Bridging Sunitinib Exposure to Time-to-Tumor Progression in Hepatocellular Carcinoma Patients With Mathematical Modeling of an Angiogenic Biomarker.

Hepatocellular carcinoma (HCC) is third in cancer-related causes of death worldwide and its treatment is a significant unmet medical need. Sunitinib is a selective tyrosine kinase inhibitor of the angiogenic biomarker: soluble vascular endothelial growth factor receptor-2 (sVEGFR2 ). Sunitinib failed its primary overall survival endpoint in patients with advanced HCC in a phase III trial compared to sorafenib. In the present study, pharmacokinetic-pharmacodynamic modeling was used to link drug-exposure to tumor-growth-inhibition (TGI) and time-to-tumor progression (TTP) through sVEGFR2 dynamics. The results suggest that 1) active drug concentration (i.e., sunitinib and its metabolite) inhibits the release of sVEGFR2 and that such inhibition is associated with TGI, and 2) daily sVEGFR2 exposure is likely a reliable predictor for the TTP in HCC patients. Moreover, the model quantitatively links the dynamics of an angiogenesis biomarker to TTP and accurately predicts observed literature-reported results of placebo treatment.

Bevacizumab for the treatment of recurrent ovarian cancer: a retrospective cohort study.

OBJECTIVE: To determine response rates (RR), progression-free survival (PFS), overall survival (OS), and toxicity in patients treated with cytotoxic chemotherapy, in combination with bevacizumab compared to cytotoxic chemotherapy alone, in the setting of recurrent ovarian cancer. MATERIALS AND METHODS: After obtaining Institutional Review Board approval, two cohorts of patients with recurrent ovarian cancer were identified: 1) patients that received cytotoxic chemotherapy with bevacizumab from January 2006 to June 2009; 2) patients that received cytotoxic chemotherapy alone. RR were measured using RECIST criteria or by CA-125 levels using modified Rustin criteria. RR, OS, and PFS were determined using Kaplan-Meier survival analysis. RESULTS: Thirty-two patients that received bevacizumab in combination with cytotoxic chemotherapy and 32 patients that received cytotoxic chemotherapy alone were identified. The control patients were matched for age, platinum response, histology, surgical outcome, grade, and number of previous chemotherapy regimens. There were no differences between the two cohorts in the rates of venous thromboembolism (VTE) (p = 0.39), bleeding (p = 0.15) or bowel obstruction (p = 0.40). The rate of hypertension in the bevacizumab cohort was greater than in the comparison cohort (p < 0.005). There were no differences in response rates PR/CR vs SD/PD (p = 0.46), OS (p = 0.79) or PFS (p = 0.43). CONCLUSIONS: With increased toxicity, increased cost of therapy and no improvement in PFS or OS, the role of bevacizumab in patients with recurrent ovarian cancer warrants further investigation.

Evaluation of the outcome benefit conferred by intensive surveillance strategies in women with early-stage endometrial cancer.

INTRODUCTION: The optimum follow-up regimen after treatment for early-stage endometrial cancer with curative intent is unknown. The National Comprehensive Cancer Network recommends a physical exam and vaginal cytology every three to six months for two years then at six to 12 month intervals with annual chest X-rays (CXR). However, there is debate as to whether intensive follow-up results in an improvement in outcomes for those with recurrent endometrial cancer. OBJECTIVE: To determine if intensive surveillance for recurrent cancer in women with early-stage endometrial cancer improves their outcomes. MATERIALS AND METHODS: The Roswell Park Cancer Institute tumor registry was used to identify patients with Stage I and II endometrial cancer initially diagnosed and treated over an 18-year period, who subsequently recurred. Clinico-pathological variables were abstracted. Patients were divided into two groups, depending on their mode of diagnosis of recurrent cancer: 1) routine screening, or 2) symptomatic. The outcomes between the two groups were compared. RESULTS: Fifty-two patients met inclusion criteria. Twenty-three patients were diagnosed via routine screening methods and 29 were symptomatic at presentation. Groups were equally represented with respect to age, stage, grade, adjuvant therapy, site of recurrence (local, distant), and time to recurrence (p > 0.05). Median survival time was 79 months for those diagnosed during routine screening and 80 months for symptomatic patients (p > 0.05). CONCLUSION: Pap smear and CXR appear to be of limited utility as the present study has shown that women diagnosed as a result of intensive surveillance did not have a better outcome than those who presented when symptomatic.

Adjuvant treatment for uterine leiomyosarcoma.

The aims of this study were to evaluate outcomes in women diagnosed with uterine leiomyosarcoma (LMS). A retrospective chart review was conducted. Fifty-eight women with LMS were identified. Of the evaluable 52 patients (six patients were excluded), 73% had Stage I/II disease, and 27% had Stage III/IV disease. Sixty-three percent of patients received chemotherapy (97% doxorubicin-based therapy), eight percent received radiation alone, and 29% received no therapy. For patients with Stage I/II disease, no improvement in OS was demonstrated when adjuvant therapy was administered. There was a significant difference in OS (p = 0.0005) for patients with advanced Stage (III/IV) disease that received adjuvant chemotherapy. OS of the entire group, when adjusted for stage, failed to reveal a significant survival advantage for those receiving chemotherapy-based (p = 0.22). The present findings suggest further research into the role of chemotherapy in early stage disease is needed to better refine optimal treatment.

A randomized phase II study of two doses of vorinostat in combination with 5-FU/LV in patients with refractory colorectal cancer.

BACKGROUND: Vorinostat is synergistic with 5-FU in vitro and in vivo models. A combination of these two agents was associated with clinical activity in 5-FU refractory colorectal cancer patients in a phase I clinical trial, therefore warranting the conduct of this prospective phase II study. PATIENTS AND METHODS: Patients with refractory metastatic colorectal cancer were randomized in a two-stage design to receive vorinostat at 800 or 1,400 mg/day once a day × 3, every 2 weeks. 5-FU, preceded by leucovorin, was administered as a bolus followed by a 46-h infusion on days 2 and 3 of vorinostat. A pre-specified 2-month progression-free survival (PFS) rate of 27/43 patients per arm was needed to deem an arm interesting for further investigation. RESULTS: The high-dose vorinostat arm did not reach the needed efficacy endpoint at completion of the first stage, with only 8 out of 15 patients being alive and progression free at 2 months. The low-dose vorinostat arm proceeded to accrue 43 patients with a 2-month PFS rate of 53% (23 out 43), including one partial response. The median PFS and overall survival on the low-dose arm were 2.4 and 6.5 months, respectively. Both treatment arms were well tolerated. No differences were noted in the pharmacokinetics of vorinostat at the 800- or 1,400-mg dose-levels, suggesting bioavailability saturation. CONCLUSIONS: While the addition of vorinostat to 5-FU resulted in 1 partial response and in some disease stabilizations, the limited activity does not warrant the unselected use of this combination in chemotherapy-refractory colorectal cancer.

A comparison of placebo and no-treatment during a hypnotic clinical trial.

OBJECTIVE: Sleep parameters commonly improve during placebo treatment in insomnia clinical trials. We examined whether the improvement seen with placebo was related to taking pills or other non-specific factors. METHOD: 95 insomniacs took either a placebo pill (pill+) or no pill (pill-) on nights of their choosing over 12 weeks. RESULTS: Pills were consumed on about half of the nights. Consistent improvement was seen with reduced reported sleep latency, wakefulness after sleep onset, number of awakenings, and total sleep time over the 12 weeks for both the pill+ and pill condition. A difference between pill+ and pill- was detected only for total sleep time, and this difference favored pill+. CONCLUSIONS: This study suggests that improvement seen during placebo treatment is more related to non-specific factors of participating in clinical trial than to pill taking behavior.

An immunohistochemical analysis to evaluate an inverse correlation between Runx2/Cbfa1 and NF kappa B in human osteosarcoma.

BACKGROUND: Dominant negative inhibition of nuclear factor kappa B (NF kappa B) signalling activity in a human osteosarcoma cell line (Saos2) results in malignant reversion and the induction of the osteoblast differentiating transcription factor, Runx2/Cbfa1. This observation suggests that there is an inverse relation between a transcription factor associated with malignant progression and chemoresistance (NF kappa B) and an osteoblast differentiating transcription factor (Runx2/Cbfa1). AIMS: To assess and correlate Runx2/Cbfa1 and NF kappa B (p65) immunoreactivity in human osteosarcoma. METHODS: Runx2/Cbfa1 and NFkappaB (p65) immunoreactivity was assessed on 11 paraffin wax embedded archival specimens of human primary osteosarcoma by standard immunohistochemical methods and scored on a scale of 0-3. A Pearson correlation analysis between Runx2/Cbfa1 and NF kappa B (p65) scores was established. RESULTS: Runx2/Cbfa1 was expressed constitutively in all pathology specimens of human osteosarcoma. Of note, a chondroblastic osteosarcoma showed the highest Runx2/Cbfa1 immunoreactivity. A Pearson correlation did not support an inverse correlation between Runx2/Cbfa1 and NF kappa B (p65) scores (r = 0.57) in human osteosarcoma. CONCLUSION: Runx2/Cbfa1 immunoreactivity does not inversely correlate with NF kappa B immunoreactivity, and thus cannot serve as an indirect measure of NF kappa B activity or an independent predictive or prognostic indicator.