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CancerSpectrum Knowledge Environment 07/2012; 104(14):1106; author reply 1109-12. · 14.07 Impact Factor
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Karen A Kurdziel,
Joanna H Shih,
Andrea B Apolo,
Liza Lindenberg,
Esther Mena,
Yolanda Y McKinney,
Stephen S Adler,
Baris Turkbey, William Dahut,
James L Gulley,
Ravi A Madan,
Ola Landgren,
Peter L Choyke
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ABSTRACT: We evaluated the kinetics of (18)F-sodium fluoride (NaF) and reassessed the recommended dose, optimal uptake period, and reproducibility using a current-generation PET/CT scanner.
In this prospective study, 73 patients (31 patients with multiple myeloma or myeloma precursor disease and 42 with prostate cancer) were injected with a mean administered dose of 141 MBq of (18)F-NaF. Sixty patients underwent 3 sequential sessions of 3-dimensional PET/CT of the torso beginning approximately 15 min after (18)F-NaF injection, followed by whole-body 3-dimensional PET/CT at 2 h. The remaining 13 prostate cancer patients were imaged only at 2 and 3 h after injection. Twenty-one prostate cancer patients underwent repeated baseline studies (mean interval, 5.9 d) to evaluate reproducibility.
The measured effective dose was 0.017 mSv/MBq, with the urinary bladder, osteogenic cells, and red marrow receiving the highest doses at 0.080, 0.077, and 0.028 mGy/MBq, respectively. Visual analysis showed that uptake in both normal and abnormal bone increased with time; however, the rate of increase decreased with time. A semiautomated workflow provided objective uptake parameters, including the mean standardized uptake value of all pixels within bone with SUVs greater than 10 and the average of the mean SUV of all malignant lesions identified by the algorithm. The values of these parameters for the images beginning at approximately 15 min and approximately 35 min were significantly different (0.3% change per minute). Differences between the later imaging time points were not significant (P < 0.01). Repeated baseline studies showed high intraclass correlations (>0.9) and relatively low critical percentage change (the value above which a change can be considered real) for these parameters. The tumor-to-normal bone ratio, based on the maximum SUV of identified malignant lesions, decreased with time; however, this difference was small, estimated at approximately 0.16%/min in the first hour.
(18)F-NaF PET/CT images obtained with modest radiation exposures can result in highly reproducible imaging parameters. Although the tumor-to-normal bone ratio decreases slightly with time, the high temporal dependence during uptake periods less than 30 min may limit accurate quantitation. An uptake period of 60 ± 30 min has limited temporal dependence while maintaining a high tumor-to-normal bone ratio.
Journal of Nuclear Medicine 06/2012; 53(8):1175-84. · 6.38 Impact Factor
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Cody J Peer,
Tristan M Sissung,
Aerang Kim,
Lokesh Jain,
Sukyung Woo,
Erin R Gardner,
C Tyler Kirkland,
Sarah M Troutman,
Bevin C English,
Emily D Richardson,
Joel Federspiel,
David Venzon, William Dahut,
Elise Kohn,
Shivaani Kummar,
Robert Yarchoan,
Giuseppe Giaccone,
Brigitte Widemann,
William D Figg
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ABSTRACT: Several case reports suggest sorafenib exposure and sorafenib-induced hyperbilirubinemia may be related to a (TA)(5/6/7) repeat polymorphism in UGT1A1*28 (UGT, uridine glucuronosyl transferase). We hypothesized that sorafenib inhibits UGT1A1 and individuals carrying UGT1A1*28 and/or UGT1A9 variants experience greater sorafenib exposure and greater increase in sorafenib-induced plasma bilirubin concentration.
Inhibition of UGT1A1-mediated bilirubin glucuronidation by sorafenib was assessed in vitro. UGT1A1*28 and UGT1A9*3 genotypes were ascertained with fragment analysis or direct sequencing in 120 cancer patients receiving sorafenib on five different clinical trials. Total bilirubin measurements were collected in prostate cancer patients before receiving sorafenib (n = 41) and 19 to 30 days following treatment and were compared with UGT1A1*28 genotype.
Sorafenib exhibited mixed-mode inhibition of UGT1A1-mediated bilirubin glucuronidation (IC(50) = 18 μmol/L; K(i) = 11.7 μmol/L) in vitro. Five patients carrying UGT1A1*28/*28 (n = 4) or UGT1A9*3/*3 (n = 1) genotypes had first dose, dose-normalized areas under the sorafenib plasma concentration versus time curve (AUC) that were in the 93rd percentile, whereas three patients carrying UGT1A1*28/*28 had AUCs in the bottom quartile of all genotyped patients. The Drug Metabolizing Enzymes and Transporters genotyping platform was applied to DNA obtained from six patients, which revealed the ABCC2-24C>T genotype cosegregated with sorafenib AUC phenotype. Sorafenib exposure was related to plasma bilirubin increases in patients carrying 1 or 2 copies of UGT1A1*28 alleles (n = 12 and n = 5; R(2) = 0.38 and R(2) = 0.77; P = 0.032 and P = 0.051, respectively). UGT1A1*28 carriers showed two distinct phenotypes that could be explained by ABCC2-24C>T genotype and are more likely to experience plasma bilirubin increases following sorafenib if they had high sorafenib exposure.
This pilot study indicates that genotype status of UGT1A1, UGT1A9, and ABCC2 and serum bilirubin concentration increases reflect abnormally high AUC in patients treated with sorafenib.
Clinical Cancer Research 02/2012; 18(7):2099-107. · 7.74 Impact Factor
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Wilfred D Stein,
James L Gulley,
Jeff Schlom,
Ravi A Madan, William Dahut,
William D Figg,
Yang-Min Ning,
Phil M Arlen,
Doug Price,
Susan E Bates,
Tito Fojo
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ABSTRACT: In solid tumors such as prostate cancer, novel paradigms are needed to assess therapeutic efficacy. We utilized a method estimating tumor growth and regression rate constants from serial PSA measurements, and assessed its potential in patients with metastatic castration resistant prostate carcinoma (mCRPC).
Patients were enrolled in five phase II studies, including an experimental vaccine trial, representing the evolution of therapy in mCRPC. PSA measurements obtained before, and during, therapy were used. Data analysis using a two-phase mathematical equation yielded concomitant PSA growth and regression rate constants.
Growth rate constants (g) can be estimated while patients receive therapy and in such patients g is superior to PSA-DT in predicting OS. Incremental reductions in growth rate constants were recorded in successive trials with a 10-fold slower g in the most recent combination therapy trial (log g = 10(-3.17)) relative to single-agent thalidomide (log g = 10(-2.08)) more than a decade earlier. Growth rate constants correlated with survival, except in patients receiving vaccine-based therapy where the evidence demonstrates prolonged survival presumably due to immunity developing subsequent to vaccine administration.
Incremental reductions in tumor growth rate constants suggest increased efficacy in successive chemotherapy trials. The derived growth rate constant correlates with survival, and may be used to assess efficacy. The PSA-TRICOM vaccine appears to have provided marked benefit not apparent during vaccination, but consistent with subsequent development of a beneficial immune response. If validated as a surrogate for survival, growth rate constants would offer an important new efficacy endpoint for clinical trials.
Clinical Cancer Research 02/2011; 17(4):907-17. · 7.74 Impact Factor
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Lokesh Jain,
Tristan Sissung,
Romano Danesi,
Elise Kohn, William Dahut,
Shivaani Kummar,
David Venzon,
David Liewehr,
Bevin English,
Caitlin Baum,
Robert Yarchoan,
Giuseppe Giaccone,
Jürgen Venitz,
Douglas Price,
William Figg
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ABSTRACT: Abstract
Background
Hypertension (HT) and hand-foot skin reactions (HFSR) may be related to the activity of bevacizumab and sorafenib. We hypothesized that these toxicities would correspond to favorable outcome in these drugs, that HT and HFSR would coincide, and that VEGFR2 genotypic variation would be related to toxicity and clinical outcomes.
Methods
Toxicities (≥ grade 2 HT or HFSR), progression-free survival (PFS), and overall survival (OS) following treatment initiation were evaluated. Toxicity incidence and VEGFR2 H472Q and V297I status were compared to clinical outcomes.
Results
Individuals experiencing HT had longer PFS following bevacizumab therapy than those without this toxicity in trials utilizing bevacizumab in patients with prostate cancer (31.5 vs 14.9 months, n = 60, P = 0.0009), and bevacizumab and sorafenib in patients with solid tumors (11.9 vs. 3.7 months, n = 27, P = 0.052). HT was also linked to a > 5-fold OS benefit after sorafenib and bevacizumab cotherapy (5.7 versus 29.0 months, P = 0.0068). HFSR was a marker for prolonged PFS during sorafenib therapy (6.1 versus 3.7 months respectively, n = 113, P = 0.0003). HT was a risk factor for HFSR in patients treated with bevacizumab and/or sorafenib (OR(95%CI) = 3.2(1.5-6.8), P = 0.0024). Carriers of variant alleles at VEGFR2 H472Q experienced greater risk of developing HT (OR(95%CI) = 2.3(1.2 - 4.6), n = 170, P = 0.0154) and HFSR (OR(95%CI) = 2.7(1.3 - 5.6), n = 170, P = 0.0136).
Conclusions
This study suggests that HT and HFSR may be markers for favorable clinical outcome, HT development may be a marker for HFSR, and VEGFR2 alleles may be related to the development of toxicities during therapy with bevacizumab and/or sorafenib.
Journal of Experimental & Clinical Cancer Research. 01/2010;
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James L Gulley,
Philip M Arlen,
Ravi A Madan,
Kwong-Yok Tsang,
Mary P Pazdur,
Lisa Skarupa,
Jacquin L Jones,
Diane J Poole,
Jack P Higgins,
James W Hodge,
Vittore Cereda,
Matteo Vergati,
Seth M Steinberg,
Susan Halabi,
Elizabeth Jones,
Clara Chen,
Howard Parnes,
John J Wright, William L Dahut,
Jeffrey Schlom
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ABSTRACT: A concurrent multicenter, randomized Phase II trial employing a recombinant poxviral vaccine provided evidence of enhanced median overall survival (OS) (p = 0.0061) in patients with metastatic castrate-resistant prostate cancer (mCRPC). The study reported here employed the identical vaccine in mCRPC to investigate the influence of GM-CSF with vaccine, and the influence of immunologic and prognostic factors on median OS. Thirty-two patients were vaccinated once with recombinant vaccinia containing the transgenes for prostate-specific antigen (PSA) and three costimulatory molecules. Patients received boosters with recombinant fowlpox containing the same four transgenes. Twelve of 32 patients showed declines in serum PSA post-vaccination and 2/12 showed decreases in index lesions. Median OS was 26.6 months (predicted median OS by the Halabi nomogram was 17.4 months). Patients with greater PSA-specific T-cell responses showed a trend (p = 0.055) toward enhanced survival. There was no difference in T-cell responses or survival in cohorts of patients receiving GM-CSF versus no GM-CSF. Patients with a Halabi predicted survival of <18 months (median predicted 12.3 months) had an actual median OS of 14.6 months, while those with a Halabi predicted survival of > or =18 months (median predicted survival 20.9 months) will meet or exceed 37.3 months, with 12/15 patients living longer than predicted (p = 0.035). Treg suppressive function was shown to decrease following vaccine in patients surviving longer than predicted, and increase in patients surviving less than predicted. This hypothesis-generating study provides evidence that patients with more indolent mCRPC (Halabi predicted survival > or =18 months) may best benefit from vaccine therapy.
Cancer Immunology and Immunotherapy 11/2009; 59(5):663-74. · 3.70 Impact Factor
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ABSTRACT: Taxane resistance is a common clinical problem in the treatment of many metastatic malignancies. Observational clues or evidence of overcoming such resistance is important for developing treatments that can extend taxane activity. We report a case of the reversal of docetaxel resistance with the addition of antiangiogenic agents bevacizumab and thalidomide to docetaxel and prednisone in a patient with metastatic castration-resistant prostate cancer after PSAWG progression on docetaxel and prednisone. The patient then responded for an additional 7 months. The addition of bevacizumab and thalidomide after progression on docetaxel/prednisone might reverse docetaxel resistance. These or other antiangiogenic agents for overcoming clinical taxane resistance are candidates for further study.
Clinical Genitourinary Cancer 09/2009; 7(2):E37-8. · 2.61 Impact Factor
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Andrea L Russo,
Kimberly Jedlicka,
Meredith Wernick,
Debbie McNally,
Melissa Kirk,
Mary Sproull,
Sharon Smith,
Uma Shankavaram,
Aradhana Kaushal,
William D Figg, William Dahut,
Deborah Citrin,
Donald P Bottaro,
Paul S Albert,
Philip J Tofilon,
Kevin Camphausen
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ABSTRACT: Metastatic prostate cancer is a major cause of death of men in the United States. Expression of met, a receptor tyrosine kinase, has been associated with progression of prostate cancer.
To investigate met as a biomarker of disease progression, urinary met was evaluated via ELISA in men with localized (n = 75) and metastatic (n = 81) prostate cancer. Boxplot analysis was used to compare the distribution of met values between each group. We estimated a receiver operating characteristic curve and the associated area under the curve to summarize the diagnostic accuracy of met for distinguishing between localized and metastatic disease. Protein-protein interaction networking via yeast two-hybrid technology supplemented by Ingenuity Pathway Analysis and Human Interactome was used to elucidate proteins and pathways related to met that may contribute to progression of disease.
Met distribution was significantly different between the metastatic group and the group with localized prostate cancer and people with no evidence of cancer (P < 0.0001). The area under the curve for localized and metastatic disease was 0.90, with a 95% confidence interval of 0.84 to 0.95. Yeast two-hybrid technology, Ingenuity Pathway Analysis, and Human Interactome identified 89 proteins that interact with met, of which 40 have previously been associated with metastatic prostate cancer.
Urinary met may provide a noninvasive biomarker indicative of metastatic prostate cancer and may be a central regulator of multiple pathways involved in prostate cancer progression.
Clinical Cancer Research 06/2009; 15(13):4292-8. · 7.74 Impact Factor
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ABSTRACT: The slow progress in developing new cancer therapies can be attributed in part to the long time spent in clinical development. To hasten development, new paradigms especially applicable to patients with metastatic disease are needed.
We present a new method to predict survival using tumor measurement data gathered while a patient with cancer is receiving therapy in a clinical trial. We developed a two-phase equation to estimate the concomitant rates of tumor regression (regression rate constant d) and tumor growth (growth rate constant g).
We evaluated the model against serial levels of prostate-specific antigen (PSA) in 112 patients undergoing treatment for prostate cancer. Survival was strongly correlated with the log of the growth rate constant, log(g) (Pearson r = -0.72) but not with the log of the regression rate constants, log(d) (r = -0.218). Values of log(g) exhibited a bimodal distribution. Patients with log(g) values above the median had a mortality hazard of 5.14 (95% confidence interval, 3.10-8.52) when compared with those with log(g) values below the median. Mathematically, the minimum PSA value (nadir) and the time to this minimum are determined by the kinetic parameters d and g, and can be viewed as surrogates.
This mathematical model has applications to many tumor types and may aid in evaluating patient outcomes. Modeling tumor progression using data gathered while patients are on study, may help evaluate the ability of therapies to prolong survival and assist in drug development.
The Oncologist 11/2008; 13(10):1046-54. · 3.91 Impact Factor
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ABSTRACT: Polymorphisms that are associated with ABCB1 expression and function may be linked to treatment efficacy and the development of neutropenia and neurotoxicity in patients with androgen-independent prostate cancer receiving docetaxel.
Patients with androgen-independent prostate cancer treated with docetaxel alone (n = 23) or docetaxel and thalidomide (n = 50) were genotyped for the ABCB1 1236C>T, 2677 G>T/A, and 3435 C>T alleles by direct sequencing, and diplotypes were constructed using an EM algorithm. The data were then compared with duration to onset of peripheral neuropathy, neutropenia grade, and survival after docetaxel.
For patients receiving docetaxel alone, individuals carrying a diplotype consisting of the 1236C-2677G-3435C linked alleles had improved overall survival after treatment (P = 0.0017). Additionally, patients treated with docetaxel and thalidomide carrying a diplotype consisting of the 2677T-3435T haplotype had a shorter median survival (P = 0.045). After adjusting for a particular set of polymorphisms and diplotype groupings, a hazard ratio of 10.87 was found for patients carrying the 2677GG genotype versus patients carrying other genotypes (P = 0.0048) in the docetaxel and thalidomide cohort. Among both treatment arms together, individuals carrying the 2677GG genotype also had a significantly longer time to neuropathy (P = 0.035). Finally, there was a strong trend toward patients carrying the 2677TT-3435TT diplotype having higher grades of neutropenia (P = 0.053).
The data suggest that docetaxel-induced neuropathy, neutropenia grade, and overall survival could be linked to ABCB1 allelic variants with ensuing negative implications for docetaxel treatment in patients carrying ABCB1 variant genotypes.
Clinical Cancer Research 07/2008; 14(14):4543-9. · 7.74 Impact Factor
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Acta oncologica (Stockholm, Sweden) 04/2008; 47(8):1600-1. · 2.27 Impact Factor
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ABSTRACT: A simple, rapid liquid chromatography/tandem mass spectrometric (LC-MS/MS) assay was developed and validated for the quantification of both unbound and total paclitaxel in plasma following treatment with Abraxane (ABI-007) or Taxol. Accurate and reproducible analysis of ABI-007, an albumin nanoparticle formulation of paclitaxel could not be achieved using previously published methodology designed for Taxol. The final validated method involved protein precipitation followed by vacuum filtration, in a 96-well format for rapid processing. The 4min run employed gradient elution on a Waters SymmetryShield C8 (2.1mmx50mm, 3.5microm) column, followed by tandem mass spectrometric detection, in electrospray positive mode. Calibrator samples were prepared daily with paclitaxel and analyzed with both ABI-007 and paclitaxel quality control samples. To measure unbound drug, sample preparation was preceded by ultrafiltration. The assay was linear over the range of 10-2500ng/mL, with dilution providing measurement up to 50,000ng/mL. Within-run and between-run precision for all QC samples was less than 5.0% and 10.4%, respectively. Accuracy was high, with deviation of less than 6.1% for all QCs. Measurement of unbound paclitaxel was precise (BRP and WRP <10%).
Journal of Chromatography B 02/2008; 862(1-2):213-8. · 2.89 Impact Factor
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ABSTRACT: A rapid and sensitive liquid chromatography/tandem mass spectrometric (LC/MS/MS) assay was developed for the quantitative determination of sorafenib in human plasma. Sample pretreatment involved simple protein precipitation by the addition of 0.5 mL acetonitrile, containing internal standard ([2H3, 15N] sorafenib), to 50 microL of plasma sample volume. Separation was achieved on a Waters SymmetryShield RP8 (2.1 mm x 50 mm, 3.5 microm) column at room temperature using an isocratic elution method with acetonitrile/0.1% formic acid in water: 65/35 (v/v) at a flow rate of 0.25 mL/min. Detection was performed using electrospray ionization in positive ion multiple reaction monitoring (MRM) mode by monitoring the ion transitions from m/z 464.9 --> 252.0 (sorafenib) and m/z 469.0 --> 259.0 (internal standard). Calibration curves were linear in the concentration range of 5-2000 ng/mL. The accuracy and precision values, calculated from three different sets of quality control samples analyzed in quintuplicate on six different days, ranged from 92.86% to 99.88% and from 1.19% to 4.53%, respectively.
Journal of Pharmaceutical and Biomedical Analysis 01/2008; 46(2):362-7. · 2.97 Impact Factor
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ABSTRACT: Despite its controversial past, the establishment of thalidomide as an anti-inflammatory, immunomodulatory, and antiangiogenic
agent bolstered intense research into its mechanism of action and therapeutic range. The precise pharmacologic mechanism through
which thalidomide exerts its activity is complex and not fully understood. The enhancement of thalidomide’s immunomodulatory
effects while minimizing the adverse reactions brought about a class of novel analogues termed the Immunomodulatory drugs
(IMiDs). This chapter reviews and highlights some of the clinical activities and development of thalidomide and its IMiDs
derivatives in the treatment of hematological cancers and various solid tumors.
12/2007: pages 387-394;
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Philip M Arlen,
Lisa Skarupa,
Mary Pazdur,
Mahesh Seetharam,
Kwong Y Tsang,
Douglas W Grosenbach,
Jarett Feldman,
Diane J Poole,
Mary Litzinger,
Seth M Steinberg,
Elizabeth Jones,
Clara Chen,
Jennifer Marte,
Howard Parnes,
John Wright, William Dahut,
Jeffrey Schlom,
James L Gulley
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ABSTRACT: The primary objective of this phase I study was to evaluate the clinical safety of a vaccine using recombinant vaccinia virus (prime) and recombinant fowlpox virus (boost) in combination with granulocyte-macrophage colony-stimulating factor in patients with prostate cancer. The vaccines contained transgenes for prostate specific antigen, a triad of co-stimulatory molecules and a tumor antigen whose amino acid sequence had been modified to enhance its immunogenicity. Secondary end points were immunological and clinical responses, changes in prostate specific antigen velocity, and the kinetics of vaccinia virus clearance from the vaccination site, serum, peripheral blood mononuclear cells, urine and saliva.
The 15 patients enrolled in this study had metastatic prostate cancer. Patients were given recombinant fowlpox-prostate specific antigen/triad of co-stimulatory molecules alone or recombinant vaccinia-prostate specific antigen/triad of co-stimulatory molecules followed by recombinant fowlpox-prostate specific antigen/triad of co-stimulatory molecules on a prime and boost schedule with or without recombinant-granulocyte-macrophage colony-stimulating factor protein or recombinant fowlpox-granulocyte-macrophage colony-stimulating factor vector. Prostate specific antigen specific immune responses were measured using an enzyme-linked immunosorbent spot assay for interferon-gamma production. Polymerase chain reaction for vaccinia DNA and a plaque assay for live virus were also used.
Some grade 2 toxicity was seen in patients who received a higher dose of recombinant fowlpox-granulocyte-macrophage colony-stimulating factor but no toxicity exceeded grade 2. Viable vaccinia was detected after vaccination at the site swab of 1 of 4 patients analyzed. Prostate specific antigen specific immune responses were seen in 4 of 6 patients who were HLA-A2+ and decreases in serum prostate specific antigen velocity were observed in 9 of 15.
Based on the safety and preliminary immunogenicity results of this trial we recommend initiating a randomized, phase II study of prostate specific antigen/triad of co-stimulatory molecules vaccines in patients with less advanced prostate cancer.
The Journal of Urology 11/2007; 178(4 Pt 1):1515-20. · 3.75 Impact Factor
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ABSTRACT: Angiogenesis is an important hallmark of RCC, reflected in the natural history, Histology, genetics and now therapeutics of this disease. Clearly, the pro-angiogenic growth factor VEGF is a functional drug target in RCC and many strategies to inhibit this biology have shown clinical benefit. Multi-targeted TKI that inhibit VEGFRs have been approved by the FDA as standard treatment for advanced RCC. Pharmacodynamyc studies suggest that these agents and others also have anti-angiogenic effects. Currently, studies combining VEGFR-targeted strategies with other anti-angiogenic agents, including anti-VEGF antibodies, IFN or mTOR inhibitors, are underway. However, to what extent the clinical benefit of anti-angiogenic strategies in RCC can be built upon is unknown.
BJU International 06/2007; 99(5 Pt B):1296-300. · 2.84 Impact Factor
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William D Figg,
Haiqing Li,
Tristan Sissung,
Avi Retter,
Shenhong Wu,
James L Gulley,
Phil Arlen,
John J Wright,
Howard Parnes,
Kathy Fedenko,
Lea Latham,
Seth M Steinberg,
Elizabeth Jones,
Clara Chen, William Dahut
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ABSTRACT: To evaluate the combination of docetaxel plus estramustine (which prolongs survival in patients with androgen-independent prostate cancer, AIPC), and thalidomide (that also adds to docetaxel activity), both pre-clinically and clinically in AIPC.
In the pre-clinical evaluation we injected PC3 cells subcutaneously into severely combined immunodeficient mice and started treatment after the tumour volume reached 50 mm3. We also evaluated the combination using luciferase-labelled PC3M-luc-C6 cells in nude mice. We enrolled 20 patients with metastatic progressive AIPC into a phase II clinical trial to evaluate this combination. Docetaxel (30 mg/m2) was administered every week, for 3 of 4 weeks. The dose of thalidomide was 200 mg/day and estramustine was given three times a day at 1, 2, 3, 8, 9, 10, 15, 16 and 17 days.
In the mice, thalidomide with docetaxel plus estramustine reduced tumour volume by 88% at 17 days vs the control treatment (p=0.001). The combination of docetaxel, estramustine and thalidomide nearly eradicated the signal from the luciferase-expressing PC3M cells in the metastasis model. Clinically, the progression-free time was 7.2 months with this combination; 18 of 20 patients had a decline of half or more in prostate-specific antigen level and two of 10 patients with soft-tissue lesions had a partial response on computed tomography. There were 24 grade 3 and two grade 4 complications associated with this combination. There was a statistically significant association between overall survival and the CYP1B1*3 genotype (P=0.013).
Docetaxel-based chemotherapy is now regarded as a standard regimen for metastatic AIPC. The combination of estramustine, docetaxel and thalidomide is an advantageous treatment in pre-clinical models of prostate cancer and is a safe, tolerable and active regimen in patients with AIPC.
BJU International 06/2007; 99(5):1047-55. · 2.84 Impact Factor
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Journal of Oncology Practice 07/2006; 2(4):202.
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Philip M Arlen,
James L Gulley,
Catherine Parker,
Lisa Skarupa,
Mary Pazdur,
Dennis Panicali,
Patricia Beetham,
Kwong Y Tsang,
Douglas W Grosenbach,
Jarett Feldman,
Seth M Steinberg,
Elizabeth Jones,
Clara Chen,
Jennifer Marte,
Jeffrey Schlom, William Dahut
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ABSTRACT: Docetaxel has activity against androgen-independent prostate cancer and preclinical studies have shown that taxane-based chemotherapy can enhance antitumor response of vaccines. The primary objective of this study was to determine if concurrent docetaxel (with dexamethasone) had any effect on generating an immune response to the vaccine. Secondary end points were whether vaccine could be given safely with docetaxel and the clinical outcome of the treatment regimen.
The vaccination regimen was composed of (a) recombinant vaccinia virus (rV) that expresses the prostate-specific antigen gene (rV-PSA) admixed with (b) rV that expresses the B7.1 costimulatory gene (rV-B7.1), and (c) sequential booster vaccinations with recombinant fowlpox virus (rF-) containing the PSA gene (rF-PSA). Patients received granulocyte macrophage colony-stimulating factor with each vaccination. Twenty-eight patients with metastatic androgen-independent prostate cancer were randomized to receive either vaccine and weekly docetaxel or vaccine alone. Patients on the vaccine alone arm were allowed to cross over to receive docetaxel alone at time of disease progression. The ELISPOT assay was used to monitor immune responses for PSA-specific T cells.
The median increase in these T-cell precursors to PSA was 3.33-fold in both arms following 3 months of therapy. In addition, immune responses to other prostate cancer-associated tumor antigens were also detected postvaccination. Eleven patients who progressed on vaccine alone crossed over to receive docetaxel at time of progression. Median progression-free survival on docetaxel was 6.1 months after receiving vaccine compared with 3.7 months with the same regimen in a historical control.
This is the first clinical trial to show that docetaxel can be administered safely with immunotherapy without inhibiting vaccine specific T-cell responses. Furthermore, patients previously vaccinated with an anticancer vaccine may respond longer to docetaxel compared with a historical control of patients receiving docetaxel alone. Larger prospective clinical studies will be required to validate these findings.
Clinical Cancer Research 03/2006; 12(4):1260-9. · 7.74 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
