help button home button The Oncologist
HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
The Oncologist, Vol. 10, No. 6, 392-398, June 2005; doi:10.1634/theoncologist.10-6-392
© 2005 AlphaMed Press

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow eLetters: Submit a response to this article
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Zhu, A. X.
Right arrow Articles by Ryan, D. P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zhu, A. X.
Right arrow Articles by Ryan, D. P.

A Phase II Study of Epirubicin and Thalidomide in Unresectable or Metastatic Hepatocellular Carcinoma

Andrew X. Zhu, Charles S. Fuchs, Jeffrey W. Clark, Alona Muzikansky, Kerry Taylor, Susan Sheehan, Kayao Tam, Elizabeth Yung, Matthew H. Kulke, David P. Ryan

Massachusetts General Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

Correspondence: Correspondence: Andrew X. Zhu, M.D., Massachusetts General Hospital Cancer Center, 100 Blossom Street, Cox 640, Boston, Massachusetts 02114, USA. Telephone: 617-724-0786; Fax: 617-724-3166; e-mail: azhu{at}partners.org


   ABSTRACT
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Background. The median survival time for patients with unresectable hepatocellular carcinoma (HCC) is <6 months, and no effective standard systemic chemotherapy is available. Both epirubicin (Ellence®; Pfizer Pharmaceuticals, New York, NY, http://www.pfizer.com) and thalidomide (Thalomid®; Celgene Corporation, Warren, NJ, http://www.celgene.com) have reported activity for HCC as single agents, and they have different mechanisms of action and nonoverlapping toxicities. Therefore, we performed a phase II study using the combination of epirubicin and thalidomide in patients with unresectable and metastatic HCC.

Methods. Nineteen patients with measurable, unresectable, or metastatic HCC were enrolled. All patients were required to have adequate major organ function and performance status. The treatment consisted of weekly epirubicin at a dose of 20 mg/m2 administered i.v. and daily thalidomide at a dose of 200 mg orally given as a 3-weeks-on/1-week-off schedule. Intrapatient dose escalation of thalidomide was allowed every 2 weeks up to 800 mg daily as long as tolerated. Physical examinations, toxicity assessments, and serum chemistry analyses were performed weekly, and tumor measurements were conducted every 8 weeks.

Results. All 19 patients enrolled into the study were evaluable for toxicity assessment and 17 patients were evaluable for response assessment. A total of 71 cycles of chemotherapy was administered, with a median of two cycles administered to each patient (range 1–14). No complete or partial responses were observed. Seven patients (41%) had stable disease, with a median duration of 6 months (range 5–14). The median survival time for all 19 patients was 196 days (95% confidence interval 93–302). The treatment was generally well tolerated. Treatment-related toxicities included constipation (grade 3, 5%; grade 2, 37%; grade 1, 21%), fatigue (grade 3, 5%; grade 2, 42%), and sensory neuropathy (grade 2, 5%; grade 1, 32%). Four patients required dose reductions of thalidomide due to treatment-related toxicities, and the median tolerated dose of thalidomide was 200 mg daily.

Conclusions. The combination of epirubicin and thalidomide was well tolerated when administered in the schedule used in this study. This regimen has limited activity in HCC, with some patients achieving stable disease and clinical benefit. There is a need for defining more effective systemic therapies for HCC.

Key Words. Hepatocellular carcinoma • Epirubicin • Thalidomide • Angiogenesis • Clinical study


   INTRODUCTION
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
Worldwide, hepatocellular carcinoma (HCC) remains a very common malignancy with a poor prognosis. In the U.S., 19,000 new cases of cancers of the liver and intrahepatic bile duct were expected in 2004, with an estimated 14,100 deaths [1]. The incidence and mortality rate of HCC continue to rise steadily. The incidence rate doubled in the U.S. during the period of 1975–1995 and continued to rise through 1998 [2,3].

Improvements in survival for patients with metastatic HCC will depend on the development of effective systemic chemotherapy. Unfortunately, no systemic therapy has demonstrated important palliative or survival benefits. Doxorubicin (Adriamycin®; Bedford Laboratories, Bedford, OH, http://www.bedfordlabs.com) is among the most extensively studied agents for the treatment of this disease. However, in both a review and a meta-analysis of published randomized trials for patients with HCC, neither doxorubicin nor any other chemotherapeutic agent nor combination of agents has produced an improvement in patient survival rates [4,5]. Despite initial, impressive results of combination chemotherapy using cisplatin (Platinol®; Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com), interferon-{alpha}, doxorubicin, and 5-fluorouracil (PIAF), with a partial response rate of 26% [6], a recently reported randomized phase III study failed to demonstrate improved overall survival in patients treated with PIAF when compared with single-agent doxorubicin [7]. The sobering conclusion is that decades of clinical research have not identified a systemic therapy with demonstrable palliative or survival benefit for patients with unresectable HCC. Enrollment into clinical trials should, therefore, be considered a standard of care for these patients.

Epirubicin (Ellence®; Pfizer Pharmaceuticals, New York, NY, http://www.pfizer.com) is the 4'-epimer of doxorubicin that has a more favorable toxicity profile with less myelosuppression and cardiotoxicity than doxorubicin. Several small studies have shown that epirubicin has limited activity in HCC. In a phase II study of epirubicin in patients with HCC, Hochster et al. observed partial responses (PRs) in 3 of 18 patients, with a response rate of 17% [8]. Dobbs et al. reported three PRs among 13 patients with HCC who were treated with epirubicin [9]. The experience with epirubicin in Hong Kong also suggests its limited activity in HCC, with a response rate of 9% [10]. A retrospective study with single-agent epirubicin, given at a dose of 20 mg/m2 weekly for three consecutive weeks every 4 weeks, demonstrated a 9% response rate in HCC [11]. Studies in breast cancer have shown that the weekly schedule of epirubicin is a valid alternative and may have a better safety profile [12,13].

HCCs are commonly viewed as very vascular tumors. Increased levels of vascular endothelial growth factor (VEGF) and high microvessel density (MVD) have been found in HCCs [14–16]. Increased VEGF expression has been associated with inferior survival in HCC [17–19]. Therefore, inhibition of angiogenesis represents a potential therapeutic target. In preclinical studies, thalidomide (Thalomid®; Celgene Corporation, Warren, NJ, http://www.celgene.com) demonstrated antiangiogenic properties [20]. In a phase II study of 31 patients with HCC treated with thalidomide, Patt et al. reported that 14 patients (45%) achieved disease stabilization and another two patients achieved a minimal response and a PR [21]. Hsu and colleagues conducted a study using thalidomide in 68 HCC patients. Of the 63 evaluable patients, one complete response (CR) and three PRs were seen, for a response rate of 6.3% (95% confidence interval [CI] 0–12.5). Ten patients had dramatic decreases in their {alpha}-fetoprotein (AFP) levels. Interestingly, all responders received thalidomide at a dose of 300 mg or less per day [22]. In another study, involving 99 patients with advanced HCC, responses were seen in six patients after treatment with single-agent thalidomide [23]. In most studies, intrapatient thalidomide dose escalation was allowed in an attempt to optimize the outcome.

Given the reported single-agent activity for both epirubicin and thalidomide in HCC, their different mechanisms of action, and their nonoverlapping toxicities, we conducted a phase II study using the combination of epirubicin and thalidomide in patients with advanced HCC.


   PATIENTS AND METHODS
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Human Subjects Protection
The protocol for this clinical trial was reviewed and approved by the Institutional Review Board at Dana-Farber/Partners CancerCare. All patients were required to provide written informed consent prior to study participation according to institutional and federal guidelines.

Eligibility
Patients were eligible for entry if they had histologically proven, locally advanced, recurrent, or metastatic HCC. Patients were permitted no more than one prior systemic chemotherapy regimen for HCC. Prior treatment with a systemic anthracycline was not permissible, but prior chemoembolization therapy was permitted. Unidimensionally measurable disease was required. Patients had to be at least 18 years of age, have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0–2, and adequate major organ function. Specific laboratory criteria included a serum bilirubin level ≤3.0 mg/dl, an aspartate transaminase (AST) level ≤7x the institutional upper limit of normal, an albumin level ≥2.0 mg/dl, and a serum creatinine level ≤2.0 mg/dl. Minimum hematologic parameters included an absolute neutrophil count (ANC) ≥1.5 x 109/l and a platelet count of ≥75 x 109/l. Patients who were not on anticoagulant medications were required to have international normalized ratios ≤1.5. A left ventricular ejection fraction >40%, as assessed by echocardiography or multi-gated acquisition (MUGA) scan, was also required. Exclusion criteria included a concurrent malignancy, significant medical comorbidities, and an inability to give written informed consent. Women could not be pregnant or lactating. Both men and women of childbearing potential had to use the birth control measures outlined by the manufacturer in the System for Thalidomide Education and Prescription Safety (S.T.E.P.S.®) protocol.

Treatment Protocol
Treatment consisted of epirubicin, 20 mg/m2, delivered as an i.v. infusion over 10–15 minutes once weekly for 3 weeks followed by a 1-week rest. Thalidomide was administered orally daily for 3 weeks. One cycle of treatment included three consecutive weekly infusions of epirubicin and daily thalidomide followed by a 1-week rest. Treatment courses were repeated every 4 weeks unless there was evidence of progressive disease (PD). No dose escalation was allowed for epirubicin. Thalidomide was started at a dose of 200 mg daily. If the patient tolerated the treatment without the development of greater than grade 1 thalidomide-associated toxicities, such as peripheral neuropathy, asthenia, rash, dizziness, or declining performance status, the dose of thalidomide could be escalated in 100-mg increments for each patient every 2 weeks up to 800 mg daily. The use of antiemetic premedication was at the discretion of the treating physician.

Before study entry, all patients provided complete medical histories and underwent physical examinations, including an assessment of performance status, recent weight loss, and concurrent nonmalignant disease and therapy. Laboratory studies included a complete blood count, differential count, platelet count, biochemical, hepatic, and renal function tests, and an AFP measurement. Required radiological studies included a chest radiograph and an abdominal/pelvic computerized tomography (CT) or magnetic resonance imaging (MRI) scan. Serum hepatitis B and C serologies were also determined before treatment. A pregnancy test was obtained from all women of childbearing potential within 24 hours of the initiation of therapy. A baseline cardiac echo or MUGA scan was performed to assess cardiac function.

During treatment, patients were seen weekly for a brief history, physical examination, and assessments of performance status and toxic side effects. A complete blood count was done before each epirubicin treatment. Renal and liver function tests were performed every 2 weeks, and AFP levels were examined every 4 weeks. Measurable disease was assessed by a CT or MRI scan every 8 weeks. Response and progression were evaluated in this study using the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) committee [24]. Treatment was continued until one of the following criteria was met: disease progression, unacceptable toxicity, patient refusal, or the need to delay chemotherapy more than 3 weeks. Patients refractory to epirubicin and thalidomide were allowed to receive alternative treatment at their physician’s discretion.

Toxicity Evaluation and Dose Modification
Toxicity was evaluated weekly, according to the National Cancer Institute Common Toxicity Criteria version 2. On days 1, 8, and 15, full-dose therapy of epirubicin was given if the patient had an ANC ≥1,000/mm3, a platelet count ≥75,000/mm3, and grade 2 or lower nonhematologic toxicities other than nausea, vomiting, or alopecia. If a patient had an ANC of 500–999/mm3 or a platelet count of 50,000–74,999/mm3, then 75% of the original epirubicin dose was given. If a patient had an ANC <500/mm3 or a platelet count <50,000/mm3, then therapy was withheld until the ANC rose to 500/mm3 and the platelet count rose to 50,000/mm3, and subsequent epirubicin doses were reduced by 50% of the original dose. Treatment was withheld in the setting of grade 3 or higher nonhematologic toxicities, with the exception of nausea, emesis, and alopecia, and the subsequent dose of epirubicin was reduced by 25% for grade 3 and by 50% for grade 4 toxicities.

The starting dose of thalidomide was 200 mg/day. Efforts were made to minimize thalidomide-related side effects. Patients were advised to take the daily thalidomide early in the evening to minimize daytime somnolence and asthenia; oral hydration was encouraged to minimize dizziness. If a thalidomide-related toxicity developed prior to any dose escalation (moderate somnolence, grade 2 dizziness or headache, decline in ECOG performance status score by 1), the dose of thalidomide was reduced to 100 mg/day. If no improvement was seen within 7 days, the dose was further reduced to 50 mg/day. If symptoms persisted, the patient was withdrawn from the study due to toxicity. If grade 3 neuropathy, rash, or other nonhematolgic toxicity developed, thalidomide was held. Treatment with thalidomide was only reinitiated if toxicities decreased to grade 1 or less. If epirubicin was held for any reason, then thalidomide was also held.

Statistical Considerations
The primary objective of this phase II study was to assess the response rate of this regimen. The secondary objectives were to evaluate the overall survival, progression-free survival, and toxicity of this combination regimen.

Simon’s two-stage accrual design was used to identify ineffective therapy with a minimum number of patients. An overall response rate of 5% was selected as a minimum response rate of interest, and a response rate of 15% was selected as an assumed target. A sample size of 32 (17 in the first stage and an additional 15 in the second) was needed to attain an {alpha}-type error of 0.18 and a ß-type error of 0.17. Progression-free survival and overall survival estimates were calculated using the Kaplan-Meier method [25]. Time to progression was defined as time from the beginning of therapy until progression or death (whichever happened first).


   RESULTS
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Patient Characteristics
Between March 2002 and January 2005, 19 patients were entered into this trial. All were eligible for assessment of toxicity, and 17 patients were evaluable for assessment of response. Baseline patient characteristics are summarized in Table 1Go. There were 15 men (79%) and four women (21%), with a median age of 63 years (range 26–82 years). The median ECOG performance status score for the population was 1 (range 0–1). Nine patients (47%) had extrahepatic metastases. Fourteen patients (74%) had received no previous chemotherapy, whereas five had received one previous therapy. The median serum bilirubin level was 0.8 mg/dl (range 0.3–2.6 mg/dl), and 15 patients (79%) had elevated AFP levels. Of note, only four patients had a positive hepatitis B or C serology.


View this table:
[in this window]
[in a new window]
  		Table 1. Patient baseline characteristics
 
Response and Survival Rates
The clinical efficacy results are shown in Table 2Go. Among all patients, 71 cycles of chemotherapy were administered. A median of two chemotherapy cycles was administered to each patient (range 1–14). Seven patients (41%) completed more than four cycles of chemotherapy. Twelve patients (63%) withdrew from therapy due to disease progression, two patients (11%) withdrew due to physician or patient discretion, two patients (11%) withdrew as a result of treatment-related toxicities, one patient (5%) withdrew due to the development of a second malignancy (lymphoma), one patient (5%) withdrew as a result of a broken hip, and one patient (5%) remained on study at 12 months (see below).


View this table:
[in this window]
[in a new window]
  		Table 2. Clinical efficacy
 
Response was evaluated in 17 patients. Two patients were not evaluable for response. One patient developed grade 3 nausea and vomiting after receiving one dose of epirubicin and 2 days of thalidomide and was removed from the study based on the patient’s decision. Another patient was diagnosed with a second malignancy (lymphoma) while receiving the first cycle of treatment and was removed from the study. No patient achieved a CR or PR, although one patient had a minor response, with 19% shrinkage of the target lesions. Seven patients (41%) had stable disease as their best response and 10 patients (59%) had PD. Among the seven patients with stable disease, the median duration of stable disease was 6 months (range 5–14+ months). In addition, a >50% decrease in AFP level was observed in 1 of 15 (7%) patients who had elevated pretreatment levels, and another three patients (20%) had >20% decreases in their AFP levels.

As of January 2005, 15 patients had died and four were still alive. The median progression-free survival period for all 19 patients was 57 days (95% CI 49–224; Fig. 1Go). The median survival period for the entire cohort was 196 days (95% CI 93–302; Fig. 2Go).



View larger version (9K):
[in this window]
[in a new window]
  		Figure 1. Progression-free survival for hepatocellular carcinoma patients in the study.

 


View larger version (9K):
[in this window]
[in a new window]
  		Figure 2. Overall survival for hepatocellular carcinoma patients in the study.

 
Toxicity
Data on treatment-related toxicities for all 19 patients are provided in Table 3Go. The toxicities recorded represent the maximum grade of toxicity observed for a given patient for the entire course of therapy. Myelosuppression was mild in general, with only one patient (5%) experiencing grade 3 neutropenia. Four patients (21%) experienced grade 3 nausea/vomiting, and one patient (5%) experienced grade 3 constipation. Neurologic toxicities, including headache and peripheral neuropathy, were mainly grade 1, with only one patient developing grade 2 peripheral neuropathy. Among all patients, there were only two toxicity-related discontinuations. There were no treatment-related deaths.


View this table:
[in this window]
[in a new window]
  		Table 3. Treatment-related toxicities
 
One patient tolerated treatment well and had radiographic shrinkage of tumors following the second through fourth cycles of treatment, although this did not meet the criteria for PR of the RECIST criteria. Unfortunately, he developed prolonged respiratory distress of unclear etiology during cycle 5 and was, therefore, unable to receive additional epirubicin/thalidomide treatment.

Four patients required dose reductions of thalidomide due to treatment-related toxicities, and the median tolerated dose of thalidomide was 200 mg/day. Intrapatient dose escalation was limited due to constipation, drowsiness, and fatigue.


   DISCUSSION
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
The prognosis for patients with locally advanced and metastatic HCC is dismal, with a median survival time of <6 months, and the development of an effective systemic therapy for HCC remains a challenge. Increasing evidence has suggested the importance of angiogenesis in hepatocarcinogenesis. In an attempt to improve the therapeutic efficacy of chemotherapy for the treatment of HCC, we postulated that an agent with antiangiogenic potential, such as thalidomide, might augment the efficacy of an anthracycline. Unfortunately, our results demonstrate that epirubicin in combination with thalidomide has limited activity in this population. No patients met the RECIST response criteria, although one patient had 19% shrinkage of the target lesions. A total of seven patients had stable disease for a median of 6 months. Patients who achieved stable disease had significant relief of disease-related symptoms, including improved pain control, sustained or improved performance status, and decreased ascites. As shown in Table 4Go, our results are consistent with those of two recently published phase II studies demonstrating limited activity of single-agent thalidomide in HCC [26,27]. Therefore, the combination of epirubicin and thalidomide was clearly not more efficacious than either drug used as a single agent. The value of combining additional agents, including the newer generation of antiangiogenic compounds, with an anthracycline remains to be determined.


View this table:
[in this window]
[in a new window]
  		Table 4. Phase II studies of thalidomide-based regimens in advanced hepatocellular carcinoma
 
The epirubicin/thalidomide combination proved to be well tolerated. Both hematologic and nonhematologic toxicities were generally mild. Major toxicities encountered included myelosuppression, gastrointestinal toxicities (including nausea, vomiting, and constipation), and peripheral neuropathy. In our study, the median daily dosage of thalidomide given was 200 mg, and intrapatient dose escalation was limited due to constipation, drowsiness, and fatigue. One patient developed respiratory failure and eventually recovered with maximum support. The etiology of that patient’s respiratory failure was not identified, and a drug effect associated with either or both agents used in the study is possible. Thalidomide-induced pulmonary toxicity has been reported previously [28].

In conclusion, despite the tolerable toxicity profile, we observed limited activity for the combination of epirubicin and thalidomide in patients with advanced HCC. In the absence of any acceptable standard systemic therapy, all eligible patients with HCC should be encouraged to participate in ongoing trials assessing the value of new agents and regimens for this disease. Inhibition of angiogenesis in HCC remains a potential therapeutic target, and other anti-angiogenic agents, including bevacizumab (Avastin®; Genentech, Inc., South San Francisco, CA, http://www.gene.com), are currently under clinical investigation in HCC. Preliminary studies using bevacizumab alone or in combination with gemcitabine (Gemzar®; Eli Lilly and Company, Indianapolis, IN, http://www.lilly.com) and oxaliplatin (Eloxatin®; Sanofi-Synthelabo Inc., New York, http://www.sanofi-synthelabo.us) in HCC have been reported, and changes in angiogenic parameters have been seen following bevacizumab administration [29,30].


   ACKNOWLEDGMENT
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
We are indebted to the patients who participated in this study, their families, and the referring physicians. We thank Dr. Bruce Chabner for critically reviewing the manuscript and Ms. Dottie Monahan for her assistance in preparing the manuscript.

DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
The authors indicated no potential conflicts of interest.


   REFERENCES
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Jemal A, Tiwari RC, Murray T et al. Cancer statistics, 2004. CA Cancer J Clin 2004;54:8–29.[Abstract/Free Full Text]
  2. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1999;340:745–750.[Abstract/Free Full Text]
  3. El-Serag HB, Davila JA, Petersen NJ et al. The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med 2003;139:817–823.[Abstract/Free Full Text]
  4. Mathurin P, Rixe O, Carbonell N et al. Review article: overview of medical treatments in unresectable hepatocellular carcinoma—an impossible meta-analysis? Aliment Pharmacol Ther 1998;12:111–126.[CrossRef][Medline]
  5. Simonetti RG, Liberati A, Angiolini C et al. Treatment of hepatocellular carcinoma: a systematic review of randomized controlled trials. Ann Oncol 1997;8:117–136.[Abstract/Free Full Text]
  6. Leung TW, Patt YZ, Lau WY et al. Complete pathological remission is possible with systemic combination chemotherapy for inoperable hepatocellular carcinoma. Clin Cancer Res 1999;5:1676–1681.[Abstract/Free Full Text]
  7. Yeo W, Zee B, Leung WT et al. A phase III study of doxorubicin (A) versus cisplatin (P)/interferon{alpha}-2b (I)/doxorubicin (A)/fluorouracil (F) combination chemotherapy (PIAF) for inoperable hepatocellular carcinoma (HCC). Proc Am Soc Clin Oncol 2004;22:4026.
  8. Hochster HS, Green MD, Speyer J et al. 4'Epidoxorubicin (epirubicin): activity in hepatocellular carcinoma. J Clin Oncol 1985;3:1535–1540.[Abstract/Free Full Text]
  9. Dobbs NA, Twelves CJ, Rizzi P et al. Epirubicin in hepatocellular carcinoma: pharmacokinetics and clinical activity. Cancer Chemother Pharmacol 1994;34:405–410.[Medline]
  10. Shiu W, Leung N, Li M et al. The efficacy of high-dose 4'epidoxorubicin in hepatocellular carcinoma. Jpn J Clin Oncol 1988;18:235–237.[Abstract/Free Full Text]
  11. Pohl J, Zuna I, Stremmel W et al. Systemic chemotherapy with epirubicin for treatment of advanced or multifocal hepatocellular carcinoma. Chemotherapy 2001;47:359–365.[CrossRef][Medline]
  12. Joensuu H, Holli K, Heikkinen M et al. Combination chemotherapy versus single-agent therapy as first- and second-line treatment in metastatic breast cancer: a prospective randomized trial. J Clin Oncol 1998;16:3720–3730.[Abstract/Free Full Text]
  13. Barni S, Archili C, Lissoni P et al. A weekly schedule of epirubicin in pretreated advanced breast cancer. Tumori 1993;79:45–48.[Medline]
  14. Yamaguchi R, Yano H, Iemura A et al. Expression of vascular endothelial growth factor in human hepatocellular carcinoma. Hepatology 1998;28:68–77.[CrossRef][Medline]
  15. Miura H, Miyazaki T, Kuroda M et al. Increased expression of vascular endothelial growth factor in human hepatocellular carcinoma. J Hepatol 1997;27:854–861.[CrossRef][Medline]
  16. Messerini L, Novelli L, Comin CE. Microvessel density and clinicopathological characteristics in hepatitis C virus and hepatitis B virus related hepatocellular carcinoma. J Clin Pathol 2004;57:867–871.[Abstract/Free Full Text]
  17. Chao Y, Li CP, Chau GY et al. Prognostic significance of vascular endothelial growth factor, basic fibroblast growth factor, and angiogenin in patients with resectable hepatocellular carcinoma after surgery. Ann Surg Oncol 2003;10:355–362.[Abstract/Free Full Text]
  18. Poon RT, Ho JW, Tong CS et al. Prognostic significance of serum vascular endothelial growth factor and endostatin in patients with hepatocellular carcinoma. Br J Surg 2004;91:1354–1360.[CrossRef][Medline]
  19. Jeng KS, Sheen IS, Wang YC et al. Prognostic significance of preoperative circulating vascular endothelial growth factor messenger RNA expression in resectable hepatocellular carcinoma: a prospective study. World J Gastroenterol 2004;10:643–648.[Medline]
  20. D’Amato RJ, Loughnan MS, Flynn E et al. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA 1994;91:4082–4085.[Abstract/Free Full Text]
  21. Patt YZ, Hassan M, Lozano R. Phase II trial of Thalomid (thalidomide) for treatment of non-resectable hepatocellular carcinoma (HCC). Proc Am Soc Clin Oncol 2000;19:1035.
  22. Hsu C, Chen CN, Chen LT et al. Low-dose thalidomide treatment for advanced hepatocellular carcinoma. Oncology 2003;65:242–249.[CrossRef][Medline]
  23. Wang TE, Kao CR, Lin SC et al. Salvage therapy for hepatocellular carcinoma with thalidomide. World J Gastroenterol 2004;10:649–653.[Medline]
  24. Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205–216.[Abstract/Free Full Text]
  25. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1959;53:457–481.[CrossRef]
  26. Lin AY, Brophy N, Fisher GA et al. Phase II study of thalidomide in patients with unresectable hepatocellular carcinoma. Cancer 2005;103:119–125.[CrossRef][Medline]
  27. Patt YZ, Hassan MM, Lozano RD et al. Thalidomide in the treatment of patients with hepatocellular carcinoma: a phase II trial. Cancer 2005;103:749–755.[CrossRef][Medline]
  28. Carrion Valero F, Bertomeu Gonzalez V. [Lung toxicity due to thalidomide]. Arch Bronconeumol 2002;38:492–494 [Spanish].[Medline]
  29. Schwartz JD, Schwartz M, Goldman J et al. Bevacizumab in hepatocellular carcinoma (HCC) for patients without metastasis and without invasion of the portal vein. American Society of Clinical Oncology Gastrointestinal Cancers Symposium, 2005. Abstract 134.
  30. Zhu AX, Sahani D, Norden-Zfoni A et al. A phase II study of gemcitabine, oxaliplatin in combination with bevacizumab (GEMOX-B) in patients with hepatocellular carcinoma. American Society of Clinical Oncology Gastrointestinal Cancers Symposium, 2005. January 27–29, 2005. Hollywood, FL. Abstract 131.
Received February 11, 2005; accepted for publication March 22, 2005.




This article has been cited by other articles:


Home page
 The OncologistHome page
A. X. Zhu
Systemic Therapy of Advanced Hepatocellular Carcinoma: How Hopeful Should We Be?
Oncologist, July 1, 2006; 11(7): 790 - 800.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
A. X. Zhu, L. S. Blaszkowsky, D. P. Ryan, J. W. Clark, A. Muzikansky, K. Horgan, S. Sheehan, K. E. Hale, P. C. Enzinger, P. Bhargava, et al.
Phase II Study of Gemcitabine and Oxaliplatin in Combination With Bevacizumab in Patients With Advanced Hepatocellular Carcinoma
J. Clin. Oncol., April 20, 2006; 24(12): 1898 - 1903.
[Abstract] [Full Text] [PDF]

Home page
 The OncologistHome page
C.-C. Lee, Y.-H. Wu, S.-H. Chung, and W.-J. Chen
Acute Tumor Lysis Syndrome After Thalidomide Therapy in Advanced Hepatocellular Carcinoma
Oncologist, January 1, 2006; 11(1): 87 - 88.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow eLetters: Submit a response to this article
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Zhu, A. X.
Right arrow Articles by Ryan, D. P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zhu, A. X.
Right arrow Articles by Ryan, D. P.

HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
THE ONCOLOGIST STEM CELLS CME ALPHAMED PRESS JOURNALS