The Chinese-German Journal of Clinical Oncology, June 2002, Vol. 1, No. 2 75

Percutaneous Ethanol Intratumoral Injection for Treatment of Small Primary Liver Cancer: Summary of 240 Cases

GUO J ia , C H E N H a n , Y A N G J i ame i , LI Bo , W U Mengchao

Objective To evaluate the therapeutic effects of percutaneons ethanol intraturnoral injection (PELT) for treatment of small primary liver

cancer (SPLC) . Methods 240 patients with surgically or pathologically proved SPLC ( < 3 cm in diameter) were treated by PElT (under the guidance of B-ultrasound). Of thd 240 patients, 163 had recurrent liver cancer, 55 had inoperable liver cancer because of cardiac, pulmonary, hepat- ic and renal dysfunctions or due to the close proximity of tumor to the major vessels, and 22 refused to receive surgical resection. In 40 pa- tients who received surgical resection after PEIT treatment, the resected tumors were pathologically evaluated for necrotic status and the pa-

tients were followed up postoperatively. Results Postoperative 1-, 2- and 3-year survival rate of the 240 patients was 94.9 %, 84.2% and 66.3 % respectively. Conclusion PEIT can be used as a non-invasive treatment for SPLC, and preoperative PEIT appears to be helpful in reducing recurrence

of postoperative liver cancer. Key words primary liver cancer; percntaneous ethanol; intratumoral; injection

T wo hundred and forty cases of small primary liver can-

cer (SPLC) were preoperatively treated by B-ultra- sound-guided percutaneous ethanol intratumoral injection

(PEIT) by using an ordinary inducer in our hospital from

April 1989 to October 2001. The outcomes have been satis-

factory.

Data and methodology

General data Of the 240 patients with SPLC ( < 3 cm in diameter),

198 were males and 42 were females (male to female ratio:

4 .7 : 1 ) with age ranging from 27 to 78 years (mean 5 2 . 5 ) . Of the 240 patients, 163 had recurrent liver cancer, 55 had

inoperable liver cancer because of cardiac, pulmonary, hep-

atic and renal dysfunctions or because of the technical diffi-

culties such as close proximity of tumor to the major vessels,

and 22 refused to receive surgical intervention, a- fetal pro- tein ( A F P ) was positive in 123 of these 240 patients

( 5 1 . 3 % ) .

Methodology Routine B ultrasound examination was performed and

clotting time was determined prior to the procedure. The pa- tient was advised to lie in horizontal or left lateral position,

depending on the location of the tumor. A 30 cm • 30 cm area around the puncture site was sterilized routinely, over

which a drape was spread. The ordinary B ultrasound induc-

er was sterilized by inserting it into a de-necked epoxy

ethane balloon. Under the guidance of ultrasound, local anesthesia with 2% lidocain was performed from the skin to

the liver capsule. Liver puncture was done from the posterior

of the inducer by using a 20 - 21 G PTC puncture needle.

Ultrasound Department, Eastern Hepatobiliary Surgery Hospitol, Second Military Medical University, Shanghai 200438, China

The moving direction of the needle and the position of the

needle tip can be seen clearly on the screen. When the nee-

dle penetrated the normal liver tissue and reached the tumor,

the stylet was pulled out and anhydrous alcohol was injected

into the tumor gently. The direction and position of the nee-

dle should be adjusted according to diffusion of the alcohol

in the tumor, avoiding penetrating the blood vessels. After

injection of the alcohol, the stylet was inserted and kept in

the same location for several seconds and then pulled out-

ward to the margin of the tumor for another several minutes.

The stylet was then further pulled out to 0 .5 - 1.0 cm under

the liver capsule. If there is no reflux of the injected drug i-

dentified, the needle can be pulled out completely. The

puncture point was covered with gauze, and the abdomen

was compression bandaged with an abdominal belt. The pa-

tient was observed for 30 rain after procedure was completed.

The similar treatments were prescribed once or twice a week

according to the condition and response of the patients. The

amount of alcohol was calculated based on the tumor size,

preferably 1 . 0 - 1 . 5 ml /cm. The dosage of alcohol is

preferably greater for the first injection and then reduced

gradually. The number of injections for each course of treat-

ment may be calculated on the basis of one time per centime-

ter of diameter + additional 1 - 2 times. In this series of

patients, each focus received 3 - 5 injections. When a

course of treatment was completed, the patient was observed

for 2 - 3 months and then received a general follow-up.

During the period of observation, repeat ultrasound examina-

tion and AFP check-up biweekly were performed. In case

having no evident shrinkage of the tumor or AFP failed to

drop to normal level, another course of treatment was start-

ed. In the present series, 46 patients received surgical re-

section 1 - 2 weeks after 1 - 4 time PEIT treatment. The

specimens of patients undergoing surgical resection were sent

to pathology department to evaluate tumor necrosis, and the

patients were followed up postoperatively to determine if

76 The Chinese-German Journal of Clinical (hlcology, June 2002, Vol. 1, No.2

recurrence take place within 3 years.

O b s e r v a t i o n indexes

The following criteria were used as observation indexes: 1) changes in tumor sizes pre- and post-treatment; 2) ad- verse reactions after treatment; 3 ) change of AFP levels, liver function and WBC and platelet count; 4) survival rate after treatment; and 5) pathological findings of the resected tumor specimens and postoperative recurrence.

Results

Most tumors began to shrink 1 - 2 months after PELT; there was no significant difference in shrinkage regardless of

the tumor size ( Table 1 ) . No tumor metastasis or local

Table 1 Shrinkage of tumors of different diameters after PElT treatment

Tumor diameter Cases (rl) Shrinkage (n) Percentage

1 - 2cm 77 40 51.9 2 - 3cm 163 91 55.8 TotN 240 131 54.6

infiltration due to PEIT treatment was found. No severe com- plications occurred in this series, however about 19% of pa- tients who received PEIT complained of chest distress, upper abdominal discomfort and pain, vomiting, dizziness and fever (temperature 38.5 ~ ) . AFP was positive in 123 pa- tients before treatment, and began to drop within about two weeks after PElT treatment were given in 84 patients (68.3 % ). Among these 84 patients, AFP levels turned to negative in 43 patients, with a conversion rate of 35 .0% (43/123) . No evidence of PElT treatment related impair- ment of the hepatic function was identified and hepatic func- tion tests for all patients were within the normal limits. In those patients who had poor hepatic function prior to the treatment, PElT in combination with liver protection treat- ment will control the tumor growth and kill the tumor cells in some cases as well, where liver function improved markedly, and postoperative WBC and platelet counts remained un- changed. The 1-, 2- and 3-year survival rate after PEIT treatment were 95 % (228/240) , 84 .2 % (202/240) and 66.3% (159/240) , respectively. In 46 patients who later received surgical resection the pathological findings on the tun,or resected are as follows : 13 cases with small numbers of residual cancer cells surrounding the major tmuors; 33 cases revealed extensive coagulative necrosis of the tumors, and the intratumoral portal veins showed thrombus with the occlusion of the vessels around the tumors and the tumor mass were well capsulated. The postoperative 1- and 2-year recurrence rate in these 46 patients was 17.4% (8/46) and 28 .3% (13 /46 ) respectively. Recurrence orrelapse was found in all patients of this series three years after PElT treatment. The new foci were managed with PElT once

again.

Discussion

Pathological features of small primary liver cancer

Pathologically, liver tumors < 3 cm in diameter are de- fined as SPLC, the pathological features of these tmnors are as follows: A complete capsule (capsule formation rate about 59 .7% ) is present; the tumor is mainly composed of cells with homogeneous consistency, with little bleeding, necrosis and fibrous tissue formation. With the tumor increasing in size, bleeding becomes visible; more necrosis and fibrous tissue formation will be seen; tumor becomes less cellular, heterogeneous, and the capsule formation rate is lower.

Princ ip le o f P E l T treatment Since Surgiural first reported the use of PEIT for treat-

ment of liver cancer in 1983, this non-invasive technique has drawn much attention and been used widely, especially for treatment of small liver cancer. Ebara et al equated the therapeutic effect of PElT with that of surgical operation for small liver cancer. PElT is based on the following princi- ples: When anhydrous alcohol is injected into the tumor, it immediately dehydrates the tumor cells and the vascular en- dothelial cells, causes coagulative necrosis of tumor, throm- bosis of the portal veins within in the focus and occlusion of the peripheral vessels, thus causing extensive ischemic and coagulative necrosis of the tumor tissue and formation of a relatively thick capsule around the tumor. The successful therapeutic effect of PEIT is consistent with the pathological features of small liver cancer: homogeneous consistency, lit- tle fibrous connective tissue and capsulazation. These char- acteristic features of small liver cancer enable anhydrous al- cohol to diffuse thoroughly within the tumor and causes tumor necrosis without causing apparent damage to the surrounding tissues. Preoperative use of PEIT can prevent tumor cells from metastasizing and tiny throndgi fi'om spreading in the liver when they are squeezed during the operation, whereby postoperative recurrence may be reduced.

Assessment of therapeutic effects

AFP decreased in 68.3% patients (84/123) and con- vetted to negativity in 35% patients ( 44/123 ) ; tumor shrinkage was found in 54 .6% patients ( 131/240). These findings suggest that PEIT has a direct killing effect on tumor ceils and indirect effect of treating tumors. The 1-, 2- and 3-year survival rate after PEIT treatment was 95%, 84.3% and 66.3 % respectively. Postoperative pathological study of 46 cases showed that PEIT is a viable option for radical or nearly radical treatment of small liver cancer. The 1- and 2- year recurrence rate in patients who received PElT treatment before surgical operation was 17.4% and 2 8 . 3 % respec- tively, suggesting that preoperative use of PElT may raise operability and reduce postoperative recurrence rate.

The Chinese-German Journal of Clinical Oncology, June 2002, Vol. 1, No.2 77

Postoperative morbidity and adverse reactions No serious PEIT treatment-related complications, tumor

metastasis and local infiltration or severe impairment to liver function were identified in this study. The adverse reaction rate was 19%, and most of side effects occurred in the early stage of treatment and disappeared gradually without any special interventions. Severity of these adverse reactions were dependent on psychological status of the patient and skills of the operaters who performed the procedure (For ex- ample, do not withdraw the needle too quickly or inject alcohol into blood vessels).

Indications PElT is indicated for patients with liver cancer who

have no evident ascites, no tendency of hemorrhage, tumor nodules are not greater than 3 in number and the tumor size is less than 3 cm in diameter, especially in candidates who are inoperable because of cardiac, pulmonary, hepatic and renal dysfunction, or because of the tumor proximal to the major vessels, and for inoperable recurrent tumors as well.

Advantages and disadvantages PElT is an easy procedure to perform as well as a flexi-

ble treatment with a high accuracy, good therapeutic effects and low morbidity. Even though it is widely accepted and used clinically at current time, it has its own limitations. Firstly, the therapeutic effect in patients with tumors > 3 cm is not quite satisfactory, possibly because larger tumors have increased fibrous connective tissue and heterogeneous consis- tency so that anhydrous alcohol is not able to diffuse homo- geneously inside the tumor; Secondly, the course of PElT treatment is relatively long due to repeated injections; Thirdly, ultrasound-guidance is needed when PEIT is per- formed.

Precautions The therapeutic effect of PEIT largely depends on accu-

rate puncture, the right anlOUnt of alcohol and the appropri- ate times of injections. Right judgment on the therapeutic ef- fect during the course of treatment is also critically impor- tant. The following four points may be used as the guidelines to judge whether the treatment is successful or not : ( 1 ) with increase in the times of injections, resistance of puncturing and injecting alcohol into the tumor is also increased; (2 ) ultrasound shows a high echo ring on the margin of the tu- mor, or a low echo halo, or both, and patchy changes with a very strong echo are seen inside the tumor; (3) shrinkage of the tumor is presently visible or AFP begins to drop grad- ually; and (4) CT scan shows low density changes in the tu- mor area, and injection of contrast medium does not induce early enhancement. If the tumor ceases to shrink or even be- comes large again, or a relatively low echo area is present a- gain in the focus, suggesting an incomplete treatment, the times of injections should be increased as the beginning of a

new course of treatment I53 .

References 1 Cong WM, Wu MC, Chen H, et al. Clinical pathology of small hepatocellu-

lar carcinoma. Chin J Tumor, 1993, 15 (5):372. 2 Sugiual N, Takara K, Ohto M, et al. Percutaneous intratumoral injection of

athanol under ultrasound imaging for treatment of small hepatocellular carci- noma. Acta Pepatol Jpn, 1983, 24:920.

3 Ebara N. Intratumoral injection of absolute elhanol for treatment of" ~kall hepatocellular carcinoma. Naika, 1988, 61:665.

4 Yah YQ, Yang JM, Tan JW, et al. Significance of intratumoral injection of ethanol in reducing postoperative recurrence of hepatocellular carcinoma. J Hepto Panc Sple Surg, 1997, 3 (2):74.

5 Yang JM, Lui P, Chen H, et al. Pereutaneous intratumoral injection of ethanol under ultrasound imaging for treatment of liver malignant tumors. Clinic Surg, 1992, ? (4):212.

( Received 2002-01-14)