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Clinical Treatment Decisions for Advanced Renal Cell Cancer

Toni K. Choueiri

Seven targeted agents have improved the prognosis of advanced renal cell carcinoma (RCC), but none are effective in the post-nephrectomy adjuvant setting. Among the available first-line options for advanced RCC, sunitinib remains the most commonly used first-line therapy, but several studies suggest pazopanib may be better tolerated. Increasingly, choice of therapy may be driven by toxicity profiles. Cytoreductive nephrectomy remains important, even in the era of targeted therapies in selected patients.

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The Right Drug for the Right Patient: Navigating Systemic Therapy Options in Metastatic Renal Cell Carcinoma and Future Directions

Toni K. Choueiri and Robert J. Motzer

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Non–Clear Cell Renal Cancer: Features and Medical Management

Daniel Y. C. Heng and Toni K. Choueiri

The treatment of metastatic renal cell carcinoma (RCC) has changed dramatically with the introduction of targeted therapies against vascular endothelial growth factor and the mammalian target of rapamycin. Because patients with clear cell histology account for more than 80% of patients with RCC, little evidence is available on treating patients with non–clear cell histologies. Most clinical trials have excluded them from enrollment, except for a randomized study investigating temsirolimus. Many retrospective studies on the use of sunitinib, sorafenib, and temsirolimus in patients with non–clear cell histology have shown response rates ranging from 3.7% to 16%. Prospective studies in non–clear cell histologies are ongoing. Although response rates may not be as high as those in patients with clear cell histologies, targeted therapy may provide a clinically meaningful response. New investigational therapies are on the horizon for papillary RCC—the most-common non–clear cell RCC histology—targeting pathways specific to this histology, such as the c-MET pathway.

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NCCN Task Force Report: Optimizing Treatment of Advanced Renal Cell Carcinoma With Molecular Targeted Therapy

Gary R. Hudes, Michael A. Carducci, Toni K. Choueiri, Peg Esper, Eric Jonasch, Rashmi Kumar, Kim A. Margolin, M. Dror Michaelson, Robert J. Motzer, Roberto Pili, Susan Roethke, and Sandy Srinivas

The outcome of patients with metastatic renal cell carcinoma has been substantially improved with administration of the currently available molecularly targeted therapies. However, proper selection of therapy and management of toxicities remain challenging. NCCN convened a multidisciplinary task force panel to address the clinical issues associated with these therapies in attempt to help practicing oncologists optimize patient outcomes. This report summarizes the background data presented at the task force meeting and the ensuing discussion.

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Racial Disparities in End-of-Life Care Among Patients With Prostate Cancer: A Population-Based Study

Firas Abdollah, Jesse D. Sammon, Kaustav Majumder, Gally Reznor, Giorgio Gandaglia, Akshay Sood, Nathanael Hevelone, Adam S. Kibel, Paul L. Nguyen, Toni K. Choueiri, Kathy J. Selvaggi, Mani Menon, and Quoc-Dien Trinh

Objective: To examine racial disparities in end-of-life (EOL) care among black and white patients dying of prostate cancer (PCa). Methods: Relying on the SEER-Medicare database, 3789 patients who died of metastatic PCa between 1999 and 2009 were identified. Information was assessed regarding diagnostic care, therapeutic interventions, hospitalizations, intensive care unit (ICU) admissions, and emergency department visits in the last 12 months, 3 months, and 1 month of life. Logistic regression tested the relationship between race and the receipt of diagnostic care, therapeutic interventions, and high-intensity EOL care. Results: Overall, 729 patients (19.24%) were black. In the 12-months preceding death, laboratory tests (odds ratio [OR], 0.51; 95% CI, 0.36–0.72), prostate-specific antigen test (OR, 0.54; 95% CI, 0.43–0.67), cystourethroscopy (OR, 0.71; 95% CI, 0.56–0.90), imaging procedure (OR, 0.58; 95% CI, 0.41–0.81), hormonal therapy (OR, 0.53; 95% CI, 0.44–0.65), chemotherapy (OR, 0.59; 95% CI, 0.48–0.72), radiotherapy (OR, 0.74; 95% CI, 0.61–0.90), and office visit (OR, 0.38; 95% CI, 0.28–0.50) were less frequent in black versus white patients. Conversely, high-intensity EOL care, such as ICU admission (OR, 1.27; 95% CI, 1.04–1.58), inpatient admission (OR, 1.49; 95% CI, 1.09–2.05), and cardiopulmonary resuscitation (OR, 1.72; 95% CI, 1.40–2.11), was more frequent in black versus white patients. Similar trends for EOL care were observed at 3-month and 1-month end points. Conclusions: Although diagnostic and therapeutic interventions are less frequent in black patients with end-stage PCa, the rate of high-intensity and aggressive EOL care is higher in these individuals. These disparities may indicate that race plays an important role in the quality of care for men with end-stage PCa.

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Cost Implications and Complications of Overtreatment of Low-Risk Prostate Cancer in the United States

Ayal A. Aizer, Xiangmei Gu, Ming-Hui Chen, Toni K. Choueiri, Neil E. Martin, Jason A. Efstathiou, Andrew S. Hyatt, Powell L. Graham, Quoc-Dien Trinh, Jim C. Hu, and Paul L. Nguyen

Background: Evidence-based consensus guidelines recommend only observation for men with low-risk prostate cancer and life expectancy less than 10 years. This report describes the incidence, drivers, cost, and morbidity of overtreatment of low-risk prostate cancer within the United States. Methods: The SEER-Medicare Program was used to identify 11,744 men aged 66 years or older diagnosed with low-risk prostate cancer in 2004 through 2007. Overtreatment of prostate cancer was defined as definitive treatment of a patient with a life expectancy of less than 10 years. Expected survival was estimated using NCCN methodology. Costs were the amount paid by Medicare in years after minus year before diagnosis. Toxicities were relevant Medicare diagnoses/interventions. P values are 2-sided. Results: Of 3001 men with low-risk prostate cancer and a life expectancy of less than 10 years, 2011 men (67%) were overtreated. On multivariable logistic regression, overtreated men were more likely to be married (odds ratio [OR], 1.29; 95% CI, 1.05–1.59; P=.02), reside in affluent regions (P<.001), and harbor more advanced disease at diagnosis (P<.001). Two-year toxicity was greater in overtreated patients (P<.001). Relative to active surveillance/watchful waiting/observation, the median additional cost per definitive treatment was $18,827 over 5 years; the cumulative annual cost attributable to overtreatment in the United States was $58.7 million. The ability to avoid treating the 80% of men with low-grade disease who will never die of prostate cancer would save $1.32 billion per year nationally. Conclusions: Overtreatment of low-risk prostate cancer is partially driven by sociodemographic factors and occurs frequently, with marked impact on patient quality of life and health-related costs.

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Variation in National Use of Long-Term ADT by Disease Aggressiveness Among Men With Unfavorable-Risk Prostate Cancer

Vinayak Muralidhar, Paul J. Catalano, Gally Reznor, Brandon A. Mahal, Toni K. Choueiri, Christopher J. Sweeney, Neil E. Martin, Clair J. Beard, Yu-Wei Chen, Michelle D. Nezolosky, Karen E. Hoffman, Felix Y. Feng, Quoc-Dien Trinh, and Paul L. Nguyen

Background: The current NCCN Clinical Practice Guidelines in Oncology for Prostate Cancer recommend long-term androgen deprivation therapy (ADT) for all men with high-risk prostate cancer treated with external-beam radiation therapy (EBRT). We determined whether the use of long-term ADT varied by the recently defined subcategories of high-risk disease (favorable, other, and very high) versus unfavorable intermediate-risk disease. Methods: We identified 5,524 patients with unfavorable-risk prostate cancer diagnosed from 2004 to 2007 and managed with EBRT using the SEER-Medicare linked database. Patients were stratified by risk group: unfavorable intermediate-risk, favorable high-risk (previously defined and validated as clinical stage T1c, Gleason score of 4 + 4 = 8, and prostate-specific antigen [PSA] level <10 ng/mL, or clinical stage T1c, Gleason score of 6, and PSA level >20 ng/mL), very-high-risk (clinical stage T3b–T4 or primary Gleason pattern 5), or other high risk (ie, neither favorable nor very high). We used multivariable competing risks regression to estimate the rates of long-term (≥2 years) ADT by group. Results: Men with favorable high-risk prostate cancer were significantly less likely to receive long-term ADT than those with other high-risk disease (15.4% vs 24.6%, adjusted hazard ratio [AHR], 0.68; 95% CI, 0.60–0.76; P<.001), and similarly likely as those with unfavorable intermediate-risk disease (AHR, 1.10; 95% CI, 0.99–1.23; P=.087). Other high-risk disease was less likely to receive long-term ADT than very high-risk cancer (24.6% vs 30.8%; AHR, 0.83; 95% CI, 0.74–0.93; P=.002). Conclusions: Despite current guidelines, patients with EBRT-managed high-risk prostate cancer received significantly different rates of long-course ADT based on subclassification. Our results suggest that oncologists view these patients as a heterogeneous group with favorable high-risk cancer warranting less aggressive therapy than other high-risk or very high-risk disease.

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NCCN Working Group Report: Designing Clinical Trials in the Era of Multiple Biomarkers and Targeted Therapies

Alan P. Venook, Maria E. Arcila, Al B. Benson III, Donald A. Berry, David Ross Camidge, Robert W. Carlson, Toni K. Choueiri, Valerie Guild, Gregory P. Kalemkerian, Razelle Kurzrock, Christine M. Lovly, Amy E. McKee, Robert J. Morgan, Anthony J. Olszanski, Mary W. Redman, Vered Stearns, Joan McClure, and Marian L. Birkeland

Defining treatment-susceptible or -resistant populations of patients with cancer through the use of genetically defined biomarkers has revolutionized cancer care in recent years for some disease/patient groups. Research continues to show that histologically defined diseases are diverse in their expression of unique mutations or other genetic alterations, however, which presents opportunities for the development of personalized cancer treatments, but increased difficulty in testing these therapies, because potential patient populations are divided into ever smaller numbers. To address some of the growing challenges in biomarker development and clinical trial design, NCCN assembled a group of experts across specialties and solid tumor disease types to begin to define the problems and to consider alternate ways of designing clinical trials in the era of multiple biomarkers and targeted therapies. Results from that discussion are presented, focusing on issues of clinical trial design from the perspective of statisticians, clinical researchers, regulators, pathologists, and information developers.

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Whole-Exome Sequencing in Two Extreme Phenotypes of Response to VEGF-Targeted Therapies in Patients With Metastatic Clear Cell Renal Cell Carcinoma

Andre P. Fay, Guillermo de Velasco, Thai H. Ho, Eliezer M. Van Allen, Bradley Murray, Laurence Albiges, Sabina Signoretti, A. Ari Hakimi, Melissa L. Stanton, Joaquim Bellmunt, David F. McDermott, Michael B. Atkins, Levi A. Garraway, David J. Kwiatkowski, and Toni K. Choueiri

Advances in next-generation sequencing have provided a unique opportunity to understand the biology of disease and mechanisms of sensitivity or resistance to specific agents. Renal cell carcinoma (RCC) is a heterogeneous disease and highly variable clinical responses have been observed with vascular endothelial growth factor (VEGF)–targeted therapy (VEGF-TT). We hypothesized that whole-exome sequencing analysis might identify genotypes associated with extreme response or resistance to VEGF-TT in metastatic (mRCC). Patients with mRCC who had received first-line sunitinib or pazopanib and were in 2 extreme phenotypes of response were identified. Extreme responders (ERs) were defined as those with partial response or complete response for 3 or more years (n=13) and primary refractory patients (PRPs) were defined as those with progressive disease within the first 3 months of therapy (n=14). International Metastatic RCC Database Consortium prognostic scores were not significantly different between the groups (P=.67). Considering the genes known to be mutated in RCC at significant frequency, PBRM1 mutations were identified in 7 ERs (54%) versus 1 PRP (7%) (P=.01). In addition, mutations in TP53 (n=4) were found only in PRPs (P=.09). Our data suggest that mutations in some genes in RCC may impact response to VEGF-TT.

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Comparing the Association Between Insurance and Mortality in Ovarian, Pancreatic, Lung, Colorectal, Prostate, and Breast Cancers

Alexander P. Cole, Chang Lu, Marieke J. Krimphove, Julie Szymaniak, Maxine Sun, Sean A. Fletcher, Stuart R. Lipsitz, Brandon A. Mahal, Paul L. Nguyen, Toni K. Choueiri, Adam S. Kibel, Adil H. Haider, and Quoc-Dien Trinh

Background: Insurance coverage is associated with better cancer outcomes; however, the relative importance of insurance coverage may differ between cancers. This study compared the association between insurance coverage at diagnosis and cancer-specific mortality (CSM; insurance sensitivity) in 6 cancers. Patients and Methods: Using the SEER cancer registry, data were abstracted for individuals diagnosed with ovarian, pancreatic, lung, colorectal, prostate, or breast cancer in 2007 through 2010. The association between insurance coverage at diagnosis and CSM was modeled using a Fine and Gray competing-risks regression adjusted for demographics. An interaction term combining insurance status and cancer type was used to test whether insurance sensitivity differed between cancers. Separate models were fit for each cancer. To control for lead-time bias and to assess whether insurance sensitivity may be mediated by earlier diagnosis and treatment, additional models were fit adjusting for disease stage and treatment. Results: Lack of insurance was associated with an increased hazard of CSM in all cancers (P<.01). The magnitude of the effect differed significantly between cancers (P interaction=.04), ranging from an adjusted hazard ratio of 1.13 (95% CI, 1.01–1.28) in ovarian and 1.19 (95% CI, 1.11–1.29) in pancreatic cancer to 2.19 (95% CI, 2.02–2.37) in breast and 2.98 (95% CI, 2.54–3.49) in prostate cancer. The benefit of insurance was attenuated after adjusting for stage and treatment (eg, screening/early treatment effect), with the largest reductions in prostate, breast, and colorectal cancers. Conclusions: Greater insurance sensitivity was seen in screening-detected malignancies with effective treatments for early-stage disease (eg, prostate, breast, and colorectal cancers). Given that this differential is significantly reduced after adjusting for stage and treatment, our results suggest that a significant portion (but not all) of the benefit of insurance coverage is due to detection and treatment of certain curable early-stage cancers.