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Phase II Trial of Systemic Continuous Fluorouracil and Subcutaneous Recombinant Interferon Alfa-2b for Treatment of Hepatocellular Carcinoma

From the Department of Gastrointestinal Medical Oncology and Digestive Diseases, the Department of Surgical Oncology, and the Division of Pharmacy, The University of Texas M. D. Anderson Cancer Center, Houston, TX.

Address reprint requests to Yehuda Z. Patt, MD, University of Maryland, Greenebaum Cancer Center, 22 South Greene St, Baltimore, MD 21201-1595; email: yzpatt{at}umm.edu.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: Because cirrhosis is extremely common in hepatocellular carcinoma (HCC) in the United States, and it precludes the use of several chemotherapy agents, this phase II trial of fluorouracil (FU) and recombinant interferon alfa-2b (rIFN2b) in HCC was launched with the assumption that it could be tolerated by cirrhotics.

Patients and Methods: Forty-three patients with HCC (34), and fibrolamellar HCC (FLHCC; nine) were treated with continuous intravenous (IV) FU (200 mg/m²/d x 21 every 28 days) and subcutaneous (SC) rIFN2b (4 million U/m²) three times weekly. Survival was determined in all 43 patients, and response could be assessed in 28 HCC and 8 FLHCC patients.

Results: The median ages of the patients were 63.5 and 19 years among HCC and FLHCC patients, respectively. Liver cirrhosis was present among 71% of HCC patients but among none of the FLHCC patients. Nine of 36 (25%; four of 28 [14%] HCC patients; five of eight [62.5%] FLHCC patients) patients in which a response could be assessed had a complete response (CR; one patient with FLHCC and no patients with HCC) or partial response (PR; eight patients [four HCC and four FLHCC patients]). Four HCC patients underwent resection, and two had a histologic CR; one HCC patient with a PR underwent orthotopic liver transplantation. One FLHCC patient also underwent resection without clear margins. Overall median survival was 19.5 months (95% confidence interval [CI], 11.2 to 27.8 months); median survival was 15.5 months (95% CI, 8.5 to 22.5 months) among HCC patients, and that of FLHCC patients was 23.1 months (95% CI, 10.3 to 35.9 months). Overall grade 3 or 4 toxicity included stomatitis (32.6%), fatigue (4.7%), and hematologic toxicity (9.3%).

Conclusion: Continuous IV FU and thrice-weekly SC rIFN2b are an effective treatment, especially for FLHCC, and may have a neoadjuvant role in this disease. This regimen has activity in HCC and can be tolerated even by cirrhotic patients.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
THE INCIDENCE of hepatocellular carcinoma (HCC) has been rising in the United States,¹ and this increase has been attributed mostly to chronic infection with hepatitis C virus (HCV).² Indeed, between the years 1993 and 2000, the incidence of primary hepatobiliary cancers in the United States increased from approximately 15,500 per year to 22,500 per year.³

It is estimated that 1.8% of the US population (approximately 3.9 million individuals) have been exposed to HCV, and approximately 2.7 million individuals are carriers of HCV RNA, indicating chronic infection.⁴ Because chronic infection with either hepatitis B virus (HBV) or HCV and heavy alcohol consumption are individually and interactively important factors in the etiology of liver cirrhosis,⁵ it is not surprising that cirrhosis is so common among patients with HCC.

The effect of liver cirrhosis on the outcome of HCC treatment is significant. The hepatocellular damage associated with cirrhosis may decrease the ability of the liver to metabolize and excrete chemotherapeutic agents. This may increase the toxic side effects of chemotherapeutic drugs, particularly in the presence of liver cirrhosis–associated thrombocytopenia and leukopenia, worsening their bone marrow suppression.

Many agents have been studied for their anti-HCC activity. The pyrimidine antimetabolite fluorouracil (FU) was the first reported chemotherapeutic agent tested in the treatment of HCC. Treatment schedule, dosage, and duration have varied. However, an overall response rate of about 10% and a median survival of 3 to 5 months have discouraged further use of FU as a single agent.^6,7 Other agents tested include doxorubicin,^6,8,9 which has a reported single-agent activity of 25% and yields a survival advantage when compared with no treatment.⁸ Recombinant interferon alfa (rIFN) has been found to be superior to doxorubicin for the treatment of inoperable HCC.¹⁰ Moreover, when added to systemic cisplatin, doxorubicin, and FU (PIAF), rIFN2b demonstrated encouraging results and even complete histologic remissions in patients with HCC who were likely to tolerate such therapy.^11,12 However, treatment was unlikely to be tolerated by patients with advanced cirrhosis.

Even though the single-agent activity of rIFN against HCC has been modest,¹⁰ many studies have established a possible role for rIFN in prevention of HCC in patients with HBV- or HCV-related cirrhosis.^13–16 In addition, rIFN has a biomodulatory effect on the cytotoxicity of fluoropyrimidines.¹⁷ rIFN upregulates thymidine phosphorylase (TP) gene expression, thereby modulating FU anabolism to its active metabolite fluorodeoxyuridine monophosphate (FdUMP).¹⁸ Moreover, this TP upregulation was shown to be rIFN-dose-dependent in some renal cell carcinoma cell lines.¹⁹ Increased levels of FdUMP inhibit thymidylate synthase activity, resulting in an increase in DNA double-strand breaks.²⁰

The use of a FU and rIFN combination had controversial results in patients with gastrointestinal malignancies. Thus, although Wadler et al²¹ suggested that the addition of rIFN to FU improved the activity of the latter in colorectal cancer patients, phase III trials of the combination in that malignancy^22,23 and phase II trials in advanced carcinoid and pancreatic cancer were negative.^24,25 Despite these results, the use of the combination in HCC seemed warranted in view of the association of HCC with HBV or HCV, by virtue of the concurrent antineoplastic and antiviral effects of rIFN and the potential synergism between rIFN and FU. Because this combination could be safely administered to HCC patients with or without liver cirrhosis, this phase II trial was launched in patients with histologically confirmed and radiologically measurable HCC and the fibrolamellar variant of HCC (FLHCC).

FLHCC is a unique and rare form of HCC that differs pathologically and radiologically from HCC; it is characterized as a vascular tumor with abundant fibrosis. FLHCC almost exclusively affects young people, mostly during the second and third decades of life, with equal sex distribution. It is not associated with either HBV or HCV infection or alcohol consumption, or is it associated with liver cirrhosis or elevated levels of alpha-fetoprotein (AFP).²⁶ The clinical course of the disease is less aggressive than that of conventional HCC, and a higher resectability rate is quite common.²⁷ However, recurrence after resection is frequent, portending a poor prognosis. Also, FLHCC is notoriously refractory to several chemotherapeutic agents.²⁸ The decision to allow registration of FLHCC patients on this protocol was based on our previous observation that the use of a FU and rIFN regimen had significant antitumor activity against this variant of HCC.²⁹

In view of the relative paucity of patients with FLHCC, this study was designed to allow registration of both groups of patients with proper stratification during analysis.

	PATIENTS AND METHODS

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Patient Eligibility
Patients with histologically confirmed and radiologically measurable HCC or FLHCC were included in the study. Disease could be confined to the liver or be metastatic. Eligibility criteria were performance status of 2 on the Zubrod scale, absolute granulocyte count of 1,500/µL, platelet count of 60 x 10³/µL, serum creatinine less than 2.0 mg/dL, serum bilirubin less than 3.5 mg/dL, and serum albumin 3.0 g/dL. Pregnant and breast-feeding women were excluded from the study. Prior exposure to chemotherapy or biologic therapy other than FU or rIFN was allowed. Patients with evidence of ascites that could be medically treated (usually with spironolactone and furosemide) were eligible for this protocol. Patients with brain metastasis that required other therapies had to complete such treatment before becoming eligible for protocol treatment. All the patients signed informed consent documents approved by the institutional review board attesting to the fact that they were aware of the investigational nature of the study.

Treatment Plan
Treatment was delivered on an outpatient basis. A dose of 200 mg/m² FU was infused continuously over 21 days by using portable infusion pumps. It was prepared in three plastic bags containing the appropriate weekly dose. A dose of 4 million U/m² rIFN was administered subcutaneously three times weekly (every Monday, Wednesday, and Friday) during the FU infusion. Treatment cycles were repeated every 28 days, provided all previous treatment-related toxic effects had resolved. Thus, subsequent treatment courses were held pending hematologic recovery to a granulocyte count of more than 1,500 and a platelet count of more than 60,000, and resolution of nonhematologic toxicity to grade 0 or to baseline. There was no dose escalation, although the doses of rIFN and FU could be decreased if needed. For grade 3 or greater stomatitis, the dose level of FU and rIFN2b were decreased to dose level 1 (FU, 175 mg/m²; rIFN2b, 3 million U/m²). Patients who developed grade 3 toxicity at dose level 1 had a further decrease in dosage of the two drugs to dose level 2 (FU, 150 mg/m²; rIFN2b, 2 million U/m²).

Response Evaluation
Treatment response was assessed by radiologic staging at the end of 8 weeks, after completion of two cycles of treatment. Liver tumors were evaluated by computed tomography (CT) or magnetic resonance imaging (MRI); and the product of the largest two perpendicular diameters was used for baseline and follow-up tumor measurements.³⁰ Dimensions of lung metastases were assessed by chest radiography. Complete response (CR) was defined as disappearance of all previously measurable lesions and absence of any new tumor lesions for at least 8 weeks. Partial response (PR) was defined as a decrease of 50% in the product of two perpendicular diameters of each measurable lesion. Minor response (MR) was defined as a 25% to 49% decrease in such measurements.³⁰ Time to disease progression among responders was counted from the date of their objective response until the date of their disease progression. Imaging response was correlated with serum AFP levels.

Statistical Methods
Simon’s two-stage design³¹ was used to calculate the sample size for this phase II trial, using two levels of response rate, P⁰ (20%) and P¹ (40%). Accordingly, 37 patients were required for this study. Seventeen patients were accrued for the first stage, and then 20 more patients were accrued once four or more responses were observed during the first stage,

Survival curves were generated by the Kaplan-Meier method,³² and the statistical significance of differences was determined according to Gehan’s modification of the Wilcoxon signed-rank test.³³ A P value < .05 was considered statistically significant. Survival time was determined from the beginning of treatment.

	RESULTS

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Patient Characteristics
Between 1997 and 2000, 43 patients were enrolled in the study (HCC, 34 [79%]; FLHCC, nine [21%]). Clinical characteristics and tumor staging for all study participants are shown in Table 1. All patients had histologically confirmed and radiologically measurable tumor.

Thirty patients (24 HCC [71%]; six FLHCC [67%]) had no prior radiotherapy, chemotherapy, or surgery, whereas seven HCC patients (21%) had been previously treated with chemotherapy. Pretreatment surgical resection of the tumor was performed in three (33%) FLHCC patients and in two (6%) HCC patients. Only one patient with HCC (3%) received injection of the tumor with alcohol before protocol registration. Disease was staged according to the American Joint Committee on Cancer tumor, node, metastasis (TNM) staging criteria as summarized in Table 1. Twenty-six patients (23 with HCC and three with FLHCC) had stage IV disease; seven patients (three with HCC and four with FLHCC) had stage IVB disease, six patients (five with HCC and one with FLHCC) had stage IIIA disease, and four patients (three with HCC and one with FLHCC) had stage IIIB disease. Neither HCC nor FLHCC patients were candidates for surgical resection because all had multifocal lesions or multilobar disease (76%) or vascular involvement (33%), as determined by contrast-enhanced, three-phase liver protocol CT scans. Fourteen patients (10 with HCC and four with FLHCC) had portal vein or hepatic vein occlusion with a tumor thrombus. Even patients with stage IIIA or stage IIIB disease were not considered surgical resection candidates because of the large size of the tumors (ranging between 5 and 12 cm in greatest dimension) or their underlying liver cirrhosis. All of the patients were examined for the signs of cirrhosis during their clinical evaluation by a hepatobiliary oncologist (Y.Z.P.); these signs included manifestations related to portal hypertension, including ascites, bleeding from esophageal varices, and hepatic encephalopathy. Minor signs, such as palmar erythema or spider angioma, were also noted clinically. In addition, CT scans of all of the HCC patients were reviewed for evidence of liver cirrhosis.³⁴ A diagnosis of liver cirrhosis was established clinically in 24 patients (56%), and 17 of those had radiologic stigmata of liver cirrhosis.

Pretreatment Baseline Data
Pretreatment laboratory findings (medians and ranges) of study participants are presented in Table 2.

The other four patients who had PR later experienced disease progression; the median time from their response date to progression was 5 months (range, 3.3 to 14.8 months). Two patients with FLHCC who had disease stability or MR to treatment also later experienced disease progression; the time to progression from treatment initiation was 16 months for the patient with SD and 19 months for the patient with MR. The overall time to progression for nonresponding patients was 2.5 months from the initiation of the treatment.

AFP Level and Radiologic Response
AFP was elevated only among patients with HCC and not among those with FLHCC. The median value of AFP among patients with HCC was 120.8 ng/mL (range, 1.2 to 375,784.8 ng/mL). Among FLHCC patients, the median value was 8.0 ng/mL (range, 2.4 to 34 ng/mL). All the patients who achieved CR or PR had a corresponding significant decrease in serum AFP level as compared with the baseline value (median decrease of 82.5%, with a range of decrease of 15.4% to 99.4%; P < .05). Conversely, 11 of 14 patients with disease progression showed an increase in their follow-up serum AFP levels. The estimated median increase compared with baseline value was 38% (range, 15% to 310%). The remaining three patients with progressive disease did not have elevated serum AFP levels at baseline, and those values remained stable throughout the study.

Patient Survival
Median survival of all 43 patients was 19.5 months (95% CI, 11.2 to 27.8 months; Fig 1). The median survival duration of patients with FLHCC was 23.1 months (95% CI, 10.3 to 35.9 months), and the median survival of the 34 patients with HCC was 15.5 months (95% CI, 8.5 to 22.5 months; Fig 2).

View larger version (9K): [in this window] [in a new window]   Fig 1. Overall median survival of 43 patients (with hepatocellular carcinoma and fibrolamellar hepatocellular carcinoma) by the Kaplan-Meier method.

View larger version (11K): [in this window] [in a new window]   Fig 2. Median survival of patients with hepatocellular carcinoma (HCC) and patients with fibrolamellar hepatocellular carcinoma (FLHCC) separately by the Kaplan-Meier method.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

The interaction between FU and rIFN hinges on the activity of a critical enzyme, TP, which seems to play a double role in tumor biology. It catalyzes the reversible phosphorolytic cleavage of thymidine and deoxyuridine and their analogues to the respective bases and to deoxyribose 1-phosphate.¹⁷ TP has also been shown to possess angiogenic activity in vivo and chemotactic activity in vitro.³⁵ In fact, TP was shown to be identical to the angiogenic factor platelet-derived endothelial cell growth factor (PD-ECGF).^36–38 In addition, Braybrooke et al¹⁸ have studied the effects of IFN on TP, demonstrating that a single dose as low as 3 million U/m² of rIFN could upregulate TP in peripheral blood lymphocytes within 2 hours of the administration and that the effect could be sustained for at least 13 days.

The interaction among TP, rIFN, and angiogenesis is complex. Clinically, rIFN has been successfully used in the treatment of hemangiomas,³⁹ with the mechanism appearing to be through the induction of apoptotic cell death.⁴⁰ Moreover, systemic administration of IFN to mice carrying a human bladder carcinoma, selected in vitro for insensitivity to interferon, was able to inhibit the expression of bFGF and reduce tumor angiogenesis, leading to a block in tumor growth.⁴¹ Conversely, an increase in tumor microvessel density was demonstrated by Marchetti et al¹⁷ in TP-transfected, as opposed to control, tumors implanted subcutaneously in nude mice, indicating that TP had a proangiogenic effect. However, this increase in tumor microvessel density was more pronounced in small tumors and disappeared as tumor size increased. On the basis of these observations, it would seem that synergism between rIFN and FU may be the result of tumor TP gene upregulation, leading to increased tumor sensitivity to FU. Because HCC tumor masses observed among our patients were rather large, the TP upregulation may have induced antiangiogenic rather that proangiogenic activity, thereby further enhancing antitumor activity.

An additional reason to study this drug combination in HCC is the frequent association of the disease with liver cirrhosis, a condition that often curtails therapeutic options. We have previously used a combination PIAF systemically to treat patients with HCC who were likely to tolerate such treatment,¹¹ and we observed impressive responses in both liver and extrahepatic disease. In Hong Kong, Leung et al¹² used a similar regimen among Chinese HCC patients, demonstrating a PR rate of 26%. In addition, disease previously considered nonresectable became resectable in nine (18%) patients, and four (9%) patients achieved complete histologic remissions. This Hong Kong study included mostly patients infected with HBV; however, 46.5% of our patients were HCV carriers, and 56% had evidence of liver cirrhosis. This raised concerns regarding patients’ ability to tolerate doxorubicin and cisplatin. These considerations prompted the investigation of the combination of continuous infusion FU and subcutaneous rIFN in hope of improved tolerance, even among cirrhotic patients, which was, indeed, observed.

Interferon-induced tumor TP upregulation¹⁸ may be even more intriguing in combination with the oral fluoropyrimidine capecitabine, a FU prodrug activated by TP to FU.⁴² A formal phase II trial of rIFN combined with capecitabine may be warranted to determine the role of the latter in the treatment. Should results of such a trial be similar to FU and rIFN, the regimen should then be subjected to a multi-institutional phase III trial.

	ACKNOWLEDGMENTS

 
Supported in part by a grant from Schering Plough, Inc., Kenilworth, NJ, and McKinley Medical, LLLP, Denver, CO.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. El Serag HB, Mason AC: Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 340:745–750, 1999[Abstract/Free Full Text]

2. El Serag HB, Mason AC: Risk factors for the rising rates of primary liver cancer in the United States. Arch Intern Med 160:3227–3230, 2000[Abstract/Free Full Text]

3. Greenlee RT, Murray T, Bolden S, et al: Cancer statistics, 2000. CA Cancer J Clin 50:7–33, 2000[Abstract]

4. Alter MJ, Kruszon-Moran D, Nainan OV, et al: The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med 341:556–562, 1999[Abstract/Free Full Text]

5. Hassan MM, Hwang LY, Hatten CJ, et al: Risk factors for hepatocellular carcinoma: Synergism of alcohol with viral hepatitis and diabetes mellitus. Hepatology 36:1206–1213, 2002[CrossRef][Medline]

6. Friedman MA: Primary hepatocellular cancer—present results and future prospects. Int J Radiat Oncol Biol Phys 9:1841–1850, 1983[Medline]

7. Lin DY, Lin SM, Liaw YF: Non-surgical treatment of hepatocellular carcinoma. J Gastroenterol Hepatol 12:S319–S328, 1997[Medline]

8. Lai CL, Wu PC, Chan GC, et al: Doxorubicin versus no antitumor therapy in inoperable hepatocellular carcinoma. A prospective randomized trial. Cancer 62:479–483, 1988[CrossRef][Medline]

9. Melia WM, Johnson PJ, Williams R: Induction of remission in hepatocellular carcinoma. A comparison of VP 16 with Adriamycin. Cancer 5:206–210, 1983

10. Lai CL, Wu PC, Lok AS, et al: Recombinant alpha 2 interferon is superior to doxorubicin for inoperable hepatocellular carcinoma: A prospective randomised trial. Br J Cancer 60:928–933, 1989[Medline]

11. Patt YZ, Hoque A, Roh M, et al: Durable clinical and pathologic response of hepatocellular carcinoma to systemic and hepatic arterial administration of platinol, recombinant interferon alpha 2B, doxorubicin, and 5-fluorouracil: A communication. Am J Clin Oncol 22:209–213, 1999[CrossRef][Medline]

12. Leung TW, Patt YZ, Lau WY, et al: Complete pathological remission is possible with systemic combination chemotherapy for inoperable hepatocellular carcinoma. Clin Cancer Res 5:1676–1681, 1999[Abstract/Free Full Text]

13. Baffis V, Shrier I, Sherker AH, et al: Use of interferon for prevention of hepatocellular carcinoma in cirrhotic patients with hepatitis B or hepatitis C virus infection. Ann Intern Med 131:696–701, 1999[Abstract/Free Full Text]

14. Nishiguchi S, Kuroki T, Nakatani S: Randomised trial of effects of interferon-alpha on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis. Lancet 346:1051–1055, 1995[CrossRef][Medline]

15. Giannini E, Fasoli A, Botta F, et al: Long-term follow up of chronic hepatitis C patients after alpha-interferon treatment: A functional study. J Gastroenterol Hepatol 16:399–405, 2001[CrossRef][Medline]

16. Okuno M, Kojima S, Moriwaki H: Chemoprevention of hepatocellular carcinoma: Concept, progress and perspectives. J Gastroenterol Hepatol 16:1329–1335, 2001[CrossRef][Medline]

17. Marchetti S, Chazal M, Dubreuil A, et al: Impact of thymidine phosphorylase superexpression on fluoropyrimidine activity and on tumour angiogenesis. Br J Cancer 85:439–445, 2001[CrossRef][Medline]

18. Braybrooke JP, Propper DJ, O’Byrne KJ, et al: Induction of thymidine phosphorylase as a pharmacodynamic end-point in patients with advanced carcinoma treated with 5-fluorouracil, folinic acid and interferon alpha. Br J Cancer 83:219–224, 2000[CrossRef][Medline]

19. Morita T, Tokue A: Biomodulation of 5-fluorouracil by interferon-alpha in human renal carcinoma cells: Relationship to the expression of thymidine phosphorylase. Cancer Chemother Pharmacol 44:91–96, 1999[CrossRef][Medline]

20. Wadler S, Horowitz R, Mao X, et al: Effect of interferon on 5-fluorouracil-induced perturbations in pools of deoxynucleotide triphosphates and DNA strand breaks. Cancer Chemother Pharmacol 38:529–535, 1996[CrossRef][Medline]

21. Wadler S, Schwartz EL, Goldman M, et al: Fluorouracil and recombinant alfa-2a-interferon: An active regimen against advanced colorectal carcinoma. J Clin Oncol 7:1769–1775, 1989[Abstract]

22. Corfu-A Study Group: Phase III randomized study of two fluorouracil combinations with either interferon alfa-2a or leucovorin for advanced colorectal cancer. J Clin Oncol 13:921–928, 1995[Abstract]

23. Greco FA, Figlin R, York M, et al: Phase III randomized study to compare interferon alfa-2a in combination with fluorouracil versus fluorouracil alone in patients with advanced colorectal cancer. J Clin Oncol 14:2674–2681, 1996[Abstract/Free Full Text]

24. Hughes MJ, Kerr DJ, Cassidy J, et al: A pilot study of combination therapy with interferon-alpha-2a and 5-fluorouracil in metastatic carcinoid and malignant endocrine pancreatic tumours. Ann Oncol 7:208–210, 1996[Abstract/Free Full Text]

25. Saltz L, Kemeny N, Schwartz G, et al: A phase II trial of alpha-interferon and 5-fluorouracil in patients with advanced carcinoid and islet cell tumors. Cancer 74:958–961, 1994[CrossRef][Medline]

26. Altmann HW: Some histological remarks on the fibrolamellar carcinoma of the liver. Pathol Res Pract 186:63–69, 1990[Medline]

27. Rolfes DB: Fibrolamellar carcinoma of the liver, in Okuda K, Ishak KG (eds): Neoplasms of the Liver. New York, NY, Springer 1987, pp 137–142

28. Stevens WR, Johnson CD, Stephens DH, et al: Fibrolamellar hepatocellular carcinoma: Stage at presentation and results of aggressive surgical management. AJR Am J Roentgenol 164:1153–1158, 1995[Abstract/Free Full Text]

29. Hassan M, Patt YZ, Lozano R, et al: Continuous I. V. infusion of 5-fluorouracil (5-FU) and subcutaneous (S. C.) recombinant interferon alpha 2b (rIFN 2b) is an active regimen in fibrolamellar hepatocellular carcinoma (FLHCC). Proc Am Soc of Clin Oncol, 19, 2000 (abstr 122)

30. WHO Handbook for Reporting Results of Cancer Treatment. World Health Organization Offset Publication No. 48. Geneva, 1979

31. Simon R: Optimal two-stage designs for phase II clinical trials. Controlled Clin Trials 10:1–10, 1989[Medline]

32. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481, 1958[CrossRef]

33. Gehan EA: A generalized Wilcoxon test for comparing arbitrarily single censored samples. Biometrics 52:203–223, 1965[CrossRef]

34. Brown JJ, Naylor MJ, Yagan N: Imaging of hepatic cirrhosis. Radiology 202:1–16, 1997[Free Full Text]

35. Brown NS, Bicknell R: Thymidine phosphorylase, 2-deoxy-D-ribose and angiogenesis. Biochem J 334:1–8, 1998

36. Ishikawa F, Miyazono K, Hellman U, et al: Identification of angiogenic activity and the cloning and expression of platelet-derived endothelial cell growth factor. Nature 338:557–562, 1989[CrossRef][Medline]

37. Moghaddam A, Bicknell R: Expression of platelet-derived endothelial cell growth factor in Escherichia coli and confirmation of its thymidine phosphorylase activity. Biochemistry 31:12141–12146, 1992[CrossRef][Medline]

38. Miyadera K, Sumizawa T, Haraguchi M, et al: Role of thymidine phosphorylase activity in the angiogenic effect of platelet derived endothelial cell growth factor/thymidine phosphorylase. Cancer Res 55:1687–1690, 1995[Abstract/Free Full Text]

39. Folkman J, Ingber D: Inhibition of angiogenesis. Semin Cancer Biol 3:89–96, 1992[Medline]

40. Sgonc R, Fuerhapter C, Boeck G, et al: Induction of apoptosis in human dermal microvascular endothelial cells and infantile hemangiomas by interferon-alpha. Int Arch Allergy Immunol 117:209–214, 1998[Medline]

41. Dinney CP, Bielenberg DR, Perrotte P, et al: Inhibition of basic fibroblast growth factor expression, angiogenesis, and growth of human bladder carcinoma in mice by systemic interferon-alpha administration. Cancer Res 58:808–814, 1998[Abstract/Free Full Text]

42. Ishikawa T, Sekiguchi F, Fukase Y, et al: Positive correlation between the efficacy of capecitabine and doxifluridine and the ratio of thymidine phosphorylase to dihydropyrimidine dehydrogenase activities in tumors in human cancer xenografts. Cancer Res 58:685–690, 1998[Abstract/Free Full Text]

Submitted October 19, 2001; accepted October 1, 2002.

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