Elizabeth Manchen

Publications of Elizabeth Manchen

• A phase II trial of gemcitabine, capecitabine, and bevacizumab in metastatic renal carcinoma.

  Authors: Elizabeth K Chung, Edwin M Posadas, Kristen Kasza, Theodore Karrison, Elizabeth Manchen, Olwen M Hahn, Walter M Stadler

  American journal of clinical oncology. 04/2011; 34(2):150-4.

  Renal cancer is resistant to most DNA and DNA repair targeted chemotherapy; although moderate response rates to nucleotide analog based therapy have been reported. Bevacizumab also has activity. WeRenal cancer is resistant to most DNA and DNA repair targeted chemotherapy; although moderate response rates to nucleotide analog based therapy have been reported. Bevacizumab also has activity. We thus performed a phase II trial of gemcitabine, capecitabine, and bevacizumab in patients with metastatic renal cancer. Following significant hematotoxicity, dosing was modified to gemcitabine 1000 mg/m (Days 1, 8), capecitabine 1000 mg twice daily (Days 1-14), and bevacizumab 15 mg/kg (Day 1) on a 21-day cycle with evaluation every 3 cycles. Primary end point was objective response rate. Twenty-nine patients were enrolled between March 2005 and May 2008. Most patients had been previously treated with a vascular endothelial growth factor receptor tyrosine kinase inhibitor. Seven patients (24%) had a partial response. Median overall and progression-free survival were 9.8 months (95% confidence interval: 6.2, 14.9) and 5.3 months (95% confidence interval: 3.9, 9.9), respectively. The regimen was well tolerated with hematologic toxicity, fatigue, and rash being most common. The trial was terminated early despite not meeting criteria for success or futility because of slow accrual and because the historical response rate became irrelevant with emerging data using sequential vascular endothelial growth factor therapies. Nevertheless, the observed progression-free and overall survival compare favorably to other phase II trials in this heavily pretreated population.

• A Randomized Phase 1 Study of Testosterone Replacement for Patients with Low-Risk Castration-Resistant Prostate Cancer.

  Authors: Russell Szmulewitz, Supriya Mohile, Edwin Posadas, Rangesh Kunnavakkam, Theodore Karrison, Elizabeth Manchen, Walter M Stadler

  European urology. 03/2009;

  BACKGROUND: Even in castration-resistant prostate cancer (CRPC), the androgen pathway remains biologically relevant. In preclinical models, androgen therapy for CRPC leads to growth arrest,BACKGROUND: Even in castration-resistant prostate cancer (CRPC), the androgen pathway remains biologically relevant. In preclinical models, androgen therapy for CRPC leads to growth arrest, apoptosis, and tumor shrinkage. OBJECTIVE: This study sought to determine the toxicity and feasibility of a testosterone therapy in early CRPC. DESIGN, SETTING, AND PARTICIPANTS: Prostate cancer patients with progressive disease following androgen ablation, antiandrogen therapy, and withdrawal and no to minimal metastatic disease who were followed at the University of Chicago were randomized to treatment with three doses of transdermal testosterone. INTERVENTION: Patients were treated with transdermal testosterone at 2.5, 5.0, or 7.5mg/day. MEASUREMENTS: Toxicity, prostate-specific antigen (PSA), imaging, quality of life (QoL), and strength were monitored. Treatment was discontinued for significant toxicity, clinical progression, or a 3-fold increase in PSA. RESULTS AND LIMITATIONS: Fifteen men with a median age of 73 yr (range: 62-92) and a median PSA of 11.1ng/ml (range: 5.2-63.6) were treated. Testosterone increased from castrate to median concentrations of 305ng/dl, 308ng/dl, and 297ng/dl for dosages of 2.5mg/day (n=4), 5.0mg/day (n=5), and 7.5mg/day (n=5), respectively. One patient was taken off of the study at 53 wk due to grade 4 cardiac toxicity. There were no other grade 3 or 4 toxicities related to the study medication, and the grade 2 toxicities were minimal. Only one patient experienced symptomatic progression, and three (20%) patients demonstrated a decrease in PSA (largest was 43%). Median time to progression was 9 wk (range: 2-96), with no detectable difference in the three dose cohorts. There was no significant improvement in QoL, and there was a borderline statistically significant improvement in hand-grip strength with treatment. The study was limited by sample size, single arm, and variability of baseline patient characteristics. CONCLUSIONS: Testosterone is a feasible and reasonably well-tolerated therapy for men with early CRPC. A larger, randomized trial is under way to further characterize efficacy and impact on QoL measures.

• Dynamic contrast-enhanced magnetic resonance imaging pharmacodynamic biomarker study of sorafenib in metastatic renal carcinoma.

  Authors: Olwen M Hahn, Cheng Yang, Milica Medved, Gregory Karczmar, Emily Kistner, Theodore Karrison, Elizabeth Manchen, Myrosia Mitchell, Mark J Ratain, Walter M Stadler

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 11/2008; 26(28):4572-8.

  PURPOSE: Sorafenib is an antiangiogenic agent with activity in renal cancer. We conducted a randomized trial to investigate dynamic contrast magnetic resonance imaging (DCE-MRI) as a pharmacodynamicPURPOSE: Sorafenib is an antiangiogenic agent with activity in renal cancer. We conducted a randomized trial to investigate dynamic contrast magnetic resonance imaging (DCE-MRI) as a pharmacodynamic biomarker. PATIENTS AND METHODS: Patients were randomly assigned to placebo or 200 or 400 mg twice per day of sorafenib. DCE-MRI was performed at baseline and 4 weeks. DCE-MRI parameters, area under the contrast concentration versus time curve 90 seconds after contrast injection (IAUC(90)), and volume transfer constant of contrast agent (K(trans)) were calculated for a metastatic site selected in a blinded manner. Primary end point was change in K(trans). RESULTS: Of the 56 assessable patients, 48 underwent two MRIs; 44 MRIs were assessable for study end points. Mean K(trans) log ratios were 0.131 (standard deviation [SD], 0.315), -0.148 (SD, 0.382), -0.271 (SD, 0.499) in placebo, 200- and 400-mg cohorts, respectively (P = .0077 for trend) corresponding to changes of +14%, -14%, and -24%. IAUC(90) log ratios were 0.041 (SD, 0.197), -0.040 (SD, 0.132), -0.356 (SD, 0.411), respectively (P = .0003 for trend), corresponding to changes of +4%, -4%, and -30%. Using a log-rank test, IAUC(90) and K(trans) changes were not associated with progression-free survival (PFS). Patients with high baseline K(trans) had a better PFS (P = .027). CONCLUSION: IAUC(90) and K(trans) are pharmacodynamic biomarkers for sorafenib, but variability is high and magnitude of effect is less than previously reported. Changes in DCE-MRI parameters after 4 weeks of sorafenib are not predictive of PFS, suggesting that these biomarkers are not surrogate end points. The value of baseline K(trans) as a prognostic or predictive biomarker requires additional study.

• A phase II study of ixabepilone (BMS-247550) in metastatic renal-cell carcinoma.

  Authors: Edwin M Posadas, Samir Undevia, Elizabeth Manchen, James L Wade, A Dimitrios Colevas, Theodore Karrison, Everett E Vokes, Walter M Stadler

  Cancer biology & therapy. 05/2007; 6(4):490-3.

  INTRODUCTION: Ixabepilone (BMS-247550) is a semi-synthetic analog of epothilone B that has been characterized as a microtubule stabilizing agent with a mechanism of action distinct from taxanes.INTRODUCTION: Ixabepilone (BMS-247550) is a semi-synthetic analog of epothilone B that has been characterized as a microtubule stabilizing agent with a mechanism of action distinct from taxanes. Suggestion of activity in renal cell carcinoma (RCC) has been seen in early clinical studies. METHODS: Eligible patients had metastatic RCC as well as ECOG performance status 0-2 and normal organ function. Patients received ixabepilone at a dose of 40 mg/m2 intravenously over three hours every 21 days. There was no restriction on RCC histology or prior treatment type, but prior treatment with tubule inhibitors was not allowed. The primary endpoint was RECIST defined response and radiographic evaluations were performed every three cycles. Toxicity evaluations utilized CTCAE v3.0 and were performed every cycle. Using a Simon two-stage optimal design with alpha = 0.1, beta = 0.1, a null hypothesized response rate of 0.05 and an alternative response rate of 0.2, an initial 12 patients were to be accrued with full accrual of 37 patients if at least one response were observed. RESULTS: A median of five cycles were administered. No objective responses were observed in the first 12 evaluable patients, and six patients showed stable disease for more than 18 weeks on therapy. Median time to progression among those with objective progression was nine weeks. One patient experienced grade 4 anemia and lymphopenia. Grade 3 adverse events included lymphopenia, neutropenia, leukopenia, diarrhea, and infection. Common grade 2 toxicities included alopecia, fatigue and anemia. CONCLUSION: Ixabepilone administered at a dose of 40 mg/m2 every 21 days should not be advanced for further study in metastatic RCC. Given previous results, however, other dosing schedules may be worthy of further investigation.

• Management of tyrosine kinase inhibitor-induced hand-foot skin reaction: viewpoints from the medical oncologist, dermatologist, and oncology nurse.

  Authors: Elizabeth Manchen, Caroline Robert, Camillo Porta

  The journal of supportive oncology. 9(1):13-23.

  One significant toxicity associated with the anticancer tyrosine kinase inhibitors (TKIs) is hand-foot skin reaction (HFSR). We provide an overview of HFSR, emphasizing experience-based preventionOne significant toxicity associated with the anticancer tyrosine kinase inhibitors (TKIs) is hand-foot skin reaction (HFSR). We provide an overview of HFSR, emphasizing experience-based prevention techniques and nursing management strategies from the viewpoints of a medical oncologist, a dermatologist, and an oncology nurse. Supporting data include (1) published preclinical and phase I-III clinical studies and (2) published abstracts of phase II-III clinical trials of sorafenib and sunitinib. HFSR has been reported in up to 60% of patients treated with sorafenib or sunitinib. TKI-induced HFSR may lead to dose reductions or treatment interruptions and reduced quality of life. Symptoms of TKI-associated HFSR can be managed by implementing supportive measures and aggressive dose modification. Patients educated about HFSR can work with their health-care teams to proactively detect and help manage this cutaneous toxicity, thus preventing or reducing the severity of TKI-associated HFSR. Successful prevention and management of TKI-associated HFSR can help to ensure that patients achieve optimal therapeutic outcomes. Implementation of such measures may increase the likelihood that therapy is continued for the appropriate interval at an appropriate dose for each patient. Optimal management of TKI-associated HFSR is predicated on establishing appropriate partnerships amongmedical oncologists, dermatologists, oncology nurses, and patients.