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A phase II study of pegylated liposomal doxorubicin for treatment of advanced hepatocellular carcinoma
Annals of Oncology 11: 113-114, 2000. © 2000 Kluwer Academic Publishers. Printed in the Netherlands.
Short report A phase II study of pegylated liposomal doxorubicin for treatment of advanced hepatocellular carcinoma U Halm,1 G. Etzrodt,1 I. Schiefke,1 F. Schmidt,2 H. Witzigmann,3 J. Mossner1 & F. Berr1 Departments of ^Internal Medicine II, 2Diagnostic Radiology, ^Surgery II, University of Leipzig, Germany Summary Background: Pegylated liposomal doxorubicin has an enhanced efficacy and reduced toxicity compared with free doxorubicin. The efficacy and toxicity of pegylated liposomal doxorubicin was investigated in patients with hepatocellular carcinoma. Patients and methods: Patients with histologically confirmed, locally advanced or metastatic hepatocellular carcinoma and a Karnofsky index > 60% were included in this prospective single-arm study. Exclusion criteria were liver cirrhosis stage Child-Pugh C, previous chemotherapy, or chemoembolization. Pegylated liposomal doxorubicin was given in a dose of 30 mg/m 2 every three weeks until progression of disease. After inclusion of five patients the dose could be escalated to 40 mg/m 2 in absence of toxicity grade 3 and 4. Results: Sixteen patients were evaluable for response. No
Introduction
Pegylated liposomal doxorubicin (PLD) is a novel formulation with markedly delayed clearance, decreased volume of distribution, and accumulation of the drug in malignant tissues, which results in both higher therapeutic efficacy and reduced toxicity [1]. The accumulation and antitumor activity of liposomal doxorubicin in hepatocellular carcinoma (HCC) has already been shown in animals [2]. This phase II trial reports both the efficacy and toxicity of PLD in patients with locally advanced or metastatic HCC.
objective response was achieved. The median survival time was 140 days (95% confidence interval: 126-154 days). Treatment toxicities grade ^ 3 comprised increased liver enzymes in patients with preexisting grade 1 or 2 elevation {n = 6), hematologic toxicity (n = 5), and hypersensitivity (n = 2). Conclusions: Pegylated liposomal doxorubicin is not effective for treatment of advanced hepatocellular carcinoma. The favorable toxicity profile was confirmed even in patients with underlying liver disease. Key words: chemotherapy, hepatocellular carcinoma, liposomal doxorubicin, phase II Abbreviations: HCC - hepatocellular carcinoma; MRI — magnetic resonance imaging; PLD - pegylated liposomal doxorubicin
nancy, or lactation. The study protocol was approved by the local ethics committee. All patients gave written informed consent prior to entry in the study.
Treatment PLD (Caelyx*, Essex, Germany) was given at a dose of 30 mg/m2 as intravenous infusion over one hour every three weeks until progression. After inclusion of five patients the dose was escalated to 40 mg/m2 in absence of grade 3 and 4 toxicities. Antiemetics were not routinely given. The dose was reduced during the following cycles withholding PLD for any grade > 2 toxicity except of alopecia grade 3. In case of thrombocytopenia <60000/ul or leucocytopenia < 3000/uJ the dose was reduced by 50% and in case of thrombocytopenia <40000/ul or leucocytopenia < 1000/ul PLD was withheld.
Patients and methods Evaluation Patients Criteria for inclusion in this prospective, single-arm study were: age <75 years; measurable, histologically confirmed HCC unsuited for resection, transarterial embolization, or ethanol injection; Karnofsky index >60%; leucocyte count >3000/ul; thrombocyte count ^80000/|il: normal left ventricular function; serum creatinine <1.5 mg/dl: serum bilirubin <3.0 mg/dl; prothrombin time < 1.7 (INR); and aspartate aminotransferase < 5 times normal. Exclusion criteria were: liver cirrhosis stage Child-Pugh C; prior chemotherapy, chemoembolization. or radiotherapy; congestive heart failure > grade 2; myocardial infarction during the past three months, instable angina pectoris; brain metastasis; evidence of other malignant disease; preg-
Baseline examinations were: complete history and examination, electrocardiogram, echocardiography, complete blood count, serum a-fetoprotein, serum chemistry, T2 weighted magnetic resonance imaging (MRI) of the liver using iron oxides as contrast medium, abdominal ultrasound, and chest X-ray. If MRI was not feasible, computed tomography was used. Response and toxicity were evaluated according to WHO criteria. Abdominal ultrasound and a-fetoprotein were performed prior to every cycle, and MRI. chest X-ray examinations, and echocardiography after cycles 3 and 6 or at the end of treatment. Objective tumor response was the primary endpoint. Progressionfree survival, overall survival, and toxicity criteria were secondary endpoints.
114 Table 1. Patient characteristics. Sex Male Female Age Median Range Karnofsky performance status Median Range Liver cirrhosis Child-PughA/B Chronic hepatitis B Alcohol
Cryptogenic Tumor stage (UICC 1997) 1Mb IVa IVb Okuda stage I II III Tumor grade 1 2 3 a-Fetoprotein (ng/ml) Median Range
Toxicity 12 5 63 39-74 80 70-100 8/2 3 6 1 1 12 4 2 13 2 6 10 1 42.3 2.0-56466
Except for two hypersensitivity grade 4 reactions, therapy was well tolerated with only few grade 3 and 4 toxicities, but no cardiac toxicity. The most predominant grade 3 and 4 toxicities were increased liver enzymes in patients with preexisting grade 1 or 2 elevations (n - 6) and hematologic toxicity (n = 5). Discussion Free doxorubicin has been shown to be superior to symptomatic treatment of HCC [3], although recently published data of a metaanalysis revealed no efficacy of free doxorubicin for treatment of HCC [4]. Delivering doxorubicin by liposomes did not result in objective tumor response. Similar results were recently described for liposomal daunorubicin [5]. These results indicate, that liposomal entrapped anthracyclines are ineffective for the treatment of locally advanced or metastatic HCC. Liver function may worsen during chemotherapy in patients with liver cirrhosis. However, toxicity of PLD was low even in patients with underlying liver disease. In conclusion, PLD has no significant activity against advanced HCC. HCC is highly chemoresistant and will require new drugs to improve the outcome of therapy.
Statistics The optimal two-stage design was used, in which the accrual would be terminated, if the response rate was < 3 of 17 patients. A response rate of > 3 of 17 patients would extend the accrual to 37 patients. This design has an a of 0.10 and p of 0.10.
Results Patients Seventeen patients were included. The characteristics of the patients are listed in Table 1. One patient was removed from the study because of acute hypersensitivity reaction during the first cycle. The median number of cycles per patient was 3 (range 1-8). A total of 64 cycles were given, of which 57 were administered on schedule. During two cycles the dose was reduced, and five cycles were delayed. In 16 cycles the dose was escalated to 40 mg/m 2 . Response Sixteen patients were evaluable for response. In 14 patients response was assessed by MRI, and in 2 by computed tomography. No objective response was achieved. The median time to progression was 64 days (95% confidence interval: 56-72 days) and the median survival time 140 days (126-154 days). In 2 of 12 patients with elevated baseline concentrations, a-fetoprotein decreased by 35% and 72% over 15 and 18 weeks, respectively, but increased thereafter.
Acknowledgement Supported in part by Essex GmbH, Munich, Germany.
References 1. Gabizon A, Martin F. Polyethylene glycol-coated (pegylated) liposomal doxorubicin. Rationale for use in solid tumours. Drugs 1997; 54 (Suppl 4): 15-21. 2. Ichinose K, Yamamoto M, Khoji T et al. Antitumor effect of polysacchande coated liposomal adriamycin on AH66 hepatoma in nude mice. Anticancer Res 1998; 18: 401-4. 3. Lai CL. Wu PC. Chan GC et al. Doxorubicin versus no antitumor therapy in inoperable hepatocellular carcinoma. A prospective randomized trial. Cancer 1988; 62: 479-83. 4. Simonetti RG, Liberati A, Angiolini C, Pagliaro L. Treatment of hepatocellular carcinoma: A systematic review of randomized controlled trials. Ann Oncol 1997; 8: 117-36. 5. Yeo W, Chan KK, Mukwaya G et al. Phase II studies with DaunoXome in patients with nonresectable hepatocellular carcinoma' Clinical and pharmacokinetic outcomes. Cancer Chemother Pharmacol 1999; 44: 124-30. Received 17 September 1999; accepted 11 November 1999.
Correspondence to: U Halm, MD Department of Internal Medicine II University of Leipzig Philipp-Rosenthal-Strasse 27 D-04103 Leipzig Germany E-mail: halmu'a medizin.uni-leipzig.de
Short report A phase II study of pegylated liposomal doxorubicin for treatment of advanced hepatocellular carcinoma U Halm,1 G. Etzrodt,1 I. Schiefke,1 F. Schmidt,2 H. Witzigmann,3 J. Mossner1 & F. Berr1 Departments of ^Internal Medicine II, 2Diagnostic Radiology, ^Surgery II, University of Leipzig, Germany Summary Background: Pegylated liposomal doxorubicin has an enhanced efficacy and reduced toxicity compared with free doxorubicin. The efficacy and toxicity of pegylated liposomal doxorubicin was investigated in patients with hepatocellular carcinoma. Patients and methods: Patients with histologically confirmed, locally advanced or metastatic hepatocellular carcinoma and a Karnofsky index > 60% were included in this prospective single-arm study. Exclusion criteria were liver cirrhosis stage Child-Pugh C, previous chemotherapy, or chemoembolization. Pegylated liposomal doxorubicin was given in a dose of 30 mg/m 2 every three weeks until progression of disease. After inclusion of five patients the dose could be escalated to 40 mg/m 2 in absence of toxicity grade 3 and 4. Results: Sixteen patients were evaluable for response. No
Introduction
Pegylated liposomal doxorubicin (PLD) is a novel formulation with markedly delayed clearance, decreased volume of distribution, and accumulation of the drug in malignant tissues, which results in both higher therapeutic efficacy and reduced toxicity [1]. The accumulation and antitumor activity of liposomal doxorubicin in hepatocellular carcinoma (HCC) has already been shown in animals [2]. This phase II trial reports both the efficacy and toxicity of PLD in patients with locally advanced or metastatic HCC.
objective response was achieved. The median survival time was 140 days (95% confidence interval: 126-154 days). Treatment toxicities grade ^ 3 comprised increased liver enzymes in patients with preexisting grade 1 or 2 elevation {n = 6), hematologic toxicity (n = 5), and hypersensitivity (n = 2). Conclusions: Pegylated liposomal doxorubicin is not effective for treatment of advanced hepatocellular carcinoma. The favorable toxicity profile was confirmed even in patients with underlying liver disease. Key words: chemotherapy, hepatocellular carcinoma, liposomal doxorubicin, phase II Abbreviations: HCC - hepatocellular carcinoma; MRI — magnetic resonance imaging; PLD - pegylated liposomal doxorubicin
nancy, or lactation. The study protocol was approved by the local ethics committee. All patients gave written informed consent prior to entry in the study.
Treatment PLD (Caelyx*, Essex, Germany) was given at a dose of 30 mg/m2 as intravenous infusion over one hour every three weeks until progression. After inclusion of five patients the dose was escalated to 40 mg/m2 in absence of grade 3 and 4 toxicities. Antiemetics were not routinely given. The dose was reduced during the following cycles withholding PLD for any grade > 2 toxicity except of alopecia grade 3. In case of thrombocytopenia <60000/ul or leucocytopenia < 3000/uJ the dose was reduced by 50% and in case of thrombocytopenia <40000/ul or leucocytopenia < 1000/ul PLD was withheld.
Patients and methods Evaluation Patients Criteria for inclusion in this prospective, single-arm study were: age <75 years; measurable, histologically confirmed HCC unsuited for resection, transarterial embolization, or ethanol injection; Karnofsky index >60%; leucocyte count >3000/ul; thrombocyte count ^80000/|il: normal left ventricular function; serum creatinine <1.5 mg/dl: serum bilirubin <3.0 mg/dl; prothrombin time < 1.7 (INR); and aspartate aminotransferase < 5 times normal. Exclusion criteria were: liver cirrhosis stage Child-Pugh C; prior chemotherapy, chemoembolization. or radiotherapy; congestive heart failure > grade 2; myocardial infarction during the past three months, instable angina pectoris; brain metastasis; evidence of other malignant disease; preg-
Baseline examinations were: complete history and examination, electrocardiogram, echocardiography, complete blood count, serum a-fetoprotein, serum chemistry, T2 weighted magnetic resonance imaging (MRI) of the liver using iron oxides as contrast medium, abdominal ultrasound, and chest X-ray. If MRI was not feasible, computed tomography was used. Response and toxicity were evaluated according to WHO criteria. Abdominal ultrasound and a-fetoprotein were performed prior to every cycle, and MRI. chest X-ray examinations, and echocardiography after cycles 3 and 6 or at the end of treatment. Objective tumor response was the primary endpoint. Progressionfree survival, overall survival, and toxicity criteria were secondary endpoints.
114 Table 1. Patient characteristics. Sex Male Female Age Median Range Karnofsky performance status Median Range Liver cirrhosis Child-PughA/B Chronic hepatitis B Alcohol
Cryptogenic Tumor stage (UICC 1997) 1Mb IVa IVb Okuda stage I II III Tumor grade 1 2 3 a-Fetoprotein (ng/ml) Median Range
Toxicity 12 5 63 39-74 80 70-100 8/2 3 6 1 1 12 4 2 13 2 6 10 1 42.3 2.0-56466
Except for two hypersensitivity grade 4 reactions, therapy was well tolerated with only few grade 3 and 4 toxicities, but no cardiac toxicity. The most predominant grade 3 and 4 toxicities were increased liver enzymes in patients with preexisting grade 1 or 2 elevations (n - 6) and hematologic toxicity (n = 5). Discussion Free doxorubicin has been shown to be superior to symptomatic treatment of HCC [3], although recently published data of a metaanalysis revealed no efficacy of free doxorubicin for treatment of HCC [4]. Delivering doxorubicin by liposomes did not result in objective tumor response. Similar results were recently described for liposomal daunorubicin [5]. These results indicate, that liposomal entrapped anthracyclines are ineffective for the treatment of locally advanced or metastatic HCC. Liver function may worsen during chemotherapy in patients with liver cirrhosis. However, toxicity of PLD was low even in patients with underlying liver disease. In conclusion, PLD has no significant activity against advanced HCC. HCC is highly chemoresistant and will require new drugs to improve the outcome of therapy.
Statistics The optimal two-stage design was used, in which the accrual would be terminated, if the response rate was < 3 of 17 patients. A response rate of > 3 of 17 patients would extend the accrual to 37 patients. This design has an a of 0.10 and p of 0.10.
Results Patients Seventeen patients were included. The characteristics of the patients are listed in Table 1. One patient was removed from the study because of acute hypersensitivity reaction during the first cycle. The median number of cycles per patient was 3 (range 1-8). A total of 64 cycles were given, of which 57 were administered on schedule. During two cycles the dose was reduced, and five cycles were delayed. In 16 cycles the dose was escalated to 40 mg/m 2 . Response Sixteen patients were evaluable for response. In 14 patients response was assessed by MRI, and in 2 by computed tomography. No objective response was achieved. The median time to progression was 64 days (95% confidence interval: 56-72 days) and the median survival time 140 days (126-154 days). In 2 of 12 patients with elevated baseline concentrations, a-fetoprotein decreased by 35% and 72% over 15 and 18 weeks, respectively, but increased thereafter.
Acknowledgement Supported in part by Essex GmbH, Munich, Germany.
References 1. Gabizon A, Martin F. Polyethylene glycol-coated (pegylated) liposomal doxorubicin. Rationale for use in solid tumours. Drugs 1997; 54 (Suppl 4): 15-21. 2. Ichinose K, Yamamoto M, Khoji T et al. Antitumor effect of polysacchande coated liposomal adriamycin on AH66 hepatoma in nude mice. Anticancer Res 1998; 18: 401-4. 3. Lai CL. Wu PC. Chan GC et al. Doxorubicin versus no antitumor therapy in inoperable hepatocellular carcinoma. A prospective randomized trial. Cancer 1988; 62: 479-83. 4. Simonetti RG, Liberati A, Angiolini C, Pagliaro L. Treatment of hepatocellular carcinoma: A systematic review of randomized controlled trials. Ann Oncol 1997; 8: 117-36. 5. Yeo W, Chan KK, Mukwaya G et al. Phase II studies with DaunoXome in patients with nonresectable hepatocellular carcinoma' Clinical and pharmacokinetic outcomes. Cancer Chemother Pharmacol 1999; 44: 124-30. Received 17 September 1999; accepted 11 November 1999.
Correspondence to: U Halm, MD Department of Internal Medicine II University of Leipzig Philipp-Rosenthal-Strasse 27 D-04103 Leipzig Germany E-mail: halmu'a medizin.uni-leipzig.de