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ABSTRACT: Twelve patients with metastatic breast cancer previously exposed to taxanes were treated on a Phase II trial with ixabepilone. Eligible patients had histologically confirmed metastatic breast cancer with measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST), and adequate hematopoietic, renal, and hepatic function. Ixabepilone 8 mg/m(2)/day was given intravenously daily for 3 days for the first 3-week cycle and increased to 10 mg/m(2)/day for subsequent cycles if patients did not have hematologic or other toxicity after the first cycle. Patients continued treatment until progressive disease or unacceptable toxicity. Three, 29, and 33 of 65 cycles administered were at the 7 mg/m(2), 8 mg/m(2) and 10 mg/m(2) dose levels respectively. Grade 4 leukopenia (n=1), grade 3 neutropenia (n=2), grade 2 neuropathy (n=3), and grade 2 transaminase elevation (n=2) were the most notable toxicities. Ten patients had stable disease for at least 6 weeks. No complete or partial responses were observed in 12 evaluable patients treated with ixabepilone daily for 3 days. Although ixabepilone was well-tolerated, the dose of 8-10 mg/m(2) daily for 3 days is not an effective therapy in metastatic breast cancer previously exposed to taxanes.
Investigational New Drugs 03/2007; 25(1):63-7. · 3.36 Impact Factor
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ABSTRACT: Increasing knowledge of drug resistance and side effects of currently approved agents, and of the biology of breast cancer, has given way to new treatment options that improve on previously available agents, or medications that target specific kinases and proteins associated with an oncogenic phenotype. This paper discusses new agents, including improved formulations of paclitaxel and epothilones, and molecularly targeted agents such as bevacizumab, sunitinib malate, pertuzumab, lapatinib, the mTOR inhibitors and farnesyl transferase inhibitors. Although endocrine therapy is a targeted therapy, it is not covered in this paper. These agents have increased excitement in the treatment of breast cancer and stand on the forefront of a potential improvement in quality of life and treatment options for patients afflicted with this deadly disease.
Expert Opinion on Emerging Drugs 10/2006; 11(3):489-501. · 3.21 Impact Factor
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ABSTRACT: Despite its controversial past, thalidomide is currently under investigation for the treatment of several disease types, ranging from inflammatory conditions to cancer. The mechanism of action of thalidomide is complex and not yet fully understood, but there is some evidence to suggest that metabolism may play a role. Consequently, there has been a considerable effort to characterize the metabolism of thalidomide in recent years. Thalidomide undergoes biotransformation by non-enzymatic hydrolysis and enzyme-mediated hydroxylation to form a multitude of metabolites. Metabolite identification and reaction phenotyping studies have been performed and will be discussed in this review in addition to interspecies differences in thalidomide metabolism.
Current Drug Metabolism 09/2006; 7(6):677-85. · 5.11 Impact Factor
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Michael C Cox,
Jennifer Low,
James Lee,
Janice Walshe,
Neelima Denduluri,
Arlene Berman,
Matthew G Permenter,
William P Petros,
Douglas K Price,
William D Figg,
Alex Sparreboom,
Sandra M Swain
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ABSTRACT: The herbal supplement garlic (Allium sativum) is commonly used by cancer patients. Preclinical studies have shown that allicin, a major component of garlic, may affect cytochrome P450 3A4 (CYP3A4) activity. This study examines the influence of garlic supplementation on the pharmacokinetics of docetaxel, a CYP3A4 substrate.
Women with metastatic breast cancer were treated with docetaxel (30 mg/m(2)) given weekly for 3 of 4 weeks. Three days after the initial dose of docetaxel, patients received 600 mg of garlic twice daily for 12 consecutive days. Docetaxel pharmacokinetics were assessed during the first three administrations.
In 10 evaluable patients, the mean baseline clearance of docetaxel was 30.8 L/h/m(2) [95% confidence intervals (95% CI), 16.7-44.9]. Coadministration of garlic reduced mean clearance of docetaxel to 23.7 L/h/m(2) (95% CI, 15.5-31.8) and 20.0 L/h/m(2) (95% CI, 13.3-26.7) on days 8 and 15, respectively (P = 0.17). Additional pharmacokinetic variables of docetaxel, including peak concentration (P = 0.79), area under the curve (P = 0.36), volume of distribution (P = 0.84), and half-life (P = 0.36), were also not statistically significantly different. The mean area under the curve ratio between day 15 and day 1 was 3.74 in three individuals with the CYP3A5*1A/*1A genotype (all African American) compared with 1.02 in six individuals with the CYP3A5*3C/*3C genotype (all Caucasian).
This study indicates that garlic does not significantly affect the disposition of docetaxel. However, it cannot be excluded that garlic decreases the clearance of docetaxel in patients carrying a CYP3A5*1A allele.
Clinical Cancer Research 09/2006; 12(15):4636-40. · 7.74 Impact Factor
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ABSTRACT: With a need for effective treatment modalities in prostate cancer, angiogenesis is a likely target for the interference of tumor progression. Angiogenesis promotes the vasculature of a tumor, allowing for tumor progression and for cancer cells to metastasize and spread throughout the circulatory system. To date, there are > 20 antiangiogenic drugs undergoing preclinical and clinical investigation alone and in conjunction with other treatment options to determine the validity of antiangiogenic agents in the treatment of prostate cancer. This article reviews several aspects of antiangiogenesis and its relationship to the treatment of prostate cancer.
Clinical Genitourinary Cancer 01/2006; 4(3):197-202. · 2.61 Impact Factor
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ABSTRACT: The authors investigated whether prostate-specific antigen (PSA) velocity was associated significantly with the time to death after randomization among patients with hormone-refractory metastatic prostate carcinoma (HRMPC) who were treated with cytotoxic, cytotatic, or combination therapy.
The study cohort included 213 men with HRMPC who were treated on 3 prospective, randomized Phase II studies between February 1996 and October 2001. Cox regression analysis was used to evaluate whether there was a significant association between PSA velocity and the time to death after randomization, controlling for treatment and known prognostic factors.
Increasing PSA velocity was associated significantly with shorter survival after randomization (P = 0.005) controlling for treatment and known prognostic factors. The adjusted hazard ratio for death was 1.8 (95% confidence interval [95% CI], 1.3-2.5; P = 0.0004) for men who had a PSA velocity > 0.0 ng/mL per month compared with men who had a PSA velocity < or = 0.0 ng/mL per month. Estimates of survival 2 years after randomization for these men were 16% (95% CI, 7-25%) and 44% (95% CI, 35-53%), respectively.
PSA velocity was associated significantly with the length of survival among men with HRMPC who received cytotoxic, cytostatic, or combination therapy.
Cancer 01/2006; 106(1):63-7. · 4.77 Impact Factor
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ABSTRACT: To evaluate whether the time to return to the baseline prostate-specific antigen (PSA) level (PSA response duration) is significantly associated with the time to death after randomization for men with hormone-refractory metastatic prostate cancer.
The study (n = 213) and validation (n = 281) cohorts constituted 494 men with hormone-refractory metastatic prostate cancer treated in four prospective randomized Phase II studies between February 1996 and October 2001. Cox regression analysis was used to evaluate whether a significant association existed between the PSA response duration and the time to death after randomization, controlling for treatment and known prognostic factors.
A decreasing PSA response duration was significantly associated with a shorter survival after randomization in the study (P = 0.001) and validation (P = 0.02) cohorts, controlling for treatment and known prognostic factors, which included serum PSA, lactate dehydrogenase, alkaline phosphatase, and hemoglobin levels and the Eastern Cooperative Oncology Group performance status. The adjusted hazard ratio for death was 1.9 (95% confidence interval 1.4 to 2.6; P = 0.0002) and 2.1 (95% CI 1.2 to 3.5; P = 0.01) for men in the study and validation cohorts, respectively, whose PSA response duration was shorter than the median value of 3 months. The PSA response duration dichotomized about the median remained significantly associated with death whether patients in the validation cohort experienced at least a 50% reduction (P = 0.05) in the PSA level or not (P = 0.03).
The duration of the PSA response to treatment is significantly associated with length of survival for men with hormone-refractory metastatic prostate cancer.
Urology 10/2005; 66(3):571-6. · 2.43 Impact Factor
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ABSTRACT: Androgen deprivation therapy is a mainstay for the treatment of advanced prostate cancer. Hormonal therapy commonly consists of injection of gonadotropin hormone-releasing hormone agonists. Based on the need for improved convenience of administration, a novel formulation of leuprolide acetate (Eligard; Atrix Laboratories Inc. & Sanofi Aventis) which incorporates a mixture of selected polymers and solvents to achieve sustained drug delivery after subcutaneous injection, was developed. The US Food and Drug Administration has approved 1-, 3-, 4- and 6-month formulations of leuprolide acetate. In clinical trials, leuprolide acetate achieves sustained suppression of serum testosterone to castration levels (< or =50 ng/dl). The adverse-event profile is consistent with the effects of testosterone suppression. This novel delivery system in addition to the availability of a 6-month formulation of leuprolide acetate, offers patients the option of a convenient twice-yearly injection schedule.
Expert Review of Anti-infective Therapy 08/2005; 5(4):605-11. · 2.65 Impact Factor
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ABSTRACT: Prostate cancer is the leading cause of cancer diagnosis in men and the second leading cause of cancer-related death. Androgen ablation is effective initially, and progression of disease often occurs in many patients. Although recent reports have noted a survival benefit when patients with androgen-independent prostate cancer are treated with docetaxel, patients still have disease progression. Angiogenesis plays a pivotal role for the growth, invasion, and metastasis of prostate cancer. Therefore, antiangiogenesis is a promising new therapeutic modality. More than 20 antiangiogenic agents are now in various stages of clinical trials. We discuss current knowledge on controlling tumor angiogenesis and advances in the development of antiangiogenic agents with promising antitumor activity in prostate cancer.
Current Oncology Reports 06/2005; 7(3):215-9. · 2.55 Impact Factor
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William D Figg,
Yinong Liu,
Philip Arlen,
James Gulley,
Seth M Steinberg,
David J Liewehr, Michael C Cox,
Suoping Zhai,
Serge Cremers,
Allyson Parr,
Xiaowei Yang,
Clara C Chen,
Elizabeth Jones,
William L Dahut
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ABSTRACT: Alendronate (AL), a potent oral bisphosphonate, blocks the secretion of matrix metalloproteinase-2 and the establishment of bone metastases in animal models. Ketoconazole (KT) has demonstrated activity in androgen independent prostate cancer (AIPC). In this study we determined whether KT plus AL produced acceptable disease responses compared with KT alone. As the experimental design, 72 patients with progressive AIPC metastatic to bone were randomized to receive KT (1,200 mg daily) plus hydrocortisone (H) (30 mg daily) with or without AL (40 mg daily). Prostate specific antigen (PSA) consensus criteria and radiographic scans were used to determine the proportion of patients with a PSA decrease, time to progression and response duration. The pharmacokinetics of KT and AL were characterized and changes in circulating angiogenic factors were assessed.
At a median potential followup of 23.9 months the proportion of patients with a greater than 50% decrease in PSA was similar in the KT/H/AL and KT/H, groups (50% and 47%, respectively). The median duration of response was 8.9 and 6.3 months in the KT/H/AL and KT/H groups, respectively (p = 0.125). Median progression-free survival was not significantly prolonged in the KT/H/AL group (4.6 vs 3.8 months, p = 0.27). There was no significant difference in overall survival between the 2 treatment arms but there was a trend toward improved survival in the KT/H arm (p = 0.074). Toxicity in the 2 groups was mild and there were no clear associations between changes in circulating angiogenic factor levels and clinical outcomes in either treatment arm.
There were no statistically significant differences in response rate, progression-free survival or overall survival between KT/H alone and KT/H plus AL treatment in patients with AIPC. The addition of AL to KT/H may increase the response duration with an acceptable safety profile compared with treatment with KT/H alone. However, the addition of AL offers no survival benefit in patients with AIPC.
The Journal of Urology 04/2005; 173(3):790-6. · 3.75 Impact Factor
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ABSTRACT: Although multiple studies have addressed the prognostic importance of tumor differentiation in patients with clinically localized prostate cancer, few data are available in patients with metastatic disease. We evaluated and compared survival data in two groups of men with Whitmore stage D2 metastatic prostate cancer initially treated with hormonal therapy. A series of 76 patients with D2 metastatic disease were evaluated and treated at the National Cancer Institute (NCI) in conjunction with an additional cohort of 141 patients from the Louisiana State University School of Medicine (LSU). Pathological specimens were classified according to the Gleason score. Fifty-two (25%) of the combined NCI/LSU specimens had a Gleason score of 6 or less, 71 (34%) had a value of 7, and remaining 87 (41%) had scores between 8 and 10. The median PSA at the time of diagnosis for the NCI patients was 294.2 ng/ml. Time to treatment failure was defined as the time that a greater than 50% increase above nadir PSA was noted. In neither group was Gleason score correlated with overall survival. There was no association between the time to progression following hormone therapy and primary tumor Gleason score. The PSA concentration at the time of diagnosis was not correlated with the Gleason score for the NCI patients; however, there was an inverse correlation between pretreatment PSA level and time to progression following hormonal ablation. Gleason score does not appear to impact survival in metastatic prostate cancer. PSA as a marker of the biological behavior in metastatic disease may also be limited. These findings should be reevaluated in larger, better matched cohorts. Novel techniques such as serum proteomics, microarrays, and metastatic cell isolation methods may better predict outcome in advanced prostate cancer.
World Journal of Urology 01/2005; 22(6):425-30. · 2.41 Impact Factor
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ABSTRACT: Interest in the use of herbal products has grown dramatically in the Western world. Recent estimates suggest an overall prevalence for herbal preparation use of 13% to 63% among cancer patients. With the narrow therapeutic range associated with most anticancer drugs, there is an increasing need for understanding possible adverse drug interactions in medical oncology.
In this article, a literature overview is provided of known or suspected interactions of the 15 best-selling herbs in the United States with conventional allopathic therapies for cancer.
Herbs with the potential to significantly modulate the activity of drug-metabolizing enzymes (notably cytochrome p450 isozymes) and/or the drug transporter P-glycoprotein include garlic (Allium sativum), ginkgo (Ginkgo biloba), echinacea (Echinacea purpurea), ginseng (Panax ginseng), St John' s wort (Hypericum perforatum), and kava (Piper methysticum). All of these products participate in potential pharmacokinetic interactions with anticancer drugs.
It is suggested that health care professionals and consumers should be aware of the potential for adverse interactions with these herbs, question their patients on their use of them, especially among patients whose disease is not responding to treatments as expected, and urge patients to avoid herbs that could confound their cancer care.
Journal of Clinical Oncology 07/2004; 22(12):2489-503. · 18.37 Impact Factor
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Michelle A Rudek,
Kenneth S Bauer,
Richard M Lush,
Sherman F Stinson,
Adrian M Senderowicz,
Donna J Headlee,
Susan G Arbuck, Michael C Cox,
Anthony J Murgo,
Edward A Sausville,
William D Figg
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ABSTRACT: Flavopiridol, a novel flavone derivative, inhibits cyclin-dependent kinase-1. We initiated a Phase I trial in patients with refractory solid tumors to determine the maximum tolerated dose and characterize the adverse effect profile.
To characterize the clinical pharmacology of flavopiridol.
Serial plasma samples were collected and analyzed by HPLC using electrochemical detection. The pharmacokinetics were analyzed by noncompartmental analysis. Enterohepatic recirculation was studied by analyzing fecal samples, with an attempt to correlate cholecystokinin and post-infusional peak concentrations. The plasma protein binding was studied using equilibrium dialysis.
Seventy-six patients were treated with flavopiridol at 13 dose levels for a total of 504 cycles of treatment. The average steady-state concentration was 26.5 and 253 nM at 4 and 122.5 mg/m2, respectively. The clearance ranged from 49.9 to 2943 mL/min, with nonlinearity at doses >50 mg/m2/d. A post-infusional increase in plasma flavopiridol concentrations was noted in a subset of patients and generally occurred between 3 and 24 hours after the end of infusion. Flavopiridol was found in fecal matter, suggesting enterohepatic recirculation. There was nonsaturable plasma protein binding of flavopiridol (fu = 6%).
The dose-limiting toxicity for the Phase I trial of flavopiridol was secretory diarrhea. We failed to identify a clear relationship between dose or concentration and diarrhea. At 50 and 78 mg/m2/d, the mean steady-state plasma concentrations were 278 and 390 nM. These concentrations were well above those noted for in vitro antiproliferative activity. Nonlinear elimination was observed at doses above 50 mg/m2/d, and postinfusional peaks appear to be related to enterohepatic recirculation.
Annals of Pharmacotherapy 10/2003; 37(10):1369-74. · 2.13 Impact Factor
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ABSTRACT: Adenocarcinoma of the prostate is the most common cancer diagnosed in men in the United States, with approximately 189,000 new cases estimated to be diagnosed in 2002. It is believed that men with this disease pass through a series of clinical states. In the intramural program of the National Cancer Institute, we have designed clinical trials that have addressed each disease state. In addition to clinical endpoints, each trial also encompasses molecular or immunologic endpoints in an attempt to determine if our therapy is acting on its presumed target. In patients with localized disease, we are evaluating cancer vaccines in combination with radiation therapy as well as comparing this vaccine against second-line hormonal therapy in patients with rising serum prostate-specific antigen (PSA) but no radiographically measurable disease. We are also evaluating the ability of the antiangiogenesis agent thalidomide to prolong the rest period in patients with a biochemical recurrence (stage D0) that are receiving intermittent hormonal therapy. In patients with metastatic prostate cancer, we are evaluating the addition of the bisphosphonate alendronate when added to ketoconazole for impact on matrix metalloproteinase (MMP)-2 and MMP-9 as well as traditional clinical endpoints. In addition, we have 3 ongoing trials involving the chemotherapeutic agent docetaxel. One trial is examining the combination of thalidomide with docetaxel. The other 2 trials are exploring the PSA vaccine with docetaxel and the combination of docetaxel with ketoconazole. As we obtain information from these ongoing studies, we will be able to take this information and integrate it in the development of newer and more successful treatment regimens as well as look for novel agents that may help in the fight against this disease.
Clinical prostate cancer 01/2003; 1(3):153-62.
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ABSTRACT: More than 200,000 men will be diagnosed with prostate cancer during the year 2006. Approximately 20% to 30% of these cases may develop advanced disease, for which there currently is no cure. Although therapy for this disease has improved significantly over the past few years, with docetaxel treatment showing improved survival times in metastatic disease, there remains the need for improved treatment options. Dr. Folkman put forth the idea of angiogenesis in 1971, and, since that time, researchers have been trying to determine the best possible way to inhibit blood vessel formation. This review summarizes the use of thalidomide in androgen-independent prostate cancer and the results of trials conducted at the National Cancer Institute.
Urologic Oncology 24(3):246-9. · 3.22 Impact Factor
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ABSTRACT: Thalidomide requires cytochrome P450 (CYP)-catalyzed biotransformation for its antiangiogenic property, and CYP2C19 is responsible for 5-hydroxylation and 5'-hydroxylation of thalidomide in human. This study explored a hypothesis that patients with poor metabolizing phenotype of CYP2C19 receive little benefit from thalidomide treatment and that the poor metabolizer genotype is associated with lower ability to form the metabolites. A case-control study was conducted with 63 patients with prostate cancer who had been enrolled in a randomized phase II trial of thalidomide monotherapy (200 to 1,200 mg/day). CYP2C19 polymorphism (CYP2C19(*)2, CYP2C19(*)3, CYP2C19(*)4) was compared with clinical events (prostate-specific antigen (PSA) decline) and formations of the hydroxylated metabolites. Two patients were homozygous for the variant CYP2C19(*)2 allele (poor metabolizing phenotype). Both of these were included in the 25 patients whose PSA failed to demonstrate a decline. While 32% and 48% of the patients had quantifiable levels of 5-hydroxythalidomide and cis-5'-hydroxythalidomide, respectively, these metabolite were below quantification in both poor metabolizing patients. None had CYP2C19(*)3 or CYP2C19(*)4 alleles. Although this study had no power to detect the statistical significance of the CYP2C19 genotype, the findings were consistent with our hypothesis. The role of CYP2C19 polymorphism in thalidomide treatments remains to be elucidated.
Cancer biology & therapy 1(6):669-73. · 2.64 Impact Factor
