Effectiveness and Safety of CT-Guided <sup>125</sup>I Brachytherapy for Lung Metastasis from Hepatocellular Carcinoma

doi:10.4236/ojrad.2013.33026

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Open Journal of Radiology, 2013, 3, 159-164

http://dx.doi.org/10.4236/ojrad.2013.33026 Published Online September 2013 (http://www.scirp.org/journal/ojrad)

Effectiveness and Safety of CT-Guided 125I Brachytherapy

for Lung Metastasis from Hepatocellular Carcinoma

Yongxin Chen1,2, Fei Gao1,2*, Lin Chen1,2, Sheng Peng1,2, Yingjie Huang1,2, Yao Wang 1,2

1Department of Interventional Radiology, Sun Yat-sen University Cancer, Guangzhou, China

2State Key Laboratory of Oncology in South China, Guangzhou, China

Email: *[email protected]

Received July 20, 2013; revised August 20, 2013; accepted August 27, 2013

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

To retrospectively evaluate effectiveness and safety of CT-guided 125I brachytherapy in patients with lung metastasis

from hepatocellular carcinoma, sixty lung metastatic lesions in 29 patients were percutaneously treated in 34 125I

brachytherapy sessions. Each metastatic lesion was treated with computed tomographic (CT) guidance. Follow-up con-

trast material-enhanced CT scans were reviewed and the efficacy of treatment was evaluated. Months are counted from

the first time of 125I brachytherapy and the median duration of follow-up was 11 months (ranging from 6 - 17 months).

The local control rates after 3, 6, 10 and 15 months were 86.2, 71.4, 60.9 and 50.0% respectively. At the time of writing,

ten patients are alive without evidence of recurrence at 11 - 15 months. The 10 patients presented good control of local

tumor and no systemic recurrence, and survived throughout the follow-up period. Other 11 patients died of multiple

hematogenous metastases 5 - 15 months after brachytherapy. A small amount of local hematoma occurred in 5 patients

that involved applicator insertion through the lung. Four patients presented pneumothorax with pulmonary compression

of 30% - 40% after the procedure and recovered after drainage. Two patients had minor displacement of radioactive

seeds. Severe complications such as massive bleeding and radiation pneumonitis did not occur. So CT-guided 125I

brachytherapy is effective and may be safely applied to lung metastasis from hepatocellular carcinoma.

Keywords: 125Iodine; Brachytherapy; Lung Metastasis; Hepatocellular Carcinoma

1. Introduction

Hepatocellular carcinoma (HCC) is a very highly inva-

sive tumor that metastasizes hematogenously and lym-

phogenously to distant sites. Most frequently affected

sites are the lungs, regional lymph nodes, bones, and

adrenal glands [1,2]. Since lung is the most common

metastatic organ for hepatocellular carcinoma, lung me-

tastasis is thus considered as a major prognostic factor

for these metastatic patients. However, treatment of lung

metastasis from hepatocellular carcinoma is usually chal-

lenging because the previous therapies (including surgery,

chemoembolization, radiofrequency ablation, and various

combinations of these treatments) limit the options avail-

able for subsequent treatment. 125I brachytherapy has

been widely applied for tumor treatment in clinic with

significant efficacy providing promising results for local

control of solid tumors such as prostate carcinoma, lung

cancer, HCC, liver metastasis and pancreatic cancer

[3-10]. When permanently implanted into the tumor, 125I

seeds send out continuous low-dose X-ray and γ-ray,

leading to a dose of 160 - 180 Gy within the local tissue

during the half-life of 125I. The killing radius of 125I seeds

is 1.7 cm, with minimal effects on normal tissues since

the radioactive energy is inversely correlated with the

square of the radius [4]. The specific effect of 125I radia-

tion on tumor cells can efficiently inhibit the prolifera-

tion and repair of tumor cells, while the surrounding

normal tissue only receives less than 25% of the doses

received by the tumor cells [8]. The slow emission of

radiation from the 125I seeds also allows the surrounding

normal tissue that receives sub-lethal or potentially lethal

dose of radiation to have sufficient time for repair and

recover [10].

However, there are few reports about the effects of

lung metastasis with the methods of 125I brachytherapy.

We considered the possibility that it might be an alterna-

tive treatment for lung metastasis. Especially for patients

whose condition is unsuitable for surgical resection, 125I

brachytherapy may provide an opportunity to achieve re-

mission. This research retrospectively evaluated the cli-

*Corresponding author.

Y. X. CHEN ET AL.

160

nical value of 125I brachytherapy for lung metastasis from

hepatocellular carcinoma.

2. Materials and Methods

2.1. Ethics

This work has been carried out in accordance with the

Declaration of Helsinki (2000) of the World Medical

Association. This study was approved ethically by Sun

Yat-sen University Cancer Center. All patients provided

informed written consent.

2.2. Patients

From March 2005 to March 2012, twenty-nine patients

underwent 125I brachytherapy of lung metastasis from

hepatocellular carcinoma. Twenty-two men and seven

women (mean age, 59 years; range, 35 - 76 years) were

enrolled in our study. All patients were pathologically

proved as hepatocellular carcinoma. Treatment of the

primary cancer were surgical resection in 16 patients,

surgical resection combined with chemoembolization in

5 patients, radiofrequency ablation in 3 patients, and ra-

diofrequency ablation combined with chemoemboliza-

tion in 5 patients. The lung metastatic lesions was seen

on computed tomographic (CT) images 6 - 13 months

(mean, 9 months) after the ﬁrst treatment of the primary

cancer.

Our diagnosis was conﬁrmed with pathologic proof at

CT-guided needle biopsy before 125I brachytherapy in all

patients. The mean size of the lung metastatic lesions

was 1.3 cm ± 0.7 (standard deviation) (range, 0.8 - 2.9

cm) in largest diameter. Our indication criteria for 125I

brachytherapy of lung metastatic lesions were as follows:

1) the metastatic lesion was solitary in the lung and the

patient was not a candidate for surgical resection; 2) the

number of lung metastatic lesions was not more than 3;

and 3) the lung metastasis was the only evidence of re-

currence.

2.3. Methods

The 125I seed (Beijing Atom High Tech) in this study was

shaped as cylindrical titanium package body with length

of 4.5 mm, diameter of 0.8 mm and 3.0 mm × 0.5 mm

inside the silver column (adsorption of 125I, radioactivity:

0.8 mci, the average energy: 27 - 35 keV, half-life: 59.6

days, half layer: 0.025 mm of lead; anti-tumor activity:

1.7 cm, the initial dose rate: 7 cGy/h), and 0.05 mm wall

thickness of titanium in its external shell.

Before 125I brachytherapy, CT images with 5 mm sec-

tion thickness were obtained for targeting the area of

interest. A treatment plan was made for each patient us-

ing a computerized treatment planning system (TPS)

(BT-RSI model TPS, YuanBo, Beijing, China) to deter-

mine the dose of radioactive seeds implanted and the

placed site. A careful delineation of the tumor target

volume was performed in every CT slice. Based on the

three perpendicular diameters within the target tumor and

a prescribed matched peripheral dose (MPD) of 100 -

140 Gy, TPS generated a dose-volume histogram (DVH),

isodose curves of different percentages, and calculated

the position (coordinates) of brachytherapy applicator,

dose and number of implanted seeds. Planning target

volume (PTV) is defined as a 1.5 cm of expansion exter-

nal to the gross tumor volume. PTV edge was covered by

isodose curve from 70% to 90% (Figure 1). The entry

site and path of the needle were determined to avoid vital

structures such as large vessels.

With CT (Siemens, Germeny) ﬂuoroscopic guidance, a

18G brachytherapy applicator (Beijing Atom High Tech)

was inserted into a lesion and positioned against its

deepest margin after local anesthesia. A turntable or clip

implant gun (Beijing Atom High Tech) was then attached

to the applicator for implantation. Every 125I seed was

placed at a distance of 0.5 - 1.0 cm from each other (Fig-

ures 2 and 3). Within one month, a CT scan was per-

Figure 1. Pre-planning of 125I brachytherapy. (A)

Two-dimensional image of tumor on computerized radioac-

tive treatment planning system (TPS), the PTV edge was

cov- ered by isodose curve from 70% to 90%. (B)

Three-dimen- sional graph of planar implantation and dose

distribution on TPS.

Y. X. CHEN ET AL. 161

formed to verify the position and intensity of 125I seeds

according to TPS (Figure 4). For tumors showing insuf-

ficient radioactivity, more 125I seeds were implanted.

2.4. Follow-Up

According to our follow-up protocol, chest CT images

were obtained each month before and after intravenous

administration of contrast medium for up to 6 months

and then at 2- to 3- month intervals (Figures 2, 3). The

efficacy of 125I brachytherapy was assessed according to

World Health Organization (WHO) response evaluation

criteria for solid tumor as follows. 1) Complete response

(CR) was defined as complete disappearance of tumor,

Figure 2. Case 1. (A) Lung metastasis from hepatocellular

carcinoma, as indicated by the arrowhead. (B) During

brachytherapy, an applicator accurately inserted into the

tumor to implant 125I seeds. (C) Three months after

brachytherapy, tumor disappeared, with well distributed

radioactive seeds remaining only, as indicated by the ar-

rowhead.

Figure 3. Case 2. (A) During brachytherapy, an applicator

accurately inserted into the tumor to implant 125I seeds. (C)

Three months after brachytherapy, tumor disappeared,

with well distributed radioactive seeds remaining only, as

indicated by the arrowhead.

Figure 4. Verification of post-125I brachytherapy. (A) Two-

dimensional image of tumor on TPS, the PTV edge was

covered by isodose curve from 70% to 90%. (B) Three-

Y. X. CHEN ET AL.

162

dimensional graph of planar implantation and dose distri-

bution on TPS.

no tumor or only accumulative metal granule shadow

detectable by imaging analysis. 2) Partial response (PR)

was defined as the shrinkage of tumor with the P value

decreasing by ≥50% compared to the pre-procedure

value. 3) No change (NC) was defined as a P value de-

crease of <50% or increase of <25% compared to the

pre-procedure value. 4) Progression of disease (PD) was

defined as a P value increase of ≥25% or the appearance

of new tumor foci. Local control rate (LCR) was calcu-

lated as cases of (CR + PR)/total × 100%. We com-

pared the products (P) of two largest and perpendicular

diameters within the tumor under CT examination before

and after the procedure.

3. Results

3.1. Implantation of 125I Radioactive Seeds

A total of 34 brachytherapies and 60 lung metastatic le-

sions were performed on the 29 patients, among which,

29 were successful at the first time, achieving the TPS

criteria, and 5 didn’t reach the TPS criteria, followed by

additional implantations. The total number of implanted

seeds was 493, with an average of 8.2 per tumor. The

satisfactory rate of seed implantation was 94.1% (32/34).

3.2. Treatment Efficacy

Months are counted from the first time of 125I brachy-

therapy and the median duration of follow-up was 11

months (range, 6 - 17 months). The local control rates

after 3, 6, 10 and 15 month were 86.2, 71.4, 60.9 and

50.0% respectively. The 15-month survival rate of our

study is 48.3% (14/29) excluding 4 patients who were

alive without evidence of recurrence at 11, 11, 12 and 14

months. At the time of writing, ten patients are alive

without evidence of recurrence at 11 - 15 months. The 10

patients presented good control of local tumor and no

systemic recurrence and survived throughout the fol-

low-up period. Eleven patients died of multiple hemato-

genous metastases 5 - 15 months after brachytherapy.

Among the 29 patients, 125I brachytherapy was repeated

in 6 patients because of local residue or local progression

of the lymph node. The clinical responses of patients to

brachytherapy were summarized in Table 1.

3.3. Side Effects

Several complications related to the procedure occurred

during or after brachytherapy. A small amount of local

hematoma occurred in 5 patients that involved applicator

insertion through the lung, probably because of injury of

small lung vessels. Four patients presented pneumotho-

rax with pulmonary compression of 30% - 40% after the

procedure and recovered after drainage. During the fol-

low-up, two patients had minor displacement of radioac-

tive seeds. Severe complications such as massive bleed-

ing and radiation pneumonitis did not occur.

4. Discussion

Extrahepatic metastases of HCC have been reported in

25 to 65 percent of autopsy series, with lung, bones, and

regional lymph nodes as the most commonly involved

sites and the most common site of metastasis is lung [2].

The prognosis of patients with extrahepatic metastases

remains poor. In two studies, the median survival time

was less than 7 months and the 1-year survival rate was

as low as 25% [11,12]. Although we recognize that our

study was small and had limited follow-up periods, the

survival rates seem promising. The 15-month survival

rate of our study is higher than the 1-year survival rate of

the above two studies. The results of our study seem bet-

ter compared with the above reports. At the time of this

writing, particularly encouraging is the outcome of 10

patients who are alive without evidence of recurrence for

11 - 15 months after 125I brachytherapy. For these pa-

tients, 125I brachytherapy has been curable treatment so

far. However, eleven patients died during follow-up. All

the 11 patients had multiple hematogenous metastases at

the time of follow-up, which resulted in death.

In our study, 125I brachytherapy for lung metastases is

not indicated if any uncontrollable recurrent foci are

recognized at the primary site. In these cases of HCC,

however, intrahepatic recurrences often occur and are not

regarded to be well controllable by re-resections or other

local treatments. In this series, we excluded patients with

a history of intrahepatic recurrences as candidates for 125I

brachytherapy when the intrahepatic recurrent tumors

could not be well controlled.

The success of 125I brachytherapy depends on the ac-

curate placement of radioactive seeds within a known

volume of tumor [13]. Using CT guidance, an image of

the implant volume can be seen and the position of each

implant needle can be adjusted to ensure proper place-

ment. In our study, the positions of the seeds are deter-

mined to provide a good dose distribution including a

Table 1. Clinical effectiveness of 125I brachytherapy on lung

metastasis.

Local control efficacy

Follow-up

time (months)

No. of

patients CRPR NC PD

Local control rate

(%)

(CR + PR)/Total

3 29 205 2 2 86.2%

6 28 164 3 5 71.4%

10 23 122 4 5 60.9%

15 14 6 1 1 6 50.0%

Y. X. CHEN ET AL. 163

Note—Months are counted from the time of ablation session. Four patients

who were alive without evidence of recurrence at 11, 11, 12 and 14 months

at the time of writing were excluded at 15 months of follow-up time.

minimum peripheral dose coverage, a uniform dose dis-

tribution, and the protection of surrounding tissues since

methods for calculating optimal seed locations are avail-

able [14,15]. The relative coordinates of the seeds are

then used for seed implantation within the lesions. Seeds

and spacers are ejected from the needle when the depth

of the needle specified by the plan is reached. Achieving

this desired seed placement is left to the surgeon, who

must take into account tissue deformations during the

implant process [16,17]. Also inserting and retracting a

needle in soft tissues cause the tissues to move, stretch

and deform. This displacement and distortion of the tu-

mor during the implantation result in misplaced seeds

[17].

During the procedure, with the guidance of CT, the

vital blood vessels and organs surrounding the tumor can

be clearly displayed, allowing better control of implant-

ing applicator and reducing the risk of damaging impor-

tant blood vessels. No severe complications such as mas-

sive bleeding occurred during procedure, suggesting it is

a safe procedure. To avoid radioactive damage on im-

portant organs such as vital blood vessels, the distance

between implanted seeds should not be less than 10 mm

to prevent accumulative radioactivity as a result of two

closely positioned seeds. A route with minimal invasion

into the lung tissue should be selected to reduce the risk

of inducing pneumothorax. After procedure, it is better to

keep patient hospitalized for 3 - 5 days and prospectively

prescribe antibiotics and hemostatics to reduce the inci-

dence of bleeding and infection.

Our study also had limitations that we only included

29 patients and followed them up for a maximum of 17

months. More cases and longer follow-up are desired for

future survival analysis. We also expect to carry out fur-

ther study on combining this local approach with sys-

temic approach for tumor treatment.

In summary, the application of 125I brachytherapy in

treating lung metastasis from hepatocellular carcinoma is

still in the developing stage. In this study, we found that

125I brachytherapy has satisfactory short- to mid-term

effect on controlling local lung metastasis, without se-

vere complications such as massive bleeding or other

complications associated with routine radiotherapy such

as bone marrow arrest, radiation pneumonitis, digestive

response or hair loss. Our study indicates that 125I bra-

chytherapy is a promising treatment for lung metastasis

from hepato- cellular carcinoma.

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Abbreviations:

Hepatocellular carcinoma (HCC)

Computed tomographic (CT)

Treatment planning system (TPS)

Matched peripheral dose (MPD)

Dose-volume histogram (DVH)

Planning target volume (PTV)

World Health Organization (WHO)

Complete response (CR)

Partial response (PR)

No change (NC)

Progression of disease (PD)

Local control rate (LCR)

Products (P)