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Rich66 · 02-02-2010, 10:48 AM

J Hepatol. 2010 Mar 30. [Epub ahead of print]
Phase II study of combining sorafenib with metronomic tegafur/uracil for advanced hepatocellular carcinoma.

Hsu CH, Shen YC, Lin ZZ, Chen PJ, Shao YY, Ding YH, Hsu C, Cheng AL.
Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; Cancer Research Center, National Taiwan University College of Medicine, Taipei, Taiwan.
Abstract

BACKGROUND & AIMS: Sorafenib, a multi-kinase inhibitor with anti-angiogenic activity, was recently approved for the treatment of advanced hepatocellular carcinoma (HCC). Metronomic chemotherapy using tegafur/uracil (4:1molar ratio), an oral fluoropyrimidine, has been shown to enhance the anti-tumor effect of anti-angiogenic agents in preclinical models. This phase II study evaluated the efficacy and safety of combining metronomic tegafur/uracil with sorafenib in patients with advanced HCC. METHODS: Patients with histologically- or cytologically-proven HCC and Child-Pugh class A liver function were treated with sorafenib (400mg twice daily) and tegafur/uracil (125mg/m(2) based on tegafur twice daily) continuously as first-line therapy for metastatic or locally advanced disease that could not be treated by loco-regional therapies. The primary endpoint was progression-free survival (PFS). RESULTS: The study enrolled 53 patients. Thirty-eight patients (72%) were hepatitis B surface antigen-positive. The median PFS was 3.7months (95% C.I., 1.9-5.5) and the median overall survival was 7.4months (95% C.I., 3.4-11.4). According to RECIST criteria, 4 patients (8%) had a partial response and 26 patients (49%) had a stable disease. Major grade 3/4 toxicities included fatigue (15%), abnormal liver function (13%), elevated serum lipase (10%) hand-foot skin reaction (HFSR) (9%), and bleeding (8%). HFSR was the major adverse event resulting in dose reduction (19%) or treatment delay (21%). CONCLUSIONS: Metronomic chemotherapy with tegafur/uracil can be safely combined with sorafenib and shows preliminary activity to improve the efficacy of sorafenib in advanced HCC patients. Copyright Â© 2010. Published by Elsevier B.V.

PMID: 20416968 [PubMed - as supplied by publisher]

Oncol Rep. 2010 Oct;24(4):1049-58.
Sorafenib enhances the in vitro anti-endothelial effects of low dose (metronomic) chemotherapy.

Murray A, Little SJ, Stanley P, Maraveyas A, Cawkwell L.
Cancer Biology Proteomics Group, Postgraduate Medical Institute, University of Hull, Hull, UK.

Abstract

Angiogenesis inhibitors may enhance the effects of low dose (metronomic) chemotherapy. However, there is a wide range of novel angiogenesis inhibitors which must be tested in combinations with oral chemotherapy agents to assess the anti-endothelial and anti-cancer effects. This preliminary testing is most suited to high throughput in vitro models, rather than clinical trials. We aimed to establish an in vitro model and test the anti-endothelial and anti-cancer effects of the multi-kinase inhibitor sorafenib when used as a single agent and in combination with oral chemotherapy agents used at low concentrations. Micro-vascular endothelial cells and 3 cancer cell lines were utilised and an extended treatment strategy (96 h) was employed in order to mimic a continuous low dose anti-angiogenic chemotherapy regimen. Sorafenib significantly enhanced the anti-endothelial effect of low dose etoposide, paclitaxel and temozolomide. Sorafenib also significantly enhanced the anti-cancer effect of low dose etoposide, paclitaxel and temozolomide in SK-MEL-2 melanoma cells, producing an additive effect on inhibition of cell growth in all cases. These combinations appear to be the most promising for in vivo pre-clinical studies, with a view to testing in melanoma patients as a continuous dosing strategy, due to the in vitro additive inhibitory effect on growth seen in both endothelial and cancer cells.

PMID: 20811688 [PubMed - in process]

Br J Cancer. 2010 Jan 5. [Epub ahead of print]
Combination therapy: intermittent sorafenib with bevacizumab yields activity and decreased toxicity.

Lee JM, Sarosy GA, Annunziata CM, Azad N, Minasian L, Kotz H, Squires J, Houston N, Kohn EC.
Medical Ovarian Cancer Team, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.

Background: We previously reported preliminary results of our phase I study of continuous daily sorafenib with bevacizumab every other week for solid tumours. Toxicity was moderate, leading to additional dose levels (DL) testing intermittent sorafenib dosing.
Methods: Seventeen patients with advanced solid tumours were treated on three additional DLs testing sorafenib days 1-5 per week. Dose level 4 was sorafenib 200 mg twice daily (b.i.d.) and bevacizumab 5 mg kg(-1). DL5 alternated between bevacizumab 10 mg kg(-1)-sorafenib 200 mg b.i.d. (A) and sorafenib 400 mg b.i.d. with bevacizumab 5 mg kg(-1) (B). Outcome and toxicity data from 19 epithelial ovarian cancer (EOC) patients from DL 1-5 were analysed.
Results: Fewer patients required sorafenib dose reduction with the intermittent schedule (41 vs 74% daily, P=0.01). Hand-foot skin reaction (HFSR) remained the primary cause of dose reduction (n=5). Partial responses (12%) or disease stabilisation >/=4 months (53%; median 6 (4-26)) occurred in most patients on the intermittent schedule. Partial response occurred in 47% EOC patients treated in pooled analysis of duration 4-37 months.
Conclusion: Intermittent sorafenib dosing with bevacizumab has promising clinical activity and less sorafenib dose reduction and side effects, but does not ameliorate HFSR. We are conducting a phase II clinical trial with intermittent sorafenib and bevacizumab in patients with EOC.British Journal of Cancer advance online publication, 5 January 2010; doi:10.1038/sj.bjc.6605514 www.bjcancer.com.

PMID: 20051952 [PubMed - as supplied by publisher]

Oncologist. 2010;15(1):85-92. Epub 2010 Jan 5.
Early skin toxicity as a predictive factor for tumor control in hepatocellular carcinoma patients treated with sorafenib.

Vincenzi B, Santini D, Russo A, Addeo R, Giuliani F, Montella L, Rizzo S, Venditti O, Frezza AM, Caraglia M, Colucci G, Del Prete S, Tonini G.
Correspondence: Antonio Russo, M.D., Ph.D., Department of Surgical and Oncological Sciences, Section of Medical Oncology; UniversitÃ* di Palermo, Palermo, Italy, Via del Vespro 127, 90127 Palermo, Italy. Telephone: 39-091-6552500; Fax: 39-091-6554529; e-mail: lab-oncobiologia@usa.net

TEXT here

Introduction. Sorafenib is an oral multikinase inhibitor that targets Raf kinase and receptor tyrosine kinases and has led to a longer median overall survival (OS) time and time to progression (TTP) in patients with advanced hepatocellular carcinoma (HCC). This study was conducted to assess the link between the antitumor efficacy of sorafenib and its early cutaneous side effects in advanced HCC patients. Materials and Methods. All patients received 800 mg daily of sorafenib until progression or unacceptable toxicities. We retrospectively analyzed the incidence of rash and hand-foot skin reactions (HFSR) during the first month of treatment, comparing tumor control (partial response plus stable disease) and TTP. Results. Sixty-five HCC patients treated with sorafenib were included in this analysis: 47 (73.3%) received sorafenib after failure of some local treatment, whereas 18 (27.7%) received it as first-line treatment. Twenty-nine patients developed at least grade 1 skin toxicity (rash, 13; HFSR, 16). In patients who developed skin toxicity, the tumor control rate was 48.3%, versus 19.4% in patients without cutaneous side effects. The median TTP was 8.1 months in the group of patients with skin toxicity versus 4.0 months in those without skin toxicity. This difference was also statistically significant on multivariate analysis. A borderline statistically significant difference was also observed in terms of OS in patients with early skin toxicity. Conclusions. Skin toxicity should be closely monitored in HCC patients treated with sorafenib in relation to its potential role as a surrogate marker of efficacy.

PMID: 20051477 [PubMed - in process]

Oncol Rep. 2010 Oct;24(4):1049-58.
Sorafenib enhances the in vitro anti-endothelial effects of low dose (metronomic) chemotherapy.

Murray A, Little SJ, Stanley P, Maraveyas A, Cawkwell L.
Cancer Biology Proteomics Group, Postgraduate Medical Institute, University of Hull, Hull, UK.

$ TEXT

Abstract

Angiogenesis inhibitors may enhance the effects of low dose (metronomic) chemotherapy. However, there is a wide range of novel angiogenesis inhibitors which must be tested in combinations with oral chemotherapy agents to assess the anti-endothelial and anti-cancer effects. This preliminary testing is most suited to high throughput in vitro models, rather than clinical trials. We aimed to establish an in vitro model and test the anti-endothelial and anti-cancer effects of the multi-kinase inhibitor sorafenib when used as a single agent and in combination with oral chemotherapy agents used at low concentrations. Micro-vascular endothelial cells and 3 cancer cell lines were utilised and an extended treatment strategy (96 h) was employed in order to mimic a continuous low dose anti-angiogenic chemotherapy regimen. Sorafenib significantly enhanced the anti-endothelial effect of low dose etoposide, paclitaxel and temozolomide. Sorafenib also significantly enhanced the anti-cancer effect of low dose etoposide, paclitaxel and temozolomide in SK-MEL-2 melanoma cells, producing an additive effect on inhibition of cell growth in all cases. These combinations appear to be the most promising for in vivo pre-clinical studies, with a view to testing in melanoma patients as a continuous dosing strategy, due to the in vitro additive inhibitory effect on growth seen in both endothelial and cancer cells.

PMID: 20811688 [PubMed - in process]

02-02-2010, 10:48 AM	#2
Rich66 Senior Member Join Date: Feb 2008 Location: South East Wisconsin Posts: 3,431	Re: Sorafenib (Nexavar) J Hepatol. 2010 Mar 30. [Epub ahead of print] Phase II study of combining sorafenib with metronomic tegafur/uracil for advanced hepatocellular carcinoma. Hsu CH, Shen YC, Lin ZZ, Chen PJ, Shao YY, Ding YH, Hsu C, Cheng AL. Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; Cancer Research Center, National Taiwan University College of Medicine, Taipei, Taiwan. Abstract BACKGROUND & AIMS: Sorafenib, a multi-kinase inhibitor with anti-angiogenic activity, was recently approved for the treatment of advanced hepatocellular carcinoma (HCC). Metronomic chemotherapy using tegafur/uracil (4:1molar ratio), an oral fluoropyrimidine, has been shown to enhance the anti-tumor effect of anti-angiogenic agents in preclinical models. This phase II study evaluated the efficacy and safety of combining metronomic tegafur/uracil with sorafenib in patients with advanced HCC. METHODS: Patients with histologically- or cytologically-proven HCC and Child-Pugh class A liver function were treated with sorafenib (400mg twice daily) and tegafur/uracil (125mg/m(2) based on tegafur twice daily) continuously as first-line therapy for metastatic or locally advanced disease that could not be treated by loco-regional therapies. The primary endpoint was progression-free survival (PFS). RESULTS: The study enrolled 53 patients. Thirty-eight patients (72%) were hepatitis B surface antigen-positive. The median PFS was 3.7months (95% C.I., 1.9-5.5) and the median overall survival was 7.4months (95% C.I., 3.4-11.4). According to RECIST criteria, 4 patients (8%) had a partial response and 26 patients (49%) had a stable disease. Major grade 3/4 toxicities included fatigue (15%), abnormal liver function (13%), elevated serum lipase (10%) hand-foot skin reaction (HFSR) (9%), and bleeding (8%). HFSR was the major adverse event resulting in dose reduction (19%) or treatment delay (21%). CONCLUSIONS: Metronomic chemotherapy with tegafur/uracil can be safely combined with sorafenib and shows preliminary activity to improve the efficacy of sorafenib in advanced HCC patients. Copyright Â© 2010. Published by Elsevier B.V. PMID: 20416968 [PubMed - as supplied by publisher] Oncol Rep. 2010 Oct;24(4):1049-58. Sorafenib enhances the in vitro anti-endothelial effects of low dose (metronomic) chemotherapy. Murray A, Little SJ, Stanley P, Maraveyas A, Cawkwell L. Cancer Biology Proteomics Group, Postgraduate Medical Institute, University of Hull, Hull, UK. Abstract Angiogenesis inhibitors may enhance the effects of low dose (metronomic) chemotherapy. However, there is a wide range of novel angiogenesis inhibitors which must be tested in combinations with oral chemotherapy agents to assess the anti-endothelial and anti-cancer effects. This preliminary testing is most suited to high throughput in vitro models, rather than clinical trials. We aimed to establish an in vitro model and test the anti-endothelial and anti-cancer effects of the multi-kinase inhibitor sorafenib when used as a single agent and in combination with oral chemotherapy agents used at low concentrations. Micro-vascular endothelial cells and 3 cancer cell lines were utilised and an extended treatment strategy (96 h) was employed in order to mimic a continuous low dose anti-angiogenic chemotherapy regimen. Sorafenib significantly enhanced the anti-endothelial effect of low dose etoposide, paclitaxel and temozolomide. Sorafenib also significantly enhanced the anti-cancer effect of low dose etoposide, paclitaxel and temozolomide in SK-MEL-2 melanoma cells, producing an additive effect on inhibition of cell growth in all cases. These combinations appear to be the most promising for in vivo pre-clinical studies, with a view to testing in melanoma patients as a continuous dosing strategy, due to the in vitro additive inhibitory effect on growth seen in both endothelial and cancer cells. PMID: 20811688 [PubMed - in process] Br J Cancer. 2010 Jan 5. [Epub ahead of print] Combination therapy: intermittent sorafenib with bevacizumab yields activity and decreased toxicity. Lee JM, Sarosy GA, Annunziata CM, Azad N, Minasian L, Kotz H, Squires J, Houston N, Kohn EC. Medical Ovarian Cancer Team, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. Background: We previously reported preliminary results of our phase I study of continuous daily sorafenib with bevacizumab every other week for solid tumours. Toxicity was moderate, leading to additional dose levels (DL) testing intermittent sorafenib dosing. Methods: Seventeen patients with advanced solid tumours were treated on three additional DLs testing sorafenib days 1-5 per week. Dose level 4 was sorafenib 200 mg twice daily (b.i.d.) and bevacizumab 5 mg kg(-1). DL5 alternated between bevacizumab 10 mg kg(-1)-sorafenib 200 mg b.i.d. (A) and sorafenib 400 mg b.i.d. with bevacizumab 5 mg kg(-1) (B). Outcome and toxicity data from 19 epithelial ovarian cancer (EOC) patients from DL 1-5 were analysed. Results: Fewer patients required sorafenib dose reduction with the intermittent schedule (41 vs 74% daily, P=0.01). Hand-foot skin reaction (HFSR) remained the primary cause of dose reduction (n=5). Partial responses (12%) or disease stabilisation >/=4 months (53%; median 6 (4-26)) occurred in most patients on the intermittent schedule. Partial response occurred in 47% EOC patients treated in pooled analysis of duration 4-37 months. Conclusion: Intermittent sorafenib dosing with bevacizumab has promising clinical activity and less sorafenib dose reduction and side effects, but does not ameliorate HFSR. We are conducting a phase II clinical trial with intermittent sorafenib and bevacizumab in patients with EOC.British Journal of Cancer advance online publication, 5 January 2010; doi:10.1038/sj.bjc.6605514 www.bjcancer.com. PMID: 20051952 [PubMed - as supplied by publisher] Oncologist. 2010;15(1):85-92. Epub 2010 Jan 5. Early skin toxicity as a predictive factor for tumor control in hepatocellular carcinoma patients treated with sorafenib. Vincenzi B, Santini D, Russo A, Addeo R, Giuliani F, Montella L, Rizzo S, Venditti O, Frezza AM, Caraglia M, Colucci G, Del Prete S, Tonini G. Correspondence: Antonio Russo, M.D., Ph.D., Department of Surgical and Oncological Sciences, Section of Medical Oncology; UniversitÃ* di Palermo, Palermo, Italy, Via del Vespro 127, 90127 Palermo, Italy. Telephone: 39-091-6552500; Fax: 39-091-6554529; e-mail: lab-oncobiologia@usa.net TEXT here Introduction. Sorafenib is an oral multikinase inhibitor that targets Raf kinase and receptor tyrosine kinases and has led to a longer median overall survival (OS) time and time to progression (TTP) in patients with advanced hepatocellular carcinoma (HCC). This study was conducted to assess the link between the antitumor efficacy of sorafenib and its early cutaneous side effects in advanced HCC patients. Materials and Methods. All patients received 800 mg daily of sorafenib until progression or unacceptable toxicities. We retrospectively analyzed the incidence of rash and hand-foot skin reactions (HFSR) during the first month of treatment, comparing tumor control (partial response plus stable disease) and TTP. Results. Sixty-five HCC patients treated with sorafenib were included in this analysis: 47 (73.3%) received sorafenib after failure of some local treatment, whereas 18 (27.7%) received it as first-line treatment. Twenty-nine patients developed at least grade 1 skin toxicity (rash, 13; HFSR, 16). In patients who developed skin toxicity, the tumor control rate was 48.3%, versus 19.4% in patients without cutaneous side effects. The median TTP was 8.1 months in the group of patients with skin toxicity versus 4.0 months in those without skin toxicity. This difference was also statistically significant on multivariate analysis. A borderline statistically significant difference was also observed in terms of OS in patients with early skin toxicity. Conclusions. Skin toxicity should be closely monitored in HCC patients treated with sorafenib in relation to its potential role as a surrogate marker of efficacy. PMID: 20051477 [PubMed - in process] Oncol Rep. 2010 Oct;24(4):1049-58. Sorafenib enhances the in vitro anti-endothelial effects of low dose (metronomic) chemotherapy. Murray A, Little SJ, Stanley P, Maraveyas A, Cawkwell L. Cancer Biology Proteomics Group, Postgraduate Medical Institute, University of Hull, Hull, UK. $ TEXT Abstract Angiogenesis inhibitors may enhance the effects of low dose (metronomic) chemotherapy. However, there is a wide range of novel angiogenesis inhibitors which must be tested in combinations with oral chemotherapy agents to assess the anti-endothelial and anti-cancer effects. This preliminary testing is most suited to high throughput in vitro models, rather than clinical trials. We aimed to establish an in vitro model and test the anti-endothelial and anti-cancer effects of the multi-kinase inhibitor sorafenib when used as a single agent and in combination with oral chemotherapy agents used at low concentrations. Micro-vascular endothelial cells and 3 cancer cell lines were utilised and an extended treatment strategy (96 h) was employed in order to mimic a continuous low dose anti-angiogenic chemotherapy regimen. Sorafenib significantly enhanced the anti-endothelial effect of low dose etoposide, paclitaxel and temozolomide. Sorafenib also significantly enhanced the anti-cancer effect of low dose etoposide, paclitaxel and temozolomide in SK-MEL-2 melanoma cells, producing an additive effect on inhibition of cell growth in all cases. These combinations appear to be the most promising for in vivo pre-clinical studies, with a view to testing in melanoma patients as a continuous dosing strategy, due to the in vitro additive inhibitory effect on growth seen in both endothelial and cancer cells. PMID: 20811688 [PubMed - in process] __________________ Mom's treatment history (link)