We evaluated oral metronomic capecitabine (MC) compared to intravenous doxorubicin in patients with advanced or metastatic hepatocellular carcinoma (HCC).
From January 2013 to December 2015, patients with Child-Pugh class A or early B were randomized either to MC group (500 mg twice daily continuously) or doxorubicin group (60 mg∕m2 every 21 days).
Forty patients were included in each group. The baseline clinical characteristics of the enrolled patients were well balanced between the two groups. No complete response (CR) was reported in either group. In MC group, 2 patients (5%) had partial response (PR), 25 patients (62.5%) stable disease (SD) and 27 patients (67.5%) had disease control. In doxorubicin group, 4 patients (10%) achieved PR, 24 patients (60%) SD and 28 patients (70%) had disease control. The 6 months overall survival (OS) was 77.5% for MC and 75% for doxorubicin. The one year OS was 47.5% for MC and 42.5% for doxorubicin (P=0.521). The median OS survival was 10.2 months for MC and 9.6 months for doxorubicin (95% confidence interval, 3.2–6.5). The 6 month progression-free survival (PFS) was 45% for MC and 50% for doxorubicin. The one year PFS was 12.5% for MC and 7.5% for doxorubicin (P=0.289). The median time to progression was 3.4 months for MC and 3.1 months for doxorubicin. On multivariate analysis no significant impact for tumor stage, previous transhepatic arterial chemoembolization, portal vein thrombosis or median baseline alpha fetoprotein on OS.
MC showed response rate and survival outcome comparable to doxorubicin in advanced HCC but with a more favorable toxicity profile.
Liver cancer is the fifth most common cancer worldwide and the third most common cause of cancer mortality with more than 500,000 deaths annually. Hepatocellular carcinoma (HCC), the most common primary liver cancer, occurs in the setting of chronic liver disease and cirrhosis and is usually diagnosed late with a median survival following diagnosis of approximately 6 to 20 months [
In Egypt, according to the 2002–2003 cancer registry, liver malignancies account for 7.5% of all cancer cases [
Prognosis of HCC and treatment options are determined by anatomical extent of tumor (stage), biological aggressiveness (grade), cirrhosis severity (indicated by the Child-Pugh classification) and functional status. Treatment options for HCC are divided into surgical therapies (resection, cryoablation, and liver transplantation) and nonsurgical therapies, which may be liver-directed (percutaneous ethanol injection, radiofrequency ablation, transarterial chemoembolization, radiation and radioembolization) or systemic treatment (chemotherapy, molecularly targeted therapy and hormone therapy) [
Systemic chemotherapy is usually not well tolerated by patients with significant underlying hepatic dysfunction. In addition, HCC has been considered to be a relatively chemotherapy-refractory tumor. This may be in part due to the high rate of expression of drug resistance genes, including p-glycoprotein, glutathione-S-transferase, heat shock proteins, and mutations in p53 [
Since advanced HCC is a highly vascular tumor, several antiangiogenic drugs have shown some efficacy in this setting. Only sorafenib, which is an oral multikinase inhibitor that suppresses tumor cell proliferation and angiogenesis has proved effective in improving overall survival (OS) in patients with Child-Pugh class A in randomized controlled trials [
Capecitabine is an antimetabolite that has shown varying degrees of efficacy with acceptable tolerability in numerous cancers with the largest amount of evidence in metastatic breast and colorectal cancer. A recent study indicated that mild-to-moderate liver dysfunction in patients with colorectal carcinoma liver metastases did not significantly affect capecitabine pharmacokinetics [
Metronomic chemotherapy refers to continuous administration of low-dose chemotherapy without treatment breaks, which was found to have both cytotoxic and antiangiogenic effects with a low toxicity profile. These features are particularly attractive in cirrhotic patients having highly vascular tumors (e.g., HCC), and are often unfit for conventional chemotherapy [
On the basis of these results, we evaluated oral capecitabine given in a metronomic schedule compared to intravenous doxorubicin (the most commonly studied chemotheraputic agent in HCC) in patients with metastatic or locally advanced HCC not candidate for or progressed after ablative or locoregional treatment modalities.
Patients aged n≥18 and diagnosed with metastatic or locally advanced HCC were eligible for the present phase II single institution study. Eligible patients were not candidate for or progressed after locoregional therapies that included surgical resection, local ablation, or chemoembolization techniques and didn’t receive previous systemic therapy for their disease. Patients had to have WHO performance status of ≤1, Child-Pugh class A or early B, serum creatinine level ≤2.0 mg/dL, absolute neutrophil count ≥1.0×109/L, platelet count of ≥100×109/L and hemoglobin of ≥8.5 g/dL. Adequate baseline ejection fraction of ≥60% detected by echocardiography was required for patients receiving doxorubicin. Patients with Child-Pugh class C or concurrent malignancy were not eligible. All patients provided written informed consent prior to therapy. Approval of the local ethics committee was obtained before study initiation.
Eligible patients presented to the clinical oncology department at Alexandria main university hospital, Alexandria, Egypt during the period from January 2013 to December 2015 were randomized either to oral MC or intravenous doxorubicin.
MC group: included patients who received oral MC in a dose of 500 mg twice daily continuously without interruption. The cycle was repeated every 21 days.
Doxorubicin group: included patients who received intravenous doxorubicin 60 mg/m2 every 21 days for 6 cycles (360 mg/m2). If continued benefit and lack of toxicity were observed, patients were allowed to continue doxorubicin to 450 mg/m2.
In both groups, treatment was continued as planned until disease (radiological) progression as defined by response evaluation criteria in solid tumors (RECIST), unacceptable toxicity, patient withdrawal, or death.
Initial patient evaluation included complete medical history, thorough physical examination, triphasic computed tomography (CT) scan of the abdomen and pelvis, hepatitis viral markers (HCV Abs, HCV RNA by PCR and HbsAg) and alpha fetoprotein (AFP) level. A complete blood count and liver and renal function tests were required initially and before each chemotherapy cycle. Metastatic work-up including CT chest and/or bone scan were performed as clinically indicated. Toxicity was monitored using the National Cancer Institute Common Toxicity Criteria for Adverse Events, version 2.0 (NCI CTCv2.0). The response was evaluated every three months by ultrasonography and/or triphasic CT scan as well as AFP levels.
Objective responses were validated by radiologists. Eligible patients who received a minimum of 3 cycles were considered evaluable for response. According to RECIST criteria: complete response (CR) was defined as the disappearance of all signs and symptoms of disease. Partial response (PR) was defined as a decrease of >30% of the sum of the largest diameters of target (measurable) lesions without appearance of new lesions or progression of non-target (evaluable) lesions. To be assigned a status of response, changes in tumor measurement were confirmed by repeat assessment that was performed not less than 4 weeks after the criteria for response were first met. Stable disease (SD) was defined as no sufficient shrinkage to qualify for PR or less than a 20% increase in the sum of the largest diameters of target lesions without appearance of new lesions or progression of non-target lesions. Progressive disease (PD) was defined as a 20% increase in the sum of the largest diameters of target lesions or as appearance of new lesions or as progression of non-target lesions.
The primary outcomes were to evaluate and compare the time to progression (TTP), and the OS between the two treatment groups. The secondary endpoints were the response rate, disease control rate, progression-free survival (PFS) and treatment related toxicities. Overall response rate per RECIST was defined as the proportion of patients with the best tumor response achieved during treatment or within 30 days after termination of chemotherapy. The time to disease progression and OS were calculated from the date of initiation of therapy to the date of progression of disease or death, respectively. For patients without documented death or progression at the time of analysis, OS was censored at the last follow-up date, and PFS was censored at the last date of tumor evaluation. Statistical analysis was done using Statistical Package for Social Sciences (SPSS ver. 20, IBM, Armonk, NY, USA) software. Kaplan-Meier survival curves were rendered for each group.
Forty eligible patients in each treatment group received a minimum of 3 cycles of chemotherapy and were evaluable for response. The baseline clinical characteristics of the enrolled patients were well balanced among the two treatment groups and are shown in (
There was no CR reported in either group. In MC group, 2 patients (5%) achieved PR and 25 patients (62.5%) had SD while in doxorubicin group, 4 patients (10%) achieved PR and 24 patients (60%) had SD. PD was seen in 13 patients (32.5%) in MC group and in 12 patients (30%) in doxorubicin group. There was no significant difference between the two groups regarding response rate (P=0.695). The disease control rate (CR+PR+SD) was 67.5% in MC group and 70% in doxorubicin group with no significant difference. The 6 month PFS was 45% for MC group and 50% for doxorubicin group, while the one year PFS was 12.5% for MC and 7.5% for doxorubicin. There was no statistically significant difference in PFS between the two groups (P=0.289) as shown in
In MC group, two patients (5%) had grade II hand and foot syndrome and 5 patients (12.5%) experienced one or more episodes of grade I/II diarrhea, which was treated by loperamid, and treatment was discontinued for up to one week then was resumed after cessation of diarrhea. In addition, 8 patients developed hyperbilirubinemia and elevated enzymes and 3 patients developed encephalopathy, which were related to disease progression. There were no grade II or higher hematological toxicities.
Meanwhile, in doxorubicin group, doxorubicin at 60 mg/m2 was well tolerated by the majority of patients. All patients experienced alopecia, 95% had nausea and vomiting, and 20% developed hyper-pigmentation that manifested by the darkening of fingers and toes, with or without the entire complexion. One patients (2.5%) developed treatment-emergent left-ventricular systolic dysfunction. Five patients (12.5%) developed elevated hepatic enzymes and 2(5%) had hyperbilirubinemia believed to be potentially doxorubicin-related, treatment was discontinued and then resumed with a dose reduction of 25%. As regarding hematological toxic effects, 6 patients had grade II anemia, 10 patients had grade II thrombocytopenia and 5 patients developed grade II neutropenia, those patients required temporal cessation of doxorubicin until hematological recovery. There were no grade III/IV hematological toxicities. In both groups, no treatment related death was reported. The difference in toxicity profile was statistically significant between the two groups as regarding diarrhea, which was seen in MC (P=0.044); nausea and vomiting (P=0.001), alopecia (P=0.0001), hyperpigmentation (P=0.013), neutropenia (P=0.028) and elevated hepatic enzymes (P=0.044) (
Treatment of patients with advanced HCC presents a major challenge because associated cirrhosis limits the choice of chemotherapeutic agents. In addition, no effective systemic therapy (hormonal therapy or cytotoxic chemotherapy) has improved survival in those patients [
Being one of the most active chemotherapeutic agents in advanced HCC [
In the current study, there was no CR documented in all study patients. The response rate was 5% in MC and 10% in doxorubicin treated patients while the disease control rate was 67.5% in MC and 70% in doxorubicin treated patients with no significant difference between the two groups. These results are comparable to the low response rate reported for many single chemotherapeutic agents in advanced HCC, which is generally less than 10% [
In our study, the median TTP was 3.4 months for MC group and 3.1 months for doxorubicin group. The median OS survival was 10.2 months for MC group and 9.6 months for doxorubicin group. The one year OS was 47.5% for MC group and 42.5% for doxorubicin group. Our survival outcomes for MC were consistent with what was reported by Patt et al. [
In the current study, we reported reductions in the level of AFP compared to baseline levels in 60% of patients in MC group and 67.5% of patients in doxorubicin group. These results were comparable to what was reported by Mateen et al. [
The toxicity profile for patients in our study was different between the two treatment groups. Nausea, vomiting, alopecia, hyper-pigmentation, and elevated hepatic enzymes were common in the doxorubicin group patients. In addition hematological toxicities were more frequent in the doxorubicin group and included grade II toxic effects, which required temporal cessation of treatment till hematological recovery. The adverse events in doxorubicin treated patients in this study were consistent with those observed in previous studies of doxorubicin in advanced HCC [
Abdel-Rahman et al. [
Based on previous results, most adverse effects of MC were mild to moderate and manageable with supportive care or a brief drugfree period, with no dose modification required. No treatment-related deaths were observed, and no patient withdrew from treatment because of adverse events.
MC was a well-tolerated oral home treatment that didn’t require hospital admission or intravenous line insertion. Treatment was convenient and side effects were considered negligible. MC showed response rate and survival outcome comparable to doxorubicin but with more favorable toxicity profile. This data supports further use of MC in advanced HCC in combination with other chemotherapeutic agents or with sorafenib to increase response rate and survival outcomes.
No potential conflict of interest relevant to this article was reported.
Comparison between the two studied groups regarding progression free survival. Group A, metronomic capecitabine group; Group B, Doxorubicin group.
Comparison between the two studied groups regarding overall survival. Group A, metronomic capecitabine group; Group B, Doxorubicin group.
Demographic and clinical data of the two studied group
Characteristic | Group A MC (n = 40) | Group B Doxorubicin (n = 40) | P-value | Confidence interval |
---|---|---|---|---|
Age | 0.658 | 0.85–1.22 | ||
Range | 39–71 | 39–76 | ||
Median | 56.0 | 56.5 | ||
Sex | 0.235 | 0.68–1.69 | ||
Male | 38 (95.0) | 35 (87.5) | ||
Female | 2 (5.0) | 5 (12.5) | ||
Smoking | 25 (62.5) | 28 (70.0) | 0.365 | 0.98–1.85 |
DM | 3 (7.5) | 4 (10.0) | 0.633 | 0.32–2.98 |
Hypertension | 18 (45.0) | 21 (52.5) | 0.625 | 0.42–2.45 |
ECOG score | 0.361 | 0.77–1.98 | ||
0 | 26 (65) | 22 (55) | ||
1 | 14 (35) | 18 (45) | ||
Bilhariziasis | 18 (45.0) | 19 (47.5) | 0.852 | 0.33–2.33 |
Hepatitis C | 40 (100.0) | 40 (100.0) | - | - |
Hepatitis B | 10 (25.0) | 12 (30.0) | 0.622 | 0.62–2.01 |
Combined C and B | 10 (25.0) | 12 (30.0) | 0.589 | 0.52–3.11 |
Cirrhosis | 40 (100.0) | 40 (100.0) | - | |
Jaundice | 8 (20.0) | 5 (12.5) | 0.108 | 0.62–2.14 |
LL oedema | 4 (10.0) | 5 (12.5) | 0.611 | 0.71–1.98 |
Ascites | 2 (5.0) | 3 (7.5) | 0.651 | 0.65–2.99 |
Child class | 0.061 | 0.33–1.21 | ||
A | 34 (85.0) | 37 (92.5) | ||
B | 6 (15.0) | 3 (7.5) | ||
Protal vein thrombosis | 31 (77.5) | 28 (70.0) | 0.411 | 0.36–1.62 |
Previous TACE | 13 (32.5) | 18 (45.0) | 0.285 | 0.52–4.22 |
TNM stage | ||||
IIB | 9 (22.5) | 8 (20.0) | 0.532 | 0.21–2.15 |
IIIA | 8 (20.0) | 10 (25.0) | 0.322 | 0.36–3.65 |
IIIB | 11 (27.5) | 7 (17.5) | 0.042 |
0.41–0.82 |
IV (extrahepatic disease) | 12 (30.0) | 15 (37.5) | 0.365 | 0.33–2.07 |
Extrahepatic disease | 12 (30.0) | 15 (42.5) | 0.106 | 0.25–1.68 |
Bone metastasis | 8 (20.0) | 7 (17.5) | 0.622 | 0.62–1.72 |
Pulmonary metastasis | 1 (2.5) | 3 (7.5) | 0.452 | 0.32–2.65 |
Nodal metastasis | 1 (2.5) | 2 (5.0) | 0.622 | 0.45–1.69 |
Pulmonary and nodal metastasis | 2 (5.0) | 3 (7.5) | 0.240 | 0.62–2.01 |
Values are presented as number (%).
MC, metronomic capecitabine; DM, diabetes Mellitus; ECOG, Eastern Cooperative Oncology Group; LL, lower limb; TACE, transhepatic arterial chemoembolization; TNM, tumor, node, metastasis.
Significant P-value ≤0.05.
Pretreatment laboratory investigations in the two studied groups
Laboratory findings | Group A MC (n = 40) | Group B Doxorubicin (n = 40) | P-value | Confidence interval |
---|---|---|---|---|
Platelet count | 0.029 |
0.11–0.95 | ||
Range | 150–350 | 150–350 | ||
Mean ± SD | 244.8 ± 52.5 | 222.4 ± 51.8 | ||
Median | 250.0 | 210.0 | ||
SGPT | 0.280 | 0.32–2.33 | ||
Range | 14–64 | 14–63 | ||
Mean ± SD | 30.4 ± 13.2 | 32.1 ± 12.0 | ||
Median | 27.5 | 30.5 | ||
SGOT | 0.097 | 0.36–1.89 | ||
Range | 26–74 | 24–85 | ||
Mean ± SD | 43.5 ± 13.7 | 47.9 ± 15.9 | ||
Median | 39.5 | 44.0 | ||
Hemoglobin | 0.173 | 0.72–3.11 | ||
Range | 9.5–13.5 | 9.5–13.5 | ||
Mean ± SD | 11.6 ± 1.1 | 14.0 ± 16.2 | ||
Median | 11.5 | 11.5 | ||
AFP | 0.346 | 0.25–3.65 | ||
Range | 1.5–3,191 | 1.5-4,426 | ||
Mean ± SD | 632.3 ± 858.1 | 720.3 ± 1,027.0 | ||
Median | 240.0 | 240.0 | ||
S bilirubin | 0.162 | 0.33–2.68 | ||
Range | 0.8–4.3 | 0.6–4.3 | ||
Mean ± SD | 1.4 ± 0.8 | 1.2 ± 0.6 | ||
Median | 1.1 | 1.1 | ||
Protein | 0.217 | 0.65–2.87 | ||
Range | 4–7 | 4–7 | ||
Mean ± SD | 5.9 ± 0.7 | 6.0 ± 0.6 | ||
Median | 6.0 | 6.0 | ||
Albumin | 0.324 | 0.75–2.33 | ||
Range | 2.5–4.0 | 2.5–4 | ||
Mean ± SD | 3.3 ± 0.4 | 3.2 ± 0.3 | ||
Median | 3.3 | 3.2 | ||
INR | 0.061 | 0.36–1.24 | ||
Range | 1–1.5 | 1–1.5 | ||
Mean ± SD | 1.1 ± 0.2 | 1.1 ± 0.1 | ||
Median | 1.0 | 1.0 |
MC, metronomic capecitabine; SD, standard deviation; SGPT, serum glutamic oxalacetic transaminase; SGOT, serum glutamic pyruvic transaminase; AFP, alpha fetoprotein; INR, international normalized ratio; TNM, tumor, node, metastasis.
Means significant P-value ≤0.05.
Comparison between the two studied groups regarding progression free survival
Progression free survival | Group A MC (n = 40) | Group B Doxorubicin (n = 40) |
---|---|---|
0 Month | 40 (100.0) | 40 (100.0) |
3 Months | 30 (75.0) | 38 (95.0) |
6 Months | 18 (45.0) | 20 (50.0) |
9 Months | 16 (40.0) | 15 (37.5) |
12 Months | 4 (10.0) | 3 (7.5) |
15 Months | 5 (12.5) | 3 (7.5) |
18 Months | 3 (7.5) | 1 (2.5) |
21 Months | 0 | 0 |
P-value | 0.289 | |
Confidence interval of mean 95.0% | 3.20–6.1 |
Values are presented as number (%).
MC, metronomic capecitabine.
Comparison between the two studied groups regarding overall survival and median survival
Overall survival | Group A MC (n = 40) | Group B Doxorubicin (n = 40) |
---|---|---|
0 Month | 40 (100.0) | 40 (100.0) |
3 Months | 36 (90.0) | 35 (87.5) |
6 Months | 31 (77.5) | 30 (75.0) |
9 Months | 28 (70.0) | 25 (62.5) |
12 Months | 17 (42.5) | 17 (42.5) |
15 Months | 15 (37.5) | 16 (40.0) |
18 Months | 10 (25.0) | 10 (25.0) |
21 Months | 5 (12.5) | 6 (10.0) |
Median survival (mo) | 10.2 | 9.6 |
P-value | 0.521 | |
Confidence interval of mean 95.0% | 3.2–6.5 | |
Confidence interval | 0.32–2.98 |
Values are presented as number (%).
MC, metronomic capecitabine.
Relation between overall survival at one year and other factors
Prognostic factors | Group A MC (n=40) |
Group B Doxorubicin (n = 40) |
||||
---|---|---|---|---|---|---|
Die (n=23) | Survive (n=17) | P-value | Die (n = 23) | Survive (n = 17) | P-value | |
Combined B and C virus | 8 (3.5) | 2 (11.8) | 0.069 | 15 (6.5) | 13 (76.5) | 0.363 |
TNM stage | 0.307 | 0.399 | ||||
IIB | 3 (33.3) | 6 (66.7) | 4 (50.0) | 4 (50.0) | ||
IIIA | 6 (75.0) | 2 (25.0) | 4 (40.0) | 6 (60.0) | ||
IIIB | 6 (54.5) | 5 (45.5) | 4 (57.1) | 3 (42.9) | ||
IV | 8 (66.7) | 4 (33.3) | 11 (73.3) | 4 (26.7) | ||
Previous TACE | 12 (5.2) | 1 (5.9) | 0.622 | 16 (7.0) | 2 (11.8) | 0.265 |
Portal vein thrombosis | 19 (63.3) | 11 (36.7) | 0.099 | 18 (66.7) | 9 (33.3) | 0.089 |
Median AFP | 245.0 | 230.0 | 0.225 | 250.0 | 235.0 | 0.199 |
Values are presented as number (%).
MC, metronomic capecitabine; TNM, tumor node metastasis; TACE, transhepatic arterial chemoembolization; AFP, alpha fetoprotein.
Comparison between the studied groups regarding treatment toxicities
Toxicity | Group A MC (n = 40) | Group B Doxorubicin (n = 40) | P-value |
---|---|---|---|
Hand and foot syndrome | 2 (5.0) | 0 | 0.32 |
Diarrhea | 5 (12.5) | 0 | 0.044 |
Nausea, vomiting | 3 (7.5) | 38 (95.0) | 0.001 |
Alopecia | 0 | 40 (100.0) | 0.0001 |
Hyper-pigmentation | 0 | 8 (20.0) | 0.013 |
Left-ventricular systolic dysfunction | 0 | 1 (2.5) | 0.65 |
Hyperbilirubinemia | 0 | 2 (5.0) | 0.32 |
Elevated hepatic enzymes | 0 | 5 (12.5) | 0.044 |
Anemia | |||
Grade 1/2 (Hgb 8–9 g/dL) | 4/0 (10/0) | 2/6 (5/15) | 0.09 |
Grade 3/4 (Hgb < 8 g/dL) | 0/0 (0/0) | 0/0 (0/0) | - |
Thrombocytopenia | |||
Grade 1/2 (PLT, 50–75 × 103 µ/L) | 3/0 (7.5/0) | 3/10 (7.5/25.0) | 0.081 |
Grade 3/4 (PLT < 50 × 103 µ/L) | 0/0 (0/0) | 2/0 (5/0) | 0.366 |
Neutropenia | |||
Grade 1/2 (ANC 1.1–1.9 × 103 µ/L) | 0/0 (10/0) | 2/5 (5.0/12.5) | 0.028 |
Grade 3/4 (ANC < 1.0 × 103 µ/L) | 0/0 (0/0) | 0/0 (0/0) | - |
Values are presented as number (%).
MC, metronomic capecitabine; Left-ventricular systolic dysfunction, defined as ejection fraction <50%; Hyperbilirubinemia, defined as total serum bilirubin >3 mg/dL; Elevated hepatic enzymes, defined as doubling of serum glutamic oxalacetic transaminase nadir level; Hgb, hemoglobin; PLT, platelet; ANC, absolute neutrophil count.
Means significant P-value ≤0.05.