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947
Progress
Percutaneous Ethanol Injection of Hepatocellular Carcinoma Shuichiro
Shiina,1
Kazumi
Tagawa,2
Tadao
Unuma,2
and
Hepatocellular carcinoma is one of the most common malignant neoplasms in the world, particularly in Asian and African countries [1 1. Recently, various imaging techniques, especially sonognaphy, and measurement of serum alphafetoprotein levels have been used successfully in the detection of these tumors. More and more early cases are being detected as a result of screening of high-risk groups, such as hepatitis B surface antigen carriers and patients with chronic liver disease. About two-thirds of hepatocellulan carcinomas found by screening of high-risk groups are unifocal and less than 3 cm in diameter [2, 3]. Curative surgical resection of the primary tumor in the liver has been the therapeutic technique most likely to result in complete remission and extended survival. The resectability rate of hepatocellulan carcinoma, however, has remained rather low. Most patients with hepatocellulan carcinoma have underlying liver cirrhosis and their severe liven dysfunction often makes hepatectomy impossible, even when the cancer is found in an early stage. The Liver Cancer Study Group in Japan reported that only 1382 (i 9%) of 7320 cases of primary liven cancer were nesectable [4]. When hepatocellulan carcinoma is unnesectable because of advanced cancer on poor surgical risk, transcatheter arterial embolization on chemotherapy has been a treatment of choice. However, the value of transcatheten arterial embolization is limited [5, 6]: even small hepatocellular carcinomas often invade the capsule (intencapsulan invasion) and sometimes extend beyond the capsule (extracapsulan invasion); transcatheten arterial embolization is ineffective against these
Received ‘Second
August 23, 1989; accepted after revision December 8, 1989. Department of Intemal Medicine, Faculty of Medicine, University
S. Shiina. 2 Department AJR 154:947-951,
of Gastroenterology, May
545-0947
© American
Akira
for the Treatment
Terano1
forms of extension. Long-term survival rates in patients treated by arterial embolization are low; Yamada et al. [7] reported that in 838 cases of hepatocellulan carcinoma treated with transcatheter arterial embolization, the 3- and 5-year survival rates were 1 2% and 6%, respectively. Results with standard chemotherapy for hepatocellulan carcinoma have also been far from satisfactory, with a response rate around 10% [8]. Sonognaphically guided percutaneous ethanol injection therapy was first reported in 1 983 by Sugiuna et al. [9] and has recently attracted a great deal of attention in the treatment of liver neoplasms [1 0-i 7]. In this procedure, absolute ethanol is injected into the lesion through a fine needle. Absolute ethanol has been widely used in various therapeutic procedures, such as transcatheter antenial embolization therapy of renal tumors [1 8], thnombotherapy of esophageal vanices [1 9], and percutaneous injection therapy of secondary hyperparathyroidism [20]. Absolute ethanol destroys tumor tissue mainly because of its dehydnative and protein degenerative effects and partly because of its thromboembolic effect [1 5]. Although some investigators have used other agents for injection therapy of hepatocellular carcinoma, such as immunochemothenapeutic agents [211 and chemotherapeutic agents [22], they were not as efficacious as absolute ethanol. In this review, we will discuss the indications and contraindications of percutaneous ethanol injection for treatment of hepatocellulan carcinoma, preparation of the patient, technical aspects, efficacy, and complications.
of Tokyo,
Mitsui Memorial Hospital, Kandaizumi-cho
1990 0361 -803X/90/1
Therapy
in Radiology
Roentgen
Hongo
7-3-1,
1, Chiyoda-ku, Tokyo Ray Society
Bunkyo-ku, 101, Japan.
Tokyo
113, Japan.
Address
reprint
requests
to
SHIINA
Downloaded from www.ajronline.org by 112.67.147.176 on 10/01/15 from IP address 112.67.147.176. Copyright ARRS. For personal use only; all rights reserved
948
ET AL.
AJR:154,
May 1990
Indications
Technique
Percutaneous ethanol injection therapy has been performed mainly in patients with hepatocellular carcinoma [9-17]. There also have been a few reports on the use of the therapy for the treatment of metastatic liven tumors [1 0, 1 4], cholangiocarcinoma [1 4], penitoneal lymph-node metastasis [1 4], adenomatous hyperplastic nodules in the cirrhotic liven [23], and tumor thrombosis of hepatocellular carcinoma in the portal vein [24]. Most investigators perform the therapy for tumors of up to 5 cm in diameter, although the optimal tumor size for ethanol injection is considered to be less than 3 cm in diameter. Histopathologic examination shows that areas of at least 3 cm in diameter are almost completely necrotic in all cases [1 1 1 2]. The injected ethanol may distribute only in a limited area; it may simply escape into the blood stream beyond this radius. Most investigators perform percutaneous ethanol injection for patients with up to three lesions, although single lesions are considered optimal for the therapy. In cases of larger tumors on multiple lesions, percutaneous ethanol injection can be performed to reduce the tumor bunden. In such cases, the tumor frequently invades vessels involved by intrahepatic metastasis. Therefore, ethanol injection, which has only local effect, should be combined with transcatheten arterial embolization. Specifically, the main tumon or tumors should be treated by the combination of ethanol injection and arterial embolization; lesions that cannot be detected by sonography should be controlled by arterial embolization. Percutaneous ethanol injection can be performed not only in patients with Child class A or B disease, but also in patients with Child class C disease (Table i) [25], as the change in liver function after ethanol injection is only mild and transient.
Preliminary sonognams should be obtained to select the optimal approach. The patient should fast for at least 6 hr before the therapy and should be given premedications for analgesia and sedation. The tumor puncture is usually performed with a 21 - on 22gauge, 1 5- on 20-cm puncture needle suitable for sonognaphic guidance. The shorter needle is easier to control than the longer one. Sterile physiologic saline is used as the coupling agent for the sonography. The lesion is scanned with a puncture transducen and the site for insertion of the needle is selected. After local anesthesia is administered, the puncture needle is introduced into the lesion under sonographic observation. It is critical to introduce the needle without bending it. Any deviation from the scanning plane makes it difficult to observe the needle tip and to puncture the lesion. During insertion of the needle, the patient is asked to hold his or her breath in the proper phase of respiration. Absolute ethanol is injected under sonognaphic observation. Ethanol is injected into the lesion at one on more locations in one treatment session. If influx of the ethanol into vessels on bile ducts is observed, the injection is stopped immediately to avoid injury of the vessels on the bile ducts. In order to reduce neflux of the injected ethanol through the puncture track into the peritoneal cavity, which is probably the main cause of abdominal discomfort, the needle is left in place for a few minutes after the injection. In most cases, 2-8 ml of ethanol is injected in one treatment session and the injection is repeated two or three times pen week until the sum of the injected ethanol reaches the intended volume [9-i 7]. The total volume of ethanol that should be injected is calculated according to the formula
,
V
=
4/31r(n + 0.5)
(ml),
Contraindications Patients with ascites, a marked bleeding tendency, on extrahepatic metastasis are excluded from percutaneous ethanol injection. Absence of ascites must be confirmed by sonognaphy, and the prothrombin time and platelet count must be checked before the therapy. The procedure is performed only in patients whose prothnombin time is more than 35% and whose platelet count is more than 40,000/mm3. TABLE
1: Condition of Patients of Child [25]
According
to Liver Disease
Classification
Category Variable
B,
c,
A, Minimal
Moderate
Advanced
Nutrition
Excellent
Good
Poor, “wasting”
Encephalopathy
None
Minimal
Ascites
None
Easily controlled
Serum bilirubin (mg/dl) Serum albumin (g/dl)
Below
2
2-3
Advanced, “coma” Poorly controlled Over 3
Over
3.5
3-3.5
Below 3
where V is the volume of ethanol and r is the radius (in centimeters) of the lesion. Addition of the 0.5 (cm) provides a safety margin, which is based on the concept that a certain amount ofthe surrounding tissue at the periphery ofthe lesion as well as the lesion itself must be destroyed to ensure cure of the lesion. For example, 1 3.5 ml of ethanol should be injected into a lesion 2.0 cm in diameter and 32 ml should be injected into a lesion 3.0 cm in diameter. However, the volume and number of injections are modified depending on patient compliance, lesion location, and postcontrast CT findings after therapy. It usually takes only 1 0-20 mm to complete the procedure. After therapy, the patient should remain in bed for at least 3 hr.
Complications Common adverse effects of percutaneous ethanol injection are transient pain at the site of the injection, fever, and alcohol intoxication. None of these requires any special treatment. The pain and fever can be reduced to a great degree by leaving the needle in place for a few minutes after the injection, which prevents reflux of the injected ethanol into the penitoneal cavity.
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AJR:154,
ETHANOL
May 1990
THERAPY
IN HEPATOCELLULAR
The alterations in liver function that follow ethanol injection are much milder than changes that occur after surgical resection or transcatheter arterial embolization. Thus, ethanol injection can be considered even in cases of advanced liver cirrhosis. Serious complications reported are intrapenitoneal hemorrhage due to necrosis of the tumor [1 2], ascites [1 3], right pleural effusion [1 3], jaundice due to hepatic decompensation [1 3], intrapenitoneal hemorrhage due to the injury of a vessel in the omentum that covered the atrophic liver [15], jaundice probably due to injury of a bile duct [15], hepatic infarction probably due to influx of the ethanol into vessels [15], and transient hypotension [15]. Fujimoto [15] reported that major complications occurred in eight (2.8%) of 289 procedures. There have been no reports of metastasis or local dissemination of tumor occurring after percutaneous ethanol injection. An animal experiment [15] showed that injected ethanol damages the cancer cells immediately, which suggests that metastasis on dissemination does not occur easily with this procedure. No deaths directly related to ethanol injection have been reported.
Histopathologic
Evaluation
of Efficacy
The short-term efficacy of the therapy is best evaluated by histopathologic examination. We have examined 1 3 cases in this way and found that the lesion was completely necrotic in nine cases, 90% necrotic in three cases, and 70% necrotic in the other case [1 1 1 2]. Other investigators also found that percutaneous ethanol injection destroyed the lesion completely in most cases. Sheu et al. [1 3] found that in the six patients who subsequently underwent surgical resection, four had complete necrosis of the tumor and the other two had only a small peripheral residual of viable tumor remaining. Suyama et al. [14] found that the tumor showed complete necrosis in two of the six cases that were histopathologically examined. Fujimoto [1 5] reported that complete necrosis of the tumor was observed in two of the four resected cases after percutaneous ethanol injection. Livraghi et al. [1 7] reported that no viable tumor cells were detected in four patients who subsequently underwent surgery. The size of the lesion, presence or absence of internal septation, volume of injected ethanol, and accuracy of the injection are the major factors that determine whether the lesion becomes completely necrotic or not. In our previous study [1 1 1 2], histopathologic examination also showed that the capsule and a certain amount of the surrounding tissue as well as the tumor itself degenerate in response to the alcohol (Fig. 1). This finding proves that, unlike transcatheter arterial embolization [26], ethanol injection can be effective for intencapsular and extracapsular invasion. The fact that ethanol injection is efficacious for these forms of extension, which are frequently found even in small hepatocellular carcinomas, is important if cure is to be expected. In the four cases in which some portion of the tumor was found intact in our previous study [ii, 12], the viable tumor tissue was along the edge of the lesion, in portions isolated by septa or in daughter nodules. Therefore, ethanol should ,
,
CARCINOMA
949
-,
,4
“:
I
Fig. 1.-Macroscopic ethanol injection of amount of surrounding
appearance of fixed resected liver specimen after hepatocellular carcinoma. Capsule and a certain liver parenchyma as well as tumor are necrotic.
be injected not only into the center of the tumor but also into sites close to the edge. The value of fine-needle biopsy in following the results of ethanol injection, although it is definitively capable of indicating necrosis of the tumor, is limited because the tissue obtained by the biopsy does not always represent that of the entire tumor. Imaging Injection
Techniques
to Evaluate
the Results
of Ethanol
Evaluation
with radiologic imaging is important to determine tumor is completely necrotic and to detect any recurrence early. CT with contrast enhancement and angiography are the most useful for this purpose [5]. In our previous study [1 2], treated lesions did not enhance after IV contrast administration in CT examinations performed 1-6 months after the therapy, a period corresponding to devasculanization of the lesions (Fig. 2). Angiography penformed 3-6 months after therapy did not show tumor stain in any case (Fig. 3). Neither of these procedures showed evidence of viable cancer tissue in any case during that period. Complete necrosis is likely if the normal liver tissue at the periphery of the tumor does not enhance on CT scans. Although the sonographic features of the tumor change after ethanol injection, sonognaphy cannot be used to confirm complete necrosis of the tumor. In general, hypoechoic tumors become hyperechoic and hyperechoic tumors become heterogeneous after ethanol injections (Fig. 4) [i 2]. To detect any growth of a small amount of viable tumor, periodic imaging studies are essential. If recurrence of the tumor is detected, the lesion can be retreated by percutaneous injection of ethanol. if the treated
Evaluation
of Efficacy
by Serum
Tumor
Markers
Serum tumor markers such as alpha-fetoprotein and plasma-abnormal prothrombin [27] are useful to evaluate the efficacy of percutaneous ethanol injection providing the markers are elevated before treatment. In our study [12], serum
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Fig. 2.-Hepatocellular carcinoma. A, Before ethanol injection. T scan with contrast enhancement shows hypodense solitary mass B, 2 weeks after six injections. CT scan shows completely nonenhanced area in right lobe. C, 1 year after treatment. CT scan shows decrease in size of nonenhanced area.
in right lobe.
Fig. 3.-Hepatocellular carcinoma. A, Before ethanol injection. Angiogram shows tumor stain 2 cm in diameter in right lobe (ar. rows). B, 6 months after treatment. Tumor stain no longer exists (arrows).
Fig. 4.-Hepatocellular carcinoma. A, Before ethanol injection. Sonogram shows hyperechoic lesion in right lobe (arrows). B, 1 week after six injections. Lesion is heterogeneous and its margin is indistinct (arrows).
alpha-fetoprotein levels decreased after therapy with a single lesion, if the serum alpha-fetoprotein more than 100 ng/ml before therapy. Long-term
Survival
in all cases level was
Rates
The follow-up periods have not been long enough to compare the long-term survival rates of patients treated by ethanol injection with those of patients treated by other techniques.
To date, the best study on long-term survival rates of patients treated by percutaneous ethanol injection is that of Ebana et al. [16]. They treated 59 cases of hepatocellular carcinoma in which the diameter of the tumor was 3 cm or less and the number of the lesions was not more than three by ethanol injection. They reported that the 1-, 2-, 3-, and 4year survival rates were 96%, 86%, 79%, and 79%, respectively. They compared these long-term survival rates with
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those of 41 patients with tumors 3 cm who underwent surgical resection and patients treated by ethanol injection had survival rates than those who underwent though they used historical controls and was only 4 years, the results suggest ethanol injection can be an alternative curative treatment of small hepatocellulan et al. [i 7] reported that the 1 -year survival was 92%. Randomized trials to compare rates of patients treated by percutaneous with those of patients treated by other been conducted. New Devices and Methods Injection Therapy
or less in diameter concluded that the significantly higher hepatectomy. Althe follow-up period that percutaneous to surgery for the carcinoma. Livraghi rate of 12 patients long-term survival ethanol injection therapies have not
for Percutaneous
Cancer i986;57: 1184-1191 7. Yamada A. Kitayama K, Sato M, et al. Transcatheter in the treatment of primary liver cancer. In: Diseases
Ethanol
REFERENCES meeting. In: World Health World Health Organization, of hepatocellular
carcinoma
during a clinical follow-up of chronic liver disease. Gastroenterology 1978;74:578-580 3. Uaw YF, Tai Dl, Chu CM, et al. Early detection of hepatocellular carcinoma in patients with chronic type B hepatitis. Gastroenterology i986;90: 263-267 4. Liver Cancer Study Group of Japan. Survey and follow-up study of primary liver cancer in Japan, report 8. Kyoto: Shinko-insatsu, i988:63-85 5. Nakamura H, Tanaka T, Hon 5, et al. Transcatheter embolization of
arterial embolization of the liver and biliary
system, vol. 2. Tokyo: Nihon Ainsho, 1988: 161 -1 66 8. Bhardwaj 5, Bruckner HW, Holland JF. Therapy of malignant tumors the liver. In: Berk JE, Haubrich WS, Kaiser MH, Roth JLA, Schaffner
9.
10.
For the treatment to be effective, the tip of the puncture needle must be accurately placed in the lesion. However, after repeated injections, the tumor often becomes difficult to identify. To solve this problem, Sheu et al. [28] implanted one on more small steel coils into the tumor before treatment. Even after the sonognaphic image of the tumor was obscured, they could still inject ethanol on the basis of the location of the coil. Their procedure, however, seems to be rather complicated. They have to puncture the lesion twice, first to place the coil and second to inject ethanol. Furthermore, they have to use relatively thick needles (1 8-gauge) so that the coil can be delivered through the needles. We have found that a small amount of Gelfoam powder (Upjohn Co., Kalamazoo, Ml) injected in the lesion can serve as a marker for ethanol injection [29]. As yet, percutaneous ethanol injection therapy has been limited to small lesions, because it is virtually impossible to inject ethanol throughout large lesions. However, if ethanol and Gelfoam are injected through the same needle, the exact place where the ethanol is injected can be identified afterward. Thus, by using the Gelfoam injection as a marker, it might be possible to inject ethanol into every part of large tumors. Sheu et al. [28] designed a new puncture needle with multiple side holes to achieve more homogeneous and even distribution of the ethanol. Ido et al. [30] injected ethanol into the tumor under peritoneoscopic sonographic guidance. With this procedure, the patient did not need to hold his on hen breath and the needle could be placed in the lesion for a long period. Thus, a large amount of ethanol could be injected at once, which enabled them to complete the therapy in one treatment session. Hirano et al. [31 ] reported that injection of a mixture of Lipiodol and ethanol showed the area of necrosis more accurately with CT.
1. Prevention of liver cancer: report of WHO Organization technical report series. Geneva: 1983:7-8 2. Kubo Y, Okuda K, Musha H, et al. Detection
hepatocellular carcinoma: assessment of efficacy in cases of resection following embolization. Radiology 1983; 147:401-405 6. Hsu HC, Wei TC, Tsang YM, et al. Histological assessment of resected hepatocellular carcinoma after transcatheter hepatic arterial embolization.
11.
12. 13.
14.
1 5.
16. 17.
18.
of F,
eds. Bockus gastroenterology, 4th ed. Philadelphia: Saunders, 1985: 3388-3397 Sugiura N, Takara K, Ohto M, et al. Percutaneous intratumoral injection of ethanol under ultrasound imaging for treatment of small hepatocellular carcinoma. Acta HepatolJpn i983;24:920 Livraghi T, Festi D, Monti F, Salmi A, Vettori C. US-guided percutaneous alcohol injection of small hepatic and abdominal tumors. Radiology 1986;161 :309-312 Tagawa K, Muto H, Yasuda H, Unuma T, Shiina S. Therapeutic effects of ultrasonically guided ethanol injection for treatment of hepatocellular carcinoma. Jpn J Med Ultrasonics i987;14:743-744 Shiina 5, Yasuda H, Muto H, et al. Percutaneous ethanol injection in the treatment of liver neoplasms. AJR i987;149:949-952 Sheu JC, Sung JL, Huang GT, et al. Intratumor injection of absolute ethanol under ultrasound guidance for the treatment of small hepatocellular carcinoma. Hepatogastroenterology i987;34: 255-261 Suyama V. Horishi M, Ebisui 5, et al. US guided intratumoral ethanol injection therapy to small liver cancer: clinical evaluation for twenty cases. Nippon Gan Chiryo Gakkai Shi 1987;22:818-826 Fujimoto T. The experimental and clinical studies of percutaneous ethanol injection therapy (PElT) under ultrasonography for small hepatocellular carcinoma. Acta Hepatol Jpn 1988;29:52-59 Ebara M, Nihei T, Ohto M. Intratumoral injection of absolute ethanol for treatment of small hepatocellular carcinoma. Naika 1988;61 :665-669 Livraghi T, Salmi A, Bolondi L, et al. Small hepatocellular carcinoma: percutaneous alcohol injection-results in 23 patients. Radiology 1988;168:313-317 Ellman BA, Parkhill BJ, Curry TS, et al. Ablation of renal tumors with
absolute ethanol: a new technique. Radiology i981;141 1 9. Yune HY, Klatte EC, Richmond BD, Rabe FE. Absolute
:619-626 ethanol
in throm-
botherapy of bleeding esophageal varices. AJR i982;138: 1137-1141 20. Solbiati L, Giangrande A, Pra LD, Bellotti E, Cant#{227} P. Ravetto C. Percutaneous ethanol injection of parathyroid tumors under US guidance: treatment for secondary hyperparathyroidism. Radiology i985;1 55:607-610 21 . Imaoka 5, Sasaki Y, Matsui Y, et al. Evaluation of intratumoral injection of an immunoprotentiator (OK-432) in patients with hepatocellular carcinoma. Nippon Gan Chiryo Gakkai Shi i982; 17:1957-1962 22. Onodera H, Oikawa M, Abe M, Chida N, Kimura 5, Gotoh Y. tJtrasonographically guided percutaneous direct injection therapy for unresectable hepatoma. Jpn J Clin Radiol 1986:31 : 1461 -1 464 23. Uvraghi T, Sangalli G, vetted c. Adenomatous hyperplastic nodules in the cirrhotic liver: a therapeutic approach. Radiology i989;1 70:155-157 24. Shinagawa T, lino Y, Ukaji H, et al. Percutaneous ethanol injection in the treatment of portal tumor thrombus in hepatocellular carcinoma. Acta Hepatol Jpn i989;30: 109 25. Child CG Ill. Hepatic circulation and portal hypertension. Philadelphia: Saunders, 1954 26. Kobayashi T, Ohto M, Sumida M, et al. A clinical and histopathological study on therapeutic effects of transcatheter arterial embolization for small hepatocellular carcinoma. Nippon Shokakibyo Gakkai Zasshi i983;80: 2574-2583 27. Fujiyama 5, Morishita T, Hashiguchi 0, Sato T. Plasma abnormal prothrombin (des-gamma-carboxy prothrombin) as a marker of hepatocellular carcinoma. Cancer i988;61 :1621-1628 28. Sheu JC, Huang GT, Chen D5, et al. Small hepatocellular carcinoma: intratumor ethanol treatment using new needle and guidance systems. Radiology i987;163:43-48 29. Shiina 5, Komatsu V. Shiratori V. et al. Sonographically guided percutaneous injection of ethanol for treatment of hepatocellular carcinoma: value 30.
31.
of Gelfoam to mark the lesion (letter). AJR i989;153:430 Ido K, Hitomi N, Kawamoto T, Tanaka H, Ohtani M, Kimura K. Ethanol injection therapy for the treatment of small hepatocellular carcinoma under peritoneoscopic ultrasound guidance. Acta HepatolJpn i988;29: 1121 Hirano M, Tohara K, Sakaguchi 5, Okumura M. Therapeutic percutaneous injection of lipiodol-ethanol solution for hepatocellular carcinoma. Acta Hepatol Jpn i989;30:383-384
947
Progress
Percutaneous Ethanol Injection of Hepatocellular Carcinoma Shuichiro
Shiina,1
Kazumi
Tagawa,2
Tadao
Unuma,2
and
Hepatocellular carcinoma is one of the most common malignant neoplasms in the world, particularly in Asian and African countries [1 1. Recently, various imaging techniques, especially sonognaphy, and measurement of serum alphafetoprotein levels have been used successfully in the detection of these tumors. More and more early cases are being detected as a result of screening of high-risk groups, such as hepatitis B surface antigen carriers and patients with chronic liver disease. About two-thirds of hepatocellulan carcinomas found by screening of high-risk groups are unifocal and less than 3 cm in diameter [2, 3]. Curative surgical resection of the primary tumor in the liver has been the therapeutic technique most likely to result in complete remission and extended survival. The resectability rate of hepatocellulan carcinoma, however, has remained rather low. Most patients with hepatocellulan carcinoma have underlying liver cirrhosis and their severe liven dysfunction often makes hepatectomy impossible, even when the cancer is found in an early stage. The Liver Cancer Study Group in Japan reported that only 1382 (i 9%) of 7320 cases of primary liven cancer were nesectable [4]. When hepatocellulan carcinoma is unnesectable because of advanced cancer on poor surgical risk, transcatheter arterial embolization on chemotherapy has been a treatment of choice. However, the value of transcatheten arterial embolization is limited [5, 6]: even small hepatocellular carcinomas often invade the capsule (intencapsulan invasion) and sometimes extend beyond the capsule (extracapsulan invasion); transcatheten arterial embolization is ineffective against these
Received ‘Second
August 23, 1989; accepted after revision December 8, 1989. Department of Intemal Medicine, Faculty of Medicine, University
S. Shiina. 2 Department AJR 154:947-951,
of Gastroenterology, May
545-0947
© American
Akira
for the Treatment
Terano1
forms of extension. Long-term survival rates in patients treated by arterial embolization are low; Yamada et al. [7] reported that in 838 cases of hepatocellulan carcinoma treated with transcatheter arterial embolization, the 3- and 5-year survival rates were 1 2% and 6%, respectively. Results with standard chemotherapy for hepatocellulan carcinoma have also been far from satisfactory, with a response rate around 10% [8]. Sonognaphically guided percutaneous ethanol injection therapy was first reported in 1 983 by Sugiuna et al. [9] and has recently attracted a great deal of attention in the treatment of liver neoplasms [1 0-i 7]. In this procedure, absolute ethanol is injected into the lesion through a fine needle. Absolute ethanol has been widely used in various therapeutic procedures, such as transcatheter antenial embolization therapy of renal tumors [1 8], thnombotherapy of esophageal vanices [1 9], and percutaneous injection therapy of secondary hyperparathyroidism [20]. Absolute ethanol destroys tumor tissue mainly because of its dehydnative and protein degenerative effects and partly because of its thromboembolic effect [1 5]. Although some investigators have used other agents for injection therapy of hepatocellular carcinoma, such as immunochemothenapeutic agents [211 and chemotherapeutic agents [22], they were not as efficacious as absolute ethanol. In this review, we will discuss the indications and contraindications of percutaneous ethanol injection for treatment of hepatocellulan carcinoma, preparation of the patient, technical aspects, efficacy, and complications.
of Tokyo,
Mitsui Memorial Hospital, Kandaizumi-cho
1990 0361 -803X/90/1
Therapy
in Radiology
Roentgen
Hongo
7-3-1,
1, Chiyoda-ku, Tokyo Ray Society
Bunkyo-ku, 101, Japan.
Tokyo
113, Japan.
Address
reprint
requests
to
SHIINA
Downloaded from www.ajronline.org by 112.67.147.176 on 10/01/15 from IP address 112.67.147.176. Copyright ARRS. For personal use only; all rights reserved
948
ET AL.
AJR:154,
May 1990
Indications
Technique
Percutaneous ethanol injection therapy has been performed mainly in patients with hepatocellular carcinoma [9-17]. There also have been a few reports on the use of the therapy for the treatment of metastatic liven tumors [1 0, 1 4], cholangiocarcinoma [1 4], penitoneal lymph-node metastasis [1 4], adenomatous hyperplastic nodules in the cirrhotic liven [23], and tumor thrombosis of hepatocellular carcinoma in the portal vein [24]. Most investigators perform the therapy for tumors of up to 5 cm in diameter, although the optimal tumor size for ethanol injection is considered to be less than 3 cm in diameter. Histopathologic examination shows that areas of at least 3 cm in diameter are almost completely necrotic in all cases [1 1 1 2]. The injected ethanol may distribute only in a limited area; it may simply escape into the blood stream beyond this radius. Most investigators perform percutaneous ethanol injection for patients with up to three lesions, although single lesions are considered optimal for the therapy. In cases of larger tumors on multiple lesions, percutaneous ethanol injection can be performed to reduce the tumor bunden. In such cases, the tumor frequently invades vessels involved by intrahepatic metastasis. Therefore, ethanol injection, which has only local effect, should be combined with transcatheten arterial embolization. Specifically, the main tumon or tumors should be treated by the combination of ethanol injection and arterial embolization; lesions that cannot be detected by sonography should be controlled by arterial embolization. Percutaneous ethanol injection can be performed not only in patients with Child class A or B disease, but also in patients with Child class C disease (Table i) [25], as the change in liver function after ethanol injection is only mild and transient.
Preliminary sonognams should be obtained to select the optimal approach. The patient should fast for at least 6 hr before the therapy and should be given premedications for analgesia and sedation. The tumor puncture is usually performed with a 21 - on 22gauge, 1 5- on 20-cm puncture needle suitable for sonognaphic guidance. The shorter needle is easier to control than the longer one. Sterile physiologic saline is used as the coupling agent for the sonography. The lesion is scanned with a puncture transducen and the site for insertion of the needle is selected. After local anesthesia is administered, the puncture needle is introduced into the lesion under sonographic observation. It is critical to introduce the needle without bending it. Any deviation from the scanning plane makes it difficult to observe the needle tip and to puncture the lesion. During insertion of the needle, the patient is asked to hold his or her breath in the proper phase of respiration. Absolute ethanol is injected under sonognaphic observation. Ethanol is injected into the lesion at one on more locations in one treatment session. If influx of the ethanol into vessels on bile ducts is observed, the injection is stopped immediately to avoid injury of the vessels on the bile ducts. In order to reduce neflux of the injected ethanol through the puncture track into the peritoneal cavity, which is probably the main cause of abdominal discomfort, the needle is left in place for a few minutes after the injection. In most cases, 2-8 ml of ethanol is injected in one treatment session and the injection is repeated two or three times pen week until the sum of the injected ethanol reaches the intended volume [9-i 7]. The total volume of ethanol that should be injected is calculated according to the formula
,
V
=
4/31r(n + 0.5)
(ml),
Contraindications Patients with ascites, a marked bleeding tendency, on extrahepatic metastasis are excluded from percutaneous ethanol injection. Absence of ascites must be confirmed by sonognaphy, and the prothrombin time and platelet count must be checked before the therapy. The procedure is performed only in patients whose prothnombin time is more than 35% and whose platelet count is more than 40,000/mm3. TABLE
1: Condition of Patients of Child [25]
According
to Liver Disease
Classification
Category Variable
B,
c,
A, Minimal
Moderate
Advanced
Nutrition
Excellent
Good
Poor, “wasting”
Encephalopathy
None
Minimal
Ascites
None
Easily controlled
Serum bilirubin (mg/dl) Serum albumin (g/dl)
Below
2
2-3
Advanced, “coma” Poorly controlled Over 3
Over
3.5
3-3.5
Below 3
where V is the volume of ethanol and r is the radius (in centimeters) of the lesion. Addition of the 0.5 (cm) provides a safety margin, which is based on the concept that a certain amount ofthe surrounding tissue at the periphery ofthe lesion as well as the lesion itself must be destroyed to ensure cure of the lesion. For example, 1 3.5 ml of ethanol should be injected into a lesion 2.0 cm in diameter and 32 ml should be injected into a lesion 3.0 cm in diameter. However, the volume and number of injections are modified depending on patient compliance, lesion location, and postcontrast CT findings after therapy. It usually takes only 1 0-20 mm to complete the procedure. After therapy, the patient should remain in bed for at least 3 hr.
Complications Common adverse effects of percutaneous ethanol injection are transient pain at the site of the injection, fever, and alcohol intoxication. None of these requires any special treatment. The pain and fever can be reduced to a great degree by leaving the needle in place for a few minutes after the injection, which prevents reflux of the injected ethanol into the penitoneal cavity.
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AJR:154,
ETHANOL
May 1990
THERAPY
IN HEPATOCELLULAR
The alterations in liver function that follow ethanol injection are much milder than changes that occur after surgical resection or transcatheter arterial embolization. Thus, ethanol injection can be considered even in cases of advanced liver cirrhosis. Serious complications reported are intrapenitoneal hemorrhage due to necrosis of the tumor [1 2], ascites [1 3], right pleural effusion [1 3], jaundice due to hepatic decompensation [1 3], intrapenitoneal hemorrhage due to the injury of a vessel in the omentum that covered the atrophic liver [15], jaundice probably due to injury of a bile duct [15], hepatic infarction probably due to influx of the ethanol into vessels [15], and transient hypotension [15]. Fujimoto [15] reported that major complications occurred in eight (2.8%) of 289 procedures. There have been no reports of metastasis or local dissemination of tumor occurring after percutaneous ethanol injection. An animal experiment [15] showed that injected ethanol damages the cancer cells immediately, which suggests that metastasis on dissemination does not occur easily with this procedure. No deaths directly related to ethanol injection have been reported.
Histopathologic
Evaluation
of Efficacy
The short-term efficacy of the therapy is best evaluated by histopathologic examination. We have examined 1 3 cases in this way and found that the lesion was completely necrotic in nine cases, 90% necrotic in three cases, and 70% necrotic in the other case [1 1 1 2]. Other investigators also found that percutaneous ethanol injection destroyed the lesion completely in most cases. Sheu et al. [1 3] found that in the six patients who subsequently underwent surgical resection, four had complete necrosis of the tumor and the other two had only a small peripheral residual of viable tumor remaining. Suyama et al. [14] found that the tumor showed complete necrosis in two of the six cases that were histopathologically examined. Fujimoto [1 5] reported that complete necrosis of the tumor was observed in two of the four resected cases after percutaneous ethanol injection. Livraghi et al. [1 7] reported that no viable tumor cells were detected in four patients who subsequently underwent surgery. The size of the lesion, presence or absence of internal septation, volume of injected ethanol, and accuracy of the injection are the major factors that determine whether the lesion becomes completely necrotic or not. In our previous study [1 1 1 2], histopathologic examination also showed that the capsule and a certain amount of the surrounding tissue as well as the tumor itself degenerate in response to the alcohol (Fig. 1). This finding proves that, unlike transcatheter arterial embolization [26], ethanol injection can be effective for intencapsular and extracapsular invasion. The fact that ethanol injection is efficacious for these forms of extension, which are frequently found even in small hepatocellular carcinomas, is important if cure is to be expected. In the four cases in which some portion of the tumor was found intact in our previous study [ii, 12], the viable tumor tissue was along the edge of the lesion, in portions isolated by septa or in daughter nodules. Therefore, ethanol should ,
,
CARCINOMA
949
-,
,4
“:
I
Fig. 1.-Macroscopic ethanol injection of amount of surrounding
appearance of fixed resected liver specimen after hepatocellular carcinoma. Capsule and a certain liver parenchyma as well as tumor are necrotic.
be injected not only into the center of the tumor but also into sites close to the edge. The value of fine-needle biopsy in following the results of ethanol injection, although it is definitively capable of indicating necrosis of the tumor, is limited because the tissue obtained by the biopsy does not always represent that of the entire tumor. Imaging Injection
Techniques
to Evaluate
the Results
of Ethanol
Evaluation
with radiologic imaging is important to determine tumor is completely necrotic and to detect any recurrence early. CT with contrast enhancement and angiography are the most useful for this purpose [5]. In our previous study [1 2], treated lesions did not enhance after IV contrast administration in CT examinations performed 1-6 months after the therapy, a period corresponding to devasculanization of the lesions (Fig. 2). Angiography penformed 3-6 months after therapy did not show tumor stain in any case (Fig. 3). Neither of these procedures showed evidence of viable cancer tissue in any case during that period. Complete necrosis is likely if the normal liver tissue at the periphery of the tumor does not enhance on CT scans. Although the sonographic features of the tumor change after ethanol injection, sonognaphy cannot be used to confirm complete necrosis of the tumor. In general, hypoechoic tumors become hyperechoic and hyperechoic tumors become heterogeneous after ethanol injections (Fig. 4) [i 2]. To detect any growth of a small amount of viable tumor, periodic imaging studies are essential. If recurrence of the tumor is detected, the lesion can be retreated by percutaneous injection of ethanol. if the treated
Evaluation
of Efficacy
by Serum
Tumor
Markers
Serum tumor markers such as alpha-fetoprotein and plasma-abnormal prothrombin [27] are useful to evaluate the efficacy of percutaneous ethanol injection providing the markers are elevated before treatment. In our study [12], serum
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Fig. 2.-Hepatocellular carcinoma. A, Before ethanol injection. T scan with contrast enhancement shows hypodense solitary mass B, 2 weeks after six injections. CT scan shows completely nonenhanced area in right lobe. C, 1 year after treatment. CT scan shows decrease in size of nonenhanced area.
in right lobe.
Fig. 3.-Hepatocellular carcinoma. A, Before ethanol injection. Angiogram shows tumor stain 2 cm in diameter in right lobe (ar. rows). B, 6 months after treatment. Tumor stain no longer exists (arrows).
Fig. 4.-Hepatocellular carcinoma. A, Before ethanol injection. Sonogram shows hyperechoic lesion in right lobe (arrows). B, 1 week after six injections. Lesion is heterogeneous and its margin is indistinct (arrows).
alpha-fetoprotein levels decreased after therapy with a single lesion, if the serum alpha-fetoprotein more than 100 ng/ml before therapy. Long-term
Survival
in all cases level was
Rates
The follow-up periods have not been long enough to compare the long-term survival rates of patients treated by ethanol injection with those of patients treated by other techniques.
To date, the best study on long-term survival rates of patients treated by percutaneous ethanol injection is that of Ebana et al. [16]. They treated 59 cases of hepatocellular carcinoma in which the diameter of the tumor was 3 cm or less and the number of the lesions was not more than three by ethanol injection. They reported that the 1-, 2-, 3-, and 4year survival rates were 96%, 86%, 79%, and 79%, respectively. They compared these long-term survival rates with
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those of 41 patients with tumors 3 cm who underwent surgical resection and patients treated by ethanol injection had survival rates than those who underwent though they used historical controls and was only 4 years, the results suggest ethanol injection can be an alternative curative treatment of small hepatocellulan et al. [i 7] reported that the 1 -year survival was 92%. Randomized trials to compare rates of patients treated by percutaneous with those of patients treated by other been conducted. New Devices and Methods Injection Therapy
or less in diameter concluded that the significantly higher hepatectomy. Althe follow-up period that percutaneous to surgery for the carcinoma. Livraghi rate of 12 patients long-term survival ethanol injection therapies have not
for Percutaneous
Cancer i986;57: 1184-1191 7. Yamada A. Kitayama K, Sato M, et al. Transcatheter in the treatment of primary liver cancer. In: Diseases
Ethanol
REFERENCES meeting. In: World Health World Health Organization, of hepatocellular
carcinoma
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system, vol. 2. Tokyo: Nihon Ainsho, 1988: 161 -1 66 8. Bhardwaj 5, Bruckner HW, Holland JF. Therapy of malignant tumors the liver. In: Berk JE, Haubrich WS, Kaiser MH, Roth JLA, Schaffner
9.
10.
For the treatment to be effective, the tip of the puncture needle must be accurately placed in the lesion. However, after repeated injections, the tumor often becomes difficult to identify. To solve this problem, Sheu et al. [28] implanted one on more small steel coils into the tumor before treatment. Even after the sonognaphic image of the tumor was obscured, they could still inject ethanol on the basis of the location of the coil. Their procedure, however, seems to be rather complicated. They have to puncture the lesion twice, first to place the coil and second to inject ethanol. Furthermore, they have to use relatively thick needles (1 8-gauge) so that the coil can be delivered through the needles. We have found that a small amount of Gelfoam powder (Upjohn Co., Kalamazoo, Ml) injected in the lesion can serve as a marker for ethanol injection [29]. As yet, percutaneous ethanol injection therapy has been limited to small lesions, because it is virtually impossible to inject ethanol throughout large lesions. However, if ethanol and Gelfoam are injected through the same needle, the exact place where the ethanol is injected can be identified afterward. Thus, by using the Gelfoam injection as a marker, it might be possible to inject ethanol into every part of large tumors. Sheu et al. [28] designed a new puncture needle with multiple side holes to achieve more homogeneous and even distribution of the ethanol. Ido et al. [30] injected ethanol into the tumor under peritoneoscopic sonographic guidance. With this procedure, the patient did not need to hold his on hen breath and the needle could be placed in the lesion for a long period. Thus, a large amount of ethanol could be injected at once, which enabled them to complete the therapy in one treatment session. Hirano et al. [31 ] reported that injection of a mixture of Lipiodol and ethanol showed the area of necrosis more accurately with CT.
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botherapy of bleeding esophageal varices. AJR i982;138: 1137-1141 20. Solbiati L, Giangrande A, Pra LD, Bellotti E, Cant#{227} P. Ravetto C. Percutaneous ethanol injection of parathyroid tumors under US guidance: treatment for secondary hyperparathyroidism. Radiology i985;1 55:607-610 21 . Imaoka 5, Sasaki Y, Matsui Y, et al. Evaluation of intratumoral injection of an immunoprotentiator (OK-432) in patients with hepatocellular carcinoma. Nippon Gan Chiryo Gakkai Shi i982; 17:1957-1962 22. Onodera H, Oikawa M, Abe M, Chida N, Kimura 5, Gotoh Y. tJtrasonographically guided percutaneous direct injection therapy for unresectable hepatoma. Jpn J Clin Radiol 1986:31 : 1461 -1 464 23. Uvraghi T, Sangalli G, vetted c. Adenomatous hyperplastic nodules in the cirrhotic liver: a therapeutic approach. Radiology i989;1 70:155-157 24. Shinagawa T, lino Y, Ukaji H, et al. Percutaneous ethanol injection in the treatment of portal tumor thrombus in hepatocellular carcinoma. Acta Hepatol Jpn i989;30: 109 25. Child CG Ill. Hepatic circulation and portal hypertension. Philadelphia: Saunders, 1954 26. Kobayashi T, Ohto M, Sumida M, et al. A clinical and histopathological study on therapeutic effects of transcatheter arterial embolization for small hepatocellular carcinoma. Nippon Shokakibyo Gakkai Zasshi i983;80: 2574-2583 27. Fujiyama 5, Morishita T, Hashiguchi 0, Sato T. Plasma abnormal prothrombin (des-gamma-carboxy prothrombin) as a marker of hepatocellular carcinoma. Cancer i988;61 :1621-1628 28. Sheu JC, Huang GT, Chen D5, et al. Small hepatocellular carcinoma: intratumor ethanol treatment using new needle and guidance systems. Radiology i987;163:43-48 29. Shiina 5, Komatsu V. Shiratori V. et al. Sonographically guided percutaneous injection of ethanol for treatment of hepatocellular carcinoma: value 30.
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of Gelfoam to mark the lesion (letter). AJR i989;153:430 Ido K, Hitomi N, Kawamoto T, Tanaka H, Ohtani M, Kimura K. Ethanol injection therapy for the treatment of small hepatocellular carcinoma under peritoneoscopic ultrasound guidance. Acta HepatolJpn i988;29: 1121 Hirano M, Tohara K, Sakaguchi 5, Okumura M. Therapeutic percutaneous injection of lipiodol-ethanol solution for hepatocellular carcinoma. Acta Hepatol Jpn i989;30:383-384
