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Journal of Gastroenterology and Hepatology (2000) 15, 346348

prevent pulmonary infarction and/or to ameliorate TT-related symptoms, such as oedema and ascites.10,11

However, the effects of such a surgical procedure will

be transient and limited, unless new extension of theTT is prevented by successive treatments for hepatictumours. Liver transplantation is another surgical treat-ment for HCC, but the unfavourable outcomesreported in advanced HCC do not encourage livertransplantation for patients with HV-TT, given theserious shortage of donor organs.12

The prognosis of patients after these surgical treat-ments is generally poor, even when hepatic resectionwith removal of TT is successfully performed.911 Theprognosis of such resected patients has been reportedto depend on the extension of TT through the HVand/or coexistence of portal vein TT (PV-TT).13,14

Patients with HV-TT alone show a better prognosis

than those with TT extending into the IVC; theoutcome of patients with IVC-TT is extremely poorbecause of early distant-organ metastasis.13 The prog-nosis of patients with HV-TT can also differ consider-ably, depending on whether they have TT in the PV; theprognosis of patients with TT in both the PV and HVis much poorer, probably because they are also at highrisk for intrahepatic metastasis through PV-TT.14

Most patients with HV-TT are not treated surgicallybecause of concomitant liver dysfunction, but receivenon-surgical treatment. In some patients, only palliativetreatments may be offered due to the advanced stage ofHCC in the liver. Non-surgical treatments include tran-scatheter arterial embolization (TAE), chemotherapy,

and radiation therapy. Successful non-surgical treat-ments may allow a small subset of patients with initiallyunresectable HCC to become candidates for surgicaltreatment.15 Moreover, given marked tumour regres-sion, the surgical procedure required for radical resec-tion may become less invasive. However, at present,little anti-tumour effects can be expected from any non-surgical treatments in patients with HV-TT.

See article inJ.Gastroenterol.Hepatol. 1999; 14: 9227.

Recently, screening of high-risk populations for hepa-

tocellular carcinoma (HCC) by using ultrasonographyand serum alpha-fetoprotein levels has facilitated theearly detection of HCC. However, at the time of diag-nosis, some HCC patients still have advanced diseasewith hepatic vein tumour thrombus (HV-TT). Hepato-cellular carcinoma has a tendency to involve vascularstructures in the liver, such as the portal veins (PV) andthe hepatic veins (HV). Although HCC involvement ofthe HV is less frequently observed compared with thatof the PV, tumour thrombus (TT) extending into theinferior vena cava (IVC) and right atrium (RA) throughthe HV has been encountered.1 Despite the progress oftherapy for HCC, HCC patients with HV-TT generallyhave an extremely poor prognosis.

A certain number of patients with HV-TT maydevelop secondary BuddChiari syndrome, pulmonaryinfarction, and/or lung metastasis, especially when TTextend into the IVC.2 Further extension of HCC intothe RA can cause cardiac failure and ball valve throm-bus syndrome.3 Because of the advances in imagingmodalities, tumour growth through the HV can be diag-nosed with certainty. On angiography, the threads andstreaks sign, indicating feeder vessels of the TT, may beobserved from the HV to the IVC and the RA.4 Inrecent years, ultrasonography and computed tomogra-phy have become the most useful and most commonlyused modalities for the diagnosis of HV-TT.5 Magneticresonance imaging may offer further detailed informa-

tion on TT, such as the presence of vascular lumensbetween the TT and IVC wall.6

In HCC patients with HV-TT, hepatic resection withremoval of the TT is the only radical treatment that mayfacilitate prolonged survival, although such extensivesurgery is applied only to patients with sufficient hepaticreserve to tolerate surgery.79 Tumour thrombusremoval without hepatic resection is also carried out to

EDITORIAL

How to manage hepatic vein tumour thrombus in

hepatocellular carcinoma

SHUICHI OKADA

Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan

Correspondence: Dr S Okada, Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital, 5-1-1

Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Email: sokada@ncc.go.jp

Accepted for publication 12 October 1999.

2000 Blackwell Science Asia Pty Ltd

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Management of hepatic vein thrombus in HCC 347

Transcatheter arterial embolization, either alone or incombination with intra-arterial chemotherapy, has amarked anti-tumour effect against HCC because thisneoplasm receives its blood supply through the hepaticartery.16,17The effect of TAE is dependent on the growthpattern of HCC; the effect is more apparent in nodular

lesions, while infiltrative HCC does not respond as wellas nodular HCC.18 The anticancer effect of TAE inHCC patients with HV-TT is usually limited, althoughHV-TT is also fed from tumour vessels derived fromthe hepatic artery. The possible reason for this refrac-toriness of HV-TT to TAE is that most such cases showan infiltrative growth pattern macroscopically.19 Seg-mental TAE, which has recently been reported to showa marked anti-tumour effect against PV-TT, should alsobe evaluated in patients with HV-TT, as it can enhancethe anti-tumour effect and can be performed moresafely than conventional TAE.2022

Chemotherapy for HCC, either systemically or intra-arterially, has been of limited value in clinical practice,

because only a small portion of patients will obtainmeaningful palliation.6,2327 In particular, patients withquite advanced HCC are inappropriate candidates forsystemic chemotherapy, because the disease is morerefractory to chemotherapy at that stage.28 However,hepatic intra-arterial infusion (HAI) may have to betested in patients with HV-TT, as HAI has beenreported to show promising results in HCC patientswith TT in the main portal branch.29 Radiation therapymay be a good palliative therapy, either alone or incombination with other treatments for HCC with TTextending through the HV; radiation therapy for TTmay induce tumour regression, resulting in palliation ofTT-related symptoms.3032

This is the background to the paper by Kashimaet al

.published in a recent issue of the Journal of Gastroen-terology and Hepatology.33 They treated five patients withadvanced HCC showing extensive tumour growththrough the HV by HAI by using aclarubicin, mito-mycin C and lipiodol. Although two patients died ofcancer within several weeks after HAI, the remainingthree demonstrated remarkable tumour regression. Asa result, two of these three patients could undergopotentially curative resection, and surgical specimensrevealed coagulation necrosis (complete necrosis in one,and partial in one) in both the hepatic tumours and theTT. Furthermore, the prognoses of the three patientswere incredibly improved, even though all patients hadTT in the IVC and/or the PV. Kashima et al. concludedthat HAI using these agents might be an effective treat-ment for HCC with extensive tumour growth throughthe HV.

However, several cautions are necessary in interpret-ing the results by Kashima et al. First, the number ofpatients enrolled in this trial was too small to accuratelyevaluate the anti-tumour and adverse effects of HAI.Moreover, according to intention-to-treat analysis,these effects must be evaluated in all patients whoreceive the therapy. Second, patient selection for HAI,which was not described in detail in the paper, mustbe optimized to achieve the potential benefits of HAIwithout inducing severe complications. The twopatients with early death after treatment might not have

been appropriate candidates for this therapy. Finally,the HAI method somewhat varied with each patient, interms of the combined use of gelatin powder and mit-omycin C.To define the real role of this HAI in patientswith HV-TT, further trials, which include a largenumber of patients, are mandatory.

Among HCC patients with HV-TT, disease status(extension of TT and associated liver disease) variesgreatly with each patient. For patients who have lessadvanced tumour stage and better liver function, surgi-cal treatment is the treatment of choice. In particular,patients with HV-TT alone may be the optimal candi-dates for surgical treatment; HV-TT can be removed byanatomical hepatic resection, and longer survival can beexpected with the removal of both the hepatic tumoursand HV-TT. In contrast, when TT extends into theIVC, and/or PV-TT coexists with HV-TT, the indica-tion for such surgical treatment should be consideredprudently. In these patients, a more drastic surgical pro-cedure is required, and its effect on prognosis remains

to be elucidated.13,14

However, surgical removal of TTin the IVC and RA may be indicated only when hepatictumours are under control or will be effectively con-trolled by non-surgical treatments.

Patients who are unsuitable for resection may beenrolled in phase II trials to evaluate the anti-tumoureffect and toxicity of various non-surgical treatments,if they are expected to be able tolerate treatment.Although none of the non-surgical treatments currentlyshows reliable anti-tumour effects in patients with HV-TT,TAE may be the most promising method of achiev-ing significant tumour necrosis. However, for patientswith TT in the main portal branch or poor hepaticreserve (Childs grade C), TAE is not applicable. Such

patients may undergo chemotherapy, especially HAI,in a clinical trial. Radiation therapy for TT may alsobe performed either alone or in combination with othernon-surgical treatments to palliate TT-related symp-toms. In addition, patients in this unresectable groupwho request treatment may be treated with more exper-imental therapies in a phase I setting.

REFERENCES

1 Tsuzuki T, Ogata Y, Iida S, Shimazu M. Hepatic resection

in 125 patients.Arch. Surg. 1984; 119: 102532.

2 Takeuchi J, Takada A, Hasumura Y, Matsuda Y, Ikegami F.

BuddChiari syndrome associated with obstruction of the

inferior vena cava: A report of seven cases.Am. J. Med.

1971; 51: 1120.

3 Hahne OH, Climie ARW. Right atrial thrombi with ball-

valve action.Am. J. Med. 1962; 32: 9429.

4 Okuda K, Jinnouchi S, Nagasaki Y et al. Angiographic

demonstration of growth of hepatocellular carcinoma in

the hepatic vein and inferior vena cava.Radiology 1977;

124: 336.

5 Didier D, Racle A, Etievent JP, Weill F. Tumor thrombus

of the inferior vena cava secondary to malignant abdom-

inal neoplasms. US and CT evaluation. Radiology 1987;

162: 839.

6 Kanematsu M, Imaeda T, Minowa Het al. Hepatocellu-

lar carcinoma with tumor thrombus in the inferior

8/12/2019 Treatment of Hvtt 1999

3/3

348 S Okada

vena cava and right atrium. Abdom. Imaging 1994; 19:

31316.

7 Fujisaki M, Kurihara E, Kikuchi K, Nishikawa K,

Uematsu Y. Hepatocellular carcinoma with tumor throm-

bus extending into the right atrium: Report of a success-

ful resection with the use of cardiopulmonary bypass.

Surgery 1991; 109: 21419.8 Hamazaki K, Yagi T, Katsuta Ket al. Extracorporeal cir-

culation and hypothermic perfusion for caval tumor

thrombus complicating hepatocellular carcinoma: A case

report.Hepatogastroenterology 1995; 42: 2825.

9 Iemura J, Aoshima M, Ishigami N, Kaneda T, Oba N.

Surgery for hepatocellular carcinoma with tumor throm-

bus in the right atrium.Hepatogastroenterology 1997; 44:

8245.

10 Masaki N, Hayashi S, Maruyama Tet al. Marked clinical

improvement in patients with hepatocellular carcinoma by

surgical removal of extended tumor mass in right atrium

and pulmonary arteries. Cancer Chemother. Pharmacol.

1994; 33 (Suppl.): S711.

11 Ohwada S, Tanahashi Y, Kawashima Yet al. Surgery fortumor thrombi in the right atrium and inferior vena cava

of patients with recurrent hepatocellular carcinoma.

Hepatogastroenterology 1994; 41: 1547.

12 Bismuth F, Chiche L, Adam R, Castaing D, Diamond T,

Dennison A. Liver resection versus transplantation for

hepatocellular carcinoma in cirrhotic patients.Ann. Surg.

1993; 218: 14551.

13 Nonami T, Nakao A, Harada A, Kaneko T, Kurokawa T,

Takagi H. Hepatic resection for hepatocellular carcinoma

with a tumor thrombus extending to inferior vena cava.

Hepatogastroenterology 1997; 44: 798802.

14 Ikai I,Yamaoka Y,Yamamoto Yet al. Surgical intervention

for patients with stage IV-A hepatocellular carcinoma

without lymph node metastasis. Proposal as a standard

therapy.Ann. Surg. 1998; 227: 4339.

15 Kashima Y, Miyazaki M, Kaiho Tet al. A successful treat-

ment for hepatocellular carcinoma with atrial tumor

thrombus.Hepatogastroenterology 1996; 43: 10405.

16 Breedis C,Young G.The blood supply of neoplasms in the

liver.Am. J. Pathol. 1954; 30: 96985.

17 Takayasu K, Shima Y, Muramatsu Yet al. Hepatocellular

carcinoma: Treatment with intraarterial iodized oil with

and without chemotherapeutic agents. Radiology 1987;

162: 34551.

18 Nakamura H, Tanaka T, Hori S et al. Transcatheter

embolization of hepatocellular carcinoma: Assessment of

efficacy in cases of resection following embolization. Radi-

ology 1983; 147: 4015.

19 Kojiro M, Nakahara H, Sugihara S, Murakami T,

Nakashima T, Kawasaki H.Hepatocellular carcinoma with

intra-atrial tumor growth. A clinicopathologic study of 18

autopsy cases.Arch. Pathol. Lab. Med. 1984; 108: 98992.

20 Matsui O, Kadoya M,Yoshikawa Jet al. Small hepatocel-

lular carcinoma: Treatment with subsegmental tran-

scatheter arterial embolization. Radiology 1993; 188:

7983.

21 Nishimine K, Uchida H, Matsuo N et al. Segmental

transarterial chemoembolization with lipiodol mixed with

anticancer drugs for non-resectable hepatocellular carci-noma: Follow-up CT and therapeutic results. Cancer

Chemother. Pharmacol. 1994; 33 (Suppl.): S608.

22 Katsumori T, Fujita M, Takahashi Tet al. Effective seg-

mental chemoembolization of advanced hepatocellular

carcinoma with tumor thrombus in the portal vein. Car-

diovasc. Intervent. Radiol. 1995; 18: 21721.

23 Colleoni M, Gaion F, Liessi G, Mastropasqua G, Nelli P,

Manente P. Medical treatment of hepatocellular carci-

noma: Any progress? Tumori1994; 80: 31516.

24 Okada S. Chemotherapy in hepatocellular carcinoma.

Hepatogastroenterology 1998; 45 (Suppl. 3): 125963.

25 Dazai Y, Katoh T, Katoh I, Sueda S,Yoshida R. Effective-

ness of chemoembolization therapy for metastatic right

atrial tumor thrombus associated with hepatocellularcarcinoma.Chest1989; 96: 4346.

26 Kanematsu T, Furuta T, Takenaka Ket al. A 5-year expe-

rience of lipiodolization: Selective regional chemotherapy

for 200 patients with hepatocellular carcinoma. Hepatol-

ogy 1989; 10: 98102.

27 Kalayci C, Johnson PJ, Raby N, Metivier EM,Williams R.

Intraarterial adriamycin and lipiodol for inoperable hepa-

tocellular carcinoma: A comparison with intravenous

adriamycin.J. Hepatol. 1990; 11: 34953.

28 Nagahama H, Okada S, Okusaka Tet al. Predictive factors

for tumor response to systemic chemotherapy in patients

with hepatocellular carcinoma.Jpn. J. Clin. Oncol. 1997;

27: 3214.

29 Ando E, Yamashita F, Tanaka M, Tanikawa K. A novel

chemotherapy for advanced hepatocellular carcinoma

with tumor thrombosis of the main trunk of the portal

vein.Cancer1997; 79: 18906.

30 Tanaka N, Matsuzaki Y, Chuuganji Y, Osuga T, Kuramoto

K, Tsuji H. Proton irradiation for hepatocellular carci-

noma.Lancet1992; 340: 1358.

31 Roca EL,Okazaki N,Okada Set al. Radiotherapy for bone

metastases of hepatocellular carcinoma.Jpn.J.Clin. Oncol.

1992; 22: 11316.

32 Chen SC, Lian SL, Chang WY. The effect of external

radiotherapy in treatment of portal vein invasion in hepa-

tocellular carcinoma.Cancer Chemother. Pharmacol. 1994;

33 (Suppl.): S1247.

33 Kashima Y, Miyazaki M, Ito H et al. Effective hepatic

artery chemoembolization for advanced hepatocellular

carcinoma with extensive tumour thrombus through the

hepatic vein.J. Gastroenterol. Hepatol. 1999; 14: 9227.