent placement prior
to treatment to treat obstructive jaundice secondary caused by HCC.
Survival Data
At the end of follow-up period (January 2014–March 2017) 46 of 55 patients had died
with 9 patients alive.
Survival after TARE
The median overall survival after TARE was 172 ± 47 days (95% confidence limit, 79–264
days). The overall survival at 3, 6, 9, and 12 months was 69, 47, 32, and 29%, respectively.
We did not have any 30-day mortality.
The median survival in days after TARE in various groups is summarized in [Table 1 ]. Percentage survival at 6 and 12 months after TARE in various groups is summarized
in [Table 2 ].
Table 1
Summary of median survival in days
Summary of median survival in days
Survival since treatment
Survival since diagnosis
Median
95% confidence limit
p -Value
Median
95% confidence limit
p -Value
Abbreviations: BCLC, Barcelona Clinic Liver Cancer; PVT, portal vein thrombosis.
Overall
172
79–264
253
108–397
Child–Pugh class
Class A
217
108–325
0.715
253
97–408
0.729
Class B
133
104–161
222
0–521
BCLC stage
Stage B
134
42–225
0.703
338
147–528
0.283
Stage C
172
77–266
238
57–418
PVT
Present
169
122–215
0.319
194
124–263
0.05
Absent
184
0–444
397
274–519
Extrahepatic spread
Present
169
54–283
0.702
253
0–505
0.614
Absent
172
51–292
281
128–433
Prior treatment
With
427
334–519
0.034
750
515–984
< 0.001
Without
134
81–186
176
144–207
Size of lesion
< 5 cm
809 (mean)
543–1,075
0.005
1,824 (mean)
1,109–2,539
0.014
5–10 cm
217
96–337
253
74–431
> 10 cm
133
93–172
185
104–265
Number of lesion
Solitary
172
0–405
0.983
386
129–642
0.961
Multifocal
169
60–277
238
154–321
Table 2
Summary of percentage survival at 6 and 12 months
Percentage (%) survival
Survival since treatment
Survival since diagnosis
6 mo
12 mo
6 mo
12 mo
Abbreviations: BCLC, Barcelona Clinic Liver Cancer; PVT, portal vein thrombosis.
Child–Pugh class
Class A
55
33
66
38
Class B
31
21
63
42
BCLC stage
Stage B
47
26
68
63
Stage C
47
30
63
36
PVT
Present
40
18
59
22
Absent
53
39
71
57
Extrahepatic spread
Present
50
29
58
37
Absent
45
29
70
42
Prior treatment
With
68
56
100
87
Without
38
18
51
20
Number of lesion
Solitary
45
30
65
45
Multifocal
48.5
31.4
65.7
37.1
Child–Pugh class A patients with solitary lesion showed median survival of 322 days
± 138 days (95% confidence limit, 50–593 days) and those with multiple lesions showed
median survival of 217 days ± 55 days (95% confidence limit, 108–325 days). Child–Pugh
class B patients with solitary lesion showed median survival of 134 days ± 20 days
(95% confidence limit, 93–174 days) and those with multiple lesions showed median
survival of 114 days ± 40 days (95% confidence limit, 34–193 days) (log rank chi-square
= 0.033, p = 0.856).
Survival after Diagnosis
The overall median survival after TARE was 253 ± 73 days (95% confidence limit, 108–397
days). The survival at 3, 6, 9, and 12 months were 85, 65, 47, and 40%, respectively.
The median survival in days after diagnosis in various groups is summarized in [Table 1 ]. Percentage survival at 6 and 12 months after diagnosis in various groups is summarized
in [Table 2 ].
Factors Associated with Survival after Treatment
Factors Associated with Survival after Treatment
A multivariate Cox regression analysis with Child–Pugh class, BCLC stage, PVT, extrahepatic
spread, prior treatment, size of the lesion, and number of lesions as predictors for
overall survival showed the presence of prior treatment to most significantly influence
survival (B = 2.161, p ≤ 0.001) followed by size of the lesion which was second in line (B = 0.536, p = 0.034).
Response Evaluation
Response evaluation could not be done in 10 patients as they did not undergo follow-up
imaging. In the rest of the 45 patients, 14 patients (31.1%) showed a partial response
([Figs. 1 ] and [2 ]), 11 patients (24.4%) showed stable disease, and 20 patients (44.4%) showed progressive
diseases. All patients with partial response showed reduction in S.AFP levels.
Fig. 1 (A ) Contrast-enhanced computerized tomography (CECT) demonstrates hypervascular lesion
in segment 6 of liver. (B ) Lipiodol deposition after transarterial radioembolization (TARE) with 131 I-lipiodol within the hypervascular lesion. (C ) CECT after 1 month demonstrates lipiodol deposition with reduction in the enhancing
areas within the tumor. Patient was considered to have partial response.
Fig. 2 (A ) Contrast-enhanced computerized tomography (CECT) demonstrates two hypervascular
lesions in right lobe of liver. (B ) Lipiodol deposition after transarterial radioembolization (TARE) with 131 I-lipiodol within the hypervascular lesion. (C ) CECT of the patient after 1 month demonstrates lipiodol deposition with reduction
in the enhancing areas within the tumor. Patient was considered to have partial response.
On follow-up, 9 patients were given additional treatment with TACE and 5 patients
were started on systemic therapy with tablet sorafenib. In one of these patients,
severe toxicity necessitated stoppage of sorafenib therapy within 1 month.
Discussion
The Indian National Association for Study of the Liver modified BCLC staging system
is recommended for prognostic prediction and treatment allocation.[2 ]
[3 ] Curative treatment options in the form of liver resections, ablations, and liver
transplant are recommended for BCLC stage 0 and stage A patients. Resection of liver
tumors still play an important role and can be performed with acceptable mortality
and morbidity as R0 resection can be achieved in as many as 91.9% of patients in early
stages.[4 ]
The treatment options for inoperable intermediate stage HCC include TACE, TARE, and
stereotactic body radiation therapy (SBRT). Systemic therapy is reserved for advanced
stage HCC (2, 3 - Puri I and II).
TACE is the most widely used treatment option in patient with HCC who are unsuitable
candidates for curative management.[5 ] Efficacy of TACE for palliation of unresectable HCC has been demonstrated in several
studies, with overall survival rate at 1, 2, and 3 years being 66, 47, and 36.4%,
respectively.[6 ] TACE can also be combined with modalities like RF ablation and SBRT.
SBRT is an important addition in the treatment armamentarium in patients with inoperable
intermediate stage HCC.[7 ] Culleton et al[8 ] published a prospective study on 29 patients with HCC with Child–Pugh class B 7
and above. They reported that patients with Child–Pugh class B 7 have a significantly
higher median overall survival of 9.9 months versus 2.8 months in Child–Pugh class
B 8 and above patients (p = 0.011). They also suggested Child–Pugh class B 8 and above and AFP level of > 4,491
ng/mL were poor prognostic factors. All these suggested that patients with Child–Pugh
class B 8 and above should not be treated with SBRT as it may not improve outcome.
TARE can successfully be used in all patients in whom TACE is indicated; however,
superiority of TARE over TACE has not been documented in literature. In a meta-analysis
that compared clinical outcomes of TACE versus TARE in unresectable HCC, there was
no statistically significant difference in survival for up to 4 years between the
two groups.[9 ] TARE is probably more suitable in patient where TACE is contraindicated like patients
with PVT. Multiple radioactive substances have been tested which includes 131 I-lipiodol, rhenium-188, and glass-based and resin-based 90 Y microspheres. 131 I-lipioldol therapy is safe and effective palliative treatment for unresectable HCC.[10 ]
Very limited recent data are available regarding effectiveness of 131 I-lipiodol therapy. One of the studies showed the overall survival benefits of 131 I-lipiodol of approximately 69, 38, 22, and 14% at 6 months, 1, 2, and 3 years, respectively.[11 ] Recent studies regarding 131 I-lipiodol treatment in unresectable HCC reported median survival ranging between
7 and 27 months. The heterogeneous survival results can be explained by the selection
of patients for treatment. A study by Boucher et al[12 ] showed median survival of 27 months. In this study, a significant proportion of
patients were in the early stage of disease with a Cancer of the Liver Italian Program
score of 0 to 1, underwent two treatments, and had one or two tumors. Study by Kanhere
et al[13 ] showed median survival of 15 months and study by Borbath et al[14 ] showed median survival of 7 months. The poorer survival outcome in the study by
Borbath et al was likely attributed to the finding that a third of patients in that
group had evidence of PVT. In our study, the overall median survival was 172 ± 47
days (95% confidence limit, 79–264 days). The survival at 3, 6, 9, and 12 months were
69, 47, 32, and 29%, respectively, with the majority of patients (65.4%) having an
advanced stage of disease and 49% having PVT.
Our study showed patients having a history of prior treatment benefited more with
131 I lipiodol as compared with those treated upfront with 131 I-lipiodol. The reason for this could be selection of patients with more advanced
disease for upfront treatment with 131 I-lipiodol as compared with patients having prior treatment with TACE. Also, the initial
size of the tumor at the time of treatment influenced survival significantly, which
is of grave importance in developing countries where the majority of patients present
with large size of the tumor at the time of diagnosis. For better treatment outcome,
it is important to implement screening programs for HCC in high-risk patients like
in developed countries, which enable early detection and early treatment.
Other radionuclide therapies including 90 Y have also been reported to be effective therapies for HCC. 90 Y embedded microspheres tend to cost up to 10 times more than 131 I-lipiodol making it a significant limiting factor in population of developing countries.
Moreover, treatment with 90 Y embedded microspheres is a multistaged treatment process requiring two separate
treatment sessions for bilobar disease unlike in treatment with 131 I-lipiodol where a single injection in the hepatic artery proper will result in tumor
uptake in both lobes. In our study, advanced stage HCC patients showed median survival
of 172 days as compared with reported median overall survivals ranging from 6 to 10
months in patients with advanced stage HCC treated by 90 Y embedded microspheres.[15 ] Another study showed a median survival of 8.4 months in patients treated with TheraSphere
as compared with 7.8 months in patients treated with SIR-Sphere.[16 ] To our knowledge no randomized control trials exists comparing treatment with 131 I-lipiodol and 90 Y embedded microspheres in patients with unresectable HCC. In future treatment with
131 I-lipiodol and 90 Y embedded microspheres in patients with unresectable HCC should be evaluated in a
randomized control trial.
Conclusion
TARE with 131 I-lipiodol can be a safe and effective palliative treatment in advanced stage HCC
and in patients with poor response to prior treatments like TACE. TARE with 131 I-lipiodol is a cheaper alternative compared with TARE with 90 Y embedded microspheres in developing countries like India.
