Oral eniluracil/5-fluorouracil in patients with inoperable hepatocellular carcinoma

A. B. Benson III1,+, E. Mitchell2, N. Abramson3, B. Klencke4, P. Ritch5, J. P. Burnham6, C. McGuirt6, T. Bonny6, J. Levin6 and J. Hohneker6

1Northwestern University, Chicago, IL; 2Thomas Jefferson University, Philadelphia, PA; 3Baptist Regional Cancer Institute, Jacksonville, FL; 4The Medical Center at the University of California San Francisco, San Francisco, CA; 5Medical College of Wisconsin, Milwaukee, WI; 6Glaxo Wellcome, Research Triangle Park, NC, USA

Received 22 January 2001; revised 17 September 2001; accepted 4 October 2001.


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background

Conventional systemic chemotherapy currently available for patients with inoperable hepatocellular carcinoma is ineffective. The purpose of this study was to evaluate the safety and efficacy of eniluracil/5-fluorouracil (5-FU) in the treatment of patients with this highly refractory disease.

Patients and methods

This multicenter, open-label study evaluated a 28-day oral regimen of 5-FU (1 mg/m2 twice daily) plus the dihydropyrimidine dehydrogenase inhibitor, eniluracil (10 mg/m2 twice daily), in patients with chemotherapy-naive or anthracycline-refractory inoperable hepatocellular carcinoma.

Results

A total of 36 patients enrolled into the study. No patient showed a confirmed partial or complete tumor response, although nine patients (25%) had a best response of stable disease. The median duration of progression-free survival was 9.6 weeks [95% confidence interval (CI) 9.1–10.6 weeks], and the median duration of overall survival was 32.7 weeks (95% CI 17.4–71.6 weeks). Eniluracil/5-FU was well tolerated. Diarrhea, the most frequent treatment-related non-hematological toxicity, occurred in 11 patients (31%). Hematological toxicities were infrequent and usually mild.

Conclusions

Eniluracil/5-FU as a 28-day oral outpatient regimen is well tolerated by patients with inoperable hepatocellular carcinoma, although minimal activity was observed when given as monotherapy at the dose used in this study.

Key words: chemotherapy, dihydropyrimidine dehydrogenase, eniluracil, 5-fluorouracil,inoperable hepatocellular carcinoma


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Worldwide, hepatocellular carcinoma is the third most common cause of cancer death in men and the seventh most common in women [1]. Despite the implementation of early detection programs [24] in areas of high incidence (e.g. southeast Asia), most cases are still diagnosed at an advanced stage when potentially curative therapies such as resection and transplantation are ineffective. Patients with unresectable hepatocellular carcinoma are often treated with palliative approaches such as chemoembolization or local alcohol injection [5], but no effective systemic therapy currently exists. Indeed, a meta-analysis of medical treatments for patients with unresectable hepatocellular carcinoma showed that no treatment has a clearly proven effect on survival [6].

5-Fluorouracil (5-FU) has minimal activity against hepatocellular carcinoma when given as a bolus agent [7]. Administration of 5-FU by continuous infusion is well tolerated and efficacious in treating patients with other cancers such as colon cancer [8], although continuous infusion regimens require a central line, which is inconvenient, expensive and potentially hazardous.

Eniluracil is an effective inactivator of dihydropyrimidine dehydrogenase (DPD), the principal enzyme in the degradative pathway of 5-FU [9]. Inactivation of DPD by eniluracil improves the oral bioavailability of 5-FU enabling oral dosing, and results in plasma concentrations of 5-FU comparable with those reported in the literature for intravenous infusion of 5-FU [10]. Eniluracil improves the pharmacokinetic profile of 5-FU resulting in more predictable plasma concentrations [10, 11] and increases the plasma half-life of 5-FU [11, 12].

The current study was based on the rationale that high DPD activity in the liver makes this organ the main site of 5-FU catabolism [13, 14], and inhibition of DPD activity by enil-uracil may therefore improve the efficacy of 5-FU in patients with hepatocellular carcinoma. In support of this hypothesis, a study in patients with colorectal tumors showed that eniluracil completely inactivated tumoral DPD [15].

The primary objective of this study (Glaxo Wellcome study protocol FUMA2007) was to estimate the objective tumor response rate of a 28-day regimen of oral eniluracil/5-FU in patients with chemotherapy-naive or anthracycline-refractory, inoperable hepatocellular carcinoma. The secondary objectives were to evaluate the duration of response, the duration of progression-free survival, the duration of overall survival and the toxicity profile of eniluracil/5-FU in this population.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
Patients aged 18 years or older were eligible for inclusion in the study if they had a histologically or cytologically confirmed diagnosis of inoperable hepatocellular carcinoma, other than the fibrolamellar variant, with at least one bidimensionally measurable lesion. Patients had to have a Karnofsky performance status (KPS) of at least 60 and could be either chemotherapy-naive (i.e. no previous systemic or regional chemotherapy) or refractory to an anthracycline. The latter was defined as previous therapy with a single anthracycline-containing regimen that resulted in one of the following: progression during or within 3 months of treatment for advanced disease; relapse during or within 6 months of adjuvant therapy; a total cumulative dose of at least 400 mg/m2 of doxorubicin (or an equivalent dose of another anthracycline) or cardiomyopathy due to treatment with an anthracycline with currently stable cardiac function. All patients provided written informed consent before entering into the study.

Patients were excluded from the study if they had a history of additional malignancy, known central nervous system metastases, or signs or symptoms of encephalopathy. Patients were not allowed to enter the study if they had undergone major surgery in the 4 weeks before the first dose of study medication or received chemotherapy, biological therapy (3 weeks before), flucytosine, interferon, or hormonal therapy with an anti-androgen or anti-estrogen (2 weeks before). Patients were not eligible if they had had previous treatment with continuous infusion 5-FU, a non-anthracycline-containing chemotherapy regimen, or a chemotherapy regimen with more than one anthracycline. Additionally, patients were excluded for any of the following: hemoglobin <9 g/dl; granulocyte count <1500/mm3; platelet count <75 000/mm3; estimated creatinine clearance <50 ml/min; total bilirubin >3 times the upper limit of normal; international normalized ratio >2 for patients not receiving anti-coagulation therapy; unstable prothrombin times; or a change in dose of anti-coagulant in the 2 weeks before the first dose of study medication if receiving anti-coagulation therapy.

Study design
This was a multicenter, open-label phase II study conducted at 13 centers in the USA and two centers in Canada. The study started in February 1997 and was terminated early in August 1997. The study was conducted according to the latest version of the Declaration of Helsinki. The Internal Review Board/Ethics Committee at each of the institutions approved the study protocol.

Treatment schedules
Patients received 10 mg/m2 eniluracil and 1 mg/m2 5-FU (10:1 ratio of eniluracil/5-FU ) orally twice daily for the first 28 days of a 5-week treatment cycle. Patients continued treatment courses until disease progression or unmanageable toxicity. Glaxo Wellcome supplied study medication.

Dose modifications were made as previously described based on drug-related toxicities and the patient’s current creatinine clearance [16]. Patients requiring other anti-cancer therapy were not allowed to continue to receive treatment with eniluracil/5-FU. Patients were permitted to receive full supportive care during the study.

Efficacy assessments
The primary measure of efficacy was objective tumor response rate. Response definitions were adapted from criteria established by the Southwest Oncology Group (SWOG) [17]. A complete response was defined as the complete disappearance of all measurable and evaluable disease and no new lesions on at least two consecutive assessments at least 4 weeks apart. All clinical signs and symptoms of cancer that were present at baseline must have disappeared, and there should have been no evidence of non-evaluable disease. A partial response was defined as the following on at least two consecutive assessments at least 4 weeks apart: >=50% decrease in the sum of the products of perpendicular diameters of all measurable lesions; no progression of evaluable disease and no new lesions. Stable disease was defined as the absence of a complete response, a partial response, or progression. In this study, the minimum duration of disease stabilization that qualified for stable disease was ~10 weeks; this was the time of the first scheduled patient reassessment. Disease progression was defined as any of the following: a 25% increase in the sum of products of all measurable lesions over the smallest sum observed; clear worsening of evaluable disease; reappearance of any lesion that had disappeared; appearance of any new lesion or site of cancer; or failure to return for evaluation due to death or deteriorating condition, unless either was clearly unrelated to cancer. Unknown was assigned if progression was not documented, and one or more measurable or evaluable sites were not assessed. Measurable disease, evaluable disease, and non-evaluable disease were classified according to standard SWOG definitions [17].

Patients were assessed for baseline disease within 2 weeks of starting the first dose of study medication by chest X-ray, abdominal computed tomography or magnetic resonance imaging scan. All other known areas of disease were assessed by X-ray, endoscopy, photography or physical examination. Patients received a bone scan within 6 weeks of the first dose of study medication. All sites of disease were monitored using the same method of assessment approximately every 10 weeks until disease progression.

The secondary measures of efficacy were durations of response, progression-free survival and overall survival. Serum {alpha}-fetoprotein (AFP) levels were assessed pre-study and before each course until disease progression. Other efficacy measures included monitoring KPS and clinical signs and symptoms of cancer before each treatment course.

Safety assessments
Adverse events were graded according to SWOG toxicity criteria [17] and assessed by the investigator for their relationship to study medication. Hematology and clinical chemistry parameters were assessed regularly throughout the study. In addition, estimated creatinine clearance, urinalysis, prothrombin time and/or international normalized ratio were assessed.

Statistical analyses
Approximately 60 chemotherapy-naive patients and 43 patients with anthracycline-refractory disease were planned to be enrolled into separate strata. A sample size of 60 chemotherapy-naive patients was sufficient to estimate a 95% confidence interval (CI) of the true response rate with a maximum width of 25%. A sample size of 43 anthracycline-refractory patients was sufficient to estimate a 95% CI of the true response rate with a maximum width of 30%.

A two-stage design was used to determine whether sufficient activity was observed to warrant complete enrollment [18]. If no objective tumor responses among the first 19 evaluable patients in either stratum were observed, the probability of a response rate >=15% was <5%, and the study was to be discontinued. Otherwise, enrollment was to continue in both strata to better estimate the response rate.

All patients in the intention-to-treat population were evaluated for safety and efficacy. This population was defined as any patient who received at least one dose of study medication. Response rate was also evaluated in a ‘per-protocol’ (PP) population, which was defined as patients who received at least 75% of the total prescribed amount of study medication during course 1 (or a total of 21 days on which any amount of study medication was taken) and had a baseline disease assessment and at least one disease assessment at a later time point. Results were summarized for the entire population and for the two strata: chemotherapy-naive and anthracycline-refractory. Time-to-event parameters were analyzed using Kaplan–Meier product limit estimates.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Accrual into the study continued until 19 patients received a 10-week disease assessment evaluation. At this point, a total of 36 patients had been enrolled. No complete or partial tumor responses were seen in the first 19 evaluable patients; therefore, the study was terminated according to the early stopping rule.

Patient characteristics
Thirty-six patients were enrolled into this study: 32 patients were chemotherapy-naive, and four were anthracycline-refractory. The baseline characteristics of the patients were similar in the two strata and are summarized in Table 1. Eighteen patients had chronic liver disease at baseline; 14 had cirrhosis of the liver and four patients had hypersplenism. Previous therapies and surgery reported for hepatocellular carcinoma were liver transplantation (two patients), cryosurgery (two patients), embolization (two patients), surgery (two patients), percutaneous alcohol injection (one patient) and chemoembolization with mitomycin (one patient).


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Table 1. Characteristics of the patients at baseline
 
Tumor response rate
All 36 patients enrolled received study medication; eight patients were excluded from the PP population.

The overall best responses in each population and strata were similar. A summary of the overall best responses is shown in Table 2. No complete or partial responses were observed. Of the nine patients who had stable disease, five had a decrease of tumor burden (1–31%), three had an increase in tumor measurements (12–18%) and one had no change in tumor measurements.


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Table 2. Summary of objective tumor response rates
 
Response duration, progression-free survival and overall survival
The median duration of stable disease for the nine patients who demonstrated stable disease was 19.6 weeks (95% CI 17.7–39.6 weeks). The median duration of progression-free survival for all patients was 9.6 weeks (95% CI 9.1–10.6 weeks). The median duration of overall survival for all patients was 32.7 weeks (95% CI 17.4–71.6 weeks) (Figure 1). For patients in the chemotherapy-naive stratum, the median duration of survival was 35.3 weeks compared with 11.4 weeks for patients in the anthracycline-refractory stratum.



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Figure 1. Duration of overall survival: Kaplan–Meier overall survival estimates.

 
Clinical benefit
Karnofsky performance status remained unchanged or improved for the majority of patients throughout the study. In courses 2 and 3, respectively, 20 of 26 patients (77%) and 11 of 13 patients (85%) had no change or improvement in KPS.

At baseline, 23 patients had signs and symptoms of cancer; the majority of signs and symptoms of cancer were grade 1 or 2 in intensity. During the study, signs and symptoms of cancer remained stable for the majority of patients; three patients had cancer signs and symptoms that worsened compared with baseline.

No patient with a best response of stable disease had a decrease in serum AFP of >=50% that lasted >4 weeks.

Toxicity
The most frequently reported adverse events that were considered reasonably attributable to study medication are shown in Table 3. In total, 24 patients (67%) experienced at least one adverse event that was considered reasonably attributable to study medication (a total of 97 adverse events). The most frequently reported of these adverse events were diarrhea, malaise and fatigue, mucositis, nausea and skin rashes (Table 3). Nine patients (25%) had at least one grade 3 or 4 adverse event considered reasonably attributable to study medication. Diarrhea was the most frequently reported grade 3 or 4 adverse event (Table 3).


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Table 3. Summary of most frequently reported (>5% incidence) non-hematological adverse events (AEs) that were reasonably attributable to study medication (n = 36)
 
Hematological toxicities are summarized in Table 4. Hematological toxicity was infrequent and usually mild; no grade 4 episodes were reported. Only one patient had grade 3 granulocytopenia, and one patient had grade 3 leukopenia.


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Table 4. Number (%) of treatment-emergent hematological and clinical chemistry abnormalities according to their severity (n = 36)
 
Treatment-related clinical chemistry abnormalities were uncommon (Table 4). One patient experienced a grade 3 elevation in alkaline phosphatase, one patient experienced a grade 3 elevation in alanine transferase and one patient had a grade 3 elevation in creatinine. Grade 3 and 4 hyperbilirubinemia, as graded by SWOG criteria, was reported for nine patients (25%). When newer National Cancer Institute Common Toxicity Criteria (NCI CTC) were applied, five patients (14%) had grade 3 hyperbilirubinemia, and none of the patients experienced a grade 4 elevation [19].

Dosing results
The 36 patients received 129 courses of study medication. The median number of courses per patient was 2 (range 1–14). The median duration of treatment was 9.0 weeks (range 0.9– 68.6 weeks). The extent of exposure to study medication was similar in the two strata.

Of the 129 courses, 57 (44%) were completed at the patient’s starting dose, and 76 (59%) were completed at the prescribed dose for that course. Fifty-three courses (41%) had dosing deviations: 11 courses (12%) were delayed, and of these, seven (8%) were delayed due to toxicity. Reasons for dosing deviations included patient non-compliance (7% of courses), diarrhea (3% of courses), granulocytopenia (2% of courses) and intercurrent illness (2% of courses).


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Hepatocellular carcinoma has a high incidence in countries with poorly developed medical facilities. An orally active treatment with low toxicity that can be administered in an outpatient setting would be particularly useful in this population. The oral regimen of eniluracil/5-FU used in this study was extremely well tolerated with few patients requiring dosing delays or reductions, a low incidence of the toxicities commonly seen with intravenous 5-FU-based treatments occurred [20]. For example, no hand–foot syndrome was observed compared with a rate of 30–40% reported for continuous infusion 5-FU [20]. In addition, mucositis and nausea were reported by 17 and 11% of patients, respectively, with all occurrences except one of each being grade 1 or 2 in intensity. The incidence of hematological abnormalities was low: no grade 4 toxicities, and only one incidence of grade 3 granulocytopenia and one incidence of grade 3 thrombocytopenia were observed.

It is difficult to compare the efficacy results from the current trial with those of other studies performed in patients with inoperable hepatocellular carcinoma mainly because of a lack of standardization of tumor response definitions. Some clinicians accept a reduction in serum AFP as evidence of tumor response, while others require a >=50% radiographic reduction in tumor size. In the current study, the 28-day oral regimen of eniluracil/5-FU showed minimal activity in the patients using SWOG response criteria. 5-FU alone shows a response rate of only 5% in patients with hepatocellular carcinoma [7], although in combination with leucovorin, response rates of 0–28% have been reported [2123]. The use of eniluracil to inhibit hepatic DPD, therefore, does not appear to enhance 5-FU anti-tumor activity, suggesting that hepatocellular carcinoma is resistant to 5-FU for reasons other than high DPD activity. For example, resistance could be due to increased expression of thymidylate synthase [24].

During this study, most patients had stable signs and symptoms of cancer, and the KPS of most patients remained unchanged, which implies that the current dose of eniluracil/ 5-FU does not have an effect patients’ performance status. However, the low observed efficacy combined with the mild safety profile may also indicate that the dose of eniluracil/5-FU used in this study was suboptimal for patients with hepatocellular carcinoma, although dose intensity is a less likely reason for lack of efficiency.

The overall median duration of survival of patients in this study was 32.7 weeks, almost twice the 14–19 week survival seen in studies of 5-FU in combination with high-dose leucovorin [2123]. The median duration of stable disease of 19.6 weeks was comparable with that seen in other trials of 5-FU-based treatments. For example, the median duration of stable disease was 12–24.7 weeks in studies using 5-FU and leucovorin [2123].

The most widely used single agent in patients with inoperable hepatocellular carcinoma is doxorubicin, which produces a median response rate of 17% (range from 0% to 79%) and a median survival of 4 months [25]. Modifications of chemotherapy, including intrahepatic arterial infusion, chemoembolization, lipiodol and isolated hepatic perfusion have led to improved tumor responses but do not affect significantly overall survival [6, 26]. Radioimmunotherapy and conformal radiotherapy have no more than a marginal impact on patient outcome. Surgical innovations such as cryosurgery and percutaneous alcohol injection have not yet been shown to offer any survival advantage [27]. Clearly a need exists for better medical treatments of this highly refractory disease.

As a 28-day oral outpatient regimen, eniluracil/5-FU is well tolerated by patients with inoperable hepatocellular carcinoma, although when given as monotherapy at the dose evaluated in this study, minimal activity was observed.


    Acknowledgements
 
Glaxo Wellcome Research and Development provided funding for the study (protocol FUMA2007). We thank all the investigators who participated in the study: Stephen A. Bernard, Thomas N. Campell, Hoo Guen Chun, Jeffrey W. Clarke, Janet E. Dancey, Francis J. Giles, Louise B. Grochow, Harry L. Rayner, Virginia Stark-Vancs and Mark M. Zalupski, as well as Michael Zvarich, Glaxo Wellcome. We thank David Harrison for writing and editing assistance during preparation of the manuscript. The study was previously presented at the American Society of Clinical Oncology: Proceedings of the American Society of Clinical Oncology 1999; 18: 256A.


    Footnotes
 
+ Correspondence to: Dr A. B. Benson, Northwestern University Medical School, Division of Hematology/Oncology, 676 North St Clair Street, 850, Chicago, IL 60611, USA. Tel: +1-312-695-6180; Fax: +1-312-695-6189; E-mail: a-benson@northwestern.edu Back


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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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