Metronomic capecitabine as second-line treatment in hepatocellular carcinoma after sorafenib failure (original) (raw)
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Journal of Clinical Oncology
Purpose Metronomic capecitabine (MC) is a well-tolerated systemic treatment showing promising results in one retrospective study, as second-line therapy after sorafenib failure, in patients with hepatocellular carcinoma (HCC). Methods 117 patients undergoing MC were compared to 112 patients, eligible for this treatment, but undergoing best supportive care (BSC) after sorafenib discontinuation for toxicity or HCC progression. The two groups were compared for demographic and clinical features. A multivariate regression analysis was conducted to detect independent prognostic factors. To balance confounding factors between the two groups, a propensity score model based on independent prognosticators (performance status, neoplastic thrombosis, causes of sorafenib discontinuation and pre-sorafenib treatment) was performed. Results Patients undergoing MC showed better performance status, lower tumor burden, lower prevalence of portal vein thrombosis, and better cancer stage. Median (95% CI) post-sorafenib survival (PSS) was longer in MC than in BSC patients [9.5 (7.5-11.6) vs 5.0 (4.2-5.7) months (p < 0.001)]. Neoplastic thrombosis, cause of sorafenib discontinuation, pre-sorafenib treatment and MC were independent prognosticators. The benefit of capecitabine was confirmed in patients after matching with propensity score [PSS: 9.9 (6.8-12.9) vs. 5.8 (4.8-6.8) months, (p = 0.001)]. MC lowered the mortality risk by about 40%. MC achieved better results in patients who stopped sorafenib for adverse events than in those who progressed during it [
Advances in Therapy
Introduction: Transcatheter arterial chemoembolization (TACE) is the first-line treatment for intermediate stage hepatocellular carcinoma (HCC) and prolongs survival in HCC patients. However, repeated TACE results in diminished therapeutic response. In addition, the superiority of sorafenib to TACE monotherapy or combined therapy in patients with HCC is still controversial. The prognosis of HCC has many variables and, thus, the effect of a specific treatment is difficult to evaluate. The frequency of treatments per year (FT rate) used in this study was obtained by dividing the total number of radiofrequency ablations and TACE or transcatheter arterial infusion treatments by the years of survival. The aim of this study was to evaluate the overall survival (OS) of TACE versus sorafenib using the FT rate. Methods: We compared the OS of patients with recurrence of HCC receiving repeated TACE monotherapy (CON) with those receiving therapy switched from TACE to sorafenib (SOR). In addition, a one-to-one FT rate matching cohort consisting of matched SOR (mSOR) and matched CON (mCON) was determined using the propensity score matching method, and OS in the cohort was evaluated. Factors influencing survival were evaluated using Cox proportional hazard regression analysis in all patients and the FT rate matched cohort. Results: In the FT rate matched cohort, the cumulative survival rate was significantly higher in the mSOR group compared with the mCON group. Multivariate regression analysis of the FT rate matched cohort showed the FT rate and sorafenib to be significant variables for survival with a hazard ratio (HR) of 2.86 (p\0.001) and 0.42 (p = 0.008), respectively. Conclusion: Early switching from TACE to sorafenib therapy may prolong OS in HCC patients unresponsive to TACE. The present study indicates that the FT rate is potentially a useful index in evaluating the outcome for patients at various stages and treatment regimens.
Metronomic Capecitabine in Advanced Hepatocellular Carcinoma Patients: A Phase II Study
The Oncologist, 2013
Background. Anti-angiogenic treatment with targeted agents is effective in advanced hepatocellular carcinoma (HCC). This trial evaluated the safety and efficacy of metronomic capecitabine in patients with HCC. Methods. This single-institution phase II trial included 59 previously untreated patients with advanced HCC and 31 patients resistant to or intolerant of sorafenib. The treatment schedule was capecitabine 500 mg twice daily until progression of disease, unacceptabletoxicitylevel,orwithdrawalofinformedconsent.Progression-free survival (PFS) was chosen as the primary endpoint. Results. A total of 59 previously untreated and 31 previously treated patients with HCC were enrolled. The first cohort achieved a median PFS of 6.03 months and an overall survival (OS) of 14.47 months. Two patients achieved a complete response, 1 patient achieved partial response, and in 30 patients, stable disease was the best outcome. The second cohort achieved a median PFS of 3.27 months and a median OS of 9.77 months. No complete or partial responses were observed, but 10 patients had stable disease. An unscheduled comparison of the first cohort of patients with 3,027 untreated patients with HCC fromtheItalianLiverCancer(ITA.LI.CA)databasewasperformed. One-to-one matching according to demographic/etiologic/oncologic features was possible for 50 patients. The median OS for these 50 capecitabine-treated patients was 15.6 months, com-paredwithamedianOSof8.0monthsforthematcheduntreated patients (p ϭ .043). Conclusion. Metronomic capecitabine is well tolerated by patients with advanced HCC and appears to have activity both in treatment-naive patients and in those previously treated with sorafenib.
Hepatitis Monthly, 2013
Introduction: Sorafenib, an oral multikinase inhibitor, is the only systemic agent proven to be effective in patients with hepatocellular carcinoma (HCC). There are no approved second line systemic therapies in patients who have had disease progression on or are not eligible to sorafenib. Case Presentation: We describe two cases of unresectable HCC that were treated with low, "metronomic" doses of capecitabine. In the first patient, capecitabine was used after sorafenib failure. In the second case, treatment with capecitabine was attempted since the patient was considered not eligible for sorafenib due to spontaneous hepatic bleeding of a large HCC lesion. Treatment was effective and well tolerated in both patients with long-lasting objective responses. Conclusions: Lacking established second-line therapy, metronomic capecitabine may be a valid alternative in the treatment of HCC patients who are judged not eligible for sorafenib or those having progression disease on sorafenib.
Hepatology, 2015
Treatment with sorafenib of patients with advanced hepatocellular carcinoma is challenged by anticipated discontinuation due to tumor progression, liver decompensation, or adverse effects. While postprogression survival is clearly determined by the pattern of tumor progression, understanding the factors that drive prognosis in patients who discontinued sorafenib for any reason may help to improve patient management and second-line trial design. Patients consecutively admitted to three referral centers who were receiving best supportive care following permanent discontinuation of sorafenib for any reason were included. Postsorafenib survival (PSS) was calculated from the last day of treatment to death or last visit available. Two hundred and sixty patients were included in this prospective study, aged 67 years, 60% with hepatitis C, 51% Child-Pugh A, 83% performance status (PS) 1, 41% with macroscopic vascular invasion, and 38% with extrahepatic tumor spread. Overall, median PSS was 4.1 (3.3-4.9) months, resulting from 4.6 (3.3-5.7) months for 123 progressors, 7.3 (6.0-10.0) months in 77 with adverse effects, and 1.8 (1.6-2.4) months in 60 decompensated patients (P < 0.001). Postsorafenib survival was independently predicted by PS, prothrombin time, extrahepatic tumor spread, macrovascular invasion, and reason for discontinuation. Two hundred patients potentially eligible for second-line therapy had a PSS of 5.3 (4.6-7.1) months, which was dependent on reasons of discontinuation (P 5 0.004), PS (P < 0.001), macrovascular invasion (P < 0.001), and extrahepatic metastases (P < 0.002). Conclusion: Discontinuation due to adverse effects in the absence of macrovascular invasion, extrahepatic metastases, and deteriorated PS predicts the best PSS in compensated patients, thereby setting the stage for both improved patient counseling and selection for second-line therapy.
Treatment with sorafenib of patients with advanced hepatocellular carcinoma is challenged by anticipated discontinuation due to tumor progression, liver decompensation, or adverse effects. While postprogression survival is clearly determined by the pattern of tumor progression, understanding the factors that drive prognosis in patients who discontinued sorafenib for any reason may help to improve patient management and second-line trial design. Patients consecutively admitted to three referral centers who were receiving best supportive care following permanent discontinuation of sorafenib for any reason were included. Postsorafenib survival (PSS) was calculated from the last day of treatment to death or last visit available. Two hundred and sixty patients were included in this prospective study, aged 67 years, 60% with hepatitis C, 51% Child-Pugh A, 83% performance status (PS) ≥1, 41% with macroscopic vascular invasion, and 38% with extrahepatic tumor spread. Overall, median PSS was 4.1 (3.3-4.9) months, resulting from 4.6 (3.3-5.7) months for 123 progressors, 7.3 (6.0-10.0) months in 77 with adverse effects, and 1.8 (1.6-2.4) months in 60 decompensated patients (P < 0.001). Postsorafenib survival was independently predicted by PS, prothrombin time, extrahepatic tumor spread, macrovascular invasion, and reason for discontinuation. Two hundred patients potentially eligible for second-line therapy had a PSS of 5.3 (4.6-7.1) months, which was dependent on reasons of discontinuation (P = 0.004), PS (P < 0.001), macrovascular invasion (P < 0.001), and extrahepatic metastases (P < 0.002). CONCLUSION: Discontinuation due to adverse effects in the absence of macrovascular invasion, extrahepatic metastases, and deteriorated PS predicts the best PSS in compensated patients, thereby setting the stage for both improved patient counseling and selection for second-line therapy. (Hepatology 2015).
Medical Oncology, 2012
Some patients with advanced hepatocellular carcinoma (HCC) progressing under sorafenib remain eligible for further systemic therapy. Little is known on the feasibility of systemic treatment beyond sorafenib in this setting. Consecutive HCC patients pre-treated with sorafenib received gemcitabine 1,000 mg/m 2 and oxaliplatin 100 mg/m 2 every 14 days. Exclusion criteria included Child C cirrhosis, PS C 3, creatinine clearance \20 ml/min, albumin\25 g/L and bilirubin [ 54 lmol/L. Pre-treatment body composition was evaluated by CT scan to detect muscle wasting (sarcopenia). The primary evaluation criterion was safety. Secondary evaluation criteria were response rate, and progression-free (PFS) and overall survival (OS). Eighteen patients (median age: 64 years, range 25-77) received a total of 90 cycles (median per patient: 4, range 1-16). Eight patients (44.4 %) had a PS of 2, 5 (27.8 %) had Child-Pugh B cirrhosis and 13 (72.2 %) had a CLIP score [3. The most frequent toxicities were thrombocytopenia (grade 2-4: n = 7, 38.9 %) and peripheral neuropathy (grade 2-3: n = 7, 38.9 %). The overall response rate was 18.8 % (95 % CI: 0-37.9), and another 18.8 % of patients had stable disease. The median PFS and OS were 3.2 (95 % CI: 2.3-3.9) and 4.7 (95 % CI: 3.8-8.1) months, respectively. Overall survival was significantly longer in patients without sarcopenia [10.0 months (95 % CI: 7.0-13.8) vs. 3.0 months (95 % CI: 2.5-3.9), p \ 0.001] and in patients with an ECOG PS \ 2 [8.1 months (95 % CI: 7.0-13.8) vs. 3.8 months (95 % CI: 2.5-3.9), p = 0.017]. In our experience, gemcitabineoxaliplatin was feasible and had detectable clinical activity in HCC patients pre-treated with sorafenib. Further studies are needed to confirm these findings.
Liver cancer, 2019
Background: Sorafenib is the first-line treatment for advanced hepatocellular carcinoma (HCC). The management of its side effects is improving. This study aimed to assess, in real life, if this translates into a better prognosis. Methods: This was a retrospective study of advanced HCC patients treated with sorafenib between 2007 and 2017. Results: 188 advanced HCC patients received > 4 weeks of sorafenib. Median treatment duration was 5.4 months and median overall survival (mOS) 10 months (95% confidence interval 15-27). Sorafenib was initiated in 65 patients in 2007-2012 and 123 in 2013-2017. Both groups were comparable except for Barcelona Clinic liver cancer class. Tumor progression, disease control (DC) rate, and incidence of toxicity were similar in the 2 periods, but the duration of treatment (4.3 vs. 5.9 months; p < 0.01) and mOS (8 vs. 12 months; p < 0.002) differed. Among progressive disease patients, mOS was similar (7 months) but for those who had DC at 8 weeks, mOS was longer in the recent period (13 vs. 27 months; p < 0.0001). In the univariate analysis of OS, the period of treatment had a prognostic value. Conclusion: When comparing 2 periods of treatment in advanced HCC patients under sorafenib, duration of treatment and mOS were higher in the recent period. While mOS did not differ for patients who progressed, it was 2-fold higher in the recent period for those who had tumor control. Improvements in the use of sorafenib seem to be associated with better outcomes limited to patients with DC.