Sarathi Kalra

Clinical Outcomes for Patients with Metastatic Renal Cell Carcinoma Treated with Alternative Sunitinib Schedules

PURPOSE We identified sunitinib alternative schedules that maintained dose intensity while decreasing adverse events in patients with metastatic renal cell cancer. We also determined the impact of alternative schedules on clinical outcomes. MATERIALS AND METHODS We retrospectively reviewed the records of patients 18 years old or older with clear cell metastatic renal cell cancer who received first line sunitinib between January 26, 2006 and March 1, 2011 at our major comprehensive cancer center. A subset of patients was switched at the first intolerable adverse event from the traditional schedule of 28 days on and 14 days off to a schedule of 14 days on and 7 days off or other alternative schedules. A control group underwent standard dose reduction. We estimated progression-free and overall survival by the Kaplan-Meier method. Predictors of progression-free and overall survival were analyzed using Cox regression. RESULTS A total of 187 patients were included in analysis, of whom 87% were on the traditional schedule at baseline. During treatment 53% of patients continued on the traditional schedule and 47% began or were transitioned to alternative schedules. Baseline characteristics were similar. Adverse events prompting schedule modification included fatigue in 64% of cases, hand-foot syndrome in 38% and diarrhea in 32%. Median time to alternative schedules was 5.6 months. Median overall survival was 17.7 months (95% CI 10.8-22.2) on the traditional schedule compared to 33.0 months (95% CI 29.3-not estimable) on alternative schedules (p <0.0001). On multivariable analysis poor Eastern Cooperative Oncology Group (ECOG) performance status, increased lactate dehydrogenase, decreased albumin, unfavorable Heng criteria and the traditional schedule were associated with decreased overall survival (p <0.05). CONCLUSIONS Sunitinib administered on alternative schedules may mitigate adverse events while achieving outcomes comparable to those of the traditional schedule in patients with metastatic renal cell cancer. Prospective investigations of alternate dosing schemas are warranted.

Adult UrologyOncology: Adrenal/Renal/Upper Tract/BladderClinical Outcomes for Patients with Metastatic Renal Cell Carcinoma Treated with Alternative Sunitinib Schedules

PURPOSE We identified sunitinib alternative schedules that maintained dose intensity while decreasing adverse events in patients with metastatic renal cell cancer. We also determined the impact of alternative schedules on clinical outcomes. MATERIALS AND METHODS We retrospectively reviewed the records of patients 18 years old or older with clear cell metastatic renal cell cancer who received first line sunitinib between January 26, 2006 and March 1, 2011 at our major comprehensive cancer center. A subset of patients was switched at the first intolerable adverse event from the traditional schedule of 28 days on and 14 days off to a schedule of 14 days on and 7 days off or other alternative schedules. A control group underwent standard dose reduction. We estimated progression-free and overall survival by the Kaplan-Meier method. Predictors of progression-free and overall survival were analyzed using Cox regression. RESULTS A total of 187 patients were included in analysis, of whom 87% were on the traditional schedule at baseline. During treatment 53% of patients continued on the traditional schedule and 47% began or were transitioned to alternative schedules. Baseline characteristics were similar. Adverse events prompting schedule modification included fatigue in 64% of cases, hand-foot syndrome in 38% and diarrhea in 32%. Median time to alternative schedules was 5.6 months. Median overall survival was 17.7 months (95% CI 10.8-22.2) on the traditional schedule compared to 33.0 months (95% CI 29.3-not estimable) on alternative schedules (p <0.0001). On multivariable analysis poor Eastern Cooperative Oncology Group (ECOG) performance status, increased lactate dehydrogenase, decreased albumin, unfavorable Heng criteria and the traditional schedule were associated with decreased overall survival (p <0.05). CONCLUSIONS Sunitinib administered on alternative schedules may mitigate adverse events while achieving outcomes comparable to those of the traditional schedule in patients with metastatic renal cell cancer. Prospective investigations of alternate dosing schemas are warranted.

Resistance to Antiangiogenic Therapy Is Associated with an Immunosuppressive Tumor Microenvironment in Metastatic Renal Cell Carcinoma

Therapeutic PD-1/PD-L1 blockade requires preexisting tumor-infiltrating T cells. In a subset of metastatic RCC patients, antiangiogenic therapy increased T-cell infiltration and PD-L1 upregulation, increasing the likelihood that they may uniquely benefit from combination checkpoint and antiangiogenic therapy. Renal cell carcinoma (RCC) is an immunogenic and proangiogenic cancer, and antiangiogenic therapy is the current mainstay of treatment. Patients with RCC develop innate or adaptive resistance to antiangiogenic therapy. There is a need to identify biomarkers that predict therapeutic resistance and guide combination therapy. We assessed the interaction between antiangiogenic therapy and the tumor immune microenvironment and determined their impact on clinical outcome. We found that antiangiogenic therapy–treated RCC primary tumors showed increased infiltration of CD4+ and CD8+ T lymphocytes, which was inversely related to patient overall survival and progression-free survival. Furthermore, specimens from patients treated with antiangiogenic therapy showed higher infiltration of CD4+FOXP3+ regulatory T cells and enhanced expression of checkpoint ligand programed death-ligand 1 (PD-L1). Both immunosuppressive features were correlated with T-lymphocyte infiltration and were negatively related to patient survival. Treatment of RCC cell lines and RCC xenografts in immunodeficient mice with sunitinib also increased tumor PD-L1 expression. Results from this study indicate that antiangiogenic treatment may both positively and negatively regulate the tumor immune microenvironment. These findings generate hypotheses on resistance mechanisms to antiangiogenic therapy and will guide the development of combination therapy with PD-1/PD-L1–blocking agents. Cancer Immunol Res; 3(9); 1017–29. ©2015 AACR.

Alternate sunitinib schedules in patients with metastatic renal cell carcinoma

Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor exhibiting antiangiogenic activity. Sunitinib demonstrated improved outcomes in comparison to interferon-α in a large phase III study of treatment naïve patients with metastatic renal cell carcinoma. Maintaining patients on sunitinib treatment is essential for a sustained disease control as higher exposure to sunitinib has been associated with an improved overall response rate, progression-free survival and overall survival. Various studies have compared the outcomes of patients undergoing sunitinib therapy based on modifications from their standard dose and schedule. Several studies have shown that switching to an alternate schedule with more frequent dose interruptions without affecting dose density over a 6-week cycle is associated with improved outcomes and increased tolerability.

Role of neutrophil gelatinase-associated lipocalin for early detection of acute kidney injury

Acute kidney injury (AKI) is characterized by abrupt or rapid decline of renal function and is usually associated with the development of serious complications as well as an independent risk of mortality in hospitalized patients. Emergency physicians play a critical role in recognizing early AKI, preventing iatrogenic injury, and reversing the course of AKI. Among the various available biomarkers for AKI, reliable and automated assay methods are commercially available for only cystatin-C and neutrophil gelatinase-associated lipocalin (NGAL). NGAL appears to be a promising marker for early detection of AKI and is likely to be adapted for wide-scale clinical use in patient management as a point-of-care test. Use of NGAL along with panel of other renal biomarkers can improve the rate of early detection of AKI. Large, multicenter studies demonstrate the association between biomarkers and hard end points such as need for renal replacement therapy (RRT), cardiovascular events, hospital stay, and death, independent of serum creatinine concentrations.

Outcomes of unselected patients with metastatic clear-cell renal cell carcinoma treated with first-line pazopanib therapy followed by vascular endothelial growth factor receptor tyrosine kinase inhibitors or mammalian target of rapamycin inhibitors: a single institution experience

To explore the efficacy and safety of pazopanib in a ‘real‐world’ setting in unselected patients, as data regarding unselected patients with metastatic clear‐cell renal cell carcinoma (ccRCC) treated with first‐line pazopanib are limited.

Prognosis of patients with metastatic renal cell carcinoma and pancreatic metastases.

To identify the clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) with pancreatic metastases (PM) treated with either pazopanib or sunitinib and assess whether PM is an independent prognostic variable in the current therapeutic environment.

Outcomes of Patients With Metastatic Non-Clear-Cell Renal Cell Carcinoma Treated With Pazopanib.

Micro‐Abstract Outcomes data in patients with metastatic non–clear‐cell renal cell carcinoma (RCC) treated with pazopanib are limited. We identified 29 patients with non–clear‐cell metastatic RCC who received pazopanib (9 in the front‐line setting, and 20 in the salvage setting). Median overall survival was 31 months (95% confidence interval [CI], 9.2‐NA [not available]) in the front‐line group compared with 13.6 months (95% CI, 6.4‐NA) in the salvage group. Background: Pazopanib is associated with increased progression‐free survival (PFS) in clear‐cell renal cell carcinoma (RCC) and has become a standard of care in this disease. The drug is used in metastatic non–clear‐cell RCC, but data on outcomes in this setting are limited. Patients and Methods: We conducted a retrospective data analysis of records of consecutive metastatic non–clear‐cell RCC patients who received pazopanib in front‐line and salvage settings between November 2009 and November 2012. Tumor response rate was assessed by a blinded radiologist using Response Evaluation Criteria in Solid Tumors version 1.1. PFS and overall survival (OS) times were estimated using Kaplan–Meier methods. Results: Twenty‐nine patients were identified with non–clear‐cell metastatic RCC, 9 received pazopanib in the front‐line setting, 20 in the salvage setting after progression of disease with other targeted therapies. Seven patients (24%) had papillary RCC, 4 (14%) had chromophobe, 5 (17%) had unclassified histopathology, and 13 (45%) had other subtypes including collecting duct, translocation Xp11.2, and various subtypes with sarcomatoid differentiation. All patients discontinued pazopanib before analysis. Median PFS was 8.1 months (95% CI, 5.7‐NA [not available]) in the front‐line group, and 4 months (95% CI, 2.1‐9.9) in the salvage group. Median OS was 31 months (95% CI, 9.2‐NA) in the front‐line group, and 13.6 months (95% CI, 6.4‐NA) in the salvage group. Conclusion: Pazopanib showed efficacy in patients with metastatic non–clear‐cell RCC in the front‐line and salvage settings. Toxicity was mild to moderate and manageable. Further studies are needed to evaluate pazopanibs role in non–clear‐cell RCC in terms of efficacy and safety.

Outcomes of Patients With Metastatic Renal Cell Carcinoma and Bone Metastases in the Targeted Therapy Era

Micro‐Abstract Bone metastases (BMs) are frequently seen in patients with metastatic renal cell carcinoma. Tyrosine kinase inhibitors (TKIs) have improved the overall outcomes. However, data on their effect in patients with BMs seems to be limited. In the present study, we describe the outcomes of patients with BMs treated with TKI therapy and compare them with the outcomes from pre‐TKI group. Our study showed that the incidence of BMs was the same in the pre‐ and post‐TKI era. Background: Bone metastases (BMs) occur commonly in patients with metastatic renal cell carcinoma (mRCC). Tyrosine kinase inhibitors (TKIs) have improved the outcomes for patients with mRCC. However, data on the outcomes of mRCC patients with BMs treated with TKIs are limited. We describe the outcomes of patients with BMs treated with TKI therapy and compare them with the outcomes from a pre‐TKI group. Patients and Methods: Using an institutional tumor registry, a retrospective review of patients with mRCC from 2002 to 2003 and 2006 to 2007 was performed. The baseline characteristics were analyzed, and overall survival (OS) was estimated using the Kaplan‐Meier method. The predictors of OS were analyzed using Cox regression analysis. Results: The data from 375 patients were reviewed. Of these patients, 188 (50%) started treatment with TKIs and 187 (50%) had started treatment in the pre‐TKI era. The distribution of patient characteristics was similar. The sites of organ metastases were equally distributed, including BMs in 48% of the patients in each cohort. The median OS for the patients treated in the TKI era was 22 months (95% confidence interval [CI], 17‐25 months) compared with 14 months (95% CI, 10‐19 months; P < .01) for the historical controls. A subset analysis of patients with BM in the TKI era demonstrated a median OS of 24 months (95% CI, 17‐28 months) compared with 18 months (95% CI, 10‐21 months; P < .01) in pre‐TKI era. The predictors of shorter OS were a higher Memorial Sloan Kettering Cancer Center score; liver, lung, and brain metastases; and multiple sites of BMs (hazard ratio, 1.38; 95% CI, 1.02‐1.91; P = .04). The rate of new BM development was the same in the pre‐ and post‐TKI era. Conclusion: The rate of BM development was the same in the pre‐ and post‐TKI era. The management of BMs in patients with mRCC remains challenging.

The implications of ageing and life expectancy in prostate cancer treatment

In patients diagnosed with prostate cancer, the selection of treatment, including the type of therapy and its aggressiveness, is often based on a patients age and life expectancy. Life expectancy estimates are too often calculated solely on the patients chronological age, overlooking comorbid conditions and their severity, which can greatly affect life expectancy. If, in addition to chronological age, comorbid conditions are used to assess a patients life expectancy, the most appropriate treatment options are more likely to be selected. Older, healthy patients might be able to tolerate more aggressive treatment than would be administered on the basis of their age alone, and younger patients with numerous comorbid conditions could avoid harsh therapy that might not be appropriate given their current state of health. The key idea to consider in treatment selection is what a patients quality of life would be like with or without a particular treatment option. In an era of precision medicine, decisions regarding the provision of health care should be made rationally and on the basis of objective estimates of the threat of disease and the benefits and costs of intervention and within the context of the patients characteristics and desires.