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Pegylated liposomal doxorubicin in treating a case of advanced hepatocellular carcinoma with severe hepatic dysfunction and pharmacokinetic study
Annals of Oncology 11: 349-353, 2000. O 2000 Kluwer Academic Publishers. Printed in the Netherlands.
Clinical case Pegylated liposomal doxorubicin in treating a case of advanced hepatocellular carcinoma with severe hepatic dysfunction and pharmacokinetic study R.-L. Hong,1 Y.-L. Tseng2 & F.-H. Chang 2 1
Department ofOncology,
2
Institute of Biochemistry, College of Medicine, National Taiwan University, Taipei, Taiwan
Introduction
Hepatocellular carcinoma (HCC) represents one of the most common malignancies in the world. The annual international incidence of the disease is about one million cases. It is the leading cause of cancer mortality in many Chinese societies. For patient with advanced disease, there are few one-year survivors. Transcatheter arterial embolization or percutaneous ethanol injection have been widely performed to treat inoperable HCC [1-3]. Survival has been claimed to be improved in some series. Nevertheless, the outcome for more advanced cases remains poor because of the lack of effective treatment. Intrahepatic arterial infusion of chemotherapy gives a moderate response rate [4], but it is not feasible for local-regionally advanced disease or metastasis, both which are common in HCC. For these cases, systemic chemotherapy may be the only choice, but the response rates have not been satisfactory [5-7]. In a recently published phase II study, none of the twenty cases responded to paclitaxel [8]. Furthermore, due to commonly co-existing hepatic dysfunction and hypersplenism, the toxicity of systemic chemotherapy is usually not acceptable [6, 8, 9]. Drugs with higher activity and lower toxicity are urgently needed for treatment of faradvanced or metastatic HCC.
Recent advances in the design of liposomes as cytotoxic drug carriers have resulted in a new formulation of doxorubicin with improved pharmacokinetic and tumor localization properties. Incorporation of doxorubicin into polyethylene glycol-coated (pegylated) liposomes has altered the pharmacokinetics of the drug [10-12]. This new generation of liposomes is characterized by a long circulation time with stable retention of drug, reduced hepatosplenic uptake, and enhanced tumor localization in animal model systems. The rationale for the use of pegylated liposomal doxorubicin (PLD) in solid tumors has been summarized as follows: change in the toxicity profile with a decrease in acute adverse effects (such as nausea and vomiting); and greater activity in highly angiogenic tumors (such as Kaposi's sarcoma) with the possibility of increased tumor response because of enhanced drug accumulation [13]. PLD monotherapy in patients with AIDS-related Kaposi's sarcoma produced overall response rates of 43% and 59% in comparative studies, which are better than combination chemotherapy [14-16]. It also has remarkable activity in breast and ovarian cancers, some of which are refractory to standard therapy [17, 18]. Having a notion of the advantages of PLD, we used it to treat a case of advanced HCC with severely impaired liver function. The tumor responded and only minimal
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increased volume of distribution of doxorubicin correlated with a large amount of ascites (P < 0.05). The clearance of Background: There is lack of effective and safe chemotherapy drug was unexpectedly higher than in cases with normal liver for advanced hepatocellular carcinoma. Polyethylene glycol- function (P < 0.05). According to the pharmacokinetic studies, coated (pegylated) liposomal doxorubicin (PLD) has long the disposition of PLD in this case has not been retarded even circulation time and enhanced drug accumulation in the tumor in the presence of severe liver dysfunction. Only minimal tissues. It has significant activity in Kaposi's sarcoma, breast toxicities including grade 2 stomatitis and moderate leukoand ovarian cancers and the acute adverse effects of free drug penia were observed. The tumor had a partial remission and the patient survived nine months after PLD treatment. are reduced. Patients and methods: A patient with advanced hepatoConclusion: PLD could serve as a safe and effective treatcellular carcinoma was treated with PLD and a pharmaco- ment for hepatocellular carcinoma even in the presence of kinetic study was performed. Initial serum total and direct impaired liver function. Its role in treating advanced hepatobilirubin were 3.6 and 6.8 folds of upper normal, respectively, cellular carcinoma is worthy of further study. and an indocyanine green clearance test at 15 minutes was 26.3% (normal < 15%). Key words: chemotherapy, doxorubicin, hepatocellular carciResults: Compared to cases with normal liver function, noma, liposome, pharmacokinetics Summary
350 toxicity was observed. This result was encouraging and may have important implications for the management of cancer patients with severe liver dysfunction. Patients and methods Drug and administration
Pharmacokinctic study Pharmacokinetic studies were performed after the first and third course of PLD treatment. Blood was sampled from an arm vein contralateral to the site of drug injection at varying time points. The method of extraction of doxorubicin was described before [19]. Both fluorometry [20] and high-pressure liquid chromatography [21] were used to quantitate doxorubicin. Pharmacokinetic analysis was done by nonlinear least-squares analysis using Pkanalyst software (MicroMath, Inc., Salt Lake City, Utah). Toxicity and measurement of response All toxicities were evaluated in each cycle according to the Eastern Cooperative Oncology Group criteria. The evaluation for response was performed with a complete work-up four weeks after the second cycle according to standard World Health Organization criteria. Complete response was denned as disappearance of all detectable malignant disease with no lesion at least for four weeks. Partial response was defined as a more than 50% reduction in the sum of the products of the greatest perpendicular dimensions for all measurable lesions for at least four weeks, without new lesions.
Case summary and results Case summary The 26-year-old male patient was an HBV carrier. He had been suffering from intermittent epigastric pain since October 1996 but did not pay attention to it until February 1997 when an abdominal mass was palpated by him. He visited a medical center and HCC was diagnosed histologically. Transcatheter arterial embolization was suggested because of advanced disease but he refused and tried traditional Chinese herb treatment for one month. Severe abdominal pain continued and he developed progressive abdominal distension, so he came to our hospital. He was bed ridden, thin, icteric
Figure I. Abdominal CT scan showed huge tumors of the liver and large amounts of ascites before PLD treatment (a). The tumors became smaller and ascites decreased after two courses of PLD (b). Partial remission was achieved.
and pale. His abdomen was markedly distended with tumor and ascites. The superficial veins of the abdominal wall were engorged. A chest PA view showed fine nodular density in the right middle and both lower portions, which was suggestive of metastatic lung tumor. A CT scan with contrast enhancement of the abdomen revealed huge masses over the liver, with diameters up to 17.5 and 11.1 cm, and some tumors pedunculated downward to the lower portion of the abdominal cavity (Figure la). There were multiple dilated vessels around the aorta, suggesting thrombosis of the portal vein. An indocyanine green (ICG) clearance test at 15 minutes was 26.3% (normal < 15%). Whilst he was being worked up he developed a change in consciousness and was found to have a serum calcium of 4.4 mmol. This responded to normal saline hydration and pamidronate infusion. Episodes of hepatic encephalopathy with ammonia elevated to 70 umol/1 (normal 9-33 umol/1) also occurred. Consciousness improved after lactulose treatment. After consent from the patient and his family, the patient received intravenous PLD 30 mg/m2 (day 0).
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Small unilamellar vesicles (SUV, size < 100 nm) were prepared by a combination of the ethanol injection method and repeated extrusion as previously described [19]. The liposome components were distearoyl-phosphatidylcholine, cholesterol, polyethylene glycol derived distearoyl-phosphatidyl-ethanolamine (PEG2000-DSPE) with a molar ratio of 3 :2 :0.3 (Avanti Polar Lipids Inc. Birmingham, Alabama). Doxorubicin concentration was 2.0 mg/ml and drug encapsulation efficiency was greater than 90%. The PLD was prepared by the liposome research group at our institution. The appropriate dose of PLD was diluted in 250 ml of 5% dextrose solution before administration and was given intravenously over a one-hour period. Premedication included cimetidine 200 mg, hydrocortisone 100 mg and diphenhydramine 30 mg. During the infusion of PLD, the patient was monitored continuously by a nurse and vital signs were recorded every 15 minutes.
351 rise after the eighth course (Figure 2). Again, his abdomen became distended with tumor and ascites. High dose tamoxifen and interferon alpha were added to the liposomal doxorubicin but there was no clinical benefit and unacceptable neutropenia developed. The patient was subsequently transferred to hospice and died nine months after the initial course of PLD treatment. Toxicity
Figure 2. Changes of SGOT, SGPT, total and direct bilirubin before and after PLD treatment. The data has been normalized against the upper normal limit. The arrows indicate the time of PLD treatment.
Pharmacokinetics His condition improved gradually although episodic hepatic encephalopathy still occurred after treatment. The treatment was repeated three weeks later and every four weeks subsequently due to slow marrow recovery. Gradually the abdominal distension and engorgement of the superficial abdominal veins subsided. His jaundice disappeared and his general condition improved. A partial remission was documented by image studies (Figure lb). Before treatment, his SGOT was 19.5 times normal and dropped rapidly after one course of treatment (Figure 2). Initial serum total and direct bilirubin were 3.6 and 6.8 folds of upper normal, respectively, and gradually returned to within the normal range. His serum alkaline phosphatase and LDH levels fluctuated during the treatment. Serum a-fetoprotein was extremely high, more than 140,000 ng/ml, and it remained high even after several courses of treatment. The patient's disease was controlled with regular PLD treatment, but his SGOT and bilirubin began to
Similar to previously published data [21], the amount of free doxorubicin in plasma was negligible compared to liposomal doxorubicin (data not shown). The total amount of doxorubicin in plasma was used for pharmacokinetic analysis. Plasma concentrations of doxorubicin are shown in Figure 3 and the pharmacokinetic parameters are displayed in Table 1. To avoid interference by bilirubin, both fluorometry and HPLC were used to determine the drug concentration: there was no significant difference in data obtained from either method in spite of the presence of elevated bilirubin. Compared with pharmacokinetic data obtained from eight cancer patients without liver disease and ascites, the initial concentration of doxorubicin (Co) and the area under the concentration-time curve (AUQ were lower but the volume of distribution and the clearance were higher (P < 0.05 by /-test). The mean residence time was not elevated even in the presence of impaired liver function.
Table I. Comparison of pharmacokinetic parameters of this case with patients without liver dysfunction. PK. parameters
Mean*
95% confidence interval
Firstb
Thirdb
Firstc
Thirdc
Co(mg/I) oc_tl/2(h)
16.9 4.4 44.8 917.9 0.042 2.2 62.7
14.4-19.4 0.6-8.2 28.4-61.2 492.6-1343.3 0.023-0.060 1.7-2.7 39.4-86.0
9.1 0.7 30.5 375.6 0.080 3.5 44.0
11.3 3.2 34.4 483.0 0.062 3.0 48.8
8.6 0.9 30.2 388.4 0.077 3.4 43.6
12.9 4.0 33.3 553.7 0.054 2.6 47.2
P_tl/2(h) AUC (mg-h/l) CL (1/h) Vss (1) Mean residence time (h)
The pharmacokinetic parameters were calculated with Pkanalyst Software, with the model of two compartments with bolus input and first-order output. * Data obtained from eight cancer patients without liver dysfunction and ascites after treatment with 30 mg/m 2 pegylated liposomal doxorubicin (by fluorometry). Data of this case obtained after first and third course of treatment of 30 mg/m 2 pegylated liposomal doxorubicin: bfluorometry method; C HPLC method. P < 0.05 by /-test.
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Time (Months before and after treatment)
Minimal gastrointestinal upset occurred during all courses of liposomal doxorubicin. Mild stomatitis developed after some courses. There was minimal alopecia. No significant changes in hemoglobin and platelet count were noted. Grade 2 to 3 leukopenia developed after each course of chemotherapy but it recovered four weeks later without growth factor.
352 the volume of distribution decreased. Unexpected, the clearance of drug was higher than that in patients with 10.0 normal liver function even in the presence of severe liver dysfunction. The high drug clearance persisted at the third course when liver function had already improved 8.0" and bilirubin levels were nearly normal. The huge tumors might have taken up part of the drug and contributed to o u the clearance of PLD, or the accumulated bile acids in plasma may have enhanced the leakage of liposome and accelerated the clearance. The possibility of the latter was low, as there was no correlation between serum bilirubin level and clearance or half-life of PLD in cases with HCC and impaired liver function (data not pub72 96 lished). According to the pharmacokinetic studies, this patient, even with severe liver dysfunction, could dispose Time (hours) of PLD as well as cases with normal liver function and Figure 3. Plasma levels of total doxorubicin after PLD treatment. Blood was sampled after thefirstcourse (square) and the third course this might be explained by the slow release of doxorubicin from liposome. These data also suggested that (circle) of treatment with 30 mg/m2 of PLD. the observed leukopenia was not due to impaired excretion of doxorubicin. Despite the advanced nature of his disease, our Discussion patient survived nine months after initial PLD treatClinical experience of systemic chemotherapy for HCC ment. His disease became refractory after eight courses, is fraught with frustration because of the refractory and did not respond to PLD plus tamoxifen and internature of the tumor and toxicities of treatment, which feron. Experience of this case demonstrated that: (1) are aggravated by hepatic dysfunction and hypersplen- The disposition of PLD in case with severe hepatic ism [6, 22]. In two randomized trials, PLD was superior dysfunction was not impaired, but pharmacokinetic to combination chemotherapy for Kaposi's sarcoma parameters, including volume of distribution, clearance [14, 15]. These studies confirmed the high therapeutic and AUC could be different from those of patients with ratio of PLD and several clinical trials are exploring its normal liver function; (2) The toxicity of PLD in this application in cancer treatment. Most HCC, similar to HCC patient was acceptable but white count should be Kaposi's sarcoma, is hypervascular [23, 24] and we felt monitored closely in patients with HCC; (3) Even in that the role of PLD in the treatment of HCC was advanced disease and impaired liver function, PLD may worthy of study. To date, there has been no reports on help some HCC patients. the toxicity and pharmacokinetics of PLD in patients From the experience of this case, we believe that the with impaired liver function. role of PLD in advanced and metastatic HCC is worthy In a previous study, grade 3-4 leukopenia, stomatitis of further study. However, pharmacokinetic properties and palmar-plantar erythrodysaesthesia affected 16%, and toxicity profiles need further investigation, espe6%, and 18% of 308 solid tumor patients, respectively cially the risk of reactivation of viral hepatitis, which [25]. Myelosuppression was not a major problem in 56 may result in acute hepatic failure [27]. A phase II trial patients with solid tumors in two phase I dose-finding of single agent PLD for treatment of metastatic or studies [26], but leukopenia was dose-limiting in pa- locally advanced HCC with portal vein thrombosis is tients with Kaposi's sarcoma [16]. In our case, platelet ongoing to evaluate its toxicity and activity. count was minimally affected, but leukopenia up to grade 3 rapidly developed. Patients with HCC, frequently associated with secondary hypersplenism, may Acknowledgements be more susceptible to myelosuppression. There was no evidence of re-activation of hepatitis B during PLD Supported in part by grants from National Science treatment in our case, but this risk should not be over- Council, Taiwan (NSC 87-2314-B-002-080 and NSC 87looked as reactivation of hepatitis frequently occurs 2314-B-002-198-M37) to Ruey-Long Hong. after chemotherapy in HBV carriers and may be fatal [27]. Clinical study of PLD for HCC should begin with a lower dose and closely monitor liver function and the References blood count. 120
1. Bayraktar Y, Balkanci F, Kayhan B et al. A comparison of chemoembolization with conventional chemotherapy and symptomatic treatment in cirrhotic patients with hepatocellular carcinoma. Hepatogastroenterology 1996; 43: 681-7. 2. Kawai S, Tani M, Okamura J et al. Prospective and randomized trial of lipiodol-transcatheter arterial chemoembolization for
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Partly explained by the presence of ascites, the volume of distribution was larger and the AUC was lower in this patient, compared with data of cancer patients without liver dysfunction (Table 1, P < 0.05). As ascites diminished clinically from the first course to the third course,
353
3.
4. 5.
6.
8.
9.
10. 11. 12. 13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26
27.
rubicin: Results of a multicenter phase II trial. J Clin Oncol 1997; 15: 3185-91. Muggia FM, Hainsworth JD, Jeffers S et al. Phase II study of liposomal doxorubicin in refractory ovarian cancer: Antitumor activity and toxicity modification by liposomal encapsulation. J Clin Oncol 1997; 15: 987-93. Tseng YL, Hong RL, Tao MH et al. Sterically stabilized antiidiotype immunoliposomes improve the therapeutic efficacy of doxorubicin in a murine B-cell lymphoma model. Inter J Cancer 1999; 80: 723-30. Gabizon A, Shiota R, Papahadjopoulos D. Pharmacokinetics and tissue distribution of doxorubicin encapsulated in stable liposomes with long circulation times. J Natl Cancer Inst 1989; 81: 1484-8. Johansen PB. Doxorubicin pharmacokinetics after intravenous and intraperitoneal administration in the nude mouse. Cancer Chemother Pharmacol 1981; 5: 267-70. Sciarrino E, Simonetti RG, Le Moli S, Pagliaro L. Adriamycin treatment for hepatocellular carcinoma. Experience with 109 patients. Cancer 1985; 56: 2751-5. Hata Y, Morita S, Noda Y et al The evaluation of weekly hepatic arterial infusion of high-dose 5-FU for liver metastases from colorectal cancer. GanTo Kagaku Ryoho 1998; 25: 901-5. Abrams RA, Pajak TF, Haulk TL et al. Survival results among patients with alpha-fetoprotein-positive, unresectable hepatocellular carcinoma: analysis of three sequential treatments of the RTOG and Johns Hopkins Oncology Center. Cancer J Sci Am 1998; 4: 178-84. Alberts DS, Garcia DJ. Safety aspects of pegylated liposomal doxorubicin in patients with cancer. Drugs 1997; 54 (Suppl 4): 30-5. Uziely B, Jeffers S, Isacson R et al. Liposomal doxorubicin: Antitumor activity and unique toxicities during two complementary phase I studies. J Clin Oncol 1995; 13: 1777-85. SatoT, Kato J, Kawanishi J et al. Acute exacerbation of hepatitis due to reactivation of hepatitis B virus with mutations in the core region after chemotherapy for malignant lymphoma. J Gastroenterol 1997; 32: 668-71.
Received 21 October 1998; accepted 9 June 1999. Correspondence to: Ruey-Long Hong, MD Department of Oncology National Taiwan University Hospital National Taiwan University 7 Chung-Shan South Road Taipei, 10016 Taiwan
E-mail: rlhong^ha.mc.ntu.edu.tw
Downloaded from https://academic.oup.com/annonc/article-abstract/11/3/349/196358 by guest on 29 July 2019
7.
treatment of hepatocellular carcinoma: A comparison of epirubicin and doxombicin (second cooperative study). The Cooperative Study Group for Liver Cancer Treatment of Japan. Semin Oncol 1997; 24. S6. 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. Blesing CH, Kerr DJ. Intra-hepatic arterial drug delivery. J Drug Targeting 1996; 3: 341-7. Chlebowski RT, Brzechwa-Adjulciewicz A, Cowden A, Block JB, Tong M, Chan KK. Doxorubicin (75 mg/m 2 ) for hepatocellular carcinoma: Clinical and pharmacokinetic results. Cancer Treat Rep 1984; 68: 487-91. Lai CL, Wu PC, Chan GC, Lok AS, Lin HJ. Doxorubicin versus no antitumor therapy in inoperable hepatocellular carcinoma. A prospective randomized trial. Cancer 1988; 62: 479-83. Wall JG, Benedetti JK, O'Rourke MA et al. Phase II trial to topotecan in hepatocellular carcinoma: A Southwest Oncology Group study. Invest New Drugs 1997; 15: 257-60. Chao Y, Chan WK, Birkhofer MJ et al. Phase II and pharmacokinetic study of paclitaxel therapy for unresectable hepatocellular carcinoma patients. Br J Cancer 1998; 78: 34-9. Lai EC, Choi TK, Cheng CH et al. Doxorubicin for unresectable hepatocellular carcinoma. A prospective study on the addition of verapamil. Cancer 1990; 66: 1685-7. Alien TM. Long-circulating (sterically stabilized) liposomes for targeted drug delivery. Trends Pharmacol Sci 1994; 15: 215-20. Woodle MC, Lasic DD. Sterically stabilized liposomes. Biochim Biophys Acta 1992; 1113: 171-99. Chonn A, Cullis PR. Recent advances in liposomal drug-delivery systems. Curr Opin Biotechnol 1995; 6: 698-708. Gabizon A, Martin F. Polyethylene glycol-coated (pegylated) liposomal doxorubicin. Rationale for use in solid tumours. Drugs 1997; 54 (Suppl 4): 15-21. Northfelt DW, Dezube BJ,Thommes JA et al. Pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, and vincristine in the treatment of AIDS-related Kaposi's sarcoma. Results of a randomized phase III clinical trial. J Clin Oncol 1998; 16. 2445-51. Stewart S, Jablonowski H, Goebel FD et al. Randomized comparative trial of pegylated liposomal doxorubicin versus bleomycin and vincristine in the treatment of AIDS-related Kaposi's sarcoma. International Pegylated Liposomal Doxorubicin Study Group. J Clin Oncol 1998; 16: 683-91. Coukell AJ, Spencer CM. Polyethylene glycol-liposomal doxorubicin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the management of AIDSrelated Kaposi's sarcoma. Drugs 1997; 53: 520-38. Ranson MR, Carmichael J, O'Byrne K et al. Treatment of advanced breast cancer with sterically stabilized liposomal doxo-
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Clinical case Pegylated liposomal doxorubicin in treating a case of advanced hepatocellular carcinoma with severe hepatic dysfunction and pharmacokinetic study R.-L. Hong,1 Y.-L. Tseng2 & F.-H. Chang 2 1
Department ofOncology,
2
Institute of Biochemistry, College of Medicine, National Taiwan University, Taipei, Taiwan
Introduction
Hepatocellular carcinoma (HCC) represents one of the most common malignancies in the world. The annual international incidence of the disease is about one million cases. It is the leading cause of cancer mortality in many Chinese societies. For patient with advanced disease, there are few one-year survivors. Transcatheter arterial embolization or percutaneous ethanol injection have been widely performed to treat inoperable HCC [1-3]. Survival has been claimed to be improved in some series. Nevertheless, the outcome for more advanced cases remains poor because of the lack of effective treatment. Intrahepatic arterial infusion of chemotherapy gives a moderate response rate [4], but it is not feasible for local-regionally advanced disease or metastasis, both which are common in HCC. For these cases, systemic chemotherapy may be the only choice, but the response rates have not been satisfactory [5-7]. In a recently published phase II study, none of the twenty cases responded to paclitaxel [8]. Furthermore, due to commonly co-existing hepatic dysfunction and hypersplenism, the toxicity of systemic chemotherapy is usually not acceptable [6, 8, 9]. Drugs with higher activity and lower toxicity are urgently needed for treatment of faradvanced or metastatic HCC.
Recent advances in the design of liposomes as cytotoxic drug carriers have resulted in a new formulation of doxorubicin with improved pharmacokinetic and tumor localization properties. Incorporation of doxorubicin into polyethylene glycol-coated (pegylated) liposomes has altered the pharmacokinetics of the drug [10-12]. This new generation of liposomes is characterized by a long circulation time with stable retention of drug, reduced hepatosplenic uptake, and enhanced tumor localization in animal model systems. The rationale for the use of pegylated liposomal doxorubicin (PLD) in solid tumors has been summarized as follows: change in the toxicity profile with a decrease in acute adverse effects (such as nausea and vomiting); and greater activity in highly angiogenic tumors (such as Kaposi's sarcoma) with the possibility of increased tumor response because of enhanced drug accumulation [13]. PLD monotherapy in patients with AIDS-related Kaposi's sarcoma produced overall response rates of 43% and 59% in comparative studies, which are better than combination chemotherapy [14-16]. It also has remarkable activity in breast and ovarian cancers, some of which are refractory to standard therapy [17, 18]. Having a notion of the advantages of PLD, we used it to treat a case of advanced HCC with severely impaired liver function. The tumor responded and only minimal
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increased volume of distribution of doxorubicin correlated with a large amount of ascites (P < 0.05). The clearance of Background: There is lack of effective and safe chemotherapy drug was unexpectedly higher than in cases with normal liver for advanced hepatocellular carcinoma. Polyethylene glycol- function (P < 0.05). According to the pharmacokinetic studies, coated (pegylated) liposomal doxorubicin (PLD) has long the disposition of PLD in this case has not been retarded even circulation time and enhanced drug accumulation in the tumor in the presence of severe liver dysfunction. Only minimal tissues. It has significant activity in Kaposi's sarcoma, breast toxicities including grade 2 stomatitis and moderate leukoand ovarian cancers and the acute adverse effects of free drug penia were observed. The tumor had a partial remission and the patient survived nine months after PLD treatment. are reduced. Patients and methods: A patient with advanced hepatoConclusion: PLD could serve as a safe and effective treatcellular carcinoma was treated with PLD and a pharmaco- ment for hepatocellular carcinoma even in the presence of kinetic study was performed. Initial serum total and direct impaired liver function. Its role in treating advanced hepatobilirubin were 3.6 and 6.8 folds of upper normal, respectively, cellular carcinoma is worthy of further study. and an indocyanine green clearance test at 15 minutes was 26.3% (normal < 15%). Key words: chemotherapy, doxorubicin, hepatocellular carciResults: Compared to cases with normal liver function, noma, liposome, pharmacokinetics Summary
350 toxicity was observed. This result was encouraging and may have important implications for the management of cancer patients with severe liver dysfunction. Patients and methods Drug and administration
Pharmacokinctic study Pharmacokinetic studies were performed after the first and third course of PLD treatment. Blood was sampled from an arm vein contralateral to the site of drug injection at varying time points. The method of extraction of doxorubicin was described before [19]. Both fluorometry [20] and high-pressure liquid chromatography [21] were used to quantitate doxorubicin. Pharmacokinetic analysis was done by nonlinear least-squares analysis using Pkanalyst software (MicroMath, Inc., Salt Lake City, Utah). Toxicity and measurement of response All toxicities were evaluated in each cycle according to the Eastern Cooperative Oncology Group criteria. The evaluation for response was performed with a complete work-up four weeks after the second cycle according to standard World Health Organization criteria. Complete response was denned as disappearance of all detectable malignant disease with no lesion at least for four weeks. Partial response was defined as a more than 50% reduction in the sum of the products of the greatest perpendicular dimensions for all measurable lesions for at least four weeks, without new lesions.
Case summary and results Case summary The 26-year-old male patient was an HBV carrier. He had been suffering from intermittent epigastric pain since October 1996 but did not pay attention to it until February 1997 when an abdominal mass was palpated by him. He visited a medical center and HCC was diagnosed histologically. Transcatheter arterial embolization was suggested because of advanced disease but he refused and tried traditional Chinese herb treatment for one month. Severe abdominal pain continued and he developed progressive abdominal distension, so he came to our hospital. He was bed ridden, thin, icteric
Figure I. Abdominal CT scan showed huge tumors of the liver and large amounts of ascites before PLD treatment (a). The tumors became smaller and ascites decreased after two courses of PLD (b). Partial remission was achieved.
and pale. His abdomen was markedly distended with tumor and ascites. The superficial veins of the abdominal wall were engorged. A chest PA view showed fine nodular density in the right middle and both lower portions, which was suggestive of metastatic lung tumor. A CT scan with contrast enhancement of the abdomen revealed huge masses over the liver, with diameters up to 17.5 and 11.1 cm, and some tumors pedunculated downward to the lower portion of the abdominal cavity (Figure la). There were multiple dilated vessels around the aorta, suggesting thrombosis of the portal vein. An indocyanine green (ICG) clearance test at 15 minutes was 26.3% (normal < 15%). Whilst he was being worked up he developed a change in consciousness and was found to have a serum calcium of 4.4 mmol. This responded to normal saline hydration and pamidronate infusion. Episodes of hepatic encephalopathy with ammonia elevated to 70 umol/1 (normal 9-33 umol/1) also occurred. Consciousness improved after lactulose treatment. After consent from the patient and his family, the patient received intravenous PLD 30 mg/m2 (day 0).
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Small unilamellar vesicles (SUV, size < 100 nm) were prepared by a combination of the ethanol injection method and repeated extrusion as previously described [19]. The liposome components were distearoyl-phosphatidylcholine, cholesterol, polyethylene glycol derived distearoyl-phosphatidyl-ethanolamine (PEG2000-DSPE) with a molar ratio of 3 :2 :0.3 (Avanti Polar Lipids Inc. Birmingham, Alabama). Doxorubicin concentration was 2.0 mg/ml and drug encapsulation efficiency was greater than 90%. The PLD was prepared by the liposome research group at our institution. The appropriate dose of PLD was diluted in 250 ml of 5% dextrose solution before administration and was given intravenously over a one-hour period. Premedication included cimetidine 200 mg, hydrocortisone 100 mg and diphenhydramine 30 mg. During the infusion of PLD, the patient was monitored continuously by a nurse and vital signs were recorded every 15 minutes.
351 rise after the eighth course (Figure 2). Again, his abdomen became distended with tumor and ascites. High dose tamoxifen and interferon alpha were added to the liposomal doxorubicin but there was no clinical benefit and unacceptable neutropenia developed. The patient was subsequently transferred to hospice and died nine months after the initial course of PLD treatment. Toxicity
Figure 2. Changes of SGOT, SGPT, total and direct bilirubin before and after PLD treatment. The data has been normalized against the upper normal limit. The arrows indicate the time of PLD treatment.
Pharmacokinetics His condition improved gradually although episodic hepatic encephalopathy still occurred after treatment. The treatment was repeated three weeks later and every four weeks subsequently due to slow marrow recovery. Gradually the abdominal distension and engorgement of the superficial abdominal veins subsided. His jaundice disappeared and his general condition improved. A partial remission was documented by image studies (Figure lb). Before treatment, his SGOT was 19.5 times normal and dropped rapidly after one course of treatment (Figure 2). Initial serum total and direct bilirubin were 3.6 and 6.8 folds of upper normal, respectively, and gradually returned to within the normal range. His serum alkaline phosphatase and LDH levels fluctuated during the treatment. Serum a-fetoprotein was extremely high, more than 140,000 ng/ml, and it remained high even after several courses of treatment. The patient's disease was controlled with regular PLD treatment, but his SGOT and bilirubin began to
Similar to previously published data [21], the amount of free doxorubicin in plasma was negligible compared to liposomal doxorubicin (data not shown). The total amount of doxorubicin in plasma was used for pharmacokinetic analysis. Plasma concentrations of doxorubicin are shown in Figure 3 and the pharmacokinetic parameters are displayed in Table 1. To avoid interference by bilirubin, both fluorometry and HPLC were used to determine the drug concentration: there was no significant difference in data obtained from either method in spite of the presence of elevated bilirubin. Compared with pharmacokinetic data obtained from eight cancer patients without liver disease and ascites, the initial concentration of doxorubicin (Co) and the area under the concentration-time curve (AUQ were lower but the volume of distribution and the clearance were higher (P < 0.05 by /-test). The mean residence time was not elevated even in the presence of impaired liver function.
Table I. Comparison of pharmacokinetic parameters of this case with patients without liver dysfunction. PK. parameters
Mean*
95% confidence interval
Firstb
Thirdb
Firstc
Thirdc
Co(mg/I) oc_tl/2(h)
16.9 4.4 44.8 917.9 0.042 2.2 62.7
14.4-19.4 0.6-8.2 28.4-61.2 492.6-1343.3 0.023-0.060 1.7-2.7 39.4-86.0
9.1 0.7 30.5 375.6 0.080 3.5 44.0
11.3 3.2 34.4 483.0 0.062 3.0 48.8
8.6 0.9 30.2 388.4 0.077 3.4 43.6
12.9 4.0 33.3 553.7 0.054 2.6 47.2
P_tl/2(h) AUC (mg-h/l) CL (1/h) Vss (1) Mean residence time (h)
The pharmacokinetic parameters were calculated with Pkanalyst Software, with the model of two compartments with bolus input and first-order output. * Data obtained from eight cancer patients without liver dysfunction and ascites after treatment with 30 mg/m 2 pegylated liposomal doxorubicin (by fluorometry). Data of this case obtained after first and third course of treatment of 30 mg/m 2 pegylated liposomal doxorubicin: bfluorometry method; C HPLC method. P < 0.05 by /-test.
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Time (Months before and after treatment)
Minimal gastrointestinal upset occurred during all courses of liposomal doxorubicin. Mild stomatitis developed after some courses. There was minimal alopecia. No significant changes in hemoglobin and platelet count were noted. Grade 2 to 3 leukopenia developed after each course of chemotherapy but it recovered four weeks later without growth factor.
352 the volume of distribution decreased. Unexpected, the clearance of drug was higher than that in patients with 10.0 normal liver function even in the presence of severe liver dysfunction. The high drug clearance persisted at the third course when liver function had already improved 8.0" and bilirubin levels were nearly normal. The huge tumors might have taken up part of the drug and contributed to o u the clearance of PLD, or the accumulated bile acids in plasma may have enhanced the leakage of liposome and accelerated the clearance. The possibility of the latter was low, as there was no correlation between serum bilirubin level and clearance or half-life of PLD in cases with HCC and impaired liver function (data not pub72 96 lished). According to the pharmacokinetic studies, this patient, even with severe liver dysfunction, could dispose Time (hours) of PLD as well as cases with normal liver function and Figure 3. Plasma levels of total doxorubicin after PLD treatment. Blood was sampled after thefirstcourse (square) and the third course this might be explained by the slow release of doxorubicin from liposome. These data also suggested that (circle) of treatment with 30 mg/m2 of PLD. the observed leukopenia was not due to impaired excretion of doxorubicin. Despite the advanced nature of his disease, our Discussion patient survived nine months after initial PLD treatClinical experience of systemic chemotherapy for HCC ment. His disease became refractory after eight courses, is fraught with frustration because of the refractory and did not respond to PLD plus tamoxifen and internature of the tumor and toxicities of treatment, which feron. Experience of this case demonstrated that: (1) are aggravated by hepatic dysfunction and hypersplen- The disposition of PLD in case with severe hepatic ism [6, 22]. In two randomized trials, PLD was superior dysfunction was not impaired, but pharmacokinetic to combination chemotherapy for Kaposi's sarcoma parameters, including volume of distribution, clearance [14, 15]. These studies confirmed the high therapeutic and AUC could be different from those of patients with ratio of PLD and several clinical trials are exploring its normal liver function; (2) The toxicity of PLD in this application in cancer treatment. Most HCC, similar to HCC patient was acceptable but white count should be Kaposi's sarcoma, is hypervascular [23, 24] and we felt monitored closely in patients with HCC; (3) Even in that the role of PLD in the treatment of HCC was advanced disease and impaired liver function, PLD may worthy of study. To date, there has been no reports on help some HCC patients. the toxicity and pharmacokinetics of PLD in patients From the experience of this case, we believe that the with impaired liver function. role of PLD in advanced and metastatic HCC is worthy In a previous study, grade 3-4 leukopenia, stomatitis of further study. However, pharmacokinetic properties and palmar-plantar erythrodysaesthesia affected 16%, and toxicity profiles need further investigation, espe6%, and 18% of 308 solid tumor patients, respectively cially the risk of reactivation of viral hepatitis, which [25]. Myelosuppression was not a major problem in 56 may result in acute hepatic failure [27]. A phase II trial patients with solid tumors in two phase I dose-finding of single agent PLD for treatment of metastatic or studies [26], but leukopenia was dose-limiting in pa- locally advanced HCC with portal vein thrombosis is tients with Kaposi's sarcoma [16]. In our case, platelet ongoing to evaluate its toxicity and activity. count was minimally affected, but leukopenia up to grade 3 rapidly developed. Patients with HCC, frequently associated with secondary hypersplenism, may Acknowledgements be more susceptible to myelosuppression. There was no evidence of re-activation of hepatitis B during PLD Supported in part by grants from National Science treatment in our case, but this risk should not be over- Council, Taiwan (NSC 87-2314-B-002-080 and NSC 87looked as reactivation of hepatitis frequently occurs 2314-B-002-198-M37) to Ruey-Long Hong. after chemotherapy in HBV carriers and may be fatal [27]. Clinical study of PLD for HCC should begin with a lower dose and closely monitor liver function and the References blood count. 120
1. Bayraktar Y, Balkanci F, Kayhan B et al. A comparison of chemoembolization with conventional chemotherapy and symptomatic treatment in cirrhotic patients with hepatocellular carcinoma. Hepatogastroenterology 1996; 43: 681-7. 2. Kawai S, Tani M, Okamura J et al. Prospective and randomized trial of lipiodol-transcatheter arterial chemoembolization for
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Partly explained by the presence of ascites, the volume of distribution was larger and the AUC was lower in this patient, compared with data of cancer patients without liver dysfunction (Table 1, P < 0.05). As ascites diminished clinically from the first course to the third course,
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4. 5.
6.
8.
9.
10. 11. 12. 13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26
27.
rubicin: Results of a multicenter phase II trial. J Clin Oncol 1997; 15: 3185-91. Muggia FM, Hainsworth JD, Jeffers S et al. Phase II study of liposomal doxorubicin in refractory ovarian cancer: Antitumor activity and toxicity modification by liposomal encapsulation. J Clin Oncol 1997; 15: 987-93. Tseng YL, Hong RL, Tao MH et al. Sterically stabilized antiidiotype immunoliposomes improve the therapeutic efficacy of doxorubicin in a murine B-cell lymphoma model. Inter J Cancer 1999; 80: 723-30. Gabizon A, Shiota R, Papahadjopoulos D. Pharmacokinetics and tissue distribution of doxorubicin encapsulated in stable liposomes with long circulation times. J Natl Cancer Inst 1989; 81: 1484-8. Johansen PB. Doxorubicin pharmacokinetics after intravenous and intraperitoneal administration in the nude mouse. Cancer Chemother Pharmacol 1981; 5: 267-70. Sciarrino E, Simonetti RG, Le Moli S, Pagliaro L. Adriamycin treatment for hepatocellular carcinoma. Experience with 109 patients. Cancer 1985; 56: 2751-5. Hata Y, Morita S, Noda Y et al The evaluation of weekly hepatic arterial infusion of high-dose 5-FU for liver metastases from colorectal cancer. GanTo Kagaku Ryoho 1998; 25: 901-5. Abrams RA, Pajak TF, Haulk TL et al. Survival results among patients with alpha-fetoprotein-positive, unresectable hepatocellular carcinoma: analysis of three sequential treatments of the RTOG and Johns Hopkins Oncology Center. Cancer J Sci Am 1998; 4: 178-84. Alberts DS, Garcia DJ. Safety aspects of pegylated liposomal doxorubicin in patients with cancer. Drugs 1997; 54 (Suppl 4): 30-5. Uziely B, Jeffers S, Isacson R et al. Liposomal doxorubicin: Antitumor activity and unique toxicities during two complementary phase I studies. J Clin Oncol 1995; 13: 1777-85. SatoT, Kato J, Kawanishi J et al. Acute exacerbation of hepatitis due to reactivation of hepatitis B virus with mutations in the core region after chemotherapy for malignant lymphoma. J Gastroenterol 1997; 32: 668-71.
Received 21 October 1998; accepted 9 June 1999. Correspondence to: Ruey-Long Hong, MD Department of Oncology National Taiwan University Hospital National Taiwan University 7 Chung-Shan South Road Taipei, 10016 Taiwan
E-mail: rlhong^ha.mc.ntu.edu.tw
Downloaded from https://academic.oup.com/annonc/article-abstract/11/3/349/196358 by guest on 29 July 2019
7.
treatment of hepatocellular carcinoma: A comparison of epirubicin and doxombicin (second cooperative study). The Cooperative Study Group for Liver Cancer Treatment of Japan. Semin Oncol 1997; 24. S6. 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. Blesing CH, Kerr DJ. Intra-hepatic arterial drug delivery. J Drug Targeting 1996; 3: 341-7. Chlebowski RT, Brzechwa-Adjulciewicz A, Cowden A, Block JB, Tong M, Chan KK. Doxorubicin (75 mg/m 2 ) for hepatocellular carcinoma: Clinical and pharmacokinetic results. Cancer Treat Rep 1984; 68: 487-91. Lai CL, Wu PC, Chan GC, Lok AS, Lin HJ. Doxorubicin versus no antitumor therapy in inoperable hepatocellular carcinoma. A prospective randomized trial. Cancer 1988; 62: 479-83. Wall JG, Benedetti JK, O'Rourke MA et al. Phase II trial to topotecan in hepatocellular carcinoma: A Southwest Oncology Group study. Invest New Drugs 1997; 15: 257-60. Chao Y, Chan WK, Birkhofer MJ et al. Phase II and pharmacokinetic study of paclitaxel therapy for unresectable hepatocellular carcinoma patients. Br J Cancer 1998; 78: 34-9. Lai EC, Choi TK, Cheng CH et al. Doxorubicin for unresectable hepatocellular carcinoma. A prospective study on the addition of verapamil. Cancer 1990; 66: 1685-7. Alien TM. Long-circulating (sterically stabilized) liposomes for targeted drug delivery. Trends Pharmacol Sci 1994; 15: 215-20. Woodle MC, Lasic DD. Sterically stabilized liposomes. Biochim Biophys Acta 1992; 1113: 171-99. Chonn A, Cullis PR. Recent advances in liposomal drug-delivery systems. Curr Opin Biotechnol 1995; 6: 698-708. Gabizon A, Martin F. Polyethylene glycol-coated (pegylated) liposomal doxorubicin. Rationale for use in solid tumours. Drugs 1997; 54 (Suppl 4): 15-21. Northfelt DW, Dezube BJ,Thommes JA et al. Pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, and vincristine in the treatment of AIDS-related Kaposi's sarcoma. Results of a randomized phase III clinical trial. J Clin Oncol 1998; 16. 2445-51. Stewart S, Jablonowski H, Goebel FD et al. Randomized comparative trial of pegylated liposomal doxorubicin versus bleomycin and vincristine in the treatment of AIDS-related Kaposi's sarcoma. International Pegylated Liposomal Doxorubicin Study Group. J Clin Oncol 1998; 16: 683-91. Coukell AJ, Spencer CM. Polyethylene glycol-liposomal doxorubicin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the management of AIDSrelated Kaposi's sarcoma. Drugs 1997; 53: 520-38. Ranson MR, Carmichael J, O'Byrne K et al. Treatment of advanced breast cancer with sterically stabilized liposomal doxo-
Downloaded from https://academic.oup.com/annonc/article-abstract/11/3/349/196358 by guest on 29 July 2019