Efficacy and Safety of Sorafenib in a Racially Diverse Patient Population with Advanced Hepatocellular Carcinoma.

BACKGROUND: There are few efficacy and toxicity data on sorafenib for patients treated for hepatocellular carcinoma (HCC) who are not Caucasian or Asian. MATERIALS AND METHODS: A retrospective analysis was carried out on 67 patients treated with sorafenib for advanced HCC at an urban referral center. Patients were categorized by race, age, sex, status, stage, and dose. Primary outcomes were time to progression (TTP), toxicity, and treatment discontinuation by race. RESULTS: African-Americans and Caucasians had significantly shorter TTP than patients of other races (Hispanic, Asian, and unidentified) [African-Americans: hazard ratio (HR)=5.01, p=0.0068; Caucasians: HR=8.25, p=0.0008). There were no significant differences in time to toxicity (p=0.99). Caucasians had the shortest time to therapy discontinuation (p=0.0298). TTP was shorter for males (HR=3.51, p=0.028), and longer for patients experiencing toxicity (HR=0.47, p=0.046). CONCLUSION: Among patients treated with sorafenib for advanced HCC, non African-American/non-Caucasian race, female sex, and toxicity were associated with significantly longer time to progression.

Capecitabine to reduce nonmelanoma skin carcinoma burden in solid organ transplant recipients.

BACKGROUND: Solidorgan transplant recipients (SOTRs) are at greater risk of nonmelanoma skin cancer (NMSC) than the general population, in large part because of their immunosuppression. Select individual SOTRs demonstrate a rate of tumor development at the upper end of their cohort. Capecitabine, a prodrug converted in the body to 5-fluorouracil (5-FU), may alter the risk for development of NMSC in an individual SOTR with a high rate of tumor development. OBJECTIVE: To report observations of a series of 10 SOTRs treated with capecitabine as adjuvant prevention for high-incidence NMSC. METHODS: Ten SOTRs were administered cycles of low-dose oral capecitabine (0.5-1.5 g/m(2) per day) for days 1 to 14 of a 21-day treatment cycle. Measurements (skin screenings, laboratory and toxicity monitoring) were performed every 1 to 3 months. Incidence rates of squamous cell carcinoma (SCC) before and during treatment were determined and compared using the Wilcoxon signed-rank test. RESULTS: The average incidence rate (mean ± SD) of SCC before treatment (0.56 ± 0.28 SCCs/month, range 0.17-1.17 SCCs/month) declined to 0.16 ± 0.11 SCCs/month (range 0-0.33 SCCs/month) during the first 12 months of treatment (mean reduction 68 ± 30.0%, range 0-100%, p < .005). Reduction in actinic keratosis was observed. Common side effects included fatigue, nausea, hand-and-foot syndrome, gout, and poor renal function. Seven of 10 participants required dose adjustment, and two of these were discontinued from the study drug because of side effects. LIMITATIONS: Case series design, small observational population. CONCLUSIONS: SOTRs experienced a clinically and statistically significant decline in incident SCCs during treatment with low-dose oral capecitabine, with varying degrees of side effects. Larger randomized trials will determine the dose and efficacy of capecitabine for adjuvant treatment of NMSC in SOTRs.

Brain metastases from renal cell carcinoma in the era of tyrosine kinase inhibitors.

BACKGROUND: The effectiveness of tyrosine kinase inhibitors (TKI) in preventing brain metastases in patients with renal cell carcinoma is unclear. METHODS: Preclinical studies were conducted to determine the steady-state brain and plasma concentrations of sorafenib and sunitinib in mice deficient in the drug efflux transporters; p-glycoprotein, and breast cancer resistance protein. A single-institution retrospective analysis of patients treated from 2008 to 2010 was conducted to assess the incidence of brain metastases before and during TKI treatment. RESULTS: Transport of sorafenib and sunitinib across the blood-brain barrier was restricted. Retrospective analysis revealed that the median time to develop metastatic brain disease was 28 months (range, 1-108 months) while on TKI therapy and 11.5 months (range, 0-64 months) in patients who did not receive TKI therapy. The incidence of brain metastases per month in patients not treated with TKI therapy was 1.6 higher than the incidence in patients treated with TKI therapy. CONCLUSIONS: Penetration of sorafenib or sunitinib through an intact blood-brain barrier to brain tissue is limited; however, the incidence of brain metastases per unit time is decreased in patients on TKI therapy in comparison with the "cytokine" era.

Sorafenib therapy for metastatic renal carcinoma in patients with low cardiac ejection fraction: report of two cases and literature review.

Targeted therapies used in the treatment of metastatic renal cell carcinoma (RCC) are known to have the potential for cardiotoxicity and should be used with caution in patients with cardiac comorbidities. A retrospective review identified two RCC cases treated with sorafenib in the context of preexisting cardiomyopathy. Sorafenib therapy resulted in disease stabilization of progressing RCC for both cases, without worsening of cardiac ejection fraction. Further evaluation of the cardiac safety of sorafenib in patients with cardiomyopathy is warranted.

Sequential therapy with sorafenib and sunitinib in renal cell carcinoma.

BACKGROUND: Sunitinib and sorafenib are small-molecule tyrosine kinase inhibitors (TKI) with antitumor activity in advanced renal cell carcinoma. A retrospective study was conducted to assess the response of renal cell carcinoma to sequential treatment with these two agents. METHODS: Tumor response was evaluated by using Response Evaluation Criteria In Solid Tumors (RECIST) criteria in patients failing first-line therapy with either sunitinib or sorafenib and subsequently receiving second-line therapy with the other TKI agent. RESULTS: Twenty-nine patients received sorafenib followed by sunitinib (Group A), and 20 patients received sunitinib followed by sorafenib (Group B). TKI drugs were terminated in 6 (12%) patients in Group A and 4 (8%) in Group B because of toxicity. Median duration of stable disease for Groups A and B was 20 and 9.5 weeks, respectively. Median time from starting first TKI to disease progression after second TKI (time to progression) in Groups A and B was 78 and 37 weeks, respectively. Multivariate analysis revealed that Group B had a shorter time to progression than Group A (risk ratio [RR] 3.0; P=.016). Median overall survival was 102 and 45 weeks in Groups A and B, respectively (P=.061). CONCLUSIONS: The longer duration of disease control in patients who received sorafenib followed by sunitinib warrants further investigation.

Protein kinase C-beta inhibitor enzastaurin (LY317615.HCI) enhances radiation control of murine breast cancer in an orthotopic model of bone metastasis.

Radiation therapy is a widely used treatment for metastatic bone cancer, but the rapid onset of tumor radioresistance is a major problem. We investigated the radiosensitizing effect of enzastaurin, a protein kinase Cbeta (PKCbeta) inhibitor, on bone tumor growth and tumor-related pain. We found that enzastaurin enhanced the effect of ionizing radiation on cultured murine 4T1 breast cancer and murine endothelial cells, suppressing their proliferation and colony formation. Enzastaurin and ionizing radiation also induced caspase-mediated apoptosis of 4T1 cells to a greater degree than radiation alone. Enzastaurin treatment of 4T1 cells blocked the phosphorylation of PKCbeta, as well as Ras and two of its downstream effectors ERK1/2 and RAL-GTP. Using an orthotopic model of bone metastasis, we observed that a combination of enzastaurin and localized radiation treatment reduced tumor blood vessel density, bone destruction and pain compared to single modality treatment. In conclusion, we demonstrate that inhibition of PKCbeta in combination with localized radiation treatment suppresses tumor growth and alleviates pain as compared to radiation-only treatment. We also show that the radiosensitizing effect of enzastaurin is associated with suppression of tumor cell proliferation and tumor-induced angiogenesis possibly through inhibition of the Ras pathway.

Pulmonary blastoma with renal metastasis responds to sorafenib.

Biphasic pulmonary blastoma is a rare malignancy of the lung composed of proliferating epithelial and mesenchymal cells with a high vessel density at the tumor periphery. We report a rare case of renal metastasis of biphasic pulmonary blastoma that responded to sorafenib, an oral multikinase inhibitor. After 2 months of treatment with sorafenib, the renal tumor size decreased sufficiently to allow a safe laparoscopic radical nephrectomy. We believe that further studies are warranted to confirm the possible effects of sorafenib on pulmonary blastomas.

Skin rash and bronchoalveolar histology correlates with clinical benefit in patients treated with gefitinib as a therapy for previously treated advanced or metastatic non-small cell lung cancer.

BACKGROUND: Only 15% of patients with non-small cell lung cancer (NSCLC) treated with oral epidermal growth factor tyrosine kinase inhibitor gefitinib, as a second-line therapy have objective responses. Fifty percent will have improvement of lung cancer related symptoms. It will be critical to identify patients who will benefit clinically from this therapy even when there is no objective response seen on imaging studies. We have performed a retrospective analysis of 76 patients who received gefitinib as a therapy for previously treated metastatic NSCLC at the University of Minnesota Comprehensive Cancer Center in order to describe characteristics of patients who will likely derive benefits from gefitinib therapy. METHODS: All patients treated with gefitinib therapy at the University of Minnesota from September 2001 to January 2004 were entered into the study. The Log-rank Test and Cox proportional hazards regression were used to assess the effect of the number of previous therapy lines, histology subtype, performance status, gender, stage of disease at initial diagnosis, and presence of skin rash on time to disease progression and overall survival (OS). Fisher's Exact Test and multiple logistic regressions were used to assess the effect of these covariates on disease response. RESULTS: Seventy-six patients entered the study, with a median age of 60 years (range 37-82). There were 37 female and 39 male patients; 47 patients had adenocarcinoma, 22 had squamous and 7 had other NSCLC histologies. Six patients had no prior therapy, 23 had one, 32 had two, 8 had three, and 7 had four prior therapies for lung cancer. Fifty-six were current smokers. Median time to disease progression was 3 months (95% CI: 3.0, 6.0). There was no difference in time to disease progression whether patients had one or more prior therapies. Patients with brain metastases (26 patients) benefited from gefitinib therapy at least equally well as those without brain metastatic disease. Patients with adenocarcinoma histology with bronchoalveolar features had superior median time to progression versus other lung cancer histology (14 months versus 3 months, p=0.076), which translated into survival advantage in this group >24 months (95% CI: 0.76, 24+) versus 6.6 months (p=0.0096). Patients with EGFR positive tumors had median survival of 10.2 months (95% CI: 1.45, 16.94) versus 3.7 months (95% CI: 2.66, 4.74) with EGFR negative tumors. Patients who developed any degree of skin rash had prolonged time to disease progression with median of 6 months (95% CI: 2.56, 15.5) versus patients without skin rash median 3 months (95% CI: 1.43, 2.83) (p=0.023). This last factor was the best predictor of improved time to disease progression in multiple regression analysis (p=0.0405). CONCLUSION: A subgroup of patients with NSCLC will benefit from gefitinib therapy. Objective responses will likely be seen in half the patients with mutation of internal domain of EGFR; however, a larger group of patients will also enjoy prolonged disease stabilization and clinical benefit. We suggest that adenocarcinoma with bronchoalveolar features and the presence of skin rash may be used as predictors of gefitinib benefit.