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ABSTRACT: Currently, the management of localized renal cell carcinoma (RCC) is surgical. Unfortunately, many cases of high-risk RCC
recur following resection and develop metastatic disease, an event that usually results in death. Because previous attempts
to improve survival with adjuvant therapy have been unsuccessful, the US Food and Drug Administration’s approval of three
new agents for metastatic RCC has generated renewed interest in evaluating agents in the adjuvant setting for high-risk RCC.
This article discusses the rationale for the use of these and other novel agents and reviews currently ongoing adjuvant trials
as well as considerations for the development of new trials for adjuvant therapies.
Current Oncology Reports 04/2012; 10(3):245-252. · 2.55 Impact Factor
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ABSTRACT: The addition of androgen deprivation therapy (ADT) to definitive external beam radiation therapy (RT) improves outcomes in higher-risk prostate cancer patients. However, the benefit of ADT with salvage RT in post-prostatectomy patients is not clearly established. Our study compares biochemical outcomes in post-prostatectomy patients who received salvage RT with or without concurrent ADT.
Of nearly 2,000 post-prostatectomy patients, we reviewed the medical records of 191 patients who received salvage RT at the University of Pennsylvania between 1987 and 2007. Follow-up data were obtained by chart review and electronic polling of the institutional laboratory database and Social Security Death Index. Biochemical failure after salvage RT was defined as a prostate-specific antigen of 2.0 ng/mL above the post-RT nadir or the initiation of ADT after completion of salvage RT.
One hundred twenty-nine patients received salvage RT alone, and 62 patients received combined ADT and salvage RT. Median follow-up was 5.4 years. Patients who received combined ADT and salvage RT were younger, had higher pathologic Gleason scores, and higher rates of seminal vesicle invasion, lymph node involvement, and pelvic nodal irradiation compared with patients who received salvage RT alone. Patients who received combined therapy had improved biochemical progression-free survival (bPFS) compared with patients who received RT alone (p = 0.048). For patients with pathologic Gleason scores ≤7, combined RT and ADT resulted in significantly improved bPFS compared to RT alone (p = 0.013).
These results suggest that initiating ADT during salvage RT in the post-prostatectomy setting may improve bPFS compared with salvage RT alone. However, prospective randomized data are necessary to definitively determine whether hormonal manipulation should be used with salvage RT. Furthermore, the optimal nature and duration of ADT and the patient subgroups in which ADT could provide the most benefit remain open questions.
International journal of radiation oncology, biology, physics 03/2012; 83(5):1493-9. · 4.59 Impact Factor
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ABSTRACT: To describe practice patterns associated with androgen suppression (AS) stratified by disease risk group in patients undergoing external-beam radiotherapy (EBRT) for localized prostate cancer.
We identified 2,184 low-risk, 2,339 intermediate-risk, and 2,897 high-risk patients undergoing EBRT for nonmetastatic prostate cancer diagnosed between January 1, 2004, and December 31, 2005, in the linked Surveillance, Epidemiology, and End Results-Medicare database. We examined the association of patient, clinical, and demographic characteristics with AS use by multivariate logistic regression.
The proportions of patients receiving AS for low-risk, intermediate-risk, and high-risk prostate cancer were 32.2%, 56.3%, and 81.5%, respectively. AS use among men in the low-risk disease category varied widely, ranging from 13.6% in Detroit to 47.8% in Kentucky. We observed a significant decline in AS use between 2004 and 2005 within all three disease risk categories. Men aged ≥75 years or with elevated comorbidity levels were more likely to receive AS.
Our results identified apparent overuse and underuse of AS among men within the low-risk and high-risk disease categories, respectively. These results highlight the need for clinician and patient education regarding the appropriate use of AS. Practice patterns among intermediate-risk patients reflect the clinical heterogeneity of this population and underscore the need for better evidence to guide the treatment of these patients.
International journal of radiation oncology, biology, physics 11/2011; 83(1):8-15. · 4.59 Impact Factor
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ABSTRACT: To describe the use and determinants of prostate-specific antigen (PSA) surveillance in a population-based cohort. PSA measurements are an important component of surveillance for men with clinically localized prostate cancer who do not receive initial treatment.
Using the linked Surveillance, Epidemiology, and End Results-Medicare program, we evaluated 7145 men, aged 65-84 years, who had been diagnosed from 1997 to 2002 with American Joint Committee on Cancer, 6th edition, Stage T1-T2, Gleason score ≤7 prostate cancer and received expectant management. For all patients, the Medicare claims were observed until a secondary cancer treatment event, death, or December 31, 2006. We performed multivariable logistic regression analysis to examine the relationship between the primary outcome of annual PSA surveillance and the patient, clinical, and demographic characteristics.
Of the men with localized Gleason score ≤7 prostate cancer who did not receive initial treatment, 39% underwent at least annual PSA measurement. On multivariable logistic regression analysis, annual PSA surveillance was positively associated with older age (75-84 vs 65-74 years, odds ratio [OR] 1.37, 95% confidence interval [CI] 1.23-1.52), more comorbidities (OR 3.38, 95% CI 2.91-3.93), and residence in a neighborhood with a greater median income (OR 1.81, 95% CI 1.46-2.25). A lower likelihood of annual PSA surveillance was associated with black race (OR 0.55, 95% CI 0.45-0.67).
Most men with localized prostate cancer who forgo initial treatment do not receive annual PSA surveillance. Additional research is necessary to clarify the benefits and harm of increased surveillance among older men and those with medical comorbidities.
Urology 09/2011; 78(5):1107-13. · 2.43 Impact Factor
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ABSTRACT: The standard of care for renal cell carcinoma (RCC) is surgical resection as a monotherapy or as part of a multimodal approach. A significant number of patients undergoing surgery for localized RCC experience recurrence, suggesting that there are some individuals in whom surgical excision is necessary but insufficient because of the presence of micrometastatic disease at diagnosis. This review summarizes current algorithms used to identify patients at high risk for disease recurrence following the surgical resection of RCC, the outcomes of contemporary adjuvant systemic therapy trials, and the rationale supporting the use of neoadjuvant therapy.
Hematology/oncology clinics of North America 08/2011; 25(4):765-91. · 2.05 Impact Factor
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ABSTRACT: This multicenter randomized trial was designed to test whether melanoma-associated helper peptides augment CD8(+) T-cell responses to a melanoma vaccine and whether cyclophosphamide (CY) pretreatment augments CD4(+) or CD8(+) T-cell responses to that vaccine.
In all, 167 eligible patients with resected stage IIB to IV melanoma were randomly assigned to four vaccination study arms. Patients were vaccinated with 12 class I major histocompatibility complex-restricted melanoma peptides (12MP) to stimulate CD8(+) T cells and were randomly assigned to receive a tetanus helper peptide or a mixture of six melanoma-associated helper peptides (6MHP) to stimulate CD4(+) T cells. Before vaccination, patients were also randomly assigned to receive CY pretreatment or not. T-cell responses were assessed by an ex vivo interferon gamma ELISpot assay. Clinical outcomes and toxicities were recorded.
Vaccination with 12MP plus tetanus induced CD8(+) T-cell responses in 78% of patients and CD4(+) T-cell responses to tetanus peptide in 93% of patients. Vaccination with 12MP plus 6MHP induced CD8(+) responses in 19% of patients and CD4(+) responses to 6MHP in 48% of patients. CY had no significant effect on T-cell responses. Overall 3-year survival was 79% (95% CI, 71% to 86%), with no significant differences (at this point) by study arm.
Melanoma-associated helper peptides paradoxically decreased CD8(+) T-cell responses to a melanoma vaccine (P < .001), and CY pretreatment had no immunologic or clinical effect. Prior work showed immunologic and clinical activity of 6MHP alone. Possible explanations for negative effects on CD8 responses include modulation of homing receptor expression or induction of antigen-specific regulatory T cells.
Journal of Clinical Oncology 06/2011; 29(21):2924-32. · 18.37 Impact Factor
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ABSTRACT: Sarcomatoid features can arise in renal cell carcinoma of any subtype and are associated with a poor prognosis. Doxorubicin and gemcitabine in a limited series showed activity in aggressive renal tumors and we wished to formally assess the combination in patients with renal cell carcinoma specifically containing sarcomatoid features. The Eastern Cooperative Oncology Group (ECOG) conducted a phase II trial of doxorubicin 50 mg/m(2) IV push and gemcitabine 1,500 mg/m(2) IV over 30 min every 2 weeks in 39 patients with locally advanced or metastatic renal cell carcinoma with sarcomatoid features. Ten patients (26%) had grade 3 toxicity, and four patients (11%) had grade 4 toxicities. Although most toxicity was from myelosuppression, one patient died on study from cardiac dysfunction after a cumulative dose of 450 mg/m(2) doxorubicin. Six (16%) patients experienced responses (5 partial responses and 1 complete response), and ten (26%) patients had stable disease. In addition, another patient had an unconfirmed partial response and an additional patient experienced over 50% decrease in her tumor burden after an initial progression. The median overall survival was 8.8 months, and the median progression-free survival was 3.5 months. We conclude that the combination of doxorubicin and gemcitabine, inactive in patients with mostly clear cell histology, demonstrated responses in patients with RCC with sarcomatoid features. We acknowledge the toxicity of this combination but note that limited treatment options exist for this aggressive histology. Only through prospective multicenter trials with comprehensive central pathology review will better treatment options be identified.
Medical Oncology 02/2011; 29(2):761-7. · 2.14 Impact Factor
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Naomi B Haas
Cancer 12/2009; 116(3):574-6. · 4.77 Impact Factor
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ABSTRACT: Granulocyte/macrophage colony-stimulating factor (GM-CSF) administered locally together with vaccines can augment T-cell responses in animal models. Human experience has been limited to small and uncontrolled trials. Thus, a multicenter randomized phase II trial was done to determine whether local administration of GM-CSF augments immunogenicity of a multipeptide vaccine. It also assessed immunogenicity of administration in one versus two vaccine sites.
One hundred twenty-one eligible patients with resected stage IIB to IV melanoma were vaccinated with 12 MHC class I-restricted melanoma peptides to stimulate CD8+ T cells plus a HLA-DR-restricted tetanus helper peptide to stimulate CD4+ T cells, emulsified in incomplete Freund's adjuvant, with or without 110 microg GM-CSF. Among 119 evaluable patients, T-cell responses were assessed by IFN-gamma ELIspot assay and tetramer analysis. Clinical outcomes were recorded.
CD8+ T-cell response rates to the 12 MHC class I-restricted melanoma peptides (by day 50) with or without GM-CSF were 34% and 73%, respectively (P < 0.001), by direct ELIspot assay. Tetramer analyses corroborated the functional data. CD4+ T-cell responses to tetanus helper peptide were higher without GM-CSF (95% versus 77%; P = 0.005). There was no significant difference by number of vaccine sites. Three-year overall and disease-free survival estimates (95% confidence interval) were 76% (67-83%) and 52% (43-61%), respectively, with too few events to assess differences by study group.
High immune response rates for this multipeptide vaccine were achieved, but CD8+ and CD4+ T-cell responses were lower when administered with GM-CSF. These data challenge the value of local GM-CSF as a vaccine adjuvant in humans.
Clinical Cancer Research 11/2009; 15(22):7036-44. · 7.74 Impact Factor
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ABSTRACT: Currently, the management of localized renal cell carcinoma (RCC) is surgical. Unfortunately, many cases of high-risk RCC recur following resection and develop metastatic disease, an event that usually results in death. Because previous attempts to improve survival with adjuvant therapy have been unsuccessful, the US Food and Drug Administration's approval of three new agents for metastatic RCC has generated renewed interest in evaluating agents in the adjuvant setting for high-risk RCC. This article discusses the rationale for the use of these and other novel agents and reviews currently ongoing adjuvant trials as well as considerations for the development of new trials for adjuvant therapies.
Current Oncology Reports 06/2008; 10(3):245-52. · 2.55 Impact Factor
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ABSTRACT: New therapeutic strategies are needed to improve treatment outcomes in men with hormone-refractory prostate cancer. A better understanding of the molecular mechanisms of cell death in response to therapeutic strategies will help avoid ineffective treatment regimens and provide a molecular basis for new therapeutic modalities targeting apoptosis-resistant forms of prostate cancer. In this review, the authors focused on the established aberrations of apoptosis in hormone-refractory prostate cancer, and they have described novel treatment strategies to overcome apoptosis resistance.
Cancer 05/2008; 112(8):1660-71. · 4.77 Impact Factor
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ABSTRACT: Paclitaxel and docetaxel are active agents in advanced urothelial cancer. BMS-247550 (ixabepilone) has activity in preclinical models in paclitaxel resistant models. A phase 2 trial of this epothilone was performed to determine the activity and toxicity of this agent in a multi-institutional setting in patients previously treated with 1 prior chemotherapy regimen.
Forty-five patients with advanced urothelial carcinoma were treated with BMS-247550 40 mg/m(2) over 3 hours intravenously on Day 1 of a 21-day cycle and continued therapy until progression or unacceptable toxicity.
Five patients obtained an objective partial response (PR) among the 42 eligible patients for an overall response rate of 11.9% (90% confidence interval [5.3%, 26.5%]). Median overall survival of the group was 8 months. Toxicity was moderate with granulocytopenia, fatigue, and sensory neuropathy being the most common side effects noted.
BMS-247550 (ixabepilone) has very modest activity as a second-line therapy for advanced urothelial cancer. Responses in visceral, nodal, and soft tissues sites were observed. Granulocytopenia without fever, fatigue, and sensory neuropathy was common.
Cancer 09/2007; 110(4):759-63. · 4.77 Impact Factor
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ABSTRACT: Renal cell carcinoma (RCC) is a heterogeneous disease as reflected in its presentation and clinical course, pathological subtypes, nuclear grades and molecular biology. Emerging data indicate that renal tumors express a variety of molecular tumor markers and unique patterns of gene expression. Clinically the disease behaves quite heterogeneously, with courses ranging from indolent to highly aggressive. Surgical monotherapy or as part of a multimodal approach remains the standard of care for most cases of RCC. Radical or partial nephrectomy is associated with a 5-year cancer specific survival (CSS) of 85-97% for pT1 tumors. Unfortunately, 20% of patients have either locally advanced or node positive (N+) RCC while another 22% have metastatic RCC (mRCC) at presentation. Unlike the outcomes in early localized disease, survival rates for N+ patients are poor and patients with mRCC are rarely cured despite aggressive multimodal therapy. Classic cytotoxic chemotherapy has repeatedly been shown to have little effect and only 5-20% of patients with mRCC respond to immunologic agents such as interferon and/or interleukin. Cytoreductive nephrectomy with systemic immunotherapy is associated with few cures with median survivals of 12-24 months. Recent advances in our understanding of the molecular origins and pathways of RCC have led to the development of more effective targeted therapies. Here we review the molecular pathways that define the pertinent therapeutic targets in RCC and the clinical data for these new and promising agents.
Current Treatment Options in Oncology 07/2007; 8(3):211-26. · 2.68 Impact Factor
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ABSTRACT: For most cases of renal cell carcinoma (RCC), the standard of care is surgical resection as monotherapy or as part of a multimodal approach. In patients with early localized disease, radical nephrectomy is associated with a favorable prognosis, whereas patients with advanced disease are rarely cured. A significant number of patients undergoing surgery for localized RCC experience recurrence, suggesting that there are some individuals in whom surgical excision is necessary but insufficient. In these patients, the development of effective adjuvant strategies is imperative. In this article, we review the prognostic variables and comprehensive staging algorithms for identifying patients at high risk for disease recurrence. Additionally, we review data from completed adjuvant RCC trials and highlight relevant ongoing trials.
Current Urology Reports 02/2007; 8(1):19-30.
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Kangshen Yao,
Seiichiro Shida,
Muthu Selvakumaran,
Robert Zimmerman,
Ephraim Simon,
Jonathan Schick, Naomi B Haas,
Marge Balke,
Howard Ross,
Steven W Johnson,
Peter J O'Dwyer
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ABSTRACT: Hypoxia contributes to cytotoxic chemotherapy and radiation resistance and may play a role in the efficacy of antiangiogenesis cancer therapy. We have generated a series of cell lines derived from the colon adenocarcinoma models HT29 and HCT116 by exposing cells in vitro to repeated sublethal periods of profound hypoxia. These cell lines have altered sensitivity to hypoxia-induced apoptosis: those derived from HT29 are resistant, whereas those from HCT116 are more susceptible. We used cDNA selected subtractive hybridization to identify novel genes mediating sensitivity to hypoxia-induced apoptosis and isolated macrophage migration inhibitory factor (MIF) from the hypoxia-conditioned cell lines. MIF expression correlates with susceptibility of the cell lines to apoptosis. In hypoxia-resistant cells, the induction of apoptosis by hypoxia can be restored by the addition of exogenous recombinant MIF protein, suggesting that resistance may result in part from down-regulation of MIF production possibly through an autocrine loop. Inhibition of MIF using small interfering RNA in the susceptible lines conferred resistance to hypoxia-induced cell death. The relative expression of MIF in the hypoxia-conditioned cells implanted s.c. in severe combined immunodeficient mice in vivo was similar to that observed in vitro. In an analysis of 12 unrelated colon tumor cell lines, MIF expression and response to hypoxia varied widely. Cell lines in which MIF was inducible by hypoxia were more sensitive to oxaliplatin. In human colon tumor specimens analyzed by immunohistochemistry, MIF expression was similarly variable. There was no detectable expression of MIF in normal colon mucosa or adenoma but positive staining in all carcinomas tested. Taken together, these data indicate that MIF may be a determinant of hypoxia-induced apoptosis in vitro and that its variable expression in human colon cancers may indicate a functional role in vivo. We suggest that MIF expression in colorectal cancer may be a marker of susceptibility to therapies that may depend on induction of hypoxia, possibly including antiangiogenic therapy.
Clinical Cancer Research 11/2005; 11(20):7264-72. · 7.74 Impact Factor
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Naomi B Haas,
Bruce J Giantonio,
Samuel Litwin,
Carl J Minniti,
Stephen Fox,
Gwen Yeslow,
Robert Reilly,
Kenneth Nahum,
Richard Greenberg,
Theresa Halbherr,
Gary R Hudes
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ABSTRACT: It is well known that metastatic renal cell carcinoma (RCC) exhibits constitutive resistance to chemotherapeutic agents. Antimicrotubule agents such as vinblastine are associated with low but reproducible response rates (approximately 12%) in patients with RCC. Estramustine has been shown to potentiate the antimicrotubule effects of vinblastine. The authors sought to increase the activity of vinblastine in RCC through the addition of estramustine.
Twenty-one patients with metastatic RCC not previously treated with chemotherapy received oral estramustine phosphate, 600 mg/m(2), on Days 1, 2, and 3 weekly for 6 weeks, and intravenous vinblastine, 4 mg/m(2) on Day 2 weekly for 6 weeks, repeated every 8 weeks. Twenty-one patients received 31 cycles of therapy.
Two patients experienced Grade 3 and 4 hematologic toxicity, and three patients had Grade 3 nonhematologic toxicity consisting of neurologic toxicity, hepatic toxicity, or angioneurotic edema. One patient had a partial response with decreased liver metastases for 48 weeks; 9 patients had stable disease, for a median duration of 14 weeks (range, 11-31 weeks); and 11 patients demonstrated disease progression. The median overall time to progression was 8 weeks and the median overall survival period was 24 weeks.
Although well tolerated, the combination of oral estramustine phosphate with vinblastine administered on this schedule had minimal activity in patients with metastatic RCC.
Cancer 12/2003; 98(9):1837-41. · 4.77 Impact Factor
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Naomi B Haas,
Mitchell Smith,
Nancy Lewis,
Lynn Littman,
Gwen Yeslow,
Indira D Joshi,
Anthony Murgo,
Joyce Bradley,
Robert Gordon,
Hao Wang,
Andre Rogatko,
Gary R Hudes
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ABSTRACT: We conducted a Phase II trial of bryostatin-1, an inhibitor of protein kinase C, in advanced renal cell carcinoma to measure toxicity, response rate, time to progression, and induction of cytokines.
A total of 32 patients (26 male and 6 female) received bryostatin-1 at 35-40 microg/m(2) i.v. over 1 h on days 1, 8, and 15 of each 4-week cycle. Plasma interleukin-6, tumor necrosis factor-alpha, and C-reactive protein levels were assayed pretreatment, 1 and 23 h after completion of bryostatin-1 infusion at weeks 1 and 5.
Cycles (102) of bryostatin-1 were given (median 2, range 1-8). The most common grade 1 or 2 toxicities were myalgias (46.8%), fatigue (59.3%), and dyspnea (18.8%). Grade 3-4 toxicity included myalgias (40.6%), ataxia (9.3%), and dyspnea (15.6%). Four (12%) patients experienced cardiac events while on study (cardiac arrhythmias and congestive heart failure occurred in 2 patients, and 2 patients had fatal cardiac arrests). Of 32 patients evaluable for response, 2 (6.3%) had partial responses lasting 9 with 6 months. A total of 15 patients (46.8%) had stable disease, and 6 (18.8%) patients had stable disease for >or=6 months. Plasma interleukin-6 increased >or=2-fold over baseline measurements in 5 of 17 patients (29.4%) but did not correlate with response or toxicity.
Although weekly bryostatin-1 at 35-40 microg/m(2) produced a low proportion of objective responses, prolonged (>6 months) stable disease or partial remission in 25% of patients suggests that this agent, or other inhibitors of protein kinase C, may have a role in the treatment of renal cell carcinoma, perhaps in combination with other agents.
Clinical Cancer Research 01/2003; 9(1):109-14. · 7.74 Impact Factor
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ABSTRACT: Twenty-nine patients with progressive hormone-refractory metastatic adenocarcinoma of the prostate were treated with daily estramustine phosphate at 10 mg/kg, and I.V. doxorubicin 50 mg/m2 every 3 weeks. Twenty-six patients were evaluable. Four of seven patients with nonosseous measurable disease had partial responses lasting 3 to 10 months. Eleven of 19 patients with osseous metastases had stable disease or improvement on bone scan, 6 of these for 7 months or longer. Median time to progression was 20 weeks, and the median survival was 43 weeks.
American Journal of Clinical Oncology 11/2000; 23(6):589-592. · 2.01 Impact Factor
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ABSTRACT: Renal cell carcinoma (RCC) is the most lethal of all genitourinary malignancies with nearly half of all patients presenting with locally advanced or metastatic disease. Systemic treatments such as chemo- or immunotherapy have historically been associated with overall response rates of 5-15% with very few durable responses. The basis of newly approved, more effective targeted therapies for metastatic RCC are based on a fundamental knowledge of the molecular mechanisms that give rise to RCC. We review the clinical data for targeted therapies in RCC and discuss the pertinent biology, side effects, and targets important to the practicing clinician.
Urologic Oncology 25(5):420-32. · 3.22 Impact Factor
