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Journal of Clinical Oncology 03/2013; 31(7):972-3. · 18.37 Impact Factor
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ABSTRACT: Radium-223 chloride ((223)Ra; Alpharadin) is an alpha-emitting radioisotope that targets areas of osteoblastic metastasis and is excreted by the small intestine. When compared with beta-emitters (eg, strontium-89, samarium-153), (223)Ra delivers a high quantity of energy per track length with short tissue penetration.
This review describes the mechanism, radiobiology, and preclinical development of (223)Ra and discusses the clinical data currently available regarding its safety and efficacy profile.
Data from clinical trials including abstracts were collected and reviewed using the PubMed Database, as well as the American Society of Clinical Oncology abstract database.
Current bone-targeted therapies fall into two main categories: antiresorptive agents (eg, zoledronic acid, denosumab), which have been shown to delay skeletal-related events, and radiopharmaceuticals (eg, samarium-153), which may have a role in pain palliation. Historically, neither antiresorptive agents nor radiopharmaceuticals have shown definitive evidence of improved overall survival or other antitumor effects in metastatic castrate-resistant prostate cancer (mCRPC). Radiopharmaceuticals are limited by myelosuppresion, thrombocytopenia, and renal excretion. In a recently reported randomized Phase III trial in men with symptomatic bone-metastatic CRPC who had received or were ineligible for docetaxel chemotherapy, (223)Ra treatment resulted in improved overall survival and delayed skeletal-related events. Toxicity consisted of minor gastrointestinal side effects and mild neutropenia and thrombocytopenia that were rarely severe. Pending regulatory approval, (223)Ra may represent a unique and distinct option for an important subgroup of patients with mCRPC; future trials should address its use in combination or in sequence with existing and novel agents.
Cancer Management and Research 01/2013; 5:1-14.
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ABSTRACT: CONTEXT: The purpose of this report is to review immunotherapies under investigation for patients with renal cell carcinoma (RCC), the most common form of kidney cancer, for which the incidence and mortality rate continue to increase. OBJECTIVE: To summarize and evaluate current data on immunotherapies for RCC and discuss issues to be resolved before integration into the RCC treatment paradigm. EVIDENCE ACQUISITION: A search of Medline, clinicaltrials.gov, and congress abstracts/treatment guidelines was performed in May 2012 using the following terms (and variations): metastatic renal cell carcinoma, practice guidelines, response/resistance to current treatments, immunotherapy, novel immunotherapeutic strategies, T-cell modulation, immune priming, innate immunity, and combination therapy. EVIDENCE SYNTHESIS: Prior to the advent of novel agents targeting the vascular endothelial growth factor and mechanistic target of rapamycin pathways, interleukin-2 (IL-2) and interferon-α were the mainstays of RCC treatment. IL-2 remains one of the only treatments capable of curing advanced RCC, albeit in few patients. Despite recent advances, unmet need still exists for patients in the adjuvant setting, those with poor prognostic factors, and those who have progressed on prior targeted therapies. Improved understanding of host-tumor immune interactions has led to development of novel immunotherapeutic agents, including antibodies against immune checkpoint proteins (eg, programmed death-1 and cytotoxic T-lymphocyte antigen-4), and various vaccines. Because many of these compounds are in development, clinical experience with them is limited, although some have demonstrated activity in preliminary studies. CONCLUSIONS: It is not yet clear where these new immunotherapies will fit into RCC treatment paradigms, but they may provide new options for patients whose current choices are limited. Furthermore, predictive biomarkers are needed to identify patients who will derive the greatest benefit from immunotherapy.
European urology 10/2012; · 7.67 Impact Factor
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ABSTRACT: PURPOSE: The activity of systemic agents after progression when using vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibition (TKI) and mammalian target of rapamycin (mTOR) inhibition in patients with metastatic renal cell carcinoma (mRCC) is poorly characterized. The anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab has a broad US Food and Drug Administration label and National Comprehensive Cancer Network guideline level 2b recommendation in this setting; we thus explored our institutional experience in this population. METHODS: We conducted a retrospective analysis of patients with mRCC who were treated with bevacizumab in the second- and/or third-line settings; the primary endpoint was progression-free survival (PFS). Overall response rates (ORR), overall survival (OS), and toxicity were analyzed. RESULTS: Twenty-one patients were treated with bevacizumab: the median age was 63 years old; 80% were white and 14% were black; 80% had clear cell histology. All the patients had prior VEGFR TKI therapy; 43% had prior mTOR inhibitor; the median number of prior therapies was 3. The median PFS was 4.4 months (95% CI, 2.8-9.6 months), and the median OS was 19.4 months (95% CI, 9.9-NR months). ORR was 9.5%; 52% of subjects had stable disease as best response, and 52% had disease progression. For subjects treated with prior VEGF and mTOR inhibitors, median PFS and OS were 4.4 and 13.2 months, respectively. Grade 3 to 4 toxicities included fatigue (29%), dehydration (24%), failure to thrive (10%), constipation (10%), and muscle weakness (10%). CONCLUSIONS: Single-agent bevacizumab has acceptable toxicity and moderate disease-stabilizing activity in selected patients with mRCC who have failed prior VEGFR TKI and mTOR inhibitors. These data support clinical benefit to continued ongoing VEGF inhibition. Further prospective studies of bevacizumab alone or with alternative targeted agents in previously treated populations with mRCC are warranted.
Clinical Genitourinary Cancer 10/2012; · 2.61 Impact Factor
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ABSTRACT: PURPOSE Lactate dehydrogenase (LDH) is an enzyme involved in anaerobic glycolysis and regulated by the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR)-containing complex 1 (PI3K/Akt/TORC1) pathway as well as tumor hypoxia/necrosis. High serum LDH levels are associated with poor prognosis in patients with cancer, including renal cell carcinoma (RCC). We tested whether serum LDH is prognostic and has predictive value in patients with metastatic RCC receiving an mTOR inhibitor. PATIENTS AND METHODS We evaluated pretreatment and post-treatment serum LDH in 404 poor-risk patients with RCC treated with the TORC1 inhibitor temsirolimus or interferon alfa in an international phase III randomized trial. The proportional hazards model was used to test for the prognostic and predictive association of LDH in predicting overall survival (OS). Results Mean baseline serum normalized LDH was 1.23 times the upper limit of normal (ULN; range, 0.05 to 28.5 × ULN). The multivariable hazard ratio for death was 2.81 (95% CI, 2.01 to 3.94; P < .001) for patients with LDH more than 1 × ULN versus patients with LDH ≤ 1 × ULN. The LDH-treatment interaction term was statistically significant for OS (P = .016). Among 140 patients with LDH above the ULN, OS was significantly improved with temsirolimus (6.9 v 4.2 months; P < .002). Among 264 patients with normal LDH, OS was not significantly improved with temsirolimus as compared with interferon therapy (11.7 v 10.4 months; P = .514). CONCLUSION Serum LDH is a prognostic and a predictive biomarker for the survival benefit conferred by TORC1 inhibition in poor-risk RCC. Further investigation of the predictive role of LDH as a measure of benefit with PI3K/TORC1 pathway inhibition in other RCC risk groups and other tumor types is warranted.
Journal of Clinical Oncology 08/2012; 30(27):3402-7. · 18.37 Impact Factor
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Oncology (Williston Park, N.Y.) 01/2012; 26(1):84, 87-8. · 1.03 Impact Factor
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Suzanne Biehn Stewart,
Lionel L Bañez,
Cary N Robertson,
Stephen J Freedland,
Thomas J Polascik,
Donghua Xie,
Bridget F Koontz,
Zeljko Vujaskovic,
W Robert Lee,
Andrew J Armstrong,
Phillip G Febbo, Daniel J George,
Judd W Moul
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ABSTRACT: The multidisciplinary approach is becoming increasingly encouraged but little is known about the multidisciplinary experience compared to routine care. For patients with prostate cancer the goal is to provide evaluations by urologists, medical and radiation oncologists at a single visit. Although additional resources are required, this strategy may enhance the overall health care experience. We compared utilization determinants between a multidisciplinary and a urology prostate cancer clinic at Duke University Medical Center and identified factors associated with pursuing treatment at the university medical center for multidisciplinary clinic patients.
We retrospectively analyzed data on patients referred for primary prostate cancer treatment evaluation at Duke University Medical Center from 2005 to 2009. Comparisons between 701 multidisciplinary clinic and 1,318 urology prostate cancer clinic patients were examined with the rank sum and chi-square tests. Predictive factors for pursuing treatment at the university medical center were assessed using multivariate adjusted logistic regression.
Compared to patients at the urology prostate cancer clinic those at the multidisciplinary clinic were more likely to be younger and white, have a higher income and travel a longer distance for evaluation. Of multidisciplinary clinic patients 58% pursued primary treatment at the university medical center. They were more likely to be younger, black and physician referred, have a lower income and reside closer to the medical center. Factors predictive of pursuing treatment at the medical center included high risk disease and physician referral. Factors predictive of not receiving care at the university medical center were income greater than $40,000 and a distance traveled of greater than 100 miles.
A different patient demographic is using the multidisciplinary approach. However, when treatment is pursued at the institution providing multidisciplinary services, the patient demographic resembles that of the treating institution.
The Journal of urology 11/2011; 187(1):103-8. · 4.02 Impact Factor
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ABSTRACT: Sunitinib treatment benefits patients with metastatic renal cell carcinoma (mRCC), but response duration can vary widely and resistance is not predicted by standard measures. [¹⁸F]fluoro-2-deoxy-2-D-glucose positron emission tomography (FDG-PET) uptake is variable in mRCC, but changes in FDG-PET uptake may be useful in monitoring disease progression. Further work is needed to personalize treatment for patients with mRCC.
Clinical Cancer Research 09/2011; 17(18):5841-3. · 7.74 Impact Factor
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ABSTRACT: Historically, the treatment of metastatic castration-resistant prostate cancer (CRPC) has been limited to chemotherapeutic regimens that did not improve patient survival. In 2004, clinical studies began to demonstrate significant improvements in patient outcomes, including overall survival, with docetaxel versus mitoxantrone chemotherapy. Since these pivotal trials, the combination of docetaxel plus prednisone has become a standard of care for patients with metastatic CRPC. However, the limited survival benefit achieved with this regimen prompted several investigations into the development of alternative therapeutic options. Recent advances have now led to an unprecedented number of new drug approvals within the past year, providing many new treatment options for patients with metastatic CRPC. Sipuleucel-T, considered a new paradigm in cancer treatment, is the first such immunotherapeutic agent approved by the US Food and Drug Administration. Other successes include abiraterone acetate, the first androgen biosynthesis inhibitor, and cabazitaxel, a novel microtubule inhibitor, both of which have demonstrated improved survival following docetaxel failure. The bone-targeting agent denosumab, also recently approved in this setting, offers these patients significant improvement in the prevention of skeletal-related events. The data supporting the approval of each of these agents are described in this monograph, as are current approaches in the treatment of metastatic CRPC and ongoing clinical trials of novel treatments and strategies. The experts also discuss several of the issues regarding the introduction of these novel agents into clinical practice for metastatic CRPC patients.
Clinical advances in hematology & oncology: H&O 06/2011; 9(6):1-11; discussion 11-5.
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Young E Whang,
Andrew J Armstrong,
W Kimryn Rathmell,
Paul A Godley,
William Y Kim,
Raj S Pruthi,
Eric M Wallen,
Jeffrey M Crane,
Dominic T Moore,
Gayle Grigson,
Karla Morris,
Catharine P Watkins, Daniel J George
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ABSTRACT: OBJECTIVES:: Epidermal growth factor receptor (EGFR) and HER-2 tyrosine kinases may be involved in activation of androgen receptor and progression of prostate cancer. They represent potential therapeutic targets in prostate cancer. Lapatinib is an oral inhibitor of EGFR and HER-2. The objective of this study is to assess the preliminary clinical efficacy of lapatinib in the therapy of castration-resistant prostate cancer. METHODS:: In this multicenter, open-label trial, patients with rising PSA on androgen deprivation therapy and not having received chemotherapy were eligible. They were treated with lapatinib at a dose of 1,500 mg once daily. The primary end point was a >50% confirmed PSA decline from baseline; safety, tolerability, and time to PSA progression were secondary outcomes. RESULTS:: Twenty-nine patients enrolled in the study had a median age of 73 years and a baseline PSA of 21.6 ng/ml. Seven patients had no radiologic evidence of metastatic disease, while the remaining patients had bone or measurable disease or both. Treatment was well tolerated with only grade 3 treatment-related toxicities being diarrhea (14%) and rash (3%). One of 21 evaluable patients had >50% reduction in PSA, while another patient had 47% reduction in PSA with an ongoing duration of response of 45+ months. The median time to PSA progression was 29 days. CONCLUSIONS:: Lapatinib showed single agent activity in a small subset of unselected patients with castration-resistant prostate cancer, as measured by PSA. Future trials should explore a trial design with time-to-event end points and predictive biomarkers and a combination with other agents.
Urologic Oncology 03/2011; · 3.22 Impact Factor
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ABSTRACT: Most prostate cancer-related deaths occur in patients with castration-resistant prostate cancer (CRPC). Until recently, only therapy with docetaxel and prednisone has been shown to prolong survival in men with metastatic CRPC. With the United States Food and Drug Administration (US FDA) approvals of sipuleucel-T, cabazitaxel, and abiraterone acetate, all based on improvement in overall survival, the landscape for management of men with metastatic CRPC has dramatically changed. In this review we will discuss the pivotal clinical trial data leading to these approvals, with particular focus on the unique indication for sipuleucel-T and the implications for optimal management and sequencing of treatment in this patient population.
Clinical Medicine Insights: Oncology 01/2011; 5:325-32.
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Journal of Clinical Oncology 10/2010; 28(33):e692-3; author reply e694. · 18.37 Impact Factor
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European urology 10/2010; 59(1):16-7. · 7.67 Impact Factor
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Andrew J Armstrong,
George J Netto,
Michelle A Rudek,
Susan Halabi,
David P Wood,
Patricia A Creel,
Kelly Mundy,
S Lindsay Davis,
Ting Wang,
Roula Albadine,
Luciana Schultz,
Alan W Partin,
Antonio Jimeno,
Helen Fedor,
Phillip G Febbo, Daniel J George,
Robin Gurganus,
Angelo M De Marzo,
Michael A Carducci
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ABSTRACT: Given discrepancies between preclinical and clinical observations of mammalian target of rapamycin (mTOR) inhibition in prostate cancer, we sought to determine the pharmacodynamic effects of the mTOR/TORC1 inhibitor rapamycin in men with intermediate- to high-risk prostate cancer undergoing radical prostatectomy.
Rapamycin was given at 3 or 6 mg orally for 14 days before radical prostatectomy in men with multifocal Gleason sum > or =7 prostate cancer; 10 untreated control subjects were included. The primary outcome was inhibition of phosphorylation of ribosomal S6 in posttreatment radical prostatectomy versus pretreatment biopsy tumor tissue, evaluated using a Simon two-stage design for pharmacodynamic efficacy.
Thirty-two subjects were accrued: 20 at 3 mg, 2 at 6 mg, and 10 controls. No dose-limiting toxicities were observed at 3 mg; however, two of two men enrolled at 6 mg experienced dose-limiting toxicities including thrombocytopenia and fever with grade 3 stomatitis. Adverse events observed at 3 mg included stomatitis, rash, ileus, and neutropenia. Pharmacodynamic studies showed tumor S6 phosphorylation inhibition in 50% of 10 evaluable rapamycin-treated men with sufficient paired tissue [median 58% inhibition (P = 0.049) versus 2% inhibition in controls (P = 0.75)] with no significant effect on AKT activity. We observed no change in Ki-67 or caspase-3 cleavage but noted a reduction in cytoplasmic p27 staining with increased nuclear localization with rapamycin treatment. Prostate tissue rapamycin concentrations were 3- to 4-fold higher than blood.
At 3 mg daily, rapamycin successfully and safely inhibited prostate cancer S6 phosphorylation and achieved relatively high prostate tissue concentrations. No effect on AKT phosphorylation, tumor proliferation, or apoptosis was observed.
Clinical Cancer Research 06/2010; 16(11):3057-66. · 7.74 Impact Factor
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ABSTRACT: The availability of molecularly targeted agents has improved outcomes for patients with renal cell carcinoma (RCC), a disease long considered refractory to systemic therapy. The hypervascularity observed in RCC tumors, which is driven by the inactivation of the vonHippel-Lindau gene, provided a rationale for targeting angiogenesis, in particular vascular endothelial growth factor (VEGF). Bevacizumab, a potent and specific anti-VEGF monoclonal antibody, has demonstrated significant clinical benefits when used in combination with interferon-alfa (IFN-alpha) for the treatment of metastatic RCC in two randomized phase III trials. The use of bevacizumab with IFN-alpha received approval in Europe for the first-line treatment of patients with advanced or metastatic RCC, and more recently this combination was approved for use in patients with mRCC in the United States. Bevacizumab with IFN-alpha has also been recommended by the National Comprehensive Cancer Network for first-line therapy of relapsed or metastatic unresectable RCC with predominantly clear cell histology. Two phase II studies suggest that bevacizumab has single-agent activity, which is characterized by encouraging progression-free survival rates and evidence of tumor regressions in patients with advanced or metastatic RCC. Here we review these trials along with recent and ongoing studies that explore the combination of bevacizumab with other targeted agents, its optimal sequencing with tyrosine kinase inhibitors, and its combination with low-dose IFN-alpha. Collectively, these studies allow the role of bevacizumab-based therapy to be defined in the context of a new and evolving algorithm for the treatment of patients with advanced RCC.
Cancer treatment reviews 05/2010; 36(3):216-23. · 5.30 Impact Factor
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ABSTRACT: There are no known predictive factors of response in men receiving chemotherapy for metastatic castration-resistant prostate cancer (mCRPC). We investigated pre-treatment factors that predicted a 30% PSA decline (30% PSAD) within 3 months of starting chemotherapy, and assessed performance of a risk group classification in predicting PSA declines and overall survival (OS) in men with mCRPC.
In TAX327, 1006 men with mCRPC were randomized to receive docetaxel (D) in two schedules, or mitoxantrone (M), each with prednisone: 989 provided data on PSA decline within 3 months. Predictive factors for a 30% PSAD were identified using multivariable regression in D-treated men (n=656) and validated in M-treated men (n=333).
Four independent risk factors predicted 30% PSAD: pain, visceral metastases, anaemia and bone scan progression. Risk groups (good: 0-1 factors, intermediate: 2 factors and poor: 3-4 factors) were developed with median OS of 25.7, 18.7 and 12.8 months (p<0.0001); 30% PSAD in 78%, 66% and 58% of men (p<0.001); and measurable disease response in 19%, 9% and 5% of men (p=0.018), respectively. In the validation cohort, similar predictive ability was noted for 30% PSAD, tumour response and OS. PCWG2 subtypes were also predictive but resulted in unequal grouping. C-indices were 0.59 and 0.62 for 30% PSAD and OS in the validation dataset, respectively.
Risk groups have been identified and validated that predict PSAD and OS in men with mCRPC and may facilitate evaluation of new systemic regimens warranting definitive testing in comparison with docetaxel and prednisone. Prospective validation of this classification system is needed.
European journal of cancer (Oxford, England: 1990) 12/2009; 46(3):517-25. · 4.12 Impact Factor
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Arthur A Caire,
Leon Sun,
Cary N Robertson,
Thomas J Polascik,
Kelly E Maloney, Daniel J George,
Marva M Price,
Danielle A Stackhouse,
Benjamin D Lack,
David M Albala,
Judd W Moul
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ABSTRACT: To evaluate the US Preventative Services Task Force (USPSTF) recommendation to discontinue prostate-specific antigen (PSA) screening at age 75.
Public survey: A cohort of 340 patients was surveyed at our PSA screening clinic and stratified by awareness of the recommendation and education level. Age (< 75, >or= 75), race, health insurance status, knowledge of prostate cancer, and opinion on screening discontinuation at age 75 was evaluated between groups. Disease risk and survival analysis: A cohort of 4196 men who underwent radical prostatectomy between 1988 and 2008 was stratified into age groups: < 65, 65-74, and >or= 75. Associations between clinicopathologic variables, disease risk, and survival were compared between age groups using univariate and multivariate analysis.
Approximately 78% of men surveyed disagreed with the USPSTF recommendation. The number of men who disagreed was not significantly different between awareness groups (P = .962). Awareness of new screening guidelines showed a significant difference (P = .006) between education groups. Age >or= 75 years was predictive of high-risk disease based on D'Amico's criteria (odds ratio = 2.72, P = .003). Kaplan-Meier and Cox regression analyses showed an association of men aged >or= 75 years with higher rate of PSA recurrence, distant metastasis, and disease specific death compared with the age groups of < 65 and 65-74 (P <.05).
Men presenting to our PSA screening clinic disagreed with discontinuation of screening at age 75. Men aged >or= 75 years had higher risk disease and poorer survival. The USPSTF recommendation was supported neither by public opinion nor disease risk and survival results.
Urology 10/2009; 75(5):1122-7. · 2.43 Impact Factor
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Leon Sun,
Arthur A Caire,
Cary N Robertson, Daniel J George,
Thomas J Polascik,
Kelly E Maloney,
Philip J Walther,
Danielle A Stackhouse,
Benjamin D Lack,
David M Albala,
Judd W Moul
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ABSTRACT: We clarified whether men older than 70 years have a higher risk of prostate cancer and poorer survival in the early and late prostate specific antigen eras.
A cohort of 4,561 men who underwent radical prostatectomy were stratified into 3 age groups (younger than 60, 60 to 70 and older than 70 years), and early and late prostate specific antigen eras based on the year of surgery (before 2000 and 2000 or later). Race, body mass index, prostate specific antigen, prostate weight, tumor volume, pathological Gleason sum, pathological tumor stage, extracapsular extension, seminal vesicle invasion and surgical margin status were submitted for univariate and multivariable analyses against the previously mentioned groups. Survivals (prostate specific antigen recurrence, distant metastasis and disease specific death) were compared among the 3 age groups using univariate and multivariable methods.
Compared with younger age groups (younger than 60, 60 to 70 years) men older than 70 years had a higher proportion of pathological tumor stage 3/4 (33.0 vs 44.3 vs 52.1%, p <0.001), pathological Gleason sum greater than 7 (9.5% vs 13.4% vs 17.2%, p <0.001) and larger tumor volume (3.7 vs 4.7 vs 5.2 cc, p <0.001). Pathological Gleason sum in men older than 70 years did not differ between the early and late prostate specific antigen eras (p = 0.071). Men older than 70 years had a higher risk of prostate specific antigen recurrence, distant metastasis and disease specific death on univariate (p <0.05) but not multivariable analysis.
Men older than 70 years had higher risk disease and poorer survival in the early and late prostate specific antigen eras. Pathological Gleason sums did not change between the 2 eras. Patient age was an important variable in prostate specific antigen screening, biopsy, treatment and prognosis.
The Journal of urology 09/2009; 182(5):2242-8. · 4.02 Impact Factor
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Andrew J Armstrong,
Patricia Creel,
James Turnbull,
Cassandra Moore,
Tracy A Jaffe,
Sherri Haley,
William Petros,
Sarah Yenser,
Jon P Gockerman,
Darryl Sleep,
Herbert Hurwitz, Daniel J George
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ABSTRACT: The primary aims of this phase I-II study were to determine the maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, and preliminary efficacy of the combination of docetaxel and the endothelin A receptor antagonist atrasentan as first-line treatment for men with metastatic castration-resistant prostate cancer.
Patients were treated with docetaxel at doses ranging from 60 to 75 mg/m(2) every 21 days, with daily oral atrasentan 10 mg starting on day 3. Patients were treated until evidence of disease progression or unacceptable toxicity.
Thirty-one patients were enrolled over three docetaxel dose levels (8 at 60 mg/m(2), 19 at 70 mg/m(2), and 4 at 75 mg/m(2)) including dose expansion at 70 mg/m(2). The maximum tolerated dose of docetaxel was 70 to 75 mg/m(2). Drug-related grade 3-4 toxicities included neutropenia (50-63%) and febrile neutropenia (16-25%); other grade 1-2 toxicities included fatigue, peripheral edema, diarrhea, headache, rhinitis, anorexia, and nausea. Confirmed prostate-specific antigen (PSA) responses were observed in 23% [95% confidence interval (95% CI), 10-41%]; the rate of >30% declines in PSA was 35% (95% CI, 19-55%). Median overall survival was 17.6 months (95% CI, 13.0-23.2) and median progression-free survival was 4.2 months (95% CI, 2.3-5.8). Significant declines in bone alkaline phosphatase and serum N-telopeptides were observed with therapy.
The maximum tolerated dose of every-3-week docetaxel with 10 mg atrasentan is 70 to 75 mg/m(2). Overall survival and progression-free survival are comparable to that seen with docetaxel and prednisone, whereas the rates of PSA decline are slightly lower than expected. A phase III study of this combination with prednisone has been initiated and is ongoing.
Clinical Cancer Research 11/2008; 14(19):6270-6. · 7.74 Impact Factor
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Brian I Rini,
M Dror Michaelson,
Jonathan E Rosenberg,
Ronald M Bukowski,
Jeffrey A Sosman,
Walter M Stadler,
Thomas E Hutson,
Kim Margolin,
Charles S Harmon,
Samuel E DePrimo,
Sindy T Kim,
Isan Chen, Daniel J George
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ABSTRACT: To assess the safety and efficacy of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma (mRCC) and explore biomarkers for sunitinib response.
Patients with mRCC and disease progression after bevacizumab-based therapy received oral sunitinib 50 mg once daily in 6-week cycles on a 4/2 schedule (4 weeks with treatment followed by 2 weeks without treatment) in a phase II multicenter study. The primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), duration of response (DR), overall survival (OS), and safety. Plasma soluble proteins (vascular endothelial growth factor [VEGF]-A, VEGF-C, soluble VEGF receptor [sVEGFR]-3, and placental growth factor [PlGF]) levels were measured.
Sixty-one patients were enrolled. The ORR was 23.0% (95% CI, 13.2% to 35.5%), median PFS was 30.4 weeks (95% CI, 18.3 to 36.7 weeks), median DR was 44.1 weeks (95% CI, 25.0 to 102.7 weeks), and median OS was 47.1 weeks (95% CI, 36.9 to 79.4 weeks). Mean plasma VEGF-A and PlGF levels significantly increased whereas VEGF-C and sVEGFR-3 levels decreased with sunitinib treatment. Lower baseline levels of sVEGFR-3 and VEGF-C were associated with longer PFS and ORR. Most treatment-related adverse events were of mild-to-moderate intensity and included fatigue, hypertension, and hand-foot syndrome.
Sunitinib has substantial antitumor activity in patients with bevacizumab-refractory mRCC and modulates circulating VEGF pathway biomarkers. These data support the hypothesis that sunitinib inhibits signaling pathways involved in bevacizumab resistance. Baseline levels of sVEGFR-3 and VEGF-C may have potential utility as biomarkers of clinical efficacy in this setting.
Journal of Clinical Oncology 09/2008; 26(22):3743-8. · 18.37 Impact Factor
