Background: Hepatocellular carcinoma (HCC) is a hypervascular tumor. Metronomic chemotherapy; the continuous administration of low-dose chemotherapy; has both cytotoxic and antiangiogenic effects with low toxicity profile. We evaluated the efficacy and toxicity of metronomic capecitabine (MC) in patients with advanced HCC. Patients and Methods: From May 2010, we enrolled pts with either metastatic or locally advanced diseases not candidate for ablative or locoregional treatment and have acceptable liver function. Patients received oral MC in dose of 1000 mg/m 2 daily in a 21 days cycle without interruption till disease progression or toxicity. Results: The study cohort consisted of 22 patients with a median age of 63 years. The median number of cycles received was 3 cycles (range 1 - 9). From 19 patients were evaluable for response we had 3 partial responders, 10 stable diseases and disease progression in 6 patients. Median time to progression (TTP) was 2.2 months (95% CI 1.4 - 6.24) and median survival time (OS) was 4.8 months (95% CI 1.8 - 7.9). For 20 patients evaluable for safety: no grade III/IV hematological toxic effects were observed. Non-hematological toxic effects included grade III vomiting and diarrhea in one patient and grade III hand-foot syndrome in one patient. There was no treatment-related mortality. Conclusions: Based on the observed response rate, TTP and OS; MC has a modest antitumor efficacy in pts with advanced HCC. However, due to its low toxicity profile it deserves further attention as a convenient, outpatient-based chemotherapy regimen.
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third most common cause of cancer-related death [
The epidemiology of HCC is characterized by marked demographic and geographic variations. In Egypt, HCC is not uncommon. In the year 2002-2003 cancer registry, liver malignancies accounts for 7.5% of all cancer cases. [
Unfortunately, only a few patients are eligible for radical treatments with curative intent (i.e., surgical resection, liver transplantation, percutaneous ablation). The majority of HCC patients (>80%) presents with advanced or unresectable disease. Even for those with resected disease, the recurrence rate can be as high as 50% at 2 years [
Sorafenib (a multikinase inhibitor which suppresses tumor cell proliferation and angiogenesis) is proven to demonstrate a large survival benefit in advanced HCC for selected patients with Child-Pugh class A, B liver function [5-7]. However, a subgroup analysis showed a relatively low survival benefit for sorafenib over placebo in patients with extrahepatic spread [
Although most of the chemotherapeutic agents failed to show encouraging results [
The pyrimidine antimetabolite 5-fluorouracil (5-FU) was the first reported chemotherapeutic agent tested in the treatment of HCC [11,12]. Capecitabine is a rationally designed, orally administered, tumor-selective fluoropyrimidine that mimics continuous infusion of 5-FU. Capecitabine is converted to 5-FU preferentially in tumor tissue by the enzyme thymidine phosphorylase [13,14]. Treatment with capecitabine showed 11% of overall response rate including one complete remission and 22% of disease control rate with tolerable toxicity in 37 HCC patients with underlying liver cirrhosis [
Metronomic chemotherapy is defined as continuous administration of low-dose cytotoxic drugs. It was found to be as effective as chemotherapeutic drugs given at the maximum tolerated dose (MTD) but with reduced toxicity [17,18]. Metronomic chemotherapy provides a way to inhibit tumor angiogenesis by targeting proliferating endothelial cells in tumor blood vessels and circulating endothelial cell precursors that are later integrated in tumor vasculature [19-21].
Metronomic chemotherapy can be considered as a variant of “dense-dose” treatment with the difference that its cumulative dose can be significantly lower than MTD-based chemotherapy [
HCC is a hypervascular tumor. So, capecitabine if given in a metronomic schedule; its cytotoxic effect on HCC cells can be potentiated by an additional effect on tumor angiogenesis.
Also, in preliminary results of a study done by Brandi et al., metronomic capecitabine (MC) showed promising effect on advanced HCC patients with a good tolerability profile [
In this study we investigate the efficacy and toxicity of MC in patients with metastatic or locally advanced HCC not candidate for ablative or locoregional treatment modalities.
Patients with either histologically proven HCC or combination of liver cirrhosis, radiologically documented hypervascular liver tumor and alphafetoprotein (AFP) level >200 ng/ml [
Other eligibility criteria were bidimensionally measurable disease, age > 18 years; World Health Organization (WHO) performance status (PS) 0 - 2; Child-Pugh score of A or B; adequate hepatic, renal and bone marrow function. Specifically, their bilirubin level had to be 2.0 mg/dL or lower, their aspartate transaminase level had to be five times or lower the institutional upper limit of normal, and their serum creatinine level had to be 2.0 mg/dL or lower. Minimum hematologic parameters included an absolute neutrophil count (ANC) greater than or equal to 1.0 × 109/L and a platelet count of greater than or equal to 100 × 109/L. Main exclusion criteria were Child-Pugh score of C, severe cardiac and/or respiratory failure, concurrent malignancy. Patients provided written informed consent.
The therapy consisted of MC orally in a dose of 1000 mg/m2/day without interruption. The cycle is repeated every 21 days.
Before study entry, all patients provided a complete medical history and underwent a physical examination, including an assessment of performance status, recent weight loss, and comorbidities. Laboratory studies included a complete blood count, differential count, platelet count, biochemical liver and renal function tests, AFP, chest radiograph, and an abdomen-pelvic computed tomographic scan.
During treatment, patients were evaluated for a brief history, physical examination, and toxicity assessment. A complete blood count, renal and liver functions were measured every 3 weeks, before each cycle. ΑFP levels were examined every 6 weeks. Measurable disease was assessed radiographically every 6 weeks.
Treatment was continued until one of the following criteria was met: disease progression, unacceptable toxicity, patient refusal. Patients stopped treatment for any reason were allowed to receive 2nd line therapy on a case by case evaluation.
All eligible patients who received two cycle of treatment (6 weeks) were considered evaluable for response. Complete response (CR) was defined as the disappearance of all radiological and clinical evidence of tumor for a minimum of 4 weeks. Partial response (PR) was defined as a ≥50% reduction in the sum of the products of the longest perpendicular diameters of all measurable lesions, with no new lesions appearing and none progressing for at least 4 consecutive weeks. If the reduction was between 25% and 49%, the response was classified as a minor partial response. A patient was considered to have progressive disease (PD) if any new lesion appeared, if the tumor size increased by ≥25% over pretreatment measurements or if the patient experienced deterioration in the clinical status consistent with disease progression. A patient who failed to meet the definition of CR, PR or PD but remained on treatment for at least 2 cycles was classified as having stable disease (SD).
All patients who received at least one cycle of treatment were considered evaluable for safety. Toxicity was assessed before every cycle in accordance with the National Cancer Institute-Common Toxicity Criteria (NCICTC) criteria.
The primary end-point was the response rate and toxicity and the secondary measures were overall survival (OS), Progression free survival (PFS), Time to progression (TTP). TTP was calculated from the first cycle of chemotherapy. OS and PFS were calculated from the starting date of chemotherapy to the date of death, progression or the last follow-up. Survival rates and time to progression were assessed by the Kaplan-Meier method.
A total number of 22 consecutive patients with advanced HCC were accrued. The clinical characteristics of the enrolled patients are shown in
All 22 patients received at least one cycle of MC. Three patients lost follow up early. Two of them didn’t attend for 2nd cycle so they were not assessed for either toxicity or response, and the 3rd patient lost follow up after starting the 2nd cycle and was not assessed for response. Finally, treatment toxicity was assessed in 20 patients, and 19 patients were evaluable for response evaluation.
A total of 74 cycles of MC were given for our patients with a median of 3 cycles (range from 1 to 9 cycles). Antitumor response could be radiologically assessed in 19 of 22 patients. Three patients were lost to follow-up, and the treatment response could not be determined. The objective response rate was 16% with 3 partial response and no complete responses. Ten patients (53%) had stable
disease; so disease control (CR+PR+SD) was 69%. The remaining 6 patients (31%) had disease progression. One patient from the partial responders later experienced disease progression; and shifted to 2nd line treatment. He received a total of 6 cycles with a TTP of 4.5 months. The median TTP for all evaluable patients was 2.2 months (95% CI 1.4 - 6.24) and median survival time was 4.8 months (95% CI 1.8 - 7.9). At 6 moths OS was 70% and PFS was 44% (
A univariate analysis was done to evaluate the effects of different prognostic factors on disease outcome in term of OS and PFS. The analysis examined the effect of age, performance status, and tumor stage, site of extrahepatic disease, Child score, and presence of ascities, AFP,
serum albumin, serum bilirubin, portal vein thrombosis, and hemoglobin and platelets counts. However none of the examined factors has a prognostic impact on the survival outcome.
No grade III/IV hematological toxic effects were observed; only grade I & II thrombocytopenia (20%) and grade I anemia (10%). Non-hematological toxic effects included grade III vomiting and diarrhea in one patient (5%) and grade III hand-foot syndrome in one patient (5%) and grade I elevated hepatic enzymes (20%). There was no treatment-related mortality.
Advanced HCC is a challenging disease. Although the results of sorafenib are encouraging [5-7], it still has its limitations. The subgroup analysis demonstrated that patients with macroscopic vascular invasion and/or extrahepatic spread showed a smaller absolute survival benefit. However, these patients represent a major part of patients with advanced HCC. Cost and availability are additional limitation to the routine use of sorafenib especially in poor countries. Its high cost will prohibit treatment of many patients in need [
This warrants confirming the role of sorafenib for advanced HCC in various clinical settings. Additional studies of potential systemic chemotherapy regimens for the treatment of advanced HCC are also needed, especially after the promising results of some chemotherapeutic regimens [8-10].
In our study we evaluated oral capecitabine administrated in a metronomic schedule in patients with advanced HCC in a daily dose of 1000 mg/m2. The optimal metronomic dose is known for only few drugs and diseases but doses of MC closely similar to dose used in our study were found to be safe and effective in HCC and other malignancies. Brandi et al. studied MC in advanced HCC, Child A disease in a slightly different schedule where the first cycle was carried out with standard capecitabine (2000 mg/m2/day; 14 over 21 days), followed by MC (1300 mg) without interruption. MC had a better tolerability than standard schedule and promises good efficacy [
We had three PR and no CR with an objective response rate of 16% of the total 19 patients evaluable for response. Disease control was 69%. These results are comparable to the result of MC in a phase II study done by Brandi et al where they had an objective response of 14.1% and disease control of 66.7% [
The response rate in our study is comparable to most of chemotherapy regimens. In advanced HCC the overall response rate to systemic chemotherapy is generally less than 10% [
Newer chemotherapeutic agents also produced comparable and sometimes lower response rates than our study. Several studies were done to evaluate the effects of taxanes [34,35], and gemcitabine [36,37] on advanced HCC. A combination of gemcitabine and oxaliplatin demonstrated an 18% response rate and 76% of patients had the disease under control [
In our study we had median TTP for all evaluable patients of 2.2 months (95% CI 1.4 - 6.24) and median survival time was 4.8 months (95% CI 1.8 - 7.9). At 6 moths overall survival was 70% and progression free survival was 44%. The low survival outcome observed here is similar to most chemotherapy agents who failed to show a survival benefit [
Categorizing our patients into different groups to evaluate the effect of different prognostic factors on outcome was done. However none of the examined variables demonstrated a significant difference on outcome. This may be due to the limited number of our patients.
The toxicity profile of MC was very low with only two cases of grade III non hematologic toxicity. This makes MC very tolerable especially in patients with impaired liver function.
The low toxicity profile and the convenient oral outpatient administration of MC may suggest its use in combination with other chemotherapeutic agents or a new targeted antiangiogenic. The results of a recent preclinical study highlight the possibility that even if metronomic chemotherapy per se fails to cause a clinical benefit, combination with a targeted antiangiogenic drug could yield results superior to the antiangiogenic drug used alone [
Based on the observed response rate, TTP and survival results; MC has a modest antitumor efficacy in pts with advanced HCC. These results are similar to most chemotherapeutic agents. However, due to its low toxicity profile it deserves further attention as a convenient, outpatient-based chemotherapy regimen. These advantages suggest for the future evaluation of MC in combination with other chemotherapeutic agents or with antiangiogenic target therapy known to have activity in HCC. A second line treatment after antiangiogenic therapy could be another area of interest for the study of MC.
The author is grateful to Dr Ahmed Marzouk, Dr Mohamed Wahman and Dr Ihsan Matar for their help and support during the preparation of this study.