Correspondence
Treatment of Unresectable Hepatocellular Carcinoma
N Engl J Med 1995; 333:877-878September 28, 1995
- Article
To the Editor:
In a group of patients with unresectable hepatocellular carcinoma but without severe liver disease, Trinchet et al. (May 11 issue)1 found that chemoembolization with Lipiodol (iodized oil) reduced tumor growth, often caused acute liver failure, and did not significantly improve survival. Because of variations in protocols and in the levels of expertise with which chemoembolization is performed, the authors' conclusion that this therapy should not be recommended may not be applicable to many patients.
Regardless of the exact method used, there will be some degree of hepatic damage after embolization, and this accumulated injury following repeated chemoembolizations may shorten survival as much as tumor growth does. Trinchet et al. treated their patients with repeated courses of chemoembolization, which may have exacerbated underlying cirrhotic damage. There was clearly better intrahepatic tumor control in the group treated with chemoembolization, as evidenced by the results of computed tomography, alpha-fetoprotein measurements, and portal-vein assessments. Most deaths were reported as related to cirrhosis (liver failure, gastrointestinal hemorrhage, and peritonitis). It therefore seems likely that the hepatic dysfunction was due to the repetitive nature of the procedure rather than to advancing tumor.
Many centers performing chemoembolization, such as the one where I work, repeat the treatment only when there is a clear sign of recurrent intrahepatic disease.2 This is done in an effort to minimize the toxic effects of the procedure. In addition, we administer intraarterial epinephrine before the chemoemulsion to constrict normal arteries, thereby shunting more blood toward the tumor and minimizing damage to uninvolved liver. We have treated more than 140 patients with hepatocellular carcinoma in this manner. Patients with well-preserved hepatic function (similar to the carefully selected population studied by Trinchet et al.) have a median survival of 24 months. Median survival in the Trinchet study's treated group was considerably shorter than this, possibly as a result of cumulative hepatic damage from repeated chemoembolizations.
2 ReferencesKeith Stuart, M.D.
Deaconess Hospital, Boston, MA 022151
Group d'Etude et de Traitement du Carcinome Hepatocellulaire
Full Text | Web of Science | Medline2
Stuart K ,Stokes K ,Jenkins R ,Trey C ,Clouse M . Treatment of hepatocellular carcinoma using doxorubicin/ethiodized oil/gelatin powder chemoembolization. Cancer 1993;72:3202-3209
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To the Editor:
Sixty-eight percent of the patients in the study by Trinchet et al. had alcohol-induced cirrhosis of the liver, and 46 percent had portal hypertension, as attested to by the presence of esophageal varices. In both study groups, liver failure, gastrointestinal hemorrhage, and spontaneous bacterial peritonitis were the main causes of death, suggesting that progressive underlying liver disease was the main factor contributing to early death (16 percent of the patients died within two months of randomization).
Although alcohol abuse is generally considered a possible contributing factor in the pathogenesis of hepatocellular carcinoma,1 hepatitis B and C are the leading causes worldwide. In many countries alcohol abuse is reported in association with hepatocellular carcinoma in a minority of patients.2 Patients with hepatocellular carcinoma present with a wide spectrum of associated liver disease, ranging from mild histopathologic changes to various degrees of hepatitis, cirrhosis, or both, with or without portal hypertension.3 Trinchet et al. do not state whether their patients who were at high risk for complications of alcoholic cirrhosis abstained from drinking alcohol during the study. This information is important because ongoing alcohol abuse may adversely affect portal flow and outcome in patients with portal hypertension.4
We suspect that the outcome reflects the natural history of underlying liver disease in the subgroup of patients with hepatocellular carcinoma and alcoholic cirrhosis. It does not allow a definitive conclusion to be drawn regarding the possible benefits of embolization or chemoembolization in the population of patients with hepatocellular carcinoma in general. In our experience with 24 embolizations without chemotherapy for hepatocellular carcinoma, we have not seen any instance of liver decompensation, in contrast to the rate of 60 percent reported by Trinchet et al.
4 ReferencesJ. Nicolas Vauthey, M.D.
Robert de W. Marsh, M.D.
Gary L. Davis, M.D.
University of Florida College of Medicine, Gainesville, FL 32610-02861
Tsukuma H ,Hiyama T ,Tanaka S , et al. Risk factors for hepatocellular carcinoma among patients with chronic liver disease. N Engl J Med 1993;328:1797-1801
Full Text | Web of Science | Medline2
Arii S, Tobe T. Epidemiology in Japan and the world. In: Okuda K, Tobe T, Kitagawa T, eds. Early detection and treatment of liver cancer. Gann monograph on cancer research no. 38. Tokyo: Japan Scientific Societies Press, 1991:17-26.
3
Vauthey JN ,Klimstra D ,Franceschi D , et al. Factors affecting long-term outcome after hepatic resection for hepatocellular carcinoma. Am J Surg 1995;169:28-35
CrossRef | Web of Science | Medline4
Kawasaki S ,Henderson JM ,Hertzler G ,Galloway JR . The role of continued drinking in loss of portal perfusion after distal splenorenal shunt. Gastroenterology 1991;100:799-804
Web of Science | Medline
To the Editor:
In the study by Trinchet et al., the enrollment of 24 institutions to perform a total of 50 chemoembolization procedures over a period of four years is a matter of concern. Chemoembolization is a highly technical, operator-dependent procedure, yet the issue of operator experience was not addressed. The use of so many centers and so few patients over such a lengthy time indicates the unavailability or nonuse of high-volume centers with experienced operators. The use of such centers might in all likelihood have yielded a higher degree of consistency and quality.
. . . One is left to wonder why the authors stopped enrolling patients when they were so close to demonstrating a significant improvement in survival after chemoembolization. Furthermore, the authors did not consider transplantation. Patients awaiting donor livers might interpret the difference in survival at eight months of nearly 20 percentage points in favor of Lipiodol chemoembolization as being quite important. The significant decreases in tumor size and invasion of the portal veins that were demonstrated in the study are also important considerations when transplantation is an option.
Chet R. Rees, M.D.
Baylor University Medical Center, Dallas, TX 75246To the Editor:
The survival rate at one year was 62 percent in the treated group and 43.5 percent in the conservative-management group. In addition, a significant decrease in tumor size and in the occurrence of new portal-vein thromboses was observed in the treated group. The authors said at the start of the study that they expected a 50 percent increase in survival in the chemoembolization group. Since in contrast to surgery or liver transplantation Lipiodol chemoembolization is a palliative and not a radical treatment for hepatocellular carcinoma, this initial objective may have been too high. Indeed, by discontinuing the enrollment of patients as a result of a sequential analysis, therefore reducing the number of patients in each group, and in turn reducing the power of the statistical test, the authors may have prematurely eliminated the possibility of demonstrating a significant difference in favor of chemoembolization at one year.
We performed liver resection and transplantation after Lipiodol chemoembolization.1 Trinchet et al., in contrast, did not, and they do not explain the absence of resection surgery in the select group of patients with tumors less than 3 cm in diameter and cirrhosis of Child–Pugh class A in whom Lipiodol chemoembolization reduced the size of the tumors. Since Lipiodol chemoembolization is only palliative, its effect on one-year survival, tumor size, and the occurrence of portal thrombosis should not be dismissed. For these reasons and because only 12 percent of all consecutive patients with hepatocellular carcinoma in the 24 participating centers were included in the study, the authors' conclusion that “since [Lipiodol chemoembolization] did not markedly improve survival, we do not believe its use can be recommended” is far from convincing.
1 ReferencesHenri Bismuth, M.D.
Didier Samuel, M.D.
Luc Engerran, M.D.
Hôpital Paul Brousse, 94800 Villejuif, France1
Bismuth H ,Morino M ,Sherlock D , et al. Primary treatment of hepatocellular carcinoma by arterial chemoembolization. Am J Surg 1992;163:387-394
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: We agree with Dr. Stuart that repeated chemoembolization may impair liver function. However, the fact that the main cause of death in our patients was liver failure should not be overinterpreted. This has also been reported in patients who did not undergo chemoembolization, mostly as a result of the spread of tumor.1 Stuart's proposal that only patients with recurrent disease be re-treated seems reasonable. Unfortunately, the persistence of tumor after treatment is often difficult to assess.
The fact that Vauthey et al. did not observe liver decompensation after chemoembolization in their patients may be due to their limited experience. Moreover, overt decompensation was observed after 6 percent (not 60 percent) of the procedures in our study. The patients with alcoholic cirrhosis mostly abstained from drinking during the study, but we agree that the natural history of hepatocellular carcinoma also reflects the course of associated cirrhosis.
As Dr. Rees points out, chemoembolization is an operator-dependent procedure. In our study, the centers were selected on the basis of their extensive experience, the procedure itself was standardized, and our results in terms of reductions in tumor size were in the range reported by previous studies with favorable results.2
Rees and Bismuth et al. suggested that our trial, planned to demonstrate a 50 percent increase in survival at eight months, may have missed a less substantial benefit. However, chemoembolization is a painful procedure that results in repeated hospital stays and a decreased quality of life. Thus, the statistically insignificant increase in survival in the treated group was not large enough to produce an important benefit from a clinical point of view.
Only patients with unresectable tumors were included in our trial. In a few patients with small tumors, surgery was not performed because of a contraindication, such as cardiac or respiratory failure.
2 ReferencesJean-Claude Trinchet, M.D., Ph.D.
Hôpital Jean Verdier, 93140 Bondy, FranceSylvie Chevret, M.D., Ph.D.
Hôpital Saint-Louis, 75010 Paris, FranceDidier Mathieu, M.D.
Hôpital Henri Mondor, 94010 Créteil, Francefor the Groupe d'Etude et de Traitement du Carcinome Hepatocéllulaire
1
Okuda K ,Ohtsuki T ,Obata H , et al. Natural history of hepatocellular carcinoma and prognosis in relation to treatment: study of 850 patients. Cancer 1985;56:918-928
CrossRef | Web of Science | Medline2
Sasaki Y ,Imaoka S ,Kasugai H , et al. A new approach to chemoembolization therapy for hepatoma using ethiodized oil, cisplatin, and gelatin sponge. Cancer 1987;60:1194-1203
CrossRef | Web of Science | Medline
- Citing Articles (3)
Citing Articles
1
Annemarie Musch, Christian Rabe, Mignon-Denise Paik, Marc Jean Berna, Volker Schmitz, Per Hoffmann, Hans Dieter Nischalke, Tilman Sauerbruch, Wolfgang H. Caselmann. (2005) Altered Expression of TGF-β Receptors in Hepatocellular Carcinoma – Effects of a Constitutively Active TGF-β Type I Receptor Mutant. Digestion 71:2, 78-91
CrossRef2
Man-Fung Yuen, Annie On-On Chan, Benjamin Chun-Yu Wong, Chee-Kin Hui, Gaik-Cheng Ooi, Wai-Kuen Tso, He-Jun Yuan, Danny Ka-Ho Wong, Ching-Lung Lai. (2003) Transarterial chemoembolization for inoperable, early stage hepatocellular carcinoma in patients with Child-Pugh grade A and B. Results of a comparative study in 96 Chinese patients. The American Journal of Gastroenterology 98:5, 1181-1185
CrossRef3
J. Nicolas Vauthey. (1998) LIVER IMAGING. Radiologic Clinics of North America 36:2, 445-457
CrossRef
