Japanese Journal of Clinical Oncology 33:570-573 (2003)
© 2003 Foundation for Promotion of Cancer Research
A Phase I Study of Hepatic Arterial Infusion Chemotherapy with Zinostatin Stimalamer Alone for Hepatocellular Carcinoma
1 Division of Hepatobiliary and Pancreatic Medical Oncology and 2 Department of Radiology, National Cancer Center Hospital East, Kashiwa, Chiba and 3 Department of Internal Medicine, Chiba Social Insurance Hospital, Chiba, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: Hepatic arterial infusion of zinostatin stimalamer and lipiodol emulsion shows a moderate activity against hepatocellular carcinoma. However, the anti-tumor activity of zinostatin stimalamer alone is uncertain.
Methods: The primary endpoint was to evaluate the frequency of dose-limiting toxicity and determine the maximum-tolerated dose of zinostatin stimalamer when used by intra-arterial infusion. The candidates for this study were patients with hepatocellular carcinoma no longer amenable to established forms of treatment. Hepatic arterial infusion chemotherapy was performed by selectively introducing a catheter into the hepatic artery with zinostatin stimalamer alone. Treatment was repeated at 4–8-week intervals until disease progression or the appearance of unacceptable toxicity. The starting dose of zinostatin stimalamer was 3 mg/m2, and doses were increased in 1 mg/m2 increments in successive cohorts. At least three patients were treated at each dose level and three additional patients were treated in the presence of dose-limiting toxicity.
Results: Twelve patients were entered into this trial. Dose-limiting toxicity was observed in one of six patients at 3 mg/m2, and in two of six patients at 4 mg/m2. The maximum-tolerated dose was judged to be 3 mg/m2 with liver dysfunction and serum creatinine increase as the dose-limiting toxicity. There was one early death suggested to be related to the protocol treatment. None of the 12 patients achieved an objective tumor response.
Conclusion: Hepatic arterial infusion with a zinostatin stimalamer of 3 mg/m2 may be tolerated, but not active, in patients with far advanced hepatocellular carcinoma.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in Japan. Whereas screening of high-risk populations for HCC has recently increased the detection of early stage cancer, there are many patients with HCC for whom the disease is so advanced that they cannot undergo effective treatments such as hepatectomy, percutaneous ablation therapy and transcatheter arterial chemoembolization. Zinostatin stimalamer (SMANCS) is a conjugate protein or copolymer of styrene-maleic acid (SMA) and an anti-tumor protein neocarzinostatin (NCS), which is a lipophilic agent that dissolves in a lipid lymphographic agent, lipiodol (1). When a SMANCS–lipiodol emulsion is injected into the artery feeding the HCC, it is deposited within the HCC, and the SMANCS is gradually released from the trapped lipiodol into tumor tissues (2). The Japanese Ministry of Labor, Health and Welfare approved this agent in 1994 after phase 1 and 2 trials (3), because its response rate was relatively high (36–40%) (3,4) and there were few agents effective in the treatment of HCC. Since then, hepatic arterial infusion (HAI) of a SMANCS–lipiodol emulsion has been used as one of the practical treatments for advanced or recurrent HCC in Japan (5,6).
However, HAI of a SMANCS–lipiodol emulsion caused hepatic vascular side effects associated with an excessive lipiodol use (7), and those sometimes resulted in fatal outcome (8). On the other hand, anti-tumor activity of HAI with SMANCS alone (without lipiodol) was uncertain. This background led us to conduct the current study, i.e. phase 1/2 trials of HAI with SMANCS alone for advanced HCC. In this article, we present the phase 1 part of the planned trial.
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PATIENTS AND METHODS |
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Patients
Only patients with HCC no longer amenable to established forms of treatment were candidates for this study. Eligibility criteria included: (i) 20–74 years of age; (ii) performance status of 0–2 according to the World Health Organization (WHO) grading system (9); (iii) more than 4 weeks rest and adequate recovery from the toxic effects of previous therapy; (iv) adequate organ function defined as white blood cell count of
3000/mm3, platelet count of 50 000/mm3, hemoglobin level of 9 g/dl, serum creatinine level of <1.5 mg/dl, serum total bilirubin level of <3.0 mg/dl and serum transaminases levels of <200 IU/l. Patients with hepatic coma and severe ascites were excluded.
Treatment
We inserted a catheter into the hepatic artery via the right femoral artery and performed celiac angiography by Seldinger’s method. Thereafter HAI chemotherapy was performed by selectively introducing a catheter into the hepatic artery. SMANCS was dissolved with 200 ml saline, and its solution was administered over 60 min. The starting dose of SMANCS was 3 mg/m2, and doses were escalated in 1 mg/m2 increments in successive cohorts. At least three patients were treated at each dose level. Three additional patients were entered at the same dose level if dose-limiting toxicity (DLT) was observed in one of the first three patients. DLT in two or more of six patients resulted in the preceding dose level being declared the maximum-tolerated dose (MTD).
DLT definition includes: (i) grade 2 serum creatinine increase; (ii) serum glutamic oxaloacetic transaminase (SGOT) or serum glutamic pyruvic transaminase (SGPT) increase >500 IU/l; (iii) prothrombin time decrease >30% of baseline; (iv) appearance of overt hepatic encephalopathy; (v) grade 3 or greater non-hematological toxicity except described above in (i)–(iv); (vi) grade 3 leukopenia or neutropenia with high fever; and (vii) grade 4 leukopenia, neutropenia or thrombocytopenia.
Treatment was repeated at 4–8-week intervals until disease progression or the appearance of unacceptable toxicity. Physical examinations and routine laboratory studies were performed weekly. Tumor response was assessed by dynamic computed tomography (CT) every 4 weeks. Response was evaluated by CT according to the WHO guidelines (9). Toxicity was evaluated according to the National Cancer Institute Common Toxicity Criteria (version 2.0) (10).
This trial was performed after receiving the approval of the investigational review board of our hospital. Written informed consent was obtained from all patients prior to study entry.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patients
Between February 2001 and October 2002, 12 patients with HCC were entered into this study at the National Cancer Center East, Japan. The baseline characteristics of the 12 patients are summarized in Table 1. All patients showed a good performance status of 0–1 and measurable cancer. According to TNM classification (11), all patients had stage 4 disease. Two patients showed lung metastasis. The number of patients with CLIP score (12) of 2, 3, 4, 5 and 6 were 3, 4, 3, 1 and 1, respectively. Three patients had a history of surgery as the primary treatment for HCC. Of the other nine, the diagnosis of HCC was made by histological findings of specimens obtained from needle biopsy in one, and by typical imaging findings on dynamic CT in eight. The 12 patients received a total of 28 courses, with a median of two courses.
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Toxicity
Toxicities are summarized in Table 2. There was no grade 3 or greater hematological toxicity in patients at level 1 or 2. As to non-hematological toxicity, fever was common but not severe in any of the patients. Grade 3 transaminase increase was observed in two of six patients at level 1. There were no DLT (transaminases >500 IU/l) cases in this protocol, and their elevated transaminase levels (grade 3) recovered to pre-treatment levels (grade 2) a few weeks after the treatment by supportive treatments. At level 1, a grade 2 serum creatinine increase, i.e. DLT in this protocol, was observed in one patient, although it recovered to pre-treatment level (grade 1) 1 month after the treatment by hydration and bed rest. At level 2, a grade 3 or greater toxicity was observed in three of six patients: one experienced grade 3 transaminase increase which was not DLT, and it recovered to pre-treatment level (grade 2) without specific treatment; one showed grade 3 transaminase and total bilirubin increases (DLT); and one patient died 20 days after treatment with grade 4 transaminase increase (DLT). This patient also showed grade 2 serum creatinine increase defined as DLT. DLT was, therefore, observed in one of six patients at level 1 (serum creatinine increase), and in two of six patients at level 2 (grade 3 total bilirubin increase in one, and grade 4 transaminase increase and serum creatinine increase in one). The MTD was judged to be 3 mg/m2 with liver dysfunction and serum creatinine increase as the DLT.
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Response
None of the 12 patients achieved an objective tumor response. Six patients showed no change and two showed progressive disease. In the remaining four, an objective tumor response could not be assessed because of deterioration in three and early death in one.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Intra-arterial treatment approaches have been widely used for advanced HCC. Among them, transcatheter arterial chemoembolization (TACE) showed some definitive anti-tumor activity (13). However, the potential benefit of TACE was limited to selected patients (14). A possible reason for this is that TACE, although effective in terms of response, does not directly translate to prolonged survival in a wide population of advanced HCC patients (15–19), and liver damage is caused by TACE. Since advanced HCC patients frequently have liver cirrhosis, HAI chemotherapy without embolic agents has been developed to preserve hepatic function of the patients.
Whereas HAI of SMANCS–lipiodol emulsion was developed as regional chemotherapy without using embolic agents such as gelatin sponge particles, several studies reported liver dysfunction caused by the use of lipiodol (7,8). Excessive use of lipiodol causes complications such as hepatic insufficiency when combined with other anti-cancer agents (20). Strictly speaking, intra-arterial infusion of lipiodol alone has no anti-tumor activity (21), and it acts only as a carrier of anti-cancer agents. There were two small scale randomized trials of HAI using SMANCS, epirubicin and/or lipiodol (22,23). Regarding the response rate of HAI, epirubicin–lipiodol was superior to epirubicin alone (42% versus 12%) (22) and SMANCS–lipiodol was superior to epirubicin–lipiodol (47% versus 7.7%) (23). However, there was no information about anti-tumor activity of HAI with SMANCS alone. This background motivated us to conduct the present study.
Our study showed the toxicity profile of HAI with SMANCS alone. As expected, hematological toxicity was mild, and DLT was non-hematological. Hepatic damage demonstrated as bilirubin increase was an expected DLT; however, we did not predict that serum creatinine increase would be a DLT. A DLT criterion of grade 2 serum creatinine increase was adopted in this protocol because acute renal failure was one of the serious adverse reactions. Although the two patients with this DLT did not develop renal failure, careful observation was required when SMANCS was used for such advanced HCC patients. At level 2, we experienced an early death after the protocol treatment. Acute onset of coma with hypertension occurred 10 days after treatment and this patient died 4 days later. This was the 12th patient in this study, and we stopped the study at the time of her death. A clinical assessment suggested that cerebral bleeding had occurred but we could not confirm this because permission to perform further examinations such as brain CT or autopsy was refused by her husband. It was suggested to be a treatment-related death from bleeding tendency evoked by hepatic insufficiency.
In the current study, we recruited patients with far advanced HCC in whom no other effective anti-cancer treatments could be applied. As a result, the subjects had huge or multiple tumors with vascular invasions or distant metastasis. Concentrations of SMANCS in the tumor tissues might be too low, without lipiodol, to treat such HCC with wide tumor beds. Although this was a phase 1 trial, the disappointing result that no one responded to the protocol treatment, led us to reconsider further the planned phase 2 study. We decided to terminate the trial at this phase 1 part of the study, and did not recommend further trials of HAI with SMANCS alone, without lipiodol, for the treatment of such advanced HCCs as those in this study setting.
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FOOTNOTES |
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+ For reprints and all correspondence: Hiroshi Ishii, Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba 277-8577, Japan. E-mail: hirishii{at}east.ncc.go.jp
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Received June 11, 2003; accepted September 25, 2003
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