Sandy Srinivas, MD

All Publications

• Efficacy of Second-line Targeted Therapy for Renal Cell Carcinoma According to Change from Baseline in International Metastatic Renal Cell Carcinoma Database Consortium Prognostic Category EUROPEAN UROLOGY Davis, I. D., Xie, W., Pezaro, C., Donskov, F., Wells, J. C., Agarwal, N., Srinivas, S., Yuasa, T., Beuselinck, B., Wood, L. A., Ernst, D. S., Kanesvaran, R., Knox, J. J., Pantuck, A., Saleem, S., Alva, A., Rini, B. I., Lee, J., Choueiri, T. K., Heng, D. Y. 2017; 71 (6): 970-978

  View details for DOI 10.1016/j.eururo.2016.09.047

  View details for Web of Science ID 000400050300031

• Characterizing the outcomes of metastatic papillary renal cell carcinoma CANCER MEDICINE Wells, J. C., Donskov, F., Fraccon, A. P., Pasini, F., Bjarnason, G. A., Beuselinck, B., Knox, J. J., Rha, S. Y., Agarwal, N., Bowman, I. A., Lee, J., Pal, S. K., Srinivas, S., Ernst, D. S., Vaishampayan, U. N., Wood, L. A., Simpson, R., de Velasco, G., Choueiri, T. K., Heng, D. Y. 2017; 6 (5): 902-909

  Abstract

  Outcomes of metastatic papillary renal cell carcinoma (pRCC) patients are poorly characterized in the era of targeted therapy. A total of 5474 patients with metastatic renal cell carcinoma (mRCC) in the International mRCC Database Consortium (IMDC) were retrospectively analyzed. Outcomes were compared between clear cell (ccRCC; n = 5008) and papillary patients (n = 466), and recorded type I and type II papillary patients (n = 30 and n = 165, respectively). Overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) favored ccRCC over pRCC. OS was 8 months longer in ccRCC patients and the hazard ratio of death was 0.71 for ccRCC patients. No differences in PFS or ORR were detected between type I and II PRCC in this limited dataset. The median OS for type I pRCC was 20.0 months while the median OS for type II was 12.6 months (P = 0.096). The IMDC prognostic model was able to stratify pRCC patients into favorable risk (OS = 34.1 months), intermediate risk (OS = 17.0 months), and poor-risk groups (OS = 6.0 months). pRCC patient outcomes were inferior to ccRCC, even after controlling for IMDC prognostic factors. The IMDC prognostic model was able to effectively stratify pRCC patients.

  View details for DOI 10.1002/cam4.1048

  View details for Web of Science ID 000401330300002

  View details for PubMedID 28414866

• CheckMate 025 Randomized Phase 3 Study: Outcomes by Key Baseline Factors and Prior Therapy for Nivolumab Versus Everolimus in Advanced Renal Cell Carcinoma. European urology Escudier, B., Sharma, P., McDermott, D. F., George, S., Hammers, H. J., Srinivas, S., Tykodi, S. S., Sosman, J. A., Procopio, G., Plimack, E. R., Castellano, D., Gurney, H., Donskov, F., Peltola, K., Wagstaff, J., Gauler, T. C., Ueda, T., Zhao, H., Waxman, I. M., Motzer, R. J. 2017

  Abstract

  The randomized, phase 3 CheckMate 025 study of nivolumab (n=410) versus everolimus (n=411) in previously treated adults (75% male; 88% white) with advanced renal cell carcinoma (aRCC) demonstrated significantly improved overall survival (OS) and objective response rate (ORR).To investigate which baseline factors were associated with OS and ORR benefit with nivolumab versus everolimus.Subgroup OS analyses were performed using Kaplan-Meier methodology. Hazard ratios were estimated using the Cox proportional hazards model.Nivolumab 3mg/kg every 2 wk or everolimus 10mg once daily.The minimum follow-up was 14 mo. Baseline subgroup distributions were balanced between nivolumab and everolimus arms. Nivolumab demonstrated an OS improvement versus everolimus across subgroups, including Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium risk groups; age <65 and ≥65 yr; one and two or more sites of metastases; bone, liver, and lung metastases; number of prior therapies; duration of prior therapy; and prior sunitinib, pazopanib, or interleukin-2 therapy. The benefit with nivolumab versus everolimus was noteworthy for patients with poor MSKCC risk (hazard ratio 0.48, 95% confidence interval 0.32-0.70). The mortality rate at 12 mo for all subgroups was lower with nivolumab compared with everolimus. ORR also favored nivolumab. The incidence of grade 3 or 4 treatment-related adverse events across subgroups was lower with nivolumab. Limitations include the post hoc analysis and differing sample sizes between groups.The trend for OS and ORR benefit with nivolumab for multiple subgroups, without notable safety concerns, may help to guide treatment decisions, and further supports nivolumab as the standard of care in previously treated patients with aRCC.We investigated the impact of demographic and pretreatment features on survival benefit and tumor response with nivolumab versus everolimus in advanced renal cell carcinoma (aRCC). Survival benefit and response were observed for multiple subgroups, supporting the use of nivolumab as a new standard of care across a broad range of patients with previously treated aRCC. The trial is registered on ClinicalTrials.gov as NCT01668784.

  View details for DOI 10.1016/j.eururo.2017.02.010

  View details for PubMedID 28262413

• Third-line Targeted Therapy in Metastatic Renal Cell Carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium EUROPEAN UROLOGY Wells, J. C., Stukalin, I., Norton, C., Srinivas, S., Lee, J. L., Donskov, F., Bjarnason, G. A., Yamamoto, H., Beuselinck, B., Rini, B. I., Knox, J. J., Agarwal, N., Ernst, D. S., Pal, S. K., Wood, L. A., Bamias, A., Alva, A. S., Kanesvaran, R., Choueiri, T. K., Heng, D. Y. 2017; 71 (2): 204-209

  Abstract

  The use of third-line targeted therapy (TTT) in metastatic renal cell carcinoma (mRCC) is not well characterized and varies due to the lack of robust data to guide treatment decisions. This study examined the use of third-line therapy in a large international population.To evaluate the use and efficacy of targeted therapy in a third-line setting.Twenty-five international cancer centers provided consecutive data on 4824 mRCC patients who were treated with an approved targeted therapy. One thousand and twelve patients (21%) received TTT and were included in the analysis.Patients were analyzed for overall survival (OS) and progression-free survival using Kaplan-Meier curves, and were evaluated for overall response. Cox regression analyses were used to determine the statistical association between OS and the six factors included in the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic model. Subgroup analysis was performed on patients stratified by their IMDC prognostic risk status.Everolimus was the most prevalent third-line therapy (27.5%), but sunitinib, sorafenib, pazopanib, temsirolimus, and axitinib were all utilized in over ≥9% of patients. Patients receiving any TTT had an OS of 12.4 mo, a progression-free survival of 3.9 mo, and 61.1% of patients experienced an overall response of stable disease or better. Patients not receiving TTT had an OS of 2.1 mo. Patients with favorable- (7.2%) or intermediate-risk (65.3%) disease had the highest OS with TTT, 29.9 mo and 15.5 mo, respectively, while poor-risk (27.5%) patients survived 5.5 mo. Results are limited by the retrospective nature of the study.TTT remains highly heterogeneous. The IMDC prognostic criteria can be used to stratify third-line patients. TTT use in favorable- and intermediate-risk patients was associated with the greatest OS.Patients with favorable- and intermediate-prognostic criteria disease treated with third-line targeted therapy have an associated longer overall survival compared with those with poor risk disease.

  View details for DOI 10.1016/j.eururo.2016.05.049

  View details for Web of Science ID 000390565700035

  View details for PubMedID 27318422

• Nomogram-based Prediction of Overall Survival in Patients with Metastatic Urothelial Carcinoma Receiving First-line Platinum-based Chemotherapy: Retrospective International Study of Invasive/Advanced Cancer of the Urothelium (RISC) EUROPEAN UROLOGY Necchi, A., Sonpavde, G., Lo Vullo, S., Giardiello, D., Bamias, A., Crabb, S. J., Harshman, L. C., Bellmunt, J., De Giorgi, U., Sternberg, C. N., Cerbone, L., Ladoire, S., Wong, Y., Yu, E. Y., Chowdhury, S., Niegisch, G., Srinivas, S., Vaishampayan, U. N., Pal, S. K., Agarwal, N., Alva, A., Baniel, J., Golshayan, A., Morales-Barrera, R., Bowles, D. W., Milowsky, M. I., Theodore, C., Berthold, D. R., Daugaard, G., Sridhar, S. S., Powles, T., Rosenberg, J. E., Galsky, M. D., Mariani, L. 2017; 71 (2): 281-289

  View details for DOI 10.1016/j.eururo.2016.09.042

  View details for Web of Science ID 000390565700047

• Discontinuing VEGF-targeted Therapy for Progression Versus Toxicity Affects Outcomes of Second-line Therapies in Metastatic Renal Cell Carcinoma. Clinical genitourinary cancer de Velasco, G., Xie, W., Donskov, F., Albiges, L., Beuselinck, B., Srinivas, S., Agarwal, N., Lee, J. L., Brugarolas, J., Wood, L. A., Rha, S., Kollmannsberger, C., North, S., Kanesvaran, R., Rini, B. I., Broom, R., Yamamoto, H., Kaymakcalan, M. D., Heng, D. Y., Choueiri, T. K. 2017

  Abstract

  A significant subgroup of metastatic renal cell carcinoma (mRCC) patients discontinue vascular endothelial growth factor-targeted therapies (VEGF-TT) because of toxicity. Whether clinical outcomes differ in patients who receive second-line (2L) targeted therapy on the basis of reason for discontinuation of first-line (1L) therapy is unknown.Patients from 15 International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) centers who started 2L targeted therapy were included and the reason for discontinuation of 1L therapy retrospectively collected. Treatment outcomes of 2L, including response, time to treatment failure, and overall survival (OS) were assessed.In total, 1124 patients were identified: 866 patients (77%) discontinued 1L VEGF-TT because of disease progression, and 208 patients (19%) because of toxicity. The reason for discontinuation of 1L therapy did not differ according to IMDC risk group. Compared with patients who stopped 1L VEGF-TT because of disease progression, patients who stopped because of toxicity had greater clinical benefit (nonprogressive disease as best response) in 2L treatment (68% vs. 56%; adjusted odds ratio, 1.58; 95% confidence interval [CI], 1.07-2.35; P = .023) and longer OS (17.4 vs. 11.2 months; adjusted hazard ratio, 0.69; 95% CI, 0.56-0.84; P = .0002) adjusted for type of therapy, time to initiation of 2L treatment, IMDC risk group, and number of metastases at initiation of 2L treatment.mRCC patients who discontinue 1L VEGF-TT because of toxicity have better outcomes with 2L therapy than patients who stop therapy because of disease progression. These findings should be taken into consideration when designing clinical trials for 2L therapies in mRCC.

  View details for DOI 10.1016/j.clgc.2017.01.005

  View details for PubMedID 28254206

• Body Mass Index and Metastatic Renal Cell Carcinoma: Clinical and Biological Correlations JOURNAL OF CLINICAL ONCOLOGY Albiges, L., Hakimi, A. A., Xie, W., McKay, R. R., Simantov, R., Lin, X., Lee, J., Rini, B. I., Srinivas, S., Bjarnason, G. A., Ernst, S., Wood, L. A., Vaishamayan, U. N., Rha, S., Agarwal, N., Yuasa, T., Pal, S. K., Bamias, A., Zabor, E. C., Skanderup, A. J., Furberg, H., Fay, A. P., de Velasco, G., Preston, M. A., Wilson, K. M., Cho, E., McDermott, D. F., Signoretti, S., Heng, D. Y., Choueiri, T. K. 2016; 34 (30): 3655-?

  Abstract

  Obesity is an established risk factor for clear cell renal cell carcinoma (RCC); however, some reports suggest that RCC developing in obese patients may be more indolent. We investigated the clinical and biologic effect of body mass index (BMI) on treatment outcomes in patients with metastatic RCC.The impact of BMI (high BMI: ≥ 25 kg/m(2) v low BMI: < 25 kg/m(2)) on overall survival (OS) and treatment outcome with targeted therapy was investigated in 1,975 patients from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) and in an external validation cohort of 4,657 patients. Gene expression profiling focusing on fatty acid metabolism pathway, in The Cancer Genome Atlas data set, and immunohistochemistry staining for fatty acid synthase (FASN) were also investigated. Cox regression was undertaken to estimate the association of BMI with OS, adjusted for the IMDC prognostic factors.In the IMDC cohort, median OS was 25.6 months (95% CI, 23.2 to 28.6) in patients with high BMI versus 17.1 months (95% CI, 15.5 to 18.5) in patients with low BMI (adjusted hazard ratio, 0.84; 95% CI, 0.73 to 0.95). In the validation cohort, high BMI was associated with improved OS (adjusted hazard ratio, 0.83; 95% CI, 0.74 to 0.93; medians: 23.4 months [95% CI, 21.9 to 25.3 months] v 14.5 months [95% CI, 13.8 to 15.9 months], respectively). In The Cancer Genome Atlas data set (n = 61), FASN gene expression inversely correlated with BMI (P = .034), and OS was longer in the low FASN expression group (medians: 36.8 v 15.0 months; P = .002). FASN immunohistochemistry positivity was more frequently detected in IMDC poor (48%) and intermediate (34%) risk groups than in the favorable risk group (17%; P-trend = .015).High BMI is a prognostic factor for improved survival and progression-free survival in patients with metastatic RCC treated with targeted therapy. Underlying biology suggests a role for the FASN pathway.

  View details for DOI 10.1200/JCO.2016.66.7311

  View details for Web of Science ID 000385972600012

  View details for PubMedID 27601543

• Phase II Study of Pazopanib and Paclitaxel in Patients With Refractory Urothelial Cancer. Clinical genitourinary cancer Narayanan, S., Lam, A., Vaishampayan, U., Harshman, L., Fan, A., Pachynski, R., Poushnejad, S., Haas, D., Li, S., Srinivas, S. 2016; 14 (5): 432-437

  Abstract

  Currently, no standard treatments are available for relapsed or refractory urothelial carcinoma (UC). Paclitaxel has demonstrated efficacy in the treatment of UC when used alone or combined with other cytotoxic therapies. We designed a phase II trial combining paclitaxel with pazopanib, a commonly used antiangiogenic agent with significant antitumor activity in various solid tumors.We enrolled 32 patients with refractory UC who had demonstrated disease progression after 2 previous chemotherapeutic regimens. The patients received paclitaxel 80 mg/m(2) on days 1, 8, and 15 of a 28-day cycle and oral pazopanib 800 mg daily. The primary endpoint was the overall response rate (ORR). The secondary endpoints included progression-free survival, overall survival, and a safety assessment of the combination.Of the 28 evaluable patients, a complete response was observed in 3 patients and a partial response in 12, with an ORR of 54% (95% confidence interval, 33.9-72.5). The median progression-free and overall survival was 6.2 and 10 months, respectively. The most frequent side effects noted (all grades) were fatigue (63%), diarrhea (44%), and nausea and vomiting (41%). Hematologic toxicities were common and included (all grades) anemia (69%), neutropenia (38%), and thrombocytopenia (47%). Growth factor support was required for 44% of the patients.The combination of paclitaxel and pazopanib resulted in a promising ORR of 54% in patients with advanced pretreated UC. This represents a greater response rate and median survival than found with other existing second-line regimens for UC and is worthy of further study.

  View details for DOI 10.1016/j.clgc.2016.03.011

  View details for PubMedID 27068017

• Overall Survival in Patients with Localized Prostate Cancer in the US Veterans Health Administration: Is PIVOT Generalizable? EUROPEAN UROLOGY Barbosa, P. V., Thomas, I., Srinivas, S., Buyyounouski, M. K., Chung, B. I., Chertow, G. M., Asch, S. M., Wagner, T. H., Brooks, J. D., Leppert, J. T. 2016; 70 (2): 227-230

  Abstract

  A better understanding of overall survival among patients with clinically localized prostate cancer (PCa) in the US Veterans Health Administration (VHA) is critical to inform PCa treatment decisions, especially in light of data from the Prostate Intervention Versus Observation Trial (PIVOT). We sought to describe patterns of survival for all patients with clinically localized PCa treated by the VHA. We created an analytic cohort of 35 954 patients with clinically localized PCa diagnosed from 1995 to 2001, approximating the PIVOT inclusion criteria (age of diagnosis ≤75 yr and clinical stage T2 or lower). Mean patient age was 65.9 yr, and median follow-up was 161 mo. Overall, 22.5% of patients were treated with surgery, 16.6% were treated with radiotherapy, and 23.1% were treated with androgen deprivation. Median survival of the entire cohort was 14 yr (25th, 75th percentiles, range: 7.9-20 yr). Among patients who received treatment with curative intent, median survival was 17.9 yr following surgery and 12.9 yr following radiotherapy. One-third of patients died within 10 yr of diagnosis compared with nearly half of the participants in PIVOT. This finding sounds a note of caution when generalizing the mortality data from PIVOT to VHA patients and those in the community.More than one-third of patients diagnosed with clinically localized prostate cancer treated through the US Veterans Health Administration from 1995 to 2001 died within 10 yr of their diagnosis. Caution should be used when generalizing the estimates of competing mortality data from PIVOT.

  View details for DOI 10.1016/j.eururo.2016.02.037

  View details for Web of Science ID 000378206600016

  View details for PubMedID 26948397

• Second-Line Chemotherapy for Metastatic Urothelial Carcinoma: Importance of Lymph Node-Only Metastasis as a Prognostic Factor and Construction of a Prognostic Model CLINICAL GENITOURINARY CANCER Salah, S., Lee, J., Rozzi, A., Kitamura, H., Matsumoto, K., Srinivas, S., Morales-Barrera, R., Carles, J., Al-Wardat, R., Al-Rabi, K., Maakoseh, M. 2016; 14 (3): 255-260

  Abstract

  A prognostic model for patients with metastatic urothelial carcinoma (UC) progressing after platinum-based therapy was constructed from data from the phase III vinflunine trial. However, prognostic information for patients treated with other regimens is limited.We pooled individual patient data from 7 second-line studies and analyzed the influence of factors of interest on overall survival (OS) through univariate and multivariate analysis. A prognostic model was constructed, and data from an independent series were used for validation.The data from 193 patients were pooled. The second-line chemotherapy regimen was single-agent taxane in 54 patients (28%), a platinum-based combination in 47 (24%), and a non-platinum combination in 92 (48%). On multivariate analysis, Eastern Cooperative Oncology Group performance status ≥ 1, hemoglobin < 10 g/dL, and metastatic patterns other than lymph node-only metastasis emerged as independent adverse prognostic factors. Patients with all 3 factors (poor risk), 1 to 2 factors (intermediate risk), and no factors (good risk) had a median OS of 3.1, 8.7, and 16.5 months, respectively (P < .0001). The corresponding median OS for the validation series (n = 44) was 3.3, 8.1, and 13.3 months (P = .023). Furthermore, platinum-based regimens were independently associated with an OS benefit compared with other regimens (hazard ratio, 0.31; 95% confidence interval, 0.18-0.53; P < .0001).We have proposed and validated a prognostic model for patients with metastatic UC who were eligible for second-line therapy. The proposed model could prove helpful for risk stratification. Furthermore, our data suggest that testing second-line platinum-based regimens in randomized trials is warranted.

  View details for DOI 10.1016/j.clgc.2015.10.006

  View details for Web of Science ID 000377409600016

  View details for PubMedID 26552764

• Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial LANCET Rosenberg, J. E., Hoffman-Censits, J., Powles, T., van der Heijden, M. S., Balar, A. V., Necchi, A., Dawson, N., O'Donnell, P. H., Balmanoukian, A., Loriot, Y., Srinivas, S., Retz, M. M., Grivas, P., Joseph, R. W., Galsky, M. D., Fleming, M. T., Petrylak, D. P., Perez-Gracia, J. L., Burris, H. A., Castellano, D., Canil, C., Bellmunt, J., Bajorin, D., Nickles, D., Bourgon, R., Frampton, G. M., Cui, N., Mariathasan, S., Abidoye, O., Fine, G. D., Dreicer, R. 2016; 387 (10031): 1909-1920

  Abstract

  Patients with metastatic urothelial carcinoma have few treatment options after failure of platinum-based chemotherapy. In this trial, we assessed treatment with atezolizumab, an engineered humanised immunoglobulin G1 monoclonal antibody that binds selectively to programmed death ligand 1 (PD-L1), in this patient population.For this multicentre, single-arm, two-cohort, phase 2 trial, patients (aged ≥18 years) with inoperable locally advanced or metastatic urothelial carcinoma whose disease had progressed after previous platinum-based chemotherapy were enrolled from 70 major academic medical centres and community oncology practices in Europe and North America. Key inclusion criteria for enrolment were Eastern Cooperative Oncology Group performance status of 0 or 1, measurable disease defined by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), adequate haematological and end-organ function, and no autoimmune disease or active infections. Formalin-fixed paraffin-embedded tumour specimens with sufficient viable tumour content were needed from all patients before enrolment. Patients received treatment with intravenous atezolizumab (1200 mg, given every 3 weeks). PD-L1 expression on tumour-infiltrating immune cells (ICs) was assessed prospectively by immunohistochemistry. The co-primary endpoints were the independent review facility-assessed objective response rate according to RECIST v1.1 and the investigator-assessed objective response rate according to immune-modified RECIST, analysed by intention to treat. A hierarchical testing procedure was used to assess whether the objective response rate was significantly higher than the historical control rate of 10% at an α level of 0·05. This study is registered with ClinicalTrials.gov, number NCT02108652.Between May 13, 2014, and Nov 19, 2014, 486 patients were screened and 315 patients were enrolled into the study. Of these patients, 310 received atezolizumab treatment (five enrolled patients later did not meet eligibility criteria and were not dosed with study drug). The PD-L1 expression status on infiltrating immune cells (ICs) in the tumour microenvironment was defined by the percentage of PD-L1-positive immune cells: IC0 (<1%), IC1 (≥1% but <5%), and IC2/3 (≥5%). The primary analysis (data cutoff May 5, 2015) showed that compared with a historical control overall response rate of 10%, treatment with atezolizumab resulted in a significantly improved RECIST v1.1 objective response rate for each prespecified immune cell group (IC2/3: 27% [95% CI 19-37], p<0·0001; IC1/2/3: 18% [13-24], p=0·0004) and in all patients (15% [11-20], p=0·0058). With longer follow-up (data cutoff Sept 14, 2015), by independent review, objective response rates were 26% (95% CI 18-36) in the IC2/3 group, 18% (13-24) in the IC1/2/3 group, and 15% (11-19) overall in all 310 patients. With a median follow-up of 11·7 months (95% CI 11·4-12·2), ongoing responses were recorded in 38 (84%) of 45 responders. Exploratory analyses showed The Cancer Genome Atlas (TCGA) subtypes and mutation load to be independently predictive for response to atezolizumab. Grade 3-4 treatment-related adverse events, of which fatigue was the most common (five patients [2%]), occurred in 50 (16%) of 310 treated patients. Grade 3-4 immune-mediated adverse events occurred in 15 (5%) of 310 treated patients, with pneumonitis, increased aspartate aminotransferase, increased alanine aminotransferase, rash, and dyspnoea being the most common. No treatment-related deaths occurred during the study.Atezolizumab showed durable activity and good tolerability in this patient population. Increased levels of PD-L1 expression on immune cells were associated with increased response. This report is the first to show the association of TCGA subtypes with response to immune checkpoint inhibition and to show the importance of mutation load as a biomarker of response to this class of agents in advanced urothelial carcinoma.F Hoffmann-La Roche Ltd.

  View details for DOI 10.1016/S0140-6736(16)00561-4

  View details for Web of Science ID 000375374200035

  View details for PubMedID 26952546

• Prognostic Value of Quantitative Metabolic Metrics on Baseline Pre-Sunitinib FDG PET/CT in Advanced Renal Cell Carcinoma PLOS ONE Minamimoto, R., Barkhodari, A., Harshman, L., Srinivas, S., Quon, A. 2016; 11 (4)

  Abstract

  The objective of this study was to prospectively evaluate various quantitative metrics on FDG PET/CT for monitoring sunitinib therapy and predicting prognosis in patients with metastatic renal cell cancer (mRCC).Seventeen patients (mean age: 59.0 ± 11.6) prospectively underwent a baseline FDG PET/CT and interim PET/CT after 2 cycles (12 weeks) of sunitinib therapy. We measured the highest maximum standardized uptake value (SUVmax) of all identified lesions (highest SUVmax), sum of SUVmax with maximum six lesions (sum of SUVmax), total lesion glycolysis (TLG) and metabolic tumor volume (MTV) from baseline PET/CT and interim PET/CT, and the % decrease in highest SUVmax of lesion (%Δ highest SUVmax), the % decrease in sum of SUVmax, the % decrease in TLG (%ΔTLG) and the % decrease in MTV (%ΔMTV) between baseline and interim PET/CT, and the imaging results were validated by clinical follow-up at 12 months after completion of therapy for progression free survival (PFS).At 12 month follow-up, 6/17 (35.3%) patients achieved PFS, while 11/17 (64.7%) patients were deemed to have progression of disease or recurrence within the previous 12 months. At baseline, PET/CT demonstrated metabolically active cancer in all cases. Using baseline PET/CT alone, all of the quantitative imaging metrics were predictive of PFS. Using interim PET/CT, the %Δ highest SUVmax, %Δ sum of SUVmax, and %ΔTLG were also predictive of PFS. Otherwise, interim PET/CT showed no significant difference between the two survival groups regardless of the quantitative metric utilized including MTV and TLG.Quantitative metabolic measurements on baseline PET/CT appears to be predictive of PFS at 12 months post-therapy in patients scheduled to undergo sunitinib therapy for mRCC. Change between baseline and interim PET/CT also appeared to have prognostic value but otherwise interim PET/CT after 12 weeks of sunitinib did not appear to be predictive of PFS.

  View details for DOI 10.1371/journal.pone.0153321

  View details for Web of Science ID 000375211700014

  View details for PubMedID 27123976

• Immunohistochemical analysis of lichenoid reactions in patients treated with anti-PD-L1 and anti-PD-1 therapy. Journal of cutaneous pathology Schaberg, K. B., Novoa, R. A., Wakelee, H. A., Kim, J., Cheung, C., Srinivas, S., Kwong, B. Y. 2016; 43 (4): 339-346

  Abstract

  Recent advances in the immunotherapeutic treatment of cancer have led to the development of multiple new directed therapies including monoclonal antibodies that block the immune checkpoint T-cell receptor programmed death 1 (PD-1) and the PD-1 ligand, programmed death ligand 1 (PD-L1). Various immune-related toxicities have been associated with these drugs including, most commonly, skin rashes.Five cases of lichenoid dermatitis, including one case of lichenoid mucositis and one case of lichen sclerosus, associated with anti-PD-L1 and anti-PD1 therapy were compared with three biopsies of non-drug-related lichen planus (LP) and three lichen planus-like keratoses (LPLK) used as controls.Histopathologic and immunophenotypic analysis of these lichenoid lesions demonstrated significantly greater histiocytic infiltrates than observed in control lichenoid reactions (p = 0.0134). We also observed increased spongiosis and epidermal necrosis. No significant differences were seen in expression of CD3, CD4:CD8, CD20, PD-1, CD25, Foxp3, CXCL13 and PD-L1 expression.These findings expand the literature of immune-related toxicities of PD-L1 and PD-1 blockade to include lichenoid dermatitis and lichenoid mucositis. Of note, these cutaneous side effects were amenable to topical treatment, without the need for medication dose reduction or discontinuation.

  View details for DOI 10.1111/cup.12666

  View details for PubMedID 26762844

• Androgen-glucocorticoid interactions in the era of novel prostate cancer therapy. Nature reviews. Urology Narayanan, S., Srinivas, S., Feldman, D. 2016; 13 (1): 47-60

  Abstract

  Great strides have been made in the treatment of castration-resistant prostate cancer (CRPC) with the development of new antiandrogens (enzalutamide) and more potent androgen synthesis inhibitors (abiraterone) that have both improved patient outcomes. These new drugs have also helped unravel the complex biology of androgen-androgen receptor driven prostate cancer and brought into prominence various mechanisms triggering the development of drug resistance and tumour cell survival despite use of androgen deprivation therapy (ADT). The complex role of glucocorticoids in the treatment, management and progression of patients with CRPC is integral to these advances. Historically, glucocorticoid treatment has resulted in both subjective and objective responses in patients with advanced-stage prostate cancer. With the use of these new therapeutic agents, however, unexpected glucocorticoid-related mechanisms that can cause iatrogenic stimulation of prostate cancer growth have emerged, which might contribute to drug resistance and disease progression despite optimal ADT. For example, the upregulation of glucocorticoid receptors (GRs) during enzalutamide therapy results in glucocorticoid-GR-mediated regulation of androgen target genes, leading to escape from enzalutamide blockade. Thus, understanding the biological role of glucocorticoids in patients with prostate cancer is of major importance in the era of new and evolving antiandrogen therapies.

  View details for DOI 10.1038/nrurol.2015.254

  View details for PubMedID 26643568

• Prostate Cancer, Version 1.2016 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Mohler, J. L., Armstrong, A. J., Bahnson, R. R., D'Amico, A. V., Davis, B. J., Eastham, J. A., Enke, C. A., Farrington, T. A., Higano, C. S., Horwitz, E. M., Hurwitz, M., Kane, C. J., Kawachi, M. H., Kuettel, M., Lee, R. J., Meeks, J. J., Penson, D. F., Plimack, E. R., Pow-Sang, J. M., Raben, D., Richey, S., Roach, M., Rosenfeld, S., Schaeffer, E., Skolarus, T. A., Small, E. J., Sonpavde, G., Srinivas, S., Strope, S. A., Tward, J., Shead, D. A., Freedman-Cass, D. A. 2016; 14 (1): 19-30

  View details for Web of Science ID 000367629000005

• Androgen-glucocorticoid interactions in the era of novel prostate cancer therapy NATURE REVIEWS UROLOGY Narayanan, S., Srinivas, S., Feldman, D. 2016; 13 (1): 47-60

  View details for DOI 10.1038/nrurol.2015.254

  View details for Web of Science ID 000367655300006

• Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma NEW ENGLAND JOURNAL OF MEDICINE Motzer, R. J., Escudier, B., McDermott, D. F., George, S., Hammers, H. J., Srinivas, S., Tykodi, S. S., Sosman, J. A., Procopio, G., Plimack, E. R., Castellano, D., Choueiri, T. K., Gurney, H., Donskov, F., Bono, P., Wagstaff, J., Gauler, T. C., Ueda, T., Tomita, Y., Schutz, F. A., Kollmannsberger, C., Larkin, J., Ravaud, A., Simon, J. S., Xu, L., Waxman, I. M., Sharma, P. 2015; 373 (19): 1803-1813

  View details for DOI 10.1056/NEJMoa1510665

  View details for Web of Science ID 000364144000004

  View details for PubMedID 26406148

• Characterizing the impact of lymph node metastases on the survival outcome for metastatic renal cell carcinoma patients treated with targeted therapies. European urology Kroeger, N., Pantuck, A. J., Wells, J. C., Lawrence, N., Broom, R., Kim, J. J., Srinivas, S., Yim, J., Bjarnason, G. A., Templeton, A., Knox, J., Bernstein, E., Smoragiewicz, M., Lee, J., Rini, B. I., Vaishampayan, U. N., Wood, L. A., Beuselinck, B., Donskov, F., Choueiri, T. K., Heng, D. Y. 2015; 68 (3): 506-515

  Abstract

  It is unknown whether lymph node metastases (LNM) and their localization negatively affect clinical outcome in metastatic renal cell carcinoma (mRCC) patients.To evaluate the clinicopathological features, survival outcome, and treatment response in mRCC patients with LNM versus those without LNM after treatment with targeted therapies (TT).Patients (n=2996) were first analyzed without consideration of lymph node (LN) localization or histologic subtype. Additional analyses (n=1536) were performed in subgroups of patients with supradiaphragmatic (SPD) LNM, subdiaphragmatic (SBD) LNM, and patients with LNM in both locations (SPD+/SBD+) without histologic considerations, and then separately in clear cell RCC (ccRCC) and non-clear cell RCC (nccRCC) patients, respectively.The primary outcome was overall survival (OS) and the secondary outcome was progression-free survival (PFS).All patients with LNM had worse PFS (p=0.001) and OS (p<0.001) compared to those without LNM. Compared to patients without LNM (PFS 8.8 mo; OS 25.1 mo), any SBD LNM involvement was associated with worse PFS (SBD, 6.8 mo; p=0.003; SPD+/SBD+, 5.5 mo; p<0.001) and OS (SBD, 16.2 mo; p<0.001; SPD+/SBD+, 11.5 mo; p<0.001). Both SBD and SPD+/SBD+ LNM were retained as independent prognostic factors in multivariate analyses (MVA) for PFS (p=0.006 and p=0.022, respectively) and OS (both p<0.001), while SPD LNM was not an independent risk factor. Likewise, in ccRCC, SBD LNM (19.8 mo) and SPD+/SBD+ LNM (12.85 mo) patients had the worst OS. SPD+/SBD+ LNM (p=0.006) and SBD LNM (p=0.028) were independent prognostic factors for OS in MVA, while SPD LNM was not significant (p=0.301). The study is limited by its retrospective design and the lack of pathologic evaluation of LNM in all cases.The metastatic spread of RCC to SBD lymph nodes is associated with poor prognosis in mRCC patients treated with TT.The presence of lymph node metastases below the diaphragm is associated with shorter survival outcome when metastatic renal cell carcinoma (mRCC) patients are treated with targeted therapies. Clinical trials should evaluate whether surgical removal of regional lymph nodes at the time of nephrectomy may improve outcomes in high-risk RCC patients.

  View details for DOI 10.1016/j.eururo.2014.11.054

  View details for PubMedID 25524810

• Characterizing the Impact of Lymph Node Metastases on the Survival Outcome for Metastatic Renal Cell Carcinoma Patients Treated with Targeted Therapies EUROPEAN UROLOGY Kroeger, N., Pantuck, A. J., Wells, J. C., Lawrence, N., Broom, R., Kim, J. J., Srinivas, S., Yim, J., Bjarnason, G. A., Templeton, A., Knox, J., Bernstein, E., Smoragiewicz, M., Lee, J., Rini, B. I., Vaishampayan, U. N., Woodm, L. A., Beuselinck, B., Donskov, F., Choueiri, T. K., Heng, D. Y. 2015; 68 (3): 506-515

  View details for DOI 10.1016/j.eururo.2014.11.054

  View details for Web of Science ID 000360572300035

• Outcome of patients with metastatic sarcomatoid renal cell carcinoma: results from the international metastatic renal cell carcinoma database consortium. Clinical genitourinary cancer Kyriakopoulos, C. E., Chittoria, N., Choueiri, T. K., Kroeger, N., Lee, J., Srinivas, S., Knox, J. J., Bjarnason, G. A., Ernst, S. D., Wood, L. A., Vaishampayan, U. N., Agarwal, N., Pal, S. K., Kanesvaran, R., Rha, S., Yuasa, T., Donskov, F., North, S. A., Heng, D. Y., Rini, B. I. 2015; 13 (2): e79-85

  Abstract

  Sarcomatoid renal cell carcinoma is associated with poor prognosis. Data regarding outcome in the targeted therapy era are lacking.Clinical, prognostic, and treatment parameters in metastatic renal cell carcinoma patients with and without sarcomatoid histology treated with targeted therapy were retrospectively analyzed.Two thousand two hundred eighty-six patients were identified (sRCC: n = 230 and non-sRCC: n = 2056). sRCC patients had significantly worse IMDC prognostic criteria compared with non-sRCC (11% vs. 19% favorable risk; 49% vs. 57% intermediate risk, and 40% vs. 24% poor risk; P < .0001). Time from original diagnosis to relapse (excluding synchronous metastatic disease) was shorter in the sRCC group (18.8 vs. 42.9 months; P < .0001). There was no significant difference in the incidence of central nervous system metastases (6%-8%) or underlying clear cell histology (87%-88%). More than 93% of patients received VEGF inhibitors as first-line therapy; objective response was less common in sRCC whereas primary refractory disease was more common (21% vs. 26% and 43% vs. 21%; P < .0001, for both). sRCC patients had significantly less use of second- (P = .018) and third-line (P < .0001) systemic therapy. The median progression-free survival (PFS)/overall survival (OS) was 4.5/10.4 months in sRCC patients and 7.8/22.5 months in non-sRCC patients (P < .0001 for both). Sarcomatoid histology was associated with a significantly worse PFS and OS after adjusting for individual IMDC risk factors in multivariable analysis (hazard ratio, 1.5; P < .0001 for both).Patients with sRCC have a shorter time to relapse, worse baseline prognostic criteria, and worse clinical outcome with targeted therapy. Additional insight into the biology of sRCC is needed to develop alternative therapeutics.

  View details for DOI 10.1016/j.clgc.2014.08.011

  View details for PubMedID 25450036

• Second-Line Therapies in Metastatic Urothelial Carcinoma HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA Narayanan, S., Harshman, L. C., Srinivas, S. 2015; 29 (2): 341-?

  Abstract

  Patients with relapsed or refractory urothelial carcinoma (UC) face a poor prognosis and a dearth of available treatment options that improve their survival. End-organ function and performance status play a vital role in the choice of second-line therapies. Evidence supporting the use of cytotoxic chemotherapy, as single agents or in combination, arises from small phase 2 studies with modest responses. With the evolution of genomic testing in UC, several pathways amenable to available targeted therapies have emerged. Encouraging patient participation in clinical trials is critical to improve patient outcomes and to advance the current modest treatment armamentarium.

  View details for DOI 10.1016/j.hoc.2014.10.007

  View details for Web of Science ID 000353430000015

  View details for PubMedID 25836939

• The International Metastatic Renal Cell Carcinoma Database Consortium model as a prognostic tool in patients with metastatic renal cell carcinoma previously treated with first-line targeted therapy: a population-based study. The Lancet. Oncology Ko, J. J., Xie, W., Kroeger, N., Lee, J., Rini, B. I., Knox, J. J., Bjarnason, G. A., Srinivas, S., Pal, S. K., Yuasa, T., Smoragiewicz, M., Donskov, F., Kanesvaran, R., Wood, L., Ernst, D. S., Agarwal, N., Vaishampayan, U. N., Rha, S., Choueiri, T. K., Heng, D. Y. 2015; 16 (3): 293-300

  Abstract

  Previous prognostic models for second-line systemic therapy in patients with metastatic renal cell carcinoma have not been studied in the setting of targeted therapy. We sought to validate the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model in patients with metastatic renal cell carcinoma receiving next-line targeted therapy after progression on first-line targeted therapy.In this population-based study, we analysed patients who received second-line targeted therapy for metastatic renal cell carcinoma at 19 centres in Canada, USA, Greece, Japan, Singapore, South Korea, and Denmark. The primary endpoint was overall survival since the initiation of second-line therapy. We compared the prognostic performance of the IMDC model with the three-factor MSKCC model used for previously treated patients for overall survival since the start of second-line targeted therapy.Between Jan 1, 2005, and Nov 30, 2012, we included 1021 patients treated with second-line targeted therapy. Median overall survival since the start of second-line targeted therapy was 12·5 months (95% CI 11·3-14·3). Five of six predefined factors in the IMDC model (anaemia, thrombocytosis, neutrophilia, Karnofsky performance status [KPS] <80, and <1 year from diagnosis to first-line targeted therapy) were independent predictors of poor overall survival on multivariable analysis. The concordance index using all six prognostic factors (ie, also including hypercalcaemia) was 0·70 (95% CI 0·67-0·72) with the IMDC model and was 0·66 (95% CI 0·64-0·68) with the three-factor MSKCC model. When patients were divided into three risk categories using IMDC criteria, median overall survival was 35·3 months (95% CI 28·3-47·8) in the favourable risk group (n=76), 16·6 months (14·9-17·9) in the intermediate risk group (n=529), and 5·4 months (4·7-6·8) in the poor risk group (n=261).The IMDC prognostic model can be applied to patients previously treated with targeted therapy, in addition to previously validated populations in first-line targeted therapy. The IMDC prognostic model in the second-line targeted therapy setting has an improved prognostic performance and is applicable to a more contemporary patient cohort than that of the three-factor MSKCC model.DF/HCC Kidney Cancer SPORE P50 CA101942-01, Kidney Cancer Research Network of Canada, Canadian Institute for Health Research, Trust Family, Loker Pinard, Michael Brigham, and Gerald DeWulf.

  View details for DOI 10.1016/S1470-2045(14)71222-7

  View details for PubMedID 25681967

• First-Line Mammalian Target of Rapamycin Inhibition in Metastatic Renal Cell Carcinoma: An Analysis of Practice Patterns From the International Metastatic Renal Cell Carcinoma Database Consortium CLINICAL GENITOURINARY CANCER Harshman, L. C., Kroeger, N., Rha, S. Y., Donskov, F., Wood, L., Tantravahi, S. K., Vaishampayan, U., Rini, B. I., Knox, J., North, S., Ernst, S., Yuasa, T., Srinivas, S., Pal, S., Heng, D. Y., Choueiri, T. K. 2014; 12 (5): 335-340

  View details for DOI 10.1016/j.clgc.2014.03.003

  View details for Web of Science ID 000342152800017

• Cytoreductive Nephrectomy in Patients with Synchronous Metastases from Renal Cell Carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium EUROPEAN UROLOGY Heng, D. Y., Wells, J. C., Rini, B. I., Beuselinck, B., Lee, J., Knox, J. J., Bjarnason, G. A., Pal, S. K., Kollmannsberger, C. K., Yuasa, T., Srinivas, S., Donskov, F., Bamias, A., Wood, L. A., Ernst, D. S., Agarwal, N., Vaishampayan, U. N., Rha, S. Y., Kim, J. J., Choueiri, T. K. 2014; 66 (4): 704-710

  View details for DOI 10.1016/j.eururo.2014.05.034

  View details for Web of Science ID 000343156500026

• A Randomized Phase 2 Trial of Gemcitabine/Cisplatin With or Without Cetuximab in Patients With Advanced Urothelial Carcinoma CANCER Hussain, M., Daignault, S., Agarwal, N., Grivas, P. D., Siefker-Radtke, A. O., Puzanov, I., MacVicar, G. R., Levine, E. G., Srinivas, S., Twardowski, P., Eisenberger, M. A., Quinn, D. I., Vaishampayan, U. N., Yu, E. Y., Dawsey, S., Day, K. C., Day, M. L., Al-Hawary, M., Smith, D. C. 2014; 120 (17): 2684-2693

  Abstract

  Epidermal growth factor receptor overexpression is associated with poor outcomes in urothelial carcinoma (UC). Cetuximab (CTX) exhibited an antitumor effect in in vivo UC models. The efficacy of gemcitabine/cisplatin (GC) with or without CTX in patients with advanced UC was evaluated.Patients with advanced UC, measurable disease, and adequate organ function were randomized 1:2 to cisplatin (70 mg/m(2) ) on day 1 plus gemcitabine (1000 mg/m(2) ) on days 1, 8, and 15 (arm A) or GC plus CTX (500 mg/m(2) ) on days 1 and 15 (arm B). The primary endpoint was the overall response rate. The secondary endpoints were the response duration, safety, progression-free survival, overall survival, determination of whether or not CTX sensitized nonresponders to GC, and exploratory biomarker analysis. The accrual targets were 27 and 54 patients for the 2 arms, respectively. The overall response rate was reported by arm with binomial confidence intervals (CIs). Kaplan-Meier methods were used for time-to-event endpoints.Eighty-eight eligible patients were randomized; 87 were toxicity-evaluable, and 85 were response-evaluable. The overall response rates were 57.1% for arm A (95% CI = 37%-76%) and 61.4% for arm B (95% CI = 48%-74%). The median progression-free survival times were 8.5 months for arm A (95% CI = 5.7-10.4 months) and 7.6 months for arm B (95% CI = 6.1-8.7 months). The median overall survival times were 17.4 months for arm A (95% CI = 12.8 months to unreached) and 14.3 months for arm B (95% CI = 11.6-22.2 months). The most common grade 3/grade 4 adverse events in both arms were myelosuppression and nausea. Thromboembolism, acneiform rash, fatigue, pain, hypersensitivity reactions, elevated transaminases, hyponatremia, and hypomagnesemia were more common in arm B; 3 grade 5 adverse events occurred in arm B. The presence of primary disease significantly correlated with thromboembolism. An increased soluble E-cadherin level after cycle 2 correlated with a higher risk of death.GC plus CTX was feasible but was associated with more adverse events and no improvements in outcomes.

  View details for DOI 10.1002/cncr.28767

  View details for Web of Science ID 000340559000009

  View details for PubMedID 24802654

• A population-based overview of sequences of targeted therapy in metastatic renal cell carcinoma. Clinical genitourinary cancer Alimohamed, N., Lee, J., Srinivas, S., Bjarnason, G. A., Knox, J. J., Mackenzie, M. J., Wood, L., Vaishampayan, U. N., Tan, M., Rha, S. Y., Donskov, F., Tantravahi, S., Kollmannsberger, C., North, S., Rini, B. I., Choueiri, T. K., Heng, D. Y. 2014; 12 (4): e127-31

  Abstract

  Several TTs are available to treat mRCC; however, the optimal sequence of therapy remains unknown.Consecutive population-based samples of patients with mRCC treated with TT were collected from 12 cancer centers via the International Metastatic Renal Cell Carcinoma Database Consortium. Patient characteristics, first-line and second-line progression-free survival rates and overall survival data were collected based on sequencing of TT. Multivariable analysis was performed when there were significant differences on univariable analysis.A total of 2106 patients were included with a median follow-up of 36 months; 907 (43%) and 318 (15%) patients received subsequent second-line and third-line TT, respectively. Baseline characteristics were well matched among different sequences apart from more patients with non-clear-cell histology in the vascular endothelial growth factor (VEGF) to mammalian target of rapamycin (mTOR) group compared with the VEGF to VEGF group sequence. When adjusting for the Heng risk criteria and non-clear-cell histology, the hazard ratio for death for the VEGF to mTOR group versus the VEGF to VEGF group was 0.833 (95% confidence interval [CI], 0.669-1.037; P = .1016). More specifically, the adjusted hazard ratio for death for the sunitinib to everolimus versus sunitinib to temsirolimus sequences was 0.774 (95% CI, 0.52-1.153; P = .2086).In this large multicenter analysis evaluating different sequences of TT in mRCC, no substantial effect on outcome based on sequence of TT was identified.

  View details for DOI 10.1016/j.clgc.2013.12.003

  View details for PubMedID 24485801

• Survival Outcome and Treatment Response of Patients with Late Relapse from Renal Cell Carcinoma in the Era of Targeted Therapy EUROPEAN UROLOGY Kroeger, N., Choueiri, T. K., Lee, J., Bjarnason, G. A., Knox, J. J., Mackenzie, M. J., Wood, L., Srinivas, S., Vaishamayan, U. N., Rha, S., Pal, S. K., Yuasa, T., Donskov, F., Agarwal, N., Tan, M., Bamias, A., Kollmannsberger, C. K., North, S. A., Rini, B. I., Heng, D. Y. 2014; 65 (6): 1086-1092

  Abstract

  A subset of primarily localized renal cell carcinoma (RCC) patients will experience disease recurrence ≥5 yr after initial nephrectomy.To characterize the clinical outcome of patients with late recurrence beyond 5 yr.Patients with metastatic RCC (mRCC) treated with targeted therapy were retrospectively characterized according to time to relapse. Relapse was defined as the diagnosis of recurrent metastatic disease >3 mo after initial curative-intent nephrectomy. Patients with synchronous metastatic disease at presentation were excluded. Patients were classified as early relapsers (ERs) if they recurred within 5 yr; late relapsers (LRs) recurred after 5 yr.Demographics were compared with the Student t test, the chi-square test, or the Fisher exact test. The survival time was estimated with the Kaplan-Meier method, and associations with survival outcome were assessed with univariable and multivariable Cox regression analyses.Among 1210 mRCC patients treated with targeted therapy after surgery for localized disease, 897 (74%) relapsed within the first 5 yr and 313 (26%) (range: 5-35 yr) after 5 yr. LRs presented with younger age (p<0.0001), fewer with sarcomatoid features (p<0.0001), more clear cell histology (p=0.001), and lower Fuhrman grade (p<0.0001). Overall objective response rates to targeted therapy were better in LRs versus ERs (31.8% vs 26.5%; p=0.004). LRs had significantly longer progression-free survival (10.7 mo vs 8.5 mo; p=0.005) and overall survival (OS; 34.0 mo vs 27.4 mo; p=0.004). The study is limited by its retrospective design, noncentralized imaging and pathology review, missing information on metastatectomy, and nonstandardized follow-up protocols.A quarter of patients who eventually developed metastatic disease and were treated with targeted therapy relapsed over 5 yr from initial nephrectomy. LRs have more favorable prognostic features and consequently better treatment response and OS.

  View details for DOI 10.1016/j.eururo.2013.07.031

  View details for Web of Science ID 000335386700029

  View details for PubMedID 23916693

• Prostate cancer, version 2.2014. Journal of the National Comprehensive Cancer Network Mohler, J. L., Kantoff, P. W., Armstrong, A. J., Bahnson, R. R., Cohen, M., D'Amico, A. V., Eastham, J. A., Enke, C. A., Farrington, T. A., Higano, C. S., Horwitz, E. M., Kane, C. J., Kawachi, M. H., Kuettel, M., Kuzel, T. M., Lee, R. J., Malcolm, A. W., Miller, D., Plimack, E. R., Pow-Sang, J. M., Raben, D., Richey, S., Roach, M., Rohren, E., Rosenfeld, S., Schaeffer, E., Small, E. J., Sonpavde, G., Srinivas, S., Stein, C., Strope, S. A., Tward, J., Shead, D. A., Ho, M. 2014; 12 (5): 686-718

  Abstract

  Prostate cancer has surpassed lung cancer as the most common cancer in men in the United States. The NCCN Guidelines for Prostate Cancer provide multidisciplinary recommendations on the clinical management of patients with prostate cancer based on clinical evidence and expert consensus. NCCN Panel guidance on treatment decisions for patients with localized disease is represented in this version. Significant updates for early disease include distinction between active surveillance and observation, a new section on principles of imaging, and revisions to radiation recommendations. The full version of these guidelines, including treatment of patients with advanced disease, can be found online at the NCCN website.

  View details for PubMedID 24812137

• Utilization of cytoreductive nephrectomy and patient survival in the targeted therapy era. International journal of cancer. Journal international du cancer Conti, S. L., Thomas, I., Hagedorn, J. C., Chung, B. I., Chertow, G. M., Wagner, T. H., Brooks, J. D., Srinivas, S., Leppert, J. T. 2014; 134 (9): 2245-2252

  Abstract

  We sought to analyze utilization and survival outcomes of cytoreductive nephrectomy in patients with metastatic renal cell carcinoma (RCC) before and after introduction of targeted therapy. We identified patients with metastatic RCC between 1993 and 2010 in the SEER registry and examined temporal trends in utilization. We performed a joinpoint regression to determine when changes in utilization of cytoreductive nephrectomy occurred. We fitted multivariable proportional hazard models in full and propensity score-matched cohorts. We performed a difference-in-difference analysis to compare survival outcomes before and after introduction of targeted therapy. The proportion of patients undergoing cytoreductive nephrectomy increased from 1993 to 2004, from 29% to 39%. We identified a primary joinpoint of 2004, just prior to the introduction of targeted therapy. Beginning in 2005, there was a modest decrease in utilization of cytoreductive nephrectomy. Cytoreductive nephrectomy was associated with a lower adjusted relative hazard (0.41, 95% confidence interval 0.34 to 0.43). Median survival among patients receiving cytoreductive nephrectomy increased in the targeted therapy era (19 versus 13 months), while median survival among patients not receiving cytoreductive nephrectomy increased only slightly (4 versus 3 months). Difference-in-difference analysis showed a significant decrease in hazard of death among patients who received cytoreductive nephrectomy in the targeted therapy era. Despite decreased utilization in the targeted therapy era, cytoreductive nephrectomy remains associated with improved survival. Prospective randomized trials are needed to confirm the benefit of cytoreductive nephrectomy among patients with metastatic RCC treated with novel targeted therapies. © 2013 Wiley Periodicals, Inc.

  View details for PubMedID 24135850

• KRAS mutation confers resistance to antibody-dependent cellular cytotoxicity of cetuximab against human colorectal cancer cells INTERNATIONAL JOURNAL OF CANCER Conti, S. L., Thomas, I., Hagedorn, J. C., Chung, B. I., Chertow, G. M., Wagner, T. H., Brooks, J. D., Srinivas, S., Leppert, J. T. 2014; 134 (9): 2245-2252

  Abstract

  We sought to analyze utilization and survival outcomes of cytoreductive nephrectomy in patients with metastatic renal cell carcinoma (RCC) before and after introduction of targeted therapy. We identified patients with metastatic RCC between 1993 and 2010 in the SEER registry and examined temporal trends in utilization. We performed a joinpoint regression to determine when changes in utilization of cytoreductive nephrectomy occurred. We fitted multivariable proportional hazard models in full and propensity score-matched cohorts. We performed a difference-in-difference analysis to compare survival outcomes before and after introduction of targeted therapy. The proportion of patients undergoing cytoreductive nephrectomy increased from 1993 to 2004, from 29% to 39%. We identified a primary joinpoint of 2004, just prior to the introduction of targeted therapy. Beginning in 2005, there was a modest decrease in utilization of cytoreductive nephrectomy. Cytoreductive nephrectomy was associated with a lower adjusted relative hazard (0.41, 95% confidence interval 0.34 to 0.43). Median survival among patients receiving cytoreductive nephrectomy increased in the targeted therapy era (19 versus 13 months), while median survival among patients not receiving cytoreductive nephrectomy increased only slightly (4 versus 3 months). Difference-in-difference analysis showed a significant decrease in hazard of death among patients who received cytoreductive nephrectomy in the targeted therapy era. Despite decreased utilization in the targeted therapy era, cytoreductive nephrectomy remains associated with improved survival. Prospective randomized trials are needed to confirm the benefit of cytoreductive nephrectomy among patients with metastatic RCC treated with novel targeted therapies. © 2013 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ijc.28550

  View details for Web of Science ID 000331006600013

• First-, second-, third-line therapy for mRCC: benchmarks for trial design from the IMDC. British journal of cancer Ko, J. J., Choueiri, T. K., Rini, B. I., Lee, J., Kroeger, N., Srinivas, S., Harshman, L. C., Knox, J. J., Bjarnason, G. A., MacKenzie, M. J., Wood, L., Vaishampayan, U. N., Agarwal, N., Pal, S. K., Tan, M., Rha, S. Y., Yuasa, T., Donskov, F., Bamias, A., Heng, D. Y. 2014; 110 (8): 1917-1922

  Abstract

  Background:Limited data exist on outcomes for metastatic renal cell carcinoma (mRCC) patients treated with multiple lines of therapy. Benchmarks for survival are required for patient counselling and clinical trial design.Methods:Outcomes of mRCC patients from the International mRCC Database Consortium database treated with 1, 2, or 3+ lines of targeted therapy (TT) were compared by proportional hazards regression. Overall survival (OS) and progression-free survival (PFS) were calculated using different population inclusion criteria.Results:In total, 2705 patients were treated with TT of which 57% received only first-line TT, 27% received two lines of TT, and 16% received 3+ lines of TT. Overall survival of patients who received 1, 2, or 3+ lines of TT were 14.9, 21.0, and 39.2 months, respectively, from first-line TT (P<0.0001). On multivariable analysis, 2 lines and 3+ lines of therapy were each associated with better OS (HR=0.738 and 0.626, P<0.0001). Survival outcomes for the subgroups were as follows: for all patients, OS 20.9 months and PFS 7.2 months; for those similar to eligible patients in the first-line ADAPT trial, OS 14.7 months and PFS 5.6 months; for those similar to patients in first-line TIVO-1 trial, OS 24.8 months and PFS 8.2 months; for those similar to patients in second-line INTORSECT trial, OS 13.0 months and PFS 3.9 months; and for those similar to patients in the third-line GOLD trial, OS 18.0 months and PFS 4.4 months.Conclusions:Patients who are able to receive more lines of TT live longer. Survival benchmarks provide context and perspective when interpreting and designing clinical trials.

  View details for DOI 10.1038/bjc.2014.25

  View details for PubMedID 24691425

• Reply. Urology Leppert, J. T., Hanley, J., Wagner, T. H., Chung, B. I., Brooks, J. D., Srinivas, S., Chertow, G. M., Saigal, C. S. 2014; 83 (4): 779-780

  View details for DOI 10.1016/j.urology.2013.10.077

  View details for PubMedID 24529590

• The impact of low serum sodium on treatment outcome of targeted therapy in metastatic renal cell carcinoma: results from the international metastatic renal cell cancer database consortium. European urology Schutz, F. A., Xie, W., Donskov, F., Sircar, M., McDermott, D. F., Rini, B. I., Agarwal, N., Pal, S. K., Srinivas, S., Kollmannsberger, C., North, S. A., Wood, L. A., Vaishampayan, U., Tan, M., Mackenzie, M. J., Lee, J. L., Rha, S., Yuasa, T., Heng, D. Y., Choueiri, T. K. 2014; 65 (4): 723-730

  Abstract

  Hyponatremia has been associated with poor survival in many solid tumors and more recently found to be of prognostic and predictive value in metastatic renal cell cancer (mRCC) patients treated with immunotherapy.To investigate the influence of baseline hyponatremia in mRCC patients treated with targeted therapy in the International Metastatic Renal Cell Carcinoma Database Consortium.Data on 1661 patients treated with first-line vascular endothelial growth factor (VEGF) or mammalian target of rapamycin (mTOR) targeted therapy for mRCC were available from 18 cancer centers to study the impact of hyponatremia (serum sodium level <135 mmol/l) on clinical outcomes.The primary objective was overall survival (OS) and secondary end points included time to treatment failure (TTF) and the disease control rate (DCR). The chi-square test was used to compare the DCR in patients with and without hyponatremia. OS and TTF were estimated with the Kaplan-Meier method and differences between groups were examined by the log-rank test. Multivariable logistic regression (for DCR) and Cox regression (for OS and TTF) were undertaken adjusted for prognostic risk factors.Median OS after treatment initiation was 18.5 mo (95% confidence interval [CI], 17.5-19.8 mo), with 552 (33.2%) of patients remaining alive on a median follow-up of 22.1 mo. Median baseline serum sodium was 138 mmol/l (range: 122-159 mmol/l), and hyponatremia was found in 14.6% of patients. On univariate analysis, hyponatremia was associated with shorter OS (7.0 vs 20.9 mo), shorter TTF (2.9 vs 7.4 mo), and lower DCR rate (54.9% vs 78.8%) (p<0.0001 for all comparisons). In multivariate analysis, these effects remain significant (hazard ratios: 1.51 [95% CI, 1.26-1.80] for OS, and 1.57 [95% CI, 1.34-1.83] for TTF; odds ratio: 0.50 [95% CI, 34-0.72] for DCR; adjusted p<0.001). Results were similar if sodium was analyzed as a continuous variable (adjusted p<0.0001 for OS, TTF, and DCR).This is the largest multi-institutional report to show that hyponatremia is independently associated with a worse outcome in mRCC patients treated with VEGF- and mTOR-targeted agents.

  View details for DOI 10.1016/j.eururo.2013.10.013

  View details for PubMedID 24184025

• Utilization of renal mass biopsy in patients with renal cell carcinoma. Urology Leppert, J. T., Hanley, J., Wagner, T. H., Chung, B. I., Srinivas, S., Chertow, G. M., Brooks, J. D., Saigal, C. S. 2014; 83 (4): 774-780

  Abstract

  To examine the patient, tumor, and temporal factors associated with receipt of renal mass biopsy (RMB) in a contemporary nationally representative sample.We queried the Surveillance, Epidemiology, and End Results-Medicare data set for incident cases of renal cell carcinoma diagnosed between 1992 and 2007. We tested for associations among receipt of RMB and patient and tumor characteristics, type of therapy, and procedure type. Temporal trends in receipt of RMB were characterized over the study period.Approximately 1 in 5 (20.7%) patients diagnosed with renal cell carcinoma (n = 24,702) underwent RMB before instituting therapy. There was a steady and modest increase in RMB utilization, with the highest utilization (30%) occurring in the final study year. Of patients who underwent radical (n = 15,666) or partial (n = 2211) nephrectomy, 17% and 20%, respectively, underwent RMB in advance of surgery. Sixty-five percent of patients who underwent ablation (n = 314) underwent RMB before or in conjunction with the procedure. Roughly half of patients (50.4%) treated with systemic therapy alone underwent RMB. Factors independently associated with use of RMB included younger age, black race, Hispanic ethnicity, tumor size <7 cm, and metastatic disease at presentation.At present, most patients who eventually undergo radical or partial nephrectomy do not undergo RMB, whereas most patients who eventually undergo ablation or systemic therapy do. The optimal use of RMB in the evaluation of kidney tumors has yet to be determined.

  View details for DOI 10.1016/j.urology.2013.10.073

  View details for PubMedID 24529579

• Impact of bone and liver metastases on patients with renal cell carcinoma treated with targeted therapy. European urology McKay, R. R., Kroeger, N., Xie, W., Lee, J., Knox, J. J., Bjarnason, G. A., Mackenzie, M. J., Wood, L., Srinivas, S., Vaishampayan, U. N., Rha, S., Pal, S. K., Donskov, F., Tantravahi, S. K., Rini, B. I., Heng, D. Y., Choueiri, T. K. 2014; 65 (3): 577-584

  Abstract

  The skeleton and liver are frequently involved sites of metastasis in patients with metastatic renal cell carcinoma (RCC).To analyze outcomes based on the presence of bone metastases (BMs) and/or liver metastases (LMs) in patients with RCC treated with targeted therapy.We conducted a review from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) of 2027 patients with metastatic RCC.We analyzed the impact of the site of metastasis on overall survival (OS) and time-to-treatment failure. Statistical analyses were performed using multivariable Cox regression.The presence of BMs was 34% overall, and when stratified by IMDC risk groups was 27%, 33%, and 43% in the favorable-, intermediate-, and poor-risk groups, respectively (p<0.001). The presence of LMs was 19% overall and higher in the poor-risk patients (23%) compared with the favorable- or intermediate-risk groups (17%) (p=0.003). When patients were classified into four groups based on the presence of BMs and/or LMs, the hazard ratio, adjusted for IMDC risk factors, was 1.4 (95% confidence interval [CI], 1.22-1.62) for BMs, 1.42 (95% CI, 1.17-1.73) for LMs, and 1.82 (95% CI, 1.47-2.26) for both BMs and LMs compared with other metastatic sites (p<0.0001). The prediction model performance for OS was significantly improved when BMs and LMs were added to the IMDC prognostic model (likelihood ratio test p<0.0001). Data in this analysis were collected retrospectively.The presence of BMs and LMs in patients treated with targeted agents has a negative impact on survival. Patients with BMs and/or LMs may benefit from earlier inclusion on clinical trials of novel agents or combination-based therapies.

  View details for DOI 10.1016/j.eururo.2013.08.012

  View details for PubMedID 23962746

• Outcomes of patients with metastatic renal cell carcinoma that do not meet eligibility criteria for clinical trials. Annals of oncology Heng, D. Y., Choueiri, T. K., Rini, B. I., Lee, J., Yuasa, T., Pal, S. K., Srinivas, S., Bjarnason, G. A., Knox, J. J., MacKenzie, M., Vaishampayan, U. N., Tan, M. H., Rha, S. Y., Donskov, F., Agarwal, N., Kollmannsberger, C., North, S., Wood, L. A. 2014; 25 (1): 149-154

  Abstract

  Targeted therapies in metastatic renal cell carcinoma (mRCC) have been approved based on registration clinical trials that have strict eligibility criteria. The clinical outcomes of patients treated with targeted agents but are ineligible for trials are unknown.mRCC patients treated with vascular endothelial growth factor-targeted therapy were retrospectively deemed ineligible for clinical trials (according to commonly used inclusion/exclusion criteria) if they had a Karnofsky performance status (KPS) <70%, nonclear-cell histology, brain metastases, hemoglobin ≤9 g/dl, creatinine >2× the upper limit of normal, corrected calcium ≥12 mg/dl, platelet count of <100 × 10(3)/uL, or neutrophil count <1500/mm(3).Overall, 768 of 2210 (35%) patients in the International Metastatic RCC Database Consortium (IMDC) were deemed ineligible for clinical trials by the above criteria. Between ineligible versus eligible patients, the response rate, median progression-free survival (PFS) and median overall survival of first-line targeted therapy were 22% versus 29% (P = 0.0005), 5.2 versus 8.6 months, and 12.5 versus 28.4 months (both P < 0.0001), respectively. Second-line PFS (if applicable) was 2.8 months in the trial ineligible versus 4.3 months in the trial eligible patients (P = 0.0039). When adjusted by the IMDC prognostic categories, the HR for death between trial ineligible and trial eligible patients was 1.55 (95% confidence interval 1.378-1.751, P < 0.0001).The number of patients that are ineligible for clinical trials is substantial and their outcomes are inferior. Specific trials addressing the unmet needs of protocol ineligible patients are warranted.

  View details for DOI 10.1093/annonc/mdt492

  View details for PubMedID 24356626

• Prostate Cancer, Version 1.2014 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Mohler, J. L., Kantoff, P. W., Armstrong, A. J., Bahnson, R. R., Cohen, M., D'Amico, A. V., Eastham, J. A., Enke, C. A., Farrington, T. A., Higano, C. S., Horwitz, E. M., Kawachi, M. H., Kuettel, M., Lee, R. J., MacVicar, G. R., Malcolm, A. W., Miller, D., Plimack, E. R., Pow-Sang, J. M., Richey, S., Roach, M., Rohren, E., Rosenfeld, S., Small, E. J., Srinivas, S., Stein, C., Strope, S. A., Tward, J., Walsh, P. C., Shead, D. A., Ho, M. 2013; 11 (12): 1471-1479

  View details for Web of Science ID 000328639000005

• Prostate cancer, version 1.2014. Journal of the National Comprehensive Cancer Network Mohler, J. L., Kantoff, P. W., Armstrong, A. J., Bahnson, R. R., Cohen, M., D'Amico, A. V., Eastham, J. A., Enke, C. A., Farrington, T. A., Higano, C. S., Horwitz, E. M., Kawachi, M. H., Kuettel, M., Lee, R. J., MacVicar, G. R., Malcolm, A. W., Miller, D., Plimack, E. R., Pow-Sang, J. M., Richey, S., Roach, M., Rohren, E., Rosenfeld, S., Small, E. J., Srinivas, S., Stein, C., Strope, S. A., Tward, J., Walsh, P. C., Shead, D. A., Ho, M. 2013; 11 (12): 1471-1479

  Abstract

  The NCCN Guidelines for Prostate Cancer provide multidisciplinary recommendations on the clinical management of patients with prostate cancer. This report highlights notable recent updates. Radium-223 dichloride is a first-in-class radiopharmaceutical that recently received approval for the treatment of patients with symptomatic bone metastases and no known visceral disease. It received a category 1 recommendation as both a first-line and second-line option. The NCCN Prostate Cancer Panel also revised recommendations on the choice of intermittent or continuous androgen deprivation therapy based on recent phase III clinical data comparing the 2 strategies in the nonmetastatic and metastatic settings.

  View details for PubMedID 24335682

• Utilization of renal mass biopsy in patients with renal cell carcinoma 12th International Kidney Cancer Symposium Leppert, J. T., Hanley, J., Wagner, T. H., Chung, B. I., Srinivas, S., Chertow, G. M., Brooks, J. D., Saigal, C. S. WILEY-BLACKWELL. 2013: 14–14

  View details for Web of Science ID 000325992100024

• Utilization of cytoreductive nephrectomy and patient survival in the targeted therapy era 12th International Kidney Cancer Symposium Conti, S. L., Thomas, I., Hagedorn, J. C., Chung, B. I., Chertow, G. M., Wagner, T. H., Brooks, J. D., Srinivas, S., Leppert, J. T. WILEY-BLACKWELL. 2013: 14–16

  View details for Web of Science ID 000325992100026

• Phase Ib study of tivozanib (AV-951) in combination with temsirolimus in patients with renal cell carcinoma EUROPEAN JOURNAL OF CANCER Fishman, M. N., Srinivas, S., Hauke, R. J., Amato, R. J., Esteves, B., Cotreau, M. M., Strahs, A. L., Slichenmyer, W. J., Bhargava, P., Kabbinavar, F. F. 2013; 49 (13): 2841-2850

  Abstract

  Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, -2 and -3, with a long half-life. Tivozanib has demonstrated clinical activity and acceptable tolerability in renal cell carcinoma (RCC). This phase Ib study determined the recommended phase II dose (RP2D) and evaluated the safety and clinical activity of tivozanib plus temsirolimus, a mammalian target of rapamycin inhibitor.Patients with advanced RCC were administered open-label tivozanib 0.5, 1.0 or 1.5mg/d orally (3 weeks on/1 week off) and temsirolimus 15 or 25 mg/week intravenously in a 3+3 dose-escalation design and subsequent expansion cohort.Of 27 patients treated, 20 patients had received ≥ 1 prior VEGF-targeted therapy. No dose-limiting toxicities occurred; the RP2D was determined to be tivozanib 1.5mg/d plus temsirolimus 25mg/week. Combination of tivozanib plus temsirolimus demonstrated acceptable tolerability and suggested no synergistic toxicity. The most common grade ≤ 3 adverse events were fatigue and thrombocytopenia (15% each). One patient each required dose reduction of tivozanib or temsirolimus due to an adverse event. Confirmed partial responses and stable disease were achieved at 23% and 68%, respectively. Pharmacokinetic analyses may suggest lack of an interaction between tivozanib and temsirolimus.In this small phase Ib study, tivozanib and temsirolimus were safely combined at the fully recommended dose and schedule of both agents. The observed clinical activity and manageable toxicity profile of this combination warrant further exploration in patients with RCC.

  View details for DOI 10.1016/j.ejca.2013.04.019

  View details for Web of Science ID 000322627300009

  View details for PubMedID 23726267

• Vaccination of castration-resistant prostate cancer patients with TroVax (MVA-5T4) in combination with docetaxel: a randomized phase II trial CANCER IMMUNOLOGY IMMUNOTHERAPY Harrop, R., Chu, F., Gabrail, N., Srinivas, S., Blount, D., Ferrari, A. 2013; 62 (9): 1511-1520

  Abstract

  The attenuated vaccinia virus, modified vaccinia Ankara, has been engineered to deliver the tumor antigen 5T4 (TroVax®). Here, we report results from a randomized open-label phase II trial in castration-resistant prostate cancer patients in which TroVax was administered in combination with docetaxel and compared against docetaxel alone. The aim was to recruit 80 patients (40 per arm), but the study was terminated early due to recruitment challenges. Therefore, this paper reports the comparative safety and immunological and clinical efficacy in 25 patients, 12 of whom were treated with TroVax plus docetaxel and 13 with docetaxel alone. 5T4-specific immune responses were monitored throughout the study. Clinical responses were assessed by measuring changes in tumor burden by CT and bone scan and by quantifying PSA concentrations. TroVax was well tolerated in all patients. Of 10 immunologically evaluable patients, 6 mounted 5T4-specific antibody responses. Patients treated with TroVax plus docetaxel showed a greater median progression-free survival of 9.67 months compared with 5.10 months for patients on the docetaxel alone arm (P = 0.097; HR = 0.31; 95% CI 0.08-1.24). Importantly, a pre-treatment biomarker previously demonstrated to predict 5T4 immune response and treatment benefit showed a strong association with 5T4 antibody response and a statistically significant association with progression-free survival in patients treated with TroVax plus docetaxel, but not docetaxel alone.

  View details for DOI 10.1007/s00262-013-1457-z

  View details for Web of Science ID 000323657500007

  View details for PubMedID 23877659

• Metastatic non-clear cell renal cell carcinoma treated with targeted therapy agents: Characterization of survival outcome and application of the International mRCC Database Consortium criteria CANCER Kroeger, N., Xie, W., Lee, J., Bjarnason, G. A., Knox, J. J., Mackenzie, M. J., Wood, L., Srinivas, S., Vaishamayan, U. N., Rha, S., Pal, S. K., Yuasa, T., Donskov, F., Agarwal, N., Kollmannsberger, C. K., Tan, M., North, S. A., Rini, B. I., Choueiri, T. K., Heng, D. Y. 2013; 119 (16): 2999-3006

  Abstract

  This study aimed to apply the International mRCC Database Consortium (IMDC) prognostic model in metastatic non-clear cell renal cell carcinoma (nccRCC). In addition, the survival outcome of metastatic nccRCC patients was characterized.Data on 2215 patients (1963 with clear-cell RCC [ccRCC] and 252 with nccRCC) treated with first-line VEGF- and mTOR-targeted therapies were collected from the IMDC. Time to treatment failure (TTF) and overall survival (OS) were compared in groups with favorable, intermediate, and poor prognoses according to IMDC prognostic criteriaThe median OS of the entire cohort was 20.9 months. nccRCC patients were younger (P < .0001) and more often presented with low hemoglobin (P = .014) and elevated neutrophils (P = .0001), but otherwise had clinicopathological features similar to those of ccRCC patients. OS (12.8 vs 22.3 months; P < .0001) and TTF (4.2 vs 7.8 months; P < .0001) were worse in nccRCC patients compared with ccRCC patients. The hazard ratio for death and TTF when adjusted for the prognostic factors was 1.41 (95% CI, 1.19-1.67; P < .0001) and 1.54 (95% CI, 1.33-1.79; P < .0001), respectively. The IMDC prognostic model reliably discriminated 3 risk groups to predict OS and TTF in nccRCC; the median OS of the favorable, intermediate, and poor prognosis groups was 31.4, 16.1, and 5.1 months, respectively (P < .0001), and the median TTF was 9.6, 4.9, and 2.1 months, respectively (P < .0001).Although targeted agents have significantly improved the outcome of patients with nccRCC, for the majority survival is still inferior compared with patients with ccRCC. The IMDC prognostic model reliably predicts OS and TTF in nccRCC and ccRCC patients. Cancer 2013;119:2999-3006. © 2013 American Cancer Society.

  View details for DOI 10.1002/cncr.28151

  View details for Web of Science ID 000322632400011

  View details for PubMedID 23696129

• A randomized, double-blind, placebo-controlled, Phase II study with and without enzastaurin in combination with docetaxel-based chemotherapy in patients with castration-resistant metastatic prostate cancer INVESTIGATIONAL NEW DRUGS Dreicer, R., Garcia, J., Rini, B., Vogelzang, N., Srinivas, S., Somer, B., Shi, P., Kania, M., Raghavan, D. 2013; 31 (4): 1044-1050

  Abstract

  Enzastaurin is an oral serine/threonine kinase inhibitor that inhibits the beta isoform of protein kinase C and which may have therapeutic activity in prostate cancer. We explored the efficacy of docetaxel/prednisone with or without enzastaurin in patients with castration-resistant metastatic prostate cancer.A nonrandomized safety cohort consisting of 14 patients was followed by a double-blind randomized Phase II trial. Patients received standard doses of docetaxel (75 mg/m(2)) with prednisone 10 mg daily with or without 500 mg/day of enzastaurin.There was no difference in the objective response rate between the enzastaurin and placebo arms (placebo: 7 [15.2 %]; enzastaurin: 6 [15.0 %]; P = 1.00). The median PFS was 229 days for patients in the enzastaurin arm versus 213 days for the placebo arm (P = 0.524). The 1-year overall survival rates were almost identical, with 76.7 % and 75.1 % in the enzastaurin and placebo arms, respectively. Therapy was well tolerated although the combination of enzastaurin and docetaxel was more myelosuppressive than with docetaxel alone.The clinical activity of docetaxel/prednisone plus enzastaurin cannot be distinguished from docetaxel/prednisone alone, given the limitations of a randomized Phase II design. Although the toxicity profile was favorable for the enzastaurin-containing regimen, there is no compelling rationale to move this combination forward for the treatment of castration-resistant metastatic prostate cancer.

  View details for DOI 10.1007/s10637-013-9940-0

  View details for Web of Science ID 000322333600026

  View details for PubMedID 23435622

• NCCN Task Force Report: Bone Health in Cancer Care JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Gralow, J. R., Biermann, J. S., Farooki, A., Fornier, M. N., Gagel, R. F., Kumar, R., Litsas, G., McKay, R., Podoloff, D. A., Srinivas, S., Van Poznak, C. H. 2013; 11: S1-S50

  View details for Web of Science ID 000209472900001

• NCCN Task Force Report: Bone Health In Cancer Care. Journal of the National Comprehensive Cancer Network Gralow, J. R., Biermann, J. S., Farooki, A., Fornier, M. N., Gagel, R. F., Kumar, R., Litsas, G., McKay, R., Podoloff, D. A., Srinivas, S., Van Poznak, C. H. 2013; 11: S1-50

  Abstract

  Bone health and maintenance of bone integrity are important components of comprehensive cancer care. Many patients with cancer are at risk for therapy-induced bone loss, with resultant osteoporotic fractures, or skeletal metastases, which may result in pathologic fractures, hypercalcemia, bone pain, and decline in motility and performance status. Effective screening and timely interventions are essential for reducing bone-related morbidity. Management of long-term bone health requires a broad knowledge base. A multidisciplinary health care team may be needed for optimal assessment and treatment of bone-related issues in patients with cancer. Since publication of the previous NCCN Task Force Report: Bone Health in Cancer Care in 2009, new data have emerged on bone health and treatment, prompting NCCN to convene this multidisciplinary task force to discuss the progress made in optimizing bone health in patients with cancer. In December 2012, the panel members provided didactic presentations on various topics, integrating expert judgment with a review of the key literature. This report summarizes issues surrounding bone health in cancer care presented and discussed during this NCCN Bone Health in Cancer Care Task Force meeting.

  View details for PubMedID 23997241

• A Phase II Study of Bevacizumab and Everolimus as Treatment for Refractory Metastatic Renal Cell Carcinoma. Clinical genitourinary cancer Harshman, L. C., Barbeau, S., McMillian, A., Srinivas, S. 2013; 11 (2): 100-106

  Abstract

  Agents that inhibit the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways in metastatic renal cell carcinoma (mRCC) prolong progression-free survival (PFS), but durable complete responses are rare. Combinations of these cytostatic therapies have great potential to improve efficacy and to escape tumoral resistance mechanisms, but supra-additive toxicity is a valid concern. We investigated whether horizontal blockade with the combination of bevacizumab, a monoclonal antibody to VEGF-A, and of everolimus, an oral mTOR inhibitor, improved PFS in patients with clear cell mRCC who had received prior VEGF blockade.In this phase II investigator-initiated study, 10 of 30 planned patients were enrolled. Bevacizumab 10 mg/kg was administered intravenously every 14 days. Everolimus was orally dosed at 10 mg daily. The patients were treated until disease progression or unacceptable toxicity. The primary endpoint was PFS.The median age was 55 years. The majority of patients were white men with an Eastern Cooperative Oncology Group performance status of 1 (80%) and intermediate risk disease by Memorial Sloan-Kettering Cancer Center criteria (70%). All the patients had received 1 prior VEGF inhibitor. The median PFS in the 10 evaluable patients was 5.1 months, which was less than the expected historical control of bevacizumab monotherapy at 6 months. The median overall survival was 21 months. The best response was a partial response in 1 patient and stable disease in 9. Forty percent of the patients were discontinued from the study due to toxicity.In our experience, the combination of bevacizumab and everolimus was toxic. The efficacy achieved did not support its combined use over sequential administration. Ongoing randomized studies will definitively evaluate the combination's efficacy and tolerability.

  View details for DOI 10.1016/j.clgc.2012.12.002

  View details for PubMedID 23352238

• Surgical outcomes and complications associated with presurgical tyrosine kinase inhibition for advanced renal cell carcinoma (RCC) UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS Harshman, L. C., Yu, R. J., Allen, G. I., Srinivas, S., Gill, H. S., Chung, B. I. 2013; 31 (3): 379-385

  Abstract

  Tyrosine kinase inhibitors (TKI) have dramatically changed the management paradigm of advanced renal cell carcinoma (RCC) and are increasingly being used preoperatively to achieve cytoreduction.To review our case series of post-TKI surgical procedures to add to the current perioperative efficacy and complication profile.Between October 2006 and February 2010, 14 cytoreductive nephrectomies, radical nephrectomies, and metastectomies were performed after neoadjuvant sunitinib or sorafenib for advanced RCC. During the same time frame, a control group of 73 consecutive patients underwent radical nephrectomy, cytoreductive nephrectomy, or metastectomy in the absence of prior systemic therapy. We compared the incidence of perioperative complications and outcomes after surgical procedures between the two cohorts.Median preoperative renal mass size was 11 cm (6.7-24.2 cm). Primary tumor shrinkage was seen in 57%; median shrinkage was 18% (8%-25%). The median treatment period was 17 weeks, and the median time from TKI discontinuation was 2 weeks. Compared with a control group and after adjusting for confounding covariates, presurgical TKI use was not associated with a significant increase in perioperative complications (50% vs. 40%, P = 0.25) or perioperative bleeding (36% vs. 34%, P = 0.97) but was associated with increased incidence and grade of intraoperative adhesions (86% vs. 58%, P = 0.001; grade 3 vs. 1, P = 0.002).Compared with the published reports, we observed less hemorrhagic and wound healing issues but a significant increase in incidence and severity of intraoperative adhesions, which can present a formidable technical challenge. Potential reasons for our lower complication rate could be increased time from TKI discontinuation to surgery, longer time to postoperative TKI re-initiation, increased use of preoperative angioembolization, and the lack of preoperative bevacizumab administration. Presurgical TKI therapy can permit effective surgical cytoreduction with a safety and complication profile equivalent to that of non-TKI-nephrectomy; however safety data continue to evolve, and preoperative TKI use requires further prospective investigation.

  View details for DOI 10.1016/j.urolonc.2011.01.005

  View details for Web of Science ID 000317169500015

  View details for PubMedID 21353796

• Cabozantinib in Patients With Advanced Prostate Cancer: Results of a Phase II Randomized Discontinuation Trial JOURNAL OF CLINICAL ONCOLOGY Smith, D. C., Smith, M. R., Sweeney, C., Elfiky, A. A., Logothetis, C., Corn, P. G., Vogelzang, N. J., Small, E. J., Harzstark, A. L., Gordon, M. S., Vaishampayan, U. N., Haas, N. B., Spira, A. I., Lara, P. N., Lin, C., Srinivas, S., Sella, A., Schoeffski, P., Scheffold, C., Weitzman, A. L., Hussain, M. 2013; 31 (4): 412-419

  Abstract

  Cabozantinib (XL184) is an orally bioavailable tyrosine kinase inhibitor with activity against MET and vascular endothelial growth factor receptor 2. We evaluated the activity of cabozantinib in patients with castration-resistant prostate cancer (CRPC) in a phase II randomized discontinuation trial with an expansion cohort.Patients received 100 mg of cabozantinib daily. Those with stable disease per RECIST at 12 weeks were randomly assigned to cabozantinib or placebo. Primary end points were objective response rate at 12 weeks and progression-free survival (PFS) after random assignment.One hundred seventy-one men with CRPC were enrolled. Random assignment was halted early based on the observed activity of cabozantinib. Seventy-two percent of patients had regression in soft tissue lesions, whereas 68% of evaluable patients had improvement on bone scan, including complete resolution in 12%. The objective response rate at 12 weeks was 5%, with stable disease in 75% of patients. Thirty-one patients with stable disease at week 12 were randomly assigned. Median PFS was 23.9 weeks (95% CI, 10.7 to 62.4 weeks) with cabozantinib and 5.9 weeks (95% CI, 5.4 to 6.6 weeks) with placebo (hazard ratio, 0.12; P < .001). Serum total alkaline phosphatase and plasma cross-linked C-terminal telopeptide of type I collagen were reduced by ≥ 50% in 57% of evaluable patients. On retrospective review, bone pain improved in 67% of evaluable patients, with a decrease in narcotic use in 56%. The most common grade 3 adverse events were fatigue (16%), hypertension (12%), and hand-foot syndrome (8%).Cabozantinib has clinical activity in men with CRPC, including reduction of soft tissue lesions, improvement in PFS, resolution of bone scans, and reductions in bone turnover markers, pain, and narcotic use.

  View details for DOI 10.1200/JCO.2012.45.0494

  View details for Web of Science ID 000314099800007

  View details for PubMedID 23169517

• The Frequency and Severity of Cardiovascular Toxicity From Targeted Therapy in Advanced Renal Cell Carcinoma Patients JACC-HEART FAILURE Hall, P. S., Harshman, L. C., Srinivas, S., Witteles, R. M. 2013; 1 (1): 72-78

  View details for DOI 10.1016/j.jchf.2012.09.001

  View details for Web of Science ID 000209535300010

• The Frequency and Severity of Cardiovascular Toxicity From Targeted Therapy in Advanced Renal Cell Carcinoma Patients. JACC. Heart failure Hall, P. S., Harshman, L. C., Srinivas, S., Witteles, R. M. 2013; 1 (1): 72-78

  Abstract

  The purpose of this study was to document the incidence and extent of cardiovascular toxicity among advanced renal cell carcinoma patients treated with newer targeted cancer agents.The potential for targeted cancer agents to induce cardiovascular toxicity has been increasingly recognized, but the overall incidence and extent of toxicity have not been well characterized. Early detection of asymptomatic patients could preempt symptomatic toxicity and reduce treatment-related morbidity and mortality.The incidence of hypertension, left ventricular dysfunction, and heart failure was assessed for all advanced renal cell carcinoma patients treated with targeted therapies at our institution between 2004 and 2011. Grading was performed according to the Common Terminology Criteria for Adverse Events version 4.0.Cardiovascular toxicity developed in 116 of 159 patients (73%), including 52 of 159 patients (33%) when hypertension was excluded. Toxicity varied from occurrences of asymptomatic drops in left ventricular ejection fraction to rises in N-terminal-pro-B-type natriuretic peptide to severe heart failure. The tyrosine kinase inhibitor sunitinib was the agent most frequently used, with 66 of 101 sunitinib-treated patients (65%) developing a form of cardiovascular toxicity, including 32 of 101 patients (32%), excluding hypertension. Other VEGF inhibitors such as bevacizumab, sorafenib, and pazopanib also elicited significant cardiovascular toxicity with incidences ranging from 51% to 68%.The frequency and severity of cardiovascular toxicity in advanced renal cell carcinoma patients treated with targeted cancer therapies are high.

  View details for DOI 10.1016/j.jchf.2012.09.001

  View details for PubMedID 24621801

• Phase II and Biomarker Study of the Dual MET/VEGFR2 Inhibitor Foretinib in Patients With Papillary Renal Cell Carcinoma JOURNAL OF CLINICAL ONCOLOGY Choueiri, T. K., Vaishampayan, U., Rosenberg, J. E., Logan, T. F., Harzstark, A. L., Bukowski, R. M., Rini, B. I., Srinivas, S., Stein, M. N., Adams, L. M., Ottesen, L. H., Laubscher, K. H., Sherman, L., McDermott, D. F., Haas, N. B., Flaherty, K. T., Ross, R., Eisenberg, P., Meltzer, P. S., Merino, M. J., Bottaro, D. P., Linehan, W. M., Srinivasan, R. 2013; 31 (2): 181-186

  Abstract

  Foretinib is an oral multikinase inhibitor targeting MET, VEGF, RON, AXL, and TIE-2 receptors. Activating mutations or amplifications in MET have been described in patients with papillary renal cell carcinoma (PRCC). We aimed to evaluate the efficacy and safety of foretinib in patients with PRCC.Patients were enrolled onto the study in two cohorts with different dosing schedules of foretinib: cohort A, 240 mg once per day on days 1 through 5 every 14 days (intermittent arm); cohort B, 80 mg daily (daily dosing arm). Patients were stratified on the basis of MET pathway activation (germline or somatic MET mutation, MET [7q31] amplification, or gain of chromosome 7). The primary end point was overall response rate (ORR).Overall, 74 patients were enrolled, with 37 in each dosing cohort. ORR by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 was 13.5%, median progression-free survival was 9.3 months, and median overall survival was not reached. The presence of a germline MET mutation was highly predictive of a response (five of 10 v five of 57 patients with and without germline MET mutations, respectively). The most frequent adverse events of any grade associated with foretinib were fatigue, hypertension, gastrointestinal toxicities, and nonfatal pulmonary emboli.Foretinib demonstrated activity in patients with advanced PRCC with a manageable toxicity profile and a high response rate in patients with germline MET mutations.

  View details for DOI 10.1200/JCO.2012.43.3383

  View details for Web of Science ID 000313345100010

  View details for PubMedID 23213094

• Targeted MET Inhibition in Castration-Resistant Prostate Cancer: A Randomized Phase II Study and Biomarker Analysis with Rilotumumab plus Mitoxantrone and Prednisone CLINICAL CANCER RESEARCH Ryan, C. J., Rosenthal, M., Ng, S., Alumkal, J., Picus, J., Gravis, G., Fizazi, K., Forget, F., Machiels, J., Srinivas, S., Zhu, M., Tang, R., Oliner, K. S., Jiang, Y., Loh, E., Dubey, S., Gerritsen, W. R. 2013; 19 (1): 215-224

  Abstract

  To evaluate the efficacy, safety, biomarkers, and pharmacokinetics of rilotumumab, a fully human, monoclonal antibody against hepatocyte growth factor (HGF)/scatter factor, combined with mitoxantrone and prednisone (MP) in patients with castration-resistant prostate cancer (CRPC).This double-blinded phase II study randomized (1:1:1) patients with progressive, taxane-refractory CRPC to receive MP (12 mg/m(2) i.v. day 1, 5 mg twice a day orally days 1-21, respectively) plus 15 mg/kg rilotumumab, 7.5 mg/kg rilotumumab, or placebo (i.v. day 1) every 3 weeks. The primary endpoint was overall survival (OS).One hundred and forty-four patients were randomized. Median OS was 12.2 versus 11.1 months [HR, 1.10; 80% confidence interval (CI), 0.82-1.48] in the combined rilotumumab versus control arms. Median progression-free survival was 3.0 versus 2.9 months (HR, 1.02; 80% CI, 0.79-1.31). Treatment appeared well tolerated with peripheral edema (24% vs. 8%) being more common with rilotumumab. A trend toward unfavorable OS was observed in patients with high tumor MET expression regardless of treatment. Soluble MET levels increased in all treatment arms. Total HGF levels increased in the rilotumumab arms. Rilotumumab showed linear pharmacokinetics when co-administered with MP.Rilotumumab plus MP had manageable toxicities and showed no efficacy improvements in this estimation study. High tumor MET expression may identify patients with CRPC with poorer prognosis.

  View details for DOI 10.1158/1078-0432.CCR-12-2605

  View details for Web of Science ID 000313051100023

  View details for PubMedID 23136195

• mRNA-Seq of Single Prostate Cancer Circulating Tumor Cells Reveals Recapitulation of Gene Expression and Pathways Found in Prostate Cancer PLOS ONE Cann, G. M., Gulzar, Z. G., Cooper, S., Li, R., Luo, S., Tat, M., Stuart, S., Schroth, G., Srinivas, S., Ronaghi, M., Brooks, J. D., Talasaz, A. H. 2012; 7 (11)

  Abstract

  Circulating tumor cells (CTC) mediate metastatic spread of many solid tumors and enumeration of CTCs is currently used as a prognostic indicator of survival in metastatic prostate cancer patients. Some evidence suggests that it is possible to derive additional information about tumors from expression analysis of CTCs, but the technical difficulty of isolating and analyzing individual CTCs has limited progress in this area. To assess the ability of a new generation of MagSweeper to isolate intact CTCs for downstream analysis, we performed mRNA-Seq on single CTCs isolated from the blood of patients with metastatic prostate cancer and on single prostate cancer cell line LNCaP cells spiked into the blood of healthy donors. We found that the MagSweeper effectively isolated CTCs with a capture efficiency that matched the CellSearch platform. However, unlike CellSearch, the MagSweeper facilitates isolation of individual live CTCs without contaminating leukocytes. Importantly, mRNA-Seq analysis showed that the MagSweeper isolation process did not have a discernible impact on the transcriptional profile of single LNCaPs isolated from spiked human blood, suggesting that any perturbations caused by the MagSweeper process on the transcriptional signature of isolated cells are modest. Although the RNA from patient CTCs showed signs of significant degradation, consistent with reports of short half-lives and apoptosis amongst CTCs, transcriptional signatures of prostate tissue and of cancer were readily detectable with single CTC mRNA-Seq. These results demonstrate that the MagSweeper provides access to intact CTCs and that these CTCs can potentially supply clinically relevant information.

  View details for DOI 10.1371/journal.pone.0049144

  View details for Web of Science ID 000311935800219

  View details for PubMedID 23145101

  View details for PubMedCentralID PMC3492322

• Variations in Normal Serum Alpha-Fetoprotein (AFP) Levels in Patients with Testicular Cancer on Surveillance ONKOLOGIE Patel, P., Balise, R., Srinivas, S. 2012; 35 (10): 588-591

  Abstract

  The aim of this study was to assess fluctuations in normal serum alpha-fetoprotein (AFP) levels in patients with germ cell cancer. Marked variations occur after serum AFP levels normalize, creating anxiety among patients and physicians during surveillance.We conducted a retrospective review of patients with germ cell tumors in clinical remission, who had normal AFP levels and were followed at our center from 1991 to 2009. 72 patients, with a median follow-up of 50 months, were identified.Of the 72 patients, 57 (79%) had a non-seminomatous germ cell histology, and 15 (21%) had seminomas. Seminomas were included as controls as serum AFP levels do not increase in this group. 68 patients underwent orchiectomy, and 50 patients received systemic chemotherapy. The majority of patients (93%) demonstrated fluctuations in serum AFP. There was no difference in the mean AFP values between patients with seminona (2.95 ng/ml) and those with non-seminomatous germ cell tumors (3.3 ng/ml) (standard deviation 1.01 ng/ml).Marked variations occur after serum AFP levels normalize in patients undergoing surveillance. Fluctuating AFP levels within normal limits did not result in relapse in our cohort of patients with extended follow-up.

  View details for DOI 10.1159/000342695

  View details for Web of Science ID 000309666500007

  View details for PubMedID 23038230

• Conditional survival of patients with metastatic renal-cell carcinoma treated with VEGF-targeted therapy: a population-based study LANCET ONCOLOGY Harshman, L. C., Xie, W., Bjarnason, G. A., Knox, J. J., MacKenzie, M., Wood, L., Srinivas, S., Vaishampayan, U. N., Tan, M., Rha, S., Donskov, F., Agarwal, N., Kollmannsberger, C., North, S., Rini, B. I., Heng, D. Y., Choueiri, T. K. 2012; 13 (9): 927-935

  Abstract

  The advent of targeted therapies in the past 7 years has extended median survival for metastatic renal-cell carcinoma. This improvement in clinical outcome has created a need for new, more accurate prognostic measures. We assessed the use of conditional survival--a measure that accounts for elapsed time since treatment initiation--for prognostication in patients with metastatic renal-cell carcinoma treated with first-line VEGF-targeted therapies.We obtained data for patients with metastatic renal-cell carcinoma who were treated with a first-line VEGF-targeted therapy between April 7, 2003, and Oct 12, 2010, from our large multi-institutional International mRCC Database Consortium (centres in Canada, the USA, Singapore, Denmark, and South Korea). All histologies, performance statuses, and prognostic risk groups were included. The primary outcome was 2-year conditional survival, defined as the probability of surviving an additional 2 years from a given timepoint since the start of targeted therapy. Secondary analyses included 1-year and 3-year conditional survival, along with stratification of patients by Heng prognostic risk criteria and Karnofsky performance score, and conditional survival based on length of time on therapy. We used the Kaplan-Meier method and a landmark analysis to calculate conditional survival.In the 1673 patients analysed, median follow-up for alive patients was 20·1 months (IQR 9·0-34·4). We recorded an increase in the 2-year conditional survival probability from 44% (95% CI 41-47) at 0 months to 51% (46-55) at 18 months since beginning targeted therapy. When stratified by the Heng prognostic risk criteria defined at therapy initiation, 2-year conditional survival changed little in the favourable and intermediate groups, but in the poor-risk group, 2-year conditional survival improved from 11% (8-15) at 0 months to 33% (18-48) after 18 months. When conditioned on time on targeted therapy from 0 months to 18 months, 2-year conditional survival improved from 44% (41-47) to 68% (60-75) in the overall population and from 74% (68-79) to 90% (77-96) in the favourable group, 49% (45-53) to 57% (45-67) in the intermediate group, and 11% (8-15) to 73% (43-89) in the poor risk group.Conditional survival is a clinically useful prediction measure that adjusts prognosis of patients with metastatic renal-cell carcinoma on the basis of survival since treatment initiation or therapy duration. Conditional survival might be especially relevant to adjust prognosis for poor-risk patients.The Trust Family Fund for Kidney Cancer Research.

  View details for DOI 10.1016/S1470-2045(12)70285-1

  View details for Web of Science ID 000308425600020

  View details for PubMedID 22877847

• Prostate Cancer, Version 3.2012 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Mohler, J. L., Armstrong, A. J., Bahnson, R. R., Boston, B., Busby, J. E., D'Amico, A. V., Eastham, J. A., Enke, C. A., Farrington, T., Higano, C. S., Horwitz, E. M., Kantoff, P. W., Kawachi, M. H., Kuettel, M., Lee, R. J., MacVicar, G. R., Malcolm, A. W., Miller, D., Plimack, E. R., Pow-Sang, J. M., Roach, M., Rohren, E., Rosenfeld, S., Srinivas, S., Strope, S. A., Tward, J., Twardowski, P., Walsh, P. C., Ho, M., Shead, D. A. 2012; 10 (9): 1081-1087

  Abstract

  The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prostate Cancer provide multidisciplinary recommendations for the clinical management of patients with prostate cancer. These NCCN Guidelines Insights highlight notable recent updates. Abiraterone acetate is a first-in-class hormonal agent that represents a new standard of care for patients with metastatic castration-recurrent prostate cancer who have previously received docetaxel (category 1 recommendation). Abiraterone acetate also received category 2B recommendations in the prechemotherapy setting for asymptomatic patients or symptomatic patients who are not candidates for docetaxel. The NCCN Prostate Cancer Panel also added new indications for existing agents, including the option of sipuleucel-T as second-line therapy. In addition, brachytherapy in combination with external beam radiation therapy with or without androgen deprivation therapy is now an alternative for patients with high-risk localized tumors or locally advanced disease.

  View details for Web of Science ID 000308575200006

  View details for PubMedID 22956807

• Incidence and severity of cardiotoxicity in metastatic renal cell carcinoma (RCC) patients treated with targeted therapies. 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Hall, P. S., Witteles, R., Srinivas, S., Harshman, L. C. AMER SOC CLINICAL ONCOLOGY. 2012

  View details for Web of Science ID 000318009803091

• Evaluation of ERCC1 and RRM1 as prognostic biomarkers in urothelial cancer (UC) treated with adjuvant platinum and gemcitabine chemotherapy. 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Harshman, L. C., Bepler, G., Quinn, D. I., McKenney, J., Hawes, D., Simon, N., Srinivas, S., Dorff, T. B. AMER SOC CLINICAL ONCOLOGY. 2012

  View details for Web of Science ID 000318009803271

• Phase 1 trial of tivozanib (AV-951) combined with temsirolimus in patients with renal cell carcinoma 10th International Kidney Cancer Symposium Srinivas, S., Kabbinavar, F. F., Hauke, R. J., Esteves, B., Cotreau, M. M., Strahs, A. L., Fishman, M. N. WILEY-BLACKWELL. 2012: 10–11

  View details for Web of Science ID 000303438400023

• Oral enzastaurin in prostate cancer: A two-cohort phase II trial in patients with PSA progression in the non-metastatic castrate state and following docetaxel-based chemotherapy for castrate metastatic disease INVESTIGATIONAL NEW DRUGS Dreicer, R., Garcia, J., Hussain, M., Rini, B., Vogelzang, N., Srinivas, S., Somer, B., Zhao, Y. D., Kania, M., Raghavan, D. 2011; 29 (6): 1441-1448

  Abstract

  Enzastaurin is an oral serine/threonine kinase inhibitor of the beta isoform of protein kinase C that may have therapeutic activity in prostate cancer. We explored the efficacy of enzastaurin on two cohorts of patients with prostate cancer progression in the castrate state.A two-cohort phase II trial was conducted, with both groups participating simultaneously. Cohort 1 consisted of patients with non-metastatic castrate prostate-specific antigen progressive disease. Cohort 2 consisted of patients with castrate metastatic disease with progression following docetaxel-based chemotherapy. Patients in both cohorts received 500 mg/day enzastaurin.Therapy was well tolerated in both cohorts. One complete response was observed in Cohort 1, with limited activity in the majority of patients. In Cohort 2, no objective responses were seen and the median progression-free survival (11 weeks [90% confidence interval: 7.6, 11.7]) did not differ from the historical control.Enzastaurin as a single agent has limited activity in castrate progressive prostate cancer. Evaluation in combination with docetaxel is ongoing.

  View details for DOI 10.1007/s10637-010-9428-0

  View details for Web of Science ID 000294824200035

  View details for PubMedID 20369375

• Multicenter Phase II Trial of the Heat Shock Protein 90 Inhibitor, Retaspimycin Hydrochloride (IPI-504), in Patients With Castration-resistant Prostate Cancer UROLOGY Oh, W. K., Galsky, M. D., Stadler, W. M., Srinivas, S., Chu, F., Bubley, G., Goddard, J., Dunbar, J., Ross, R. W. 2011; 78 (3): 626-630

  Abstract

  To evaluate clinical activity and safety of retaspimycin hydrochloride (IPI-504) in patients with castration-resistant prostate cancer (CRPC).A single-arm trial was conducted in 2 cohorts: group 1, chemotherapy naive; group 2, docetaxel-treated. IPI-504 was administered intravenously at 400 mg/m2 on days 1, 4, 8, and 11 of a 21-day cycle. Trial expansion was planned if ≥1 prostate-specific antigen (PSA) or radiographic response was noted per cohort. Pharmacokinetic samples were collected after the first dose; safety was assessed throughout.A total of 19 patients were enrolled (4 in group 1; 15 in group 2), with a median age of 66 years (range 49-78). Group 2 had received a median of 2 previous chemotherapy regimens. All group 2 patients had bone metastases; 66% had measurable soft tissue or visceral metastases. One group 1 patient remained on-trial for 9 cycles; his PSA level declined 48% from baseline. No PSA response was observed in the other patients. Adverse events reported in >25% of the study population included nausea (47%), diarrhea (42%), fatigue (32%), anorexia (26%), and arthralgia (26%). Two patients in group 2 died on-trial, involving study drug-related events of hepatic failure and ketoacidosis, respectively.Heat shock protein 90 inhibition with IPI-504 administered as a single agent had a minimal effect on the PSA level or tumor burden and was associated with unacceptable toxicity in several patients. Therefore, additional evaluation in CRPC patients is not warranted. IPI-504 is being investigated at less-intensive doses and schedules in other tumor types.

  View details for DOI 10.1016/j.urology.2011.04.041

  View details for Web of Science ID 000294483300049

  View details for PubMedID 21762967

• Toxicities of targeted agents in advanced renal cell carcinoma. Current clinical pharmacology Patel, P., Srinivas, S. 2011; 6 (3): 181-188

  Abstract

  The targeted therapies available to treat metastatic kidney cancer include vascular endothelial growth factor (VEGF) inhibitors, bevacizumab, sorafenib, sunitinib, pazopanib, and the mTor inhibitors temsirolimus and everolimus. These agents have significantly improved patient outcomes but are associated with toxicities. The most common toxicities seen with the VEGF inhibitors are hypertension, fatigue, and hand- foot syndrome. The mTor inhibitors exhibit a different toxicity profile which includes hyperglycemia and hypertriglyceridemia. Recognition and understanding the mechanism of the toxicities is crucial for optimal patient management.

  View details for PubMedID 21827392

• Pyoderma Gangrenosum With the Use of Sunitinib JOURNAL OF CLINICAL ONCOLOGY Nadauld, L. D., Miller, M. B., Srinivas, S. 2011; 29 (10): E266-E267

  View details for DOI 10.1200/JCO.2010.32.6165

  View details for Web of Science ID 000288990100005

  View details for PubMedID 21220606

• NCCN Task Force Report: Optimizing Treatment of Advanced Renal Cell Carcinoma With Molecular Targeted Therapy JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Hudes, G. R., Carducci, M. A., Choueiri, T. K., Esper, P., Jonasch, E., Kumar, R., Margolin, K. A., Michaelson, D., Motzer, R. J., Pili, R., Roethke, S., Srinivas, S. 2011; 9: S1-S29

  Abstract

  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.

  View details for Web of Science ID 000292045400001

  View details for PubMedID 21335444

• NCCN Task Force Report: Optimizing Treatment of Advanced Renal Cell Carcinoma With Molecular Targeted Therapy J Natl Compr Canc Network Hudes GR, Carducci MA, Choueiri TK, Esper P, Jonasch E, KumarR, Margolin KA, Michaelson D, Motzer RJ, Pili P, Roethke S, Srinivas S 2011; 9: 29
• Ribonucleotide reductase subunit M1 expression in resectable, muscle-invasive urothelial cancer correlates with survival in younger patients BJU INTERNATIONAL Harshman, L. C., Bepler, G., Zheng, Z., Higgins, J. P., Allen, G. I., Srinivas, S. 2010; 106 (11): 1805-1811

  Abstract

  To assess whether high ribonucleotide reductase subunit M1 (RRM1) expression in patients with resected, muscle-invasive (T2-4NxM0) urothelial carcinoma (UC) correlated with longer overall survival (OS). RRM1 is the primary cellular target of gemcitabine and previous studies in resected early-stage lung cancer have shown a survival benefit for patients with high expression.In all, 84 radical cystectomy specimens with muscle-invasive UC were identified from existing tissue microarrays. The patients' medical records were retrospectively reviewed to confirm pathology and stage. Specimens were analysed for RRM1 expression using automated quantitative analysis. The median value of RRM1 was established a priori as the threshold for high and low expression.The median age of the patients was 69 years. Stages were nearly equally distributed: 30%, 38%, and 32% for stage II, III, and IV, respectively. Most were high grade (99%) with no nodal involvement (69%). The median (range) OS was 2.0 (0-13.1) years. Tumoral RRM1 levels did not correlate with OS for the entire cohort, but when adjusted for age, high tumoral RRM1 expression in younger patients (aged <70 years) correlated with increased survival. Younger patients with high RRM1 expression had a median OS of 10.6 years compared with 1.6 years in older patients (P= 0.001). There was no difference in OS among low RRM1 expressors: 2.3 vs 1.6 years in younger and older patients, respectively (P= 0.22).Our results suggest that high RRM1 expression may be prognostic for improved survival in patients with muscle-invasive UC aged <70 years.

  View details for DOI 10.1111/j.1464-410X.2010.09327.x

  View details for Web of Science ID 000284275200049

  View details for PubMedID 20438561

• Phase II Study on the Addition of ASA404 (Vadimezan; 5,6-Dimethylxanthenone-4-Acetic Acid) to Docetaxel in CRMPC CLINICAL CANCER RESEARCH Pili, R., Rosenthal, M. A., Mainwaring, P. N., van Hazel, G., Srinivas, S., Dreicer, R., Goel, S., Leach, J., Wong, S., Clingan, P. 2010; 16 (10): 2906-2914

  Abstract

  This randomized phase II study evaluated ASA404 (vadimezan; 5,6-dimethylxanthenone-4-acetic acid) in combination with docetaxel in castration-refractory metastatic prostate cancer (CRMPC).Seventy-four patients with histopathologically confirmed CRMPC previously untreated with chemotherapy were randomized to receive either

  View details for DOI 10.1158/1078-0432.CCR-09-3026

  View details for Web of Science ID 000278597600023

  View details for PubMedID 20460477

• NCCN clinical practice guidelines in oncology: prostate cancer. Journal of the National Comprehensive Cancer Network Mohler, J., Bahnson, R. R., Boston, B., Busby, J. E., D'Amico, A., Eastham, J. A., Enke, C. A., George, D., Horwitz, E. M., Huben, R. P., Kantoff, P., Kawachi, M., Kuettel, M., Lange, P. H., MacVicar, G., Plimack, E. R., Pow-Sang, J. M., Roach, M., Rohren, E., Roth, B. J., Shrieve, D. C., Smith, M. R., Srinivas, S., Twardowski, P., Walsh, P. C. 2010; 8 (2): 162-200

  View details for PubMedID 20141676

• Prostate Cancer JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Mohler, J., Bahnson, R. R., Boston, B., Busby, J. E., D'Amico, A., Eastham, J. A., Enke, C. A., George, D., Horwitz, E. M., Huben, R. P., Kantoff, P., Kawachi, M., Kuettel, M., Lange, P. H., MacVicar, G., Plimack, E. R., Pow-Sang, J. M., Roach, M., Rohren, E., Roth, B. J., Shrieve, D. C., Smith, M. R., Srinivas, S., Twardowski, P., Walsh, P. C. 2010; 8 (2): 162-200

  View details for Web of Science ID 000274541700004

• Adjuvant Docetaxel and androgen deprivation therapy in patients with High Risk Prostate Cancer Open Prostate Cancer Journal Bazan JG, King CR, Brooks JD, Srinivas S 2010; 3: 99-104
• The bevacizumab experience in advanced renal cell carcinoma ONCOTARGETS AND THERAPY Harshman, L. C., Srinivas, S. 2010; 3: 179-189

  Abstract

  Bevacizumab in combination with interferon alfa is now approved for treatment-naïve advanced renal cell carcinoma (RCC) in both the US and Europe. Its objective response rates of 30% and progression-free survival rates of 9-10 months are comparable to the other approved first-line multityrosine kinase inhibitors, sunitinib and pazopanib. Its advantages include a different toxicity profile and assurance of administration compliance given its intravenous formulation. Enthusiasm for its use is blunted by the increased costs, the potential infusion-related reactions, the associated interferon-related toxicities, and the inconvenience of its nonoral formulation. Further study is warranted to assess its efficacy both as a single agent and in combination with the targeted agents and other immunotherapies. With multiple agents now available for the treatment of advanced RCC, identification of patient and tumor-specific biomarkers to inform our choice of first-line therapy and the proper sequence of subsequent therapies is imperative.

  View details for Web of Science ID 000286671700001

  View details for PubMedID 21049084

• RRM1 expression in muscle invasive, locally advanced urothelial cancer is associated with survival in younger patients Annual Meeting of the EORTC/NCI/ASCO on Molecular Markers in Cancer Harshman, L., Bepler, G., Zheng, Z., Higgins, J., Allen, G., Srinivas, S. PERGAMON-ELSEVIER SCIENCE LTD. 2009: 19–19

  View details for Web of Science ID 000273018800069

• Phase II Study of Sunitinib Administered in a Continuous Once-Daily Dosing Regimen in Patients With Cytokine-Refractory Metastatic Renal Cell Carcinoma 14th European Cancer Conference (ECCO 14) Escudier, B., Roigas, J., Gillessen, S., Harmenberg, U., Srinivas, S., Mulder, S. F., Fountzilas, G., Peschel, C., Flodgren, P., Maneval, E. C., Chen, I., Vogelzang, N. J. AMER SOC CLINICAL ONCOLOGY. 2009: 4068–75

  Abstract

  Sunitinib has demonstrated antitumor activity in metastatic renal cell carcinoma (mRCC) when given at 50 mg/d on a 4-weeks-on 2-weeks-off regimen. Herein, we report results of an open-label, multicenter phase II mRCC study of sunitinib administered on a continuous once-daily dosing regimen.Eligibility criteria included histologically proven mRCC with measurable disease, failure of one prior cytokine regimen, and good performance status. Patients were randomly assigned to a sunitinib starting dose of 37.5 mg/d in the morning (AM) or evening (PM). RECIST-defined objective response rate (ORR) was the primary end point. Secondary end points included progression-free survival (PFS), overall survival (OS), adverse events (AEs), and quality-of-life measures.One hundred seven patients were randomly assigned to AM (n = 54) or PM (n = 53) dosing and on study for a median 8.3 months. Eighty-three patients discontinued, 65 due to disease progression and 16 because of AEs; two patients withdrew consent. Dosing was reduced to 25 mg/d in 46 patients (43%) due to grade 3/4 AEs. The most common grade 3 treatment-related AEs were asthenia/fatigue (16%), diarrhea (11%), hypertension (11%), hand-foot syndrome (9%), and anorexia (8%). ORR was 20% with a 7.2-month median response duration. Median PFS and OS were 8.2 and 19.8 months, respectively, at median follow-up of 26.4 months. Efficacy, tolerability, and quality-of-life results were similar between patients dosed in the AM or PM.Sunitinib 37.5 mg, administered on a continuous once-daily dosing regimen, has a manageable safety profile as second-line mRCC therapy, providing flexible dosing, which can be explored in combination studies.

  View details for DOI 10.1200/JCO.2008.20.5476

  View details for Web of Science ID 000269381100008

  View details for PubMedID 19652072

• A Phase II Trial of Calcitriol and Naproxen in Recurrent Prostate Cancer 3rd International Symposium on Vitamin D Analogs in Cancer Prevention and Therapy Srinivas, S., Feldman, D. INT INST ANTICANCER RESEARCH. 2009: 3605–10

  Abstract

  Androgen-deprivation therapy is commonly used in patients with progressive prostate cancer (PCa), but can be associated with unpleasant side-effects. The objective of the study was to determine whether treatment with calcitriol and naproxen is effective in safely delaying the growth and progression of PCa in men with early recurrent disease.Patients with biochemical relapse after local therapy for prostate cancer were treated with high dose calcitriol (DN101, Novacea) (45 microg once per week) and naproxen (375 mg twice daily) for one year and followed with serum PSA levels as well as imaging studies.Twenty-one patients were enrolled in the trial. Four patients met criteria for progression, with a PSA doubling time (PSADT) that decreased while on therapy. Fourteen patients had a prolongation of PSADT compared to baseline.Combination therapy with weekly calcitriol and daily naproxen is well tolerated by most patients and prolongation of PSADT was achieved in 75% of patients.

  View details for Web of Science ID 000268846900016

  View details for PubMedID 19667155

• Laparoscopic radical nephrectomy after shrinkage of a caval tumor thrombus with sunitinib NATURE REVIEWS UROLOGY Harshman, L. C., Srinivas, S., Kamaya, A., Chung, B. I. 2009; 6 (6): 338-343

  Abstract

  A 57-year-old woman presented to the emergency department at a community hospital with a 2-month history of fatigue and right-sided flank and abdominal pain. Noncontrast CT of the abdomen and pelvis revealed a 9.1 cm right renal mass.Contrast CT of the chest, abdomen and pelvis, MRI of the abdomen and pelvis with gadolinium, radionuclide bone scan, lung nodule biopsy, complete blood count, comprehensive metabolic profile, and measurement of serum lactate dehydrogenase.Stage IV, T3bN0M1 clear cell renal cell carcinoma, with an associated tumor thrombus extending into the vena cava.The patient was treated with neoadjuvant sunitinib, which resulted in a marked response in the primary tumor and metastatic lesions as well as regression of the tumor thrombus well into the renal vein. Thus, laparoscopic radical nephrectomy was feasible and was achieved without hemorrhagic or wound healing complications. One month after surgery, she had evidence of disease progression in the lung and a periaortic lymph node. She was restarted on sunitinib with resultant disease stabilization, but discontinued the drug owing to toxicity. Eight months after cessation of sunitinib, she received a dendritic cell vaccine. She remains alive without evidence of disease progression 2 years after her diagnosis.

  View details for DOI 10.1038/nrurol.2009.84

  View details for Web of Science ID 000266773900012

  View details for PubMedID 19498412

• NCCN Task Force Report: Bone Health in Cancer Care JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Gralow, J. R., Biermann, J. S., Farooki, A., Fornier, M. N., Gagel, R. F., Kumar, R. N., Shapiro, C. L., Shields, A., Smith, M. R., Srinivas, S., Van Poznak, C. H. 2009; 7: S1-S32

  Abstract

  Bone health and maintenance of bone integrity are important components of comprehensive cancer care in both early and late stages of disease. Risk factors for osteoporosis are increased in patients with cancer, including women with chemotherapy-induced ovarian failure, those treated with aromatase inhibitors for breast cancer, men receiving androgen-deprivation therapy for prostate cancer, and patients undergoing glucocorticoid therapy. The skeleton is a common site of metastatic cancer recurrence, and skeletal-related events are the cause of significant morbidity. The National Comprehensive Cancer Network (NCCN) convened a multidisciplinary task force on Bone Health in Cancer Care to discuss the progress made in identifying effective screening and therapeutic options for management of treatment-related bone loss; understanding the factors that result in bone metastases; managing skeletal metastases; and evolving strategies to reduce bone recurrences. This report summarizes presentations made at the meeting.

  View details for Web of Science ID 000270360200001

  View details for PubMedID 19555589

• Correlation of RRM1 expression in muscle invasive locally advanced urothelial cancer with age 45th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Harshman, L. C., Bepler, G., Zheng, Z., Higgins, J. P., ALLEN, G. I., Tibshirani, R., Srinivas, S. AMER SOC CLINICAL ONCOLOGY. 2009

  View details for Web of Science ID 000276606604062

• Increased Hemoglobin Associated with VEGF Inhibitors in Advanced Renal Cell Carcinoma CANCER INVESTIGATION Harshman, L. C., Kuo, C. J., Wong, B. Y., Vogelzang, N. J., Srinivas, S. 2009; 27 (8): 851-856

  Abstract

  We retrospectively analyzed whether increased hemoglobin is a surrogate biomarker of efficacy for vascular endothelial growth factor (VEGF) inhibitors in advanced renal cell carcinoma (RCC) patients. Twelve patients were identified who had received bevacizumab alone or as combination therapy. Eleven patients experienced a rise in hemoglobin. Median change was 1.6 g/dL (0-4.0). Degree of peak increase correlated with longer progression-free survival (PFS) in metastatic patients: increase of < 15% yielded a 3.1-month median PFS compared to 8.2 months with rises > 15%. This study identifies increased hemoglobin as a possible consequence of VEGF inhibitors. The correlation with longer PFS suggests that rise in hemoglobin may be a surrogate biomarker of efficacy.

  View details for DOI 10.1080/07357900902744528

  View details for Web of Science ID 000269542600007

  View details for PubMedID 19603304

• A Phase II Study of Docetaxel and Oxaliplatin for Second-Line Treatment of Urothelial Carcinoma CHEMOTHERAPY Srinivas, S., Harshman, L. C. 2009; 55 (5): 321-326

  Abstract

  Despite high response rates with front-line platinum-based therapies, 80% of patients with metastatic urothelial cancer progress. Multiple agents and couplets have been investigated, but no standard second-line regimen exists. We conducted a phase II study to evaluate the efficacy and safety of docetaxel and oxaliplatin in metastatic urothelial cancer patients who had received prior platinum therapy.Patients with metastatic urothelial cancer, who had disease progression after platinum therapy, were treated with docetaxel 75 mg/m(2) and oxaliplatin 85 mg/m(2) every 3 weeks until disease progression or intolerable toxicity.Between November 2004 and September 2005, 11 patients were enrolled. All patients had low or intermediate Bajorin risk. The median number of cycles administered was 2 (range 2-8). One patient achieved near complete response. Three patients experienced disease stabilization, resulting in a disease-control rate of 36%. Median overall survival was 7 months. The most common toxicities were fatigue and anemia (50%).Second-line docetaxel and oxaliplatin in metastatic urothelial cancer is safe and tolerable but did not achieve an appreciable response rate.

  View details for DOI 10.1159/000230695

  View details for Web of Science ID 000270361800004

  View details for PubMedID 19641314

• High dose chemotherapy followed by stem cell rescue for high risk germ cell tumors: the Stanford experience. Bone Marrow Transplant Agarwal R, Dvorak CC, Stockerl- Goldstein KE, Johnson L, Srinivas S 2009; 43 (7): 547-52
• Inhibition of prostaglandin synthesis and actions contributes to the beneficial effects of calcitriol in prostate cancer. Dermato-endocrinology Krishnan, A. V., Srinivas, S., Feldman, D. 2009; 1 (1): 7-11

  Abstract

  Our research is aimed at obtaining a better understanding of the molecular mechanisms of the anti-proliferative and cancer preventive effects of calcitriol with the goal of developing strategies to improve the treatment of prostate cancer (PCa). In PCa cells calcitriol inhibits the synthesis and biological actions of prostaglandins (PGs) by three actions: (i) the inhibition of the expression of cyclooxygenase-2 (COX-2), the enzyme that synthesizes PGs, (ii) the upregulation of the expression of 15-prostaglandin dehydrogenase (15-PGDH), the enzyme that inactivates PGs and (iii) decreasing the expression of EP and FP PG receptors that are essential for PG signaling. Since PGs have been shown to promote carcinogenesis and progression of multiple cancers, we hypothesize that the inhibition of the PG pathway contributes to the ability of calcitriol to prevent or inhibit PCa development and growth. We have shown that the combination of calcitriol and non-steroidal anti-inflammatory drugs (NSAIDs) result in a synergistic inhibition of the growth of PCa cell cultures and this combination therapy offers a potential therapeutic strategy. These findings led us to embark on a clinical trial combining the non-selective NSAID naproxen with calcitriol in men with early recurrent PCa. The results indicate that the combination of high dose weekly calcitriol with naproxen slows the rate of rise (doubling time) of PSA in most patients indicating the slowing of disease progression. Further studies are warranted to determine the role of this combination therapy in the management of recurrent PCa.

  View details for PubMedID 20046582

  View details for PubMedCentralID PMC2715203

• Combination therapy with calcitriol and non-steroidal anti-inflammatory drugs in the treatment of prostate cancer Dermato Endocrinolgy Krishnan AV, Srinivas S, Feldman D 2009; 1: 7-11
• Increased Hemoglobin Associated with VEGF Inhibitors in Advanced Renal Cell Carcinoma 50th Annual Meeting of the American-Society-of-Hematology/ASH/ASCO Joint Symposium Harshman, L. C., Kuo, C. J., Wong, B. Y., Vogelzang, N. J., Srinivas, S. AMER SOC HEMATOLOGY. 2008: 1185–85

  View details for Web of Science ID 000262104704071

• The Combination of Thalidomide and Capecitabine in Metastatic Renal Cell Carcinoma - Is Not the Answer AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS Harshman, L. C., Li, M., Srinivas, S. 2008; 31 (5): 417-423

  Abstract

  Despite the introduction of newer treatment approaches in metastatic renal cell carcinoma (mRCC), overall survival remains disappointing and further exploration of current chemotherapeutic agents for second or third-line treatment is imperative. We conducted a phase II trial to determine the efficacy and safety of the combination of thalidomide and capecitabine in mRCC.We enrolled 13 eligible patients, who had progressive measurable metastatic disease, between May 2003 and January 2005. Treatment consisted of thalidomide 200 mg daily for 21 days per cycle, and capecitabine 1250 mg/m(2) twice daily for 14 days per cycle. The primary end point was response rate. Secondary endpoints included overall survival and toxicity assessment.Twelve patients were eligible for statistical analysis. The median age was 59 years, and most patients had an Eastern Cooperative Oncology Group performance status of 0-1 (92%). Nine patients had previous nephrectomy. The median number of administered cycles was 4 (range 2-10). Anemia was the only grade 3 toxicity. Grade 2 toxicities included fatigue, constipation, anemia, hand-foot syndrome, diarrhea, and peripheral neuropathy. Although no radiographic responses were observed, 5 patients (42%) achieved stable disease. Seven patients (58%) experienced disease progression. The median overall survival was 10.2 months.Despite being well tolerated with manageable side effects, the use of thalidomide and capecitabine in patients with mRCC did not significantly impact response or survival.

  View details for DOI 10.1097/COC.0b013e318168ef47

  View details for Web of Science ID 000260123000003

  View details for PubMedID 18838876

• Cardiotoxicity associated with the cancer therapeutic agent sunitinib malate ANNALS OF ONCOLOGY Telli, M. L., Witteles, R. M., Fisher, G. A., Srinivas, S. 2008; 19 (9): 1613-1618

  Abstract

  In the pivotal phase III metastatic renal cell carcinoma trial, updated data indicates that 21% of sunitinib-treated patients experienced a decline in left ventricular ejection fraction to below normal. This cardiotoxicity was reported to be reversible and without clinical sequelae. We conducted a retrospective analysis of our institutional experience of cardiotoxicity with sunitinib after observing a high incidence of symptomatic heart failure.Patients receiving sunitinib at Stanford University from 1 July 2004 to 1 July 2007 were identified. Medical records were reviewed and those patients experiencing symptomatic grade 3/4 left ventricular systolic dysfunction were identified. Potential cardiac risk factors were analyzed.Forty-eight patients treated with sunitinib were assessable. Seven patients experienced symptomatic grade 3/4 left ventricular dysfunction 22-435 days after initiation of sunitinib. Three patients had persistent cardiac dysfunction after discontinuation of sunitinib and initiation of heart failure therapy. A history of congestive heart failure, coronary artery disease and lower body mass index were factors associated with increased risk.Among patients treated with sunitinib at our institution, 15% developed symptomatic grade 3/4 heart failure. Future studies of sunitinib-related cardiotoxicity are urgently needed, particularly as the oncologic indications for this drug continue to expand.

  View details for DOI 10.1093/annonc/mdn168

  View details for Web of Science ID 000259505400015

  View details for PubMedID 18436521

• Phase 2 trial of talactoferrin in previously treated patients with metastatic renal cell carcinoma CANCER Jonasch, E., Stadler, W. M., Bukowski, R. M., Hayes, T. G., Varadhachary, A., Malik, R., Figlin, R. A., Srinivas, S. 2008; 113 (1): 72-77

  Abstract

  Talactoferrin (TLF), a recombinant form of human lactoferrin (hLF), is an immunomodulatory iron-binding glycoprotein first identified in breast milk. Its immunomodulatory functions include activation of natural killer (NK) and lymphokine-activated killer cells and enhancement of polymorphonuclear cells and macrophage cytotoxicity. Studies in animal models have shown promising anticancer activity, and clinical antitumor activity has been observed in nonsmall cell lung cancer and other tumor types. The purpose of the current study was to evaluate the activity and safety of TLF in patients with refractory metastatic renal cell carcinoma (RCC).Forty-four adult patients with progressive advanced or metastatic RCC who had failed prior systemic therapy received oral talactoferrin at a dose of 1.5 g twice daily on a 12-week-on 2-week-off schedule. Patients were evaluated for progression-free survival at 14 weeks, overall response rate, and progression-free and overall survival.TLF was well tolerated. No significant hematologic, hepatic, or renal toxicities were reported. The study met its predefined target with a 14-week progression-free survival rate of 59%. The response rate was 4.5%. The mMedian progression-free survival was 6.4 months and the median overall survival was 21.1 months.TLF is a well-tolerated new agent that has demonstrated preliminary signs of clinical activity. Given the lack of toxicity, the lack of rapid disease progression in this cohort, and the preclinical data on immune activation, a randomized study assessing its effects on disease progression in patients with metastatic RCC is rational.

  View details for DOI 10.1002/cncr.23519

  View details for Web of Science ID 000256914200010

  View details for PubMedID 18484647

• Bevacizumab-associated erythrocytosis in metastatic renal cell carcinoma (mRCC) Harshman, L. C., Kuo, C. J., Srinivas, S. AMER SOC CLINICAL ONCOLOGY. 2008

  View details for Web of Science ID 000208457401736

• Continuous daily dosing of sunitinib in patients with metastatic renal cell cancer ONKOLOGIE Harshman, L., Srinivas, S. 2008; 31 (8-9): 432-433

  View details for DOI 10.1159/000144179

  View details for Web of Science ID 000259273700004

  View details for PubMedID 18787349

• A Phase 2 study of the dual MET/VEGFR2 inhibitor XL880 in patients (pts) with papillary renal carcinoma (PRC) Ross, R. W., Srinivasan, R., Vaishampayan, U., Bukowski, R., Rosenberg, J., Eisenberg, P., Logan, T., Srinivas, S., Stein, M., Mueller, T., Keer, H. N. AMER ASSOC CANCER RESEARCH. 2007: 3511S–3511S

  View details for Web of Science ID 000251969000541

• Current status of cytoreductive nephrectomy in metastatic renal cell carcinoma EXPERT REVIEW OF ANTICANCER THERAPY Harshman, L. C., Srinivas, S. 2007; 7 (12): 1749-1761

  Abstract

  The incidence of metastatic renal cell carcinoma (mRCC) continues to rise. While treatment options have increased dramatically in the last few years, few patients achieve a cure. The standard of care for mRCC in cytokine-eligible candidates is nephrectomy followed by high-dose IL-2. High-dose IL-2 can induce durable complete remissions, but only select patients can enjoy its benefits owing to toxicities. While not curative, the newer targeted therapies offer a broader patient population the chance for treatment response and prolonged survival. This review highlights the historical background of cytoreductive nephrectomy in mRCC, discusses the available treatment options and considers alternative treatment paradigms, such as the integration of the targeted agents with nephrectomy and the use of systemic therapy as medical selection for determining appropriate nephrectomy candidates.

  View details for DOI 10.1586/14737140.7-12.1749

  View details for Web of Science ID 000251891100016

  View details for PubMedID 18062749

• Randomized phase II study of erlotinib combined with bevacizumab compared with bevacizumab alone in metastatic renal cell cancer 42nd Annual Meeting of the American-Society-of-Clinical-Oncology Bukowski, R. M., Kabbinavar, F. F., Figlin, R. A., Flaherty, K., Srinivas, S., Vaishampayan, U., Drabkin, H. A., Dutcher, J., Ryba, S., Xia, Q., Scappaticci, F. A., McDermott, D. AMER SOC CLINICAL ONCOLOGY. 2007: 4536–41

  Abstract

  Bevacizumab (Bev) has clinical activity in advanced renal cell carcinoma (RCC), and, when combined with erlotinib (Erl), has shown encouraging objective response rate (ORR) and progression-free survival (PFS). We performed a phase II, randomized, double-blind, multicenter, placebo-controlled trial to assess whether Erl provides additional clinical benefit with regard to PFS and ORR when combined with Bev in first-line treatment of metastatic RCC.One hundred four patients received intravenous Bev (10 mg/kg) every 2 weeks in combination with oral Erl (150 mg) or placebo daily. Patients were treated until progression or toxicity.A landmark analysis was performed 9 months after enrollment was completed (median follow-up, 9.8 months). Sixty-five patients had discontinued therapy; time to study discontinuation did not differ between the two treatment groups. The median PFS was 9.9 months (Bev + Erl [B+E]) versus 8.5 months (Bev; hazard ratio = 0.86; 95% CI, 0.5 to 1.49; P = .58). ORR (complete plus partial) was 14% (B+E) versus 13% (Bev). One complete response occurred in the B+E group. Median survival was 20 months for B+E but not reached for Bev. The most common grade 3/4 adverse events (> 5% of patients) were hypertension, rash, proteinuria, diarrhea, and hemorrhage. One treatment-related death occurred on study (GI perforation, B+E group).The addition of Erl to Bev was well tolerated, but did not provide additional clinical benefit compared with Bev alone. Bev has encouraging clinical activity for previously untreated metastatic RCC patients.

  View details for DOI 10.1200/JCO.2007.11.5154

  View details for Web of Science ID 000251073600008

  View details for PubMedID 17876014

• Acute pancreatitis associated with sorafenib SOUTHERN MEDICAL JOURNAL Li, M., Srinivas, S. 2007; 100 (9): 909-911

  Abstract

  Since its FDA approval in December 2005, sorafenib (Nexavar) has been in use for the treatment of metastatic renal cell carcinoma. With this increased use have come reports of adverse effects of sorafenib. To the best of the authors' knowledge, they are the first to describe an 80-year-old Asian male with a history of metastatic renal cell carcinoma who developed acute pancreatitis confirmed by computed tomography (CT) one month after taking sorafenib 400 mg orally twice a day. Sorafenib was eventually discontinued, and the pancreatitis resolved. The molecular biologic mechanism causing this side effect is discussed. Patients should be informed of this rare but potentially serious adverse effect before initiation of sorafenib therapy. Early recognition of this complication and complete discontinuation of sorafenib are recommended.

  View details for Web of Science ID 000249669600014

  View details for PubMedID 17902294

• Prostate cancer. Clinical practice guidelines in oncology. Journal of the National Comprehensive Cancer Network Mohler, J., Babaian, R. J., Bahnson, R. R., Boston, B., D'Amico, A., Eastham, J. A., Hauke, R. J., Huben, R. P., Kantoff, P., Kawachi, M., Kuettel, M., Lange, P. H., Logothetis, C., MacVicar, G., Pollack, A., Pow-Sang, J. M., Roach, M., Sandler, H., Shrieve, D., Srinivas, S., Twardowski, P., Urban, D. A., Walsh, P. C. 2007; 5 (7): 650-683

  View details for PubMedID 17692170

• Vitamin D inhibition of the prostaglandin pathway as therapy for prostate cancer Conference on Vitamin D and Cancer - Current Dilemas/Future Needs Feldman, D., Krishnan, A., Moreno, J., Swami, S., Peehl, D. M., Srinivas, S. BLACKWELL PUBLISHING. 2007: S113–S115

  View details for Web of Science ID 000248995500012

  View details for PubMedID 17867384

• Bone related events in high risk prostate cancer JOURNAL OF UROLOGY Srinivas, S., Colocci, N. 2006; 176 (6): S50-S54

  Abstract

  We provide recommendations for defining and treating bone related events in high risk prostate cancer.A focused literature review was done.Men with prostate cancer often have osteoporosis and osteopenia even before initiating androgen deprivation therapy. After starting androgen deprivation therapy they experience accelerated bone loss. Bone mineral density is the most common tool to assess the degree of bone loss, although the use of bone turnover markers for this purpose is being actively explored. Bisphosphonates are effective for increasing bone mineral density and treating osteoporosis. The benefits derived from bisphosphonates should be weighed against the adverse effects, including the risk of osteonecrosis of the jaw. Treatment is indicated in patients with prostate cancer with osteoporosis and it may be considered in patients with osteopenia and/or additional risk factors. The time of initiation of therapy and duration of treatment have not been conclusively established.Prolonged androgen deprivation therapy results in bone loss and it has a potential to impact quality of life. Additional research is needed to characterize patients who would benefit from therapy and optimize strategies to prevent osteoporosis.

  View details for DOI 10.1016/j.juro.2006.06.076

  View details for Web of Science ID 000242029200011

  View details for PubMedID 17084167

• Reliability of small amounts of cancer in prostate biopsies to reveal pathologic grade UROLOGY King, C. R., McNeal, J. E., Gill, H., Brooks, J. D., Srinivas, S., Presti, J. C. 2006; 67 (6): 1229-1234

  Abstract

  To examine grade reliability when biopsies contain very small amounts of prostate cancer. Prostate biopsy findings are known to undergrade prostate cancer compared with the pathologic specimens yet remain the only grade guiding disease management.The presence of a clinically significant grade change from biopsy cores to matched prostatectomy specimens was examined in 371 patients. The biopsies were characterized for primary and secondary Gleason grade, number of positive cores, and total linear length of cancer. The pathologic specimens were characterized for cancer volume and relative percentage by grade. The rates of upgrading or downgrading were tested against all clinical and biopsy information for any significant predictive value.The overall rate of upgrading was 40.7% and downgrading was 16.1%. Upgrading was constant and independent of any clinical or biopsy tumor volume indexes. Specifically, when cancer was present in only one biopsy core and measured 2 mm or less (n = 48), it was just as predictive of the pathologic grade as that from any greater number of positive cores and any greater extent of cancer length present. Downgrading was less frequent for biopsies with small amounts of cancer.Histologic grading from small amounts of cancer in prostate biopsies is reliable and not more prone to grading errors. A repeat biopsy for these patients may not be indicated.

  View details for DOI 10.1016/j.urology.2005.12.031

  View details for Web of Science ID 000238390900026

  View details for PubMedID 16765184

• Nonplatinum therapy in advanced bladder cancer EXPERT REVIEW OF ANTICANCER THERAPY Srinivas, S., Colocci, N. 2006; 6 (6): 887-894

  Abstract

  Carcinoma of the bladder is the second most prevalent genitourinary malignancy and the fifth most common solid malignancy in the USA. Combination chemotherapy is used in most patients with advanced disease. Traditionally, on the basis of favorable response rates and survival data, cisplatin-based regimens have been the preferred chemotherapy for patients with metastatic bladder cancer. However, the toxicity profile of cisplatin precludes its use in a significant subset of patients with advanced bladder cancer. Conversely, noncisplatin-containing regimens have been shown to have a more favorable toxicity profile and to have activity in advanced bladder cancer. Here, various nonplatinum chemotherapy regimens for advanced disease are reviewed.

  View details for DOI 10.1586/14737140.6.6.887

  View details for Web of Science ID 000240923100013

  View details for PubMedID 16761932

• Phase II study evaluating oral triamcinolone in patients with androgen-independent prostate cancer UROLOGY Srinivas, S., Krishnan, A. V., Colocci, N., Feldman, D. 2006; 67 (5): 1001-1006

  Abstract

  To assess the effect of triamcinolone administration on the serum prostate-specific antigen (PSA) response and the time to progression in patients with androgen-independent prostate cancer (AIPC).Patients with AIPC were prospectively treated with oral triamcinolone 4 mg twice daily, and their serum PSA and cortisol levels were measured monthly. Patients with greater than 25% increases in serum PSA from baseline were considered to have progressive disease and were removed from the study. Those patients who had a decrease in serum PSA levels or stable disease continued in the study until disease progression. Bone scans were obtained every 12 weeks and at progression.Twenty-four patients with AIPC were treated from November 2002 to June 2004. A partial response with a more than 50% decrease in serum PSA level was seen in 29%. Another 21% achieved stable disease. No statistically significant difference was found in the time to progression in the partial responders and patients with stable disease. The median time to progression in both groups was 7.5 months. Treatment was well tolerated without any grade 3 or 4 toxicity.Oral triamcinolone was well tolerated by patients with AIPC, with 50% of the patients exhibiting a good response to therapy in terms of serum PSA level and time to progression.

  View details for DOI 10.1016/j.urology.2005.11.004

  View details for Web of Science ID 000238390800026

  View details for PubMedID 16698360

• Evaluation of fluorodeoxyglucose positron emission tomography imaging in metastatic transitional cell carcinoma with and without prior chemotherapy UROLOGIA INTERNATIONALIS Liu, I. J., Lai, Y., Espiritu, J. I., Segall, G. M., Srinivas, S., Nino-Murcia, M., Terris, M. K. 2006; 77 (1): 69-75

  Abstract

  This study was designed to determine the value of fluorodeoxyglucose (FDG) positron emission tomography (PET) in the evaluation of metastatic transitional cell carcinoma (TCC).Fifty-eight FDG PET scans were performed on 46 consecutive patients with TCC. Results were correlated with radiologic, pathologic, and histologic findings in these patients and the sensitivity of PET for detecting malignancy in untreated TCC patients (n = 48) was compared to the sensitivity in patients who had undergone prior chemotherapy (n = 10).Of 48 scans in patients who had no prior systemic chemotherapy, 10 had increased uptake in proven metastatic TCC lesions and 3 PET studies failed to reveal metastatic TCC (sensitivity 76.9%). In patients free of metastatic disease, 33 revealed no abnormal uptake and 1 study revealed a suspicious area in a patient free of metastases (specificity = 97.1%). However, in 10 patients imaged after receiving chemotherapy, the sensitivity fell to 50% for the detection of histologically confirmed residual/recurrent tumor by PET.FDG PET detects increased metabolic activity. After chemotherapy, viable cancer cells may still be present but with a diminished metabolic rate. As a result, PET imaging is often useful in the evaluation of untreated metastatic TCC metastasis but should be interpreted with caution in patients who have received prior chemotherapy.

  View details for DOI 10.1159/000092937

  View details for Web of Science ID 000238913100014

  View details for PubMedID 16825819

• Double diagnosis in cancer patients and cutaneous reaction related to gemcitabine: CASE 3. Photo therapy recall with gemcitabine following ultraviolet B treatment. Journal of clinical oncology Badger, J., Kang, S., Uzieblo, A., Srinivas, S. 2005; 23 (28): 7224-7225

  View details for PubMedID 16192608

• A lower dose of thalidomide is better than a high dose in metastatic renal cell carcinoma BJU INTERNATIONAL Srinivas, S., Guardino, A. E. 2005; 96 (4): 536-539

  Abstract

  To conduct a dose-finding trial using a single low dose and dose escalation of a higher dose of thalidomide in patients with metastatic renal cell carcinoma (RCC), and to evaluate the antineoplastic effectiveness of thalidomide as an anti-angiogenic agent on RCC.The 14 patients enrolled in the study had progressive measurable metastatic RCC and consented to participate. Patients were randomized to either a fixed low dose of 200 mg of thalidomide or to a high dose of 800 mg that was increased to a maximum dose of 1200 mg daily. Patients were evaluated for response after 8 weeks of therapy.Stable disease was achieved in six patients and was seen in both the low-dose and high-dose thalidomide groups. The median overall survival was 9 months. The low-dose thalidomide regimen was better tolerated and patients survived longer than those on the high-dose regimen (16 vs 6 months, P = 0.04)The use of low-dose thalidomide in patients with metastatic RCC was well tolerated and they survived for longer than those on the high-dose regimen.

  View details for DOI 10.1111/j.1464-410X.2005.05680.x

  View details for Web of Science ID 000231387900017

  View details for PubMedID 16104906

• A nonplatinum combination in metastatic transitional cell carcinoma AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS Srinivas, S., Guardino, A. E. 2005; 28 (2): 114-118

  Abstract

  Cisplatin-based chemotherapy is the most effective standard treatment available for patients with metastatic bladder cancer. For those patients who are unable to receive cisplatin, other effective combination treatments are needed. The objective of this research was to determine if a combination of paclitaxel and gemcitabine would be effective in patients who were unable to receive cisplatin or have failed cisplatin treatment.Patients with histologic-proven metastatic bladder cancer who had measurable disease were eligible. Patients received chemotherapy (in an outpatient clinic) with paclitaxel at 110 mg/m2 plus 1000 mg/m2 gemcitabine on days 1 and 15 of a 28-day cycle. Patients were evaluated after 2 cycles of therapy using computed tomography and bone scan imaging.An objective response rate was achieved in 61% of the patients (13 of 18 subjects). Fifty-five percent of the patients who were previously treated with chemotherapy had an objective response (11 of 18 subjects). The median duration of response was 5 months and the toxicity was mild. All patients with low-risk disease had a response (8 of 18 subjects), compared with a 30% response rate in the intermediate-/high-risk group (P = 0.001, 10 of 18 subjects).The combination of paclitaxel and gemcitabine given in an every 2-week regimen is very well tolerated and has significant activity in previously treated patients with metastatic transitional cell carcinoma. The combination of paclitaxel and gemcitabine appears to be effective for patients with good-risk disease who are unable to take cisplatin-based chemotherapy.

  View details for DOI 10.1097/01.coc.0000143018.04650.f9

  View details for Web of Science ID 000228240600002

  View details for PubMedID 15803002

• Node Positive Bladder Cancer Arab J Urology Srinivas S, Freiha F 2005; 3: 7-11
• Synchronous solitary metastasis of transitional cell carcinoma of the bladder to the testis UROLOGY Morgan, K., Srinivas, S., Freiha, F. S. 2004; 64 (4)

  Abstract

  Primary tumors known to metastasize to the testis, in order of decreasing frequency, are prostate, lung, gastrointestinal tract, melanoma, and kidney tumors. Metastasis from bladder cancer to the testis is extremely rare, occurs with advanced and metastatic disease, and is usually a finding at autopsy. We report a rare, and probably the first, case of solitary and synchronous metastatic transitional cell carcinoma of the bladder to the testis, discovered on the preoperative workup. An incidentally discovered testicular mass in a man with high-grade, invasive bladder cancer should be considered a metastatic lesion until proven otherwise.

  View details for Web of Science ID 000224680300054

  View details for PubMedID 15491734

• Gemcitabine and paclitaxel chemotherapy effective for good risk advanced urothelial malignancies. 40th Annual Meeting of the American-Society-of-Clinical-Oncology Srinivas, S., Guardino, A. E. AMER SOC CLINICAL ONCOLOGY. 2004: 425S–425S

  View details for Web of Science ID 000223512401686

• Flutamide administration at 500 mg daily has similar effects on serum testosterone to 750 mg daily JOURNAL OF ANDROLOGY Murphy, J. C., Srinivas, S., Terris, M. K. 2004; 25 (4): 630-634

  Abstract

  A prior comparison of 750 mg flutamide daily to 500 mg daily with an LHRH analog or orchiectomy showed no difference in effect on prostate specific antigen (PSA). However, any difference was likely masked by hypogonadism from concomitant LHRH analog or orchiectomy. We sought to evaluate different flutamide dosing schedules without this confounding factor. We recruited 50 men with advanced prostate cancer who elected to receive hormonal therapy to be randomized to 1 of 3 flutamide treatment groups: 1) 250 mg once daily, 2) 250 mg twice daily, or 3) 250 mg 3 times daily for 3 months, after which the therapy of their choice was instituted. Serum samples at the initiation of therapy and at the 1- and 3-month time point were assessed for PSA, testosterone, liver function tests, hematology, and renal function. Prostate volume, androgen deficiency symptoms, and a compliance diary were also recorded. Testosterone and PSA levels show a dose-dependent response to flutamide monotherapy. Loss of libido and erectile dysfunction occurred in all 3 treatment groups, with a trend toward worsening sexual function with higher flutamide dosing, but this trend did not reach statistical significance. Prostate volumes decreased by an average of 34.3% in the patients receiving 250 mg flutamide 3 times daily, 27.8% in patients receiving 250 mg flutamide twice daily, and 19.2% in those receiving a once daily dose of 250 mg flutamide. There was a significant difference between the once daily group and the 3 times daily group (P =.047). Flutamide at 500 mg did not result in significant changes in testosterone, PSA, prostate volume, or androgen deficiency symptoms compared to 750 mg daily after 3 months.

  View details for Web of Science ID 000222455000022

  View details for PubMedID 15223852

• Positron emission tomography in the initial staging of esophageal cancer 73rd Annual Meeting of the Pacific-Coast-Surgical-Association Wren, S. M., Stijns, P., Srinivas, S. AMER MEDICAL ASSOC. 2002: 1001–6

  Abstract

  To assess the value of positron emission tomography (PET) compared with computed tomography (CT) in the initial staging of esophageal cancer.Case series.Tertiary care veterans hospital.Patients with newly diagnosed esophageal cancers from January 1996 through May 2001 who underwent both CT and PET scanning within 4 weeks were included in the study (n = 24). Only patients who underwent pathological or radiographic follow-up were included.The sensitivity, specificity, and negative and positive predictive values of CT and PET were determined based on a criterion standard of pathological staging in 16 patients (67%) and follow-up imaging in 8 patients (33%).For staging regional lymph node involvement, CT and PET scans showed no statistically significant difference in sensitivity (57% and 71%, respectively) and specificity (71% and 86%, respectively). For detection of metastatic disease, CT and PET showed no significant difference in sensitivity (83% and 67%, respectively) and specificity (75% and 92%, respectively). There was no significant difference in clinical decision making when the results of both tests were discordant.There was no significant difference between the 2 imaging modalities in the initial staging of esophageal cancer. The CT scan was a sensitive indicator of distant metastases, whereas PET was more specific. It is unclear what additional role PET scanning should have in the initial screening of patients.

  View details for Web of Science ID 000177920800004

  View details for PubMedID 12215149

• Utility of bone scan post primary therapy in prostate cancer UroOncology Srinivas S 2002; 2: 37-39
• Management choices in stage I non-seminomatous Germ Cell Tumor UroOncology Srinivas S, Terris MK 2001; 1: 1-4
• Progressive decrease in bone density over 10 years of androgen deprivation therapy in patients with prostate cancer 95th Annual Meeting of the American-Urological-Association Kiratli, B. J., Srinivas, S., Perkash, I., Terris, M. K. ELSEVIER SCIENCE INC. 2001: 127–32

  Abstract

  Several reports suggest an increased incidence of osteoporosis and concomitant fractures in men receiving androgen deprivation therapy (ADT) for prostate cancer. We sought to estimate the longitudinal effects of ADT on loss of bone density in this cross-sectional study.Hip and spine bone mineral density (BMD) studies were performed by dual-energy x-ray absorptiometry on 36 patients with prostate cancer. The year 0 cohort (n = 8) consisted of patients who had not yet begun planned ADT. These men were compared to patients receiving ADT who underwent BMD evaluation at year 2 (n = 6), year 4 (n = 7), year 6 (n = 5), year 8 (n = 5), and year 10 (n = 5) of therapy. All BMD values for the patients with prostate cancer were compared to age-matched control subjects.Hip BMD was significantly lower in patients on ADT (mean BMD 0.802 g/cm(2)) compared with those not on ADT (mean BMD 0.935 g/cm(2)). Patients at year 0 had hip and spine BMD similar to age-matched control subjects. There was a significant trend for decreased hip BMD with increasing years of ADT (r = 0.46, P = 0.00008). This relationship was more dramatic when hip BMD at each time point was compared to age-matched control subjects (r = 0.55, P = 0.5 x 10(-16)). This bone loss was evident even up to year 10. BMD loss was more dramatic in patients who had undergone surgical castration than those receiving medical ADT (P = 0.08). Patients on intermittent ADT had similar BMD loss as patients on continuous ADT at year 2 and year 4 but demonstrated less bone loss at year 6 (P = 0.07) despite equivalently low testosterone levels.There is diminished BMD with increasing duration of ADT. Continuous ADT and surgical castration may be more deleterious than medical therapy, particularly when the medical therapy is given in an intermittent fashion.

  View details for Web of Science ID 000166663000025

  View details for PubMedID 11164157

• High-dose chemotherapy in poor-risk germ-cell tumors ONCOLOGY-NEW YORK Srinivas, S. 2000; 14 (10): 1419-1423

  Abstract

  Testicular cancer is a highly curable cancer. However, 30% of patients are refractory to standard therapy and will need additional therapy. This article focuses on the use of high-dose chemotherapy in germ-cell tumors. High-dose chemotherapy use is discussed both in the refractory setting and as either first-salvage or first-line therapy. Various criteria for risk assessment are also discussed.

  View details for Web of Science ID 000090129800010

  View details for PubMedID 11098508

• Spontaneous pneumothorax in malignancy: A case report and review of the literature ANNALS OF ONCOLOGY Srinivas, S., Varadhachary, G. 2000; 11 (7): 887-889

  Abstract

  Pneumothorax occurring in the absence of obvious lung disease is defined as spontaneous pneumothorax. Spontaneous pneumothorax occurs in a variety of settings in patients with malignancies.We present a case report of spontaneous pneumothorax in malignancy and review the literature.No correlation was found between the occurrence of pneumothorax with age, sex or smoking history. Pneumothorax occurred with a variety of primary tumors. However it was always associated with lung metastases or lung involvement with tumor. In certain cases the metastases were detected after the occurrence of pneumothorax.The occurrence of pneumothorax in a patient with malignancy should prompt a search for lung metastases.

  View details for Web of Science ID 000089244400026

  View details for PubMedID 10997821

• Comparison of FDG-PET and Bone Scans for Detecting Skeletal Metastases in Patients with Non-small Cell Lung Cancer. Clinical positron imaging : official journal of the Institute for Clinical P.E.T Durski, J. M., Srinivas, S., Segall, G. 2000; 3 (3): 97–105

  Abstract

  Purpose: Positron Emission Tomography (PET) with F18-fluorodeoxyglucose has been proven useful for staging non-small cell lung cancer. Bone scans are frequently performed for suspected skeletal metastases. The purpose of this study was to evaluate if bone scans compared to PET scans provide additional information that changes the stage of disease.Procedures: Nineteen patients with non-small cell lung cancer had PET and bone scans done for staging of the malignancy. The results of both studies were compared.Results: Bone and PET scans agreed on the presence or absence of skeletal metastases in all nineteen patients. The addition of a bone scan to a PET scan did not change the stage of the disease or the management in any of the patients. Bone scans allowed for more precise localization of the lesions in some patients.Conclusions: Bone scans do not change the stage of disease when performed in addition to PET scans, but provide more precise localization of skeletal abnormalities.

  View details for PubMedID 11008099

• Actinomycin D revisited in testicular cancer. A case report TUMORI Srinivas, S., Freiha, F. S. 1999; 85 (1): 78-79

  Abstract

  Between 20-30% of patients with advanced germ cell tumors relapse or fail to achieve a complete response to conventional cisplatin based chemotherapy. Ifosphamide has been used very effectively in combination with cisplatin and etoposide (VIP) or in combination with cisplatin and vinblastine (VeIP). Actinomycin D with chlorambucil and methotrexate was widely used in the 1960s with complete responses in 20% of patients and long term survival of 6-10%. There exists no information on the use of actinomycin as a salvage in cisplatin refractory patients.One patient with metastatic germ cell tumor who failed chemotherapy with cisplatin and ifosphamide was successfully treated with an actinomycin D based regimen.Actinomycin D is an active agent in testicular cancer and maybe used in patients refractory to platinum.

  View details for Web of Science ID 000080742700018

  View details for PubMedID 10228505

• Tool support for authoring eligibility criteria for cancer trials Annual Symposium of the American-Medical-Informatics-Association Rubin, D. L., Gennari, J. H., Srinivas, S., Yuen, A., Kaizer, H., Musen, M. A., Silva, J. S. BMJ PUBLISHING GROUP. 1999: 369–373

  Abstract

  A critical component of authoring new clinical trial protocols is assembling a set of eligibility criteria for patient enrollment. We found that clinical protocols in three different cancer domains can be categorized according to a set of clinical states that describe various clinical scenarios for that domain. Classifying protocols in this manner revealed similarities among the eligibility criteria and permitted some standardization of criteria based on clinical state. We have developed an eligibility criteria authoring tool which uses a standard set of eligibility criteria and a diagram of the clinical states to present the relevant eligibility criteria to the protocol author. We demonstrate our ideas with phase-3 protocols from breast cancer, prostate cancer, and non-small cell lung cancer. Based on measurements of redundancy and percentage coverage of criteria included in our tool, we conclude that our model reduces redundancy in the number of criteria needed to author multiple protocols, and it allows some eligibility criteria to be authored automatically based on the clinical state of interest for a protocol.

  View details for Web of Science ID 000170207300077

  View details for PubMedID 10566383

• Methotrexate tolerance in patients with ileal conduits and continent diversions CANCER Srinivas, S., Mahalati, K., Freiha, F. S. 1998; 82 (6): 1134-1136

  Abstract

  Methotrexate is readily absorbed from the intestinal tract. When given to patients with urinary diversion to the intestinal tract, methotrexate may be reabsorbed into the circulation, thus increasing its serum concentration and potentially increasing its toxicity.Forty-eight patients with transitional cell carcinoma of the urinary tract who had undergone cystectomy and either an ileal conduit or a continent diversion were evaluated for their tolerance of chemotherapy. Of the 42 evaluable patients, 23 had a continent diversion and 19 had an ileal conduit. None of the patients with the continent diversion had an indwelling Foley catheter during the course of chemotherapy.There were no statistically significant differences in incidence of fever or neutropenia, mucositis, dose modification, or delay in chemotherapy between the two groups. When compared with a group of patients with native bladders who received the same chemotherapy, patients with continent diversions did not have increased incidence or severe toxicity from chemotherapy.Patients with continent diversions tolerated chemotherapy as well as patients with ileal conduits.

  View details for Web of Science ID 000072376400018

  View details for PubMedID 9506360

• Doxorubicin and dose-escalated cyclophosphamide with granulocyte colony-stimulating factor for the treatment of hormone-resistant prostate cancer JOURNAL OF CLINICAL ONCOLOGY Small, E. J., Srinivas, S., Egan, B., McMillan, A., Rearden, T. P. 1996; 14 (5): 1617-1625

  Abstract

  The goals of this study were to define the efficacy and toxicity of doxorubicin and dose-escalated cyclophosphamide (Cy) along with granulocyte colony-stimulating factor (G-CSF) in the treatment of hormone-refractory prostate cancer (HRPC), to determine the maximal-tolerated dose (MTD) of Cy in this regimen, and to evaluate the impact of prior pelvic irradiation (XRT) on MTD and toxicity.Thirty-five patients were treated every 21 days with fixed-dose doxorubicin (40 mg/m2) and Cy 800 to 2,000 mg/m2 (in a cohort dose-escalation schema) along with G-CSF.Five of 15 patients (33%) with measurable disease obtained an objective response. Sixteen of 35 patients (46%) had a greater than 50% decrease in prostate-specific antigen (PSA) level (95% confidence interval [CI], 28.8% to 63.4%). Ten of 35 patients (28.6%) had a greater than 75% decrease in PSA level. The median survival time was 11 months. The median survival duration of patients with a greater than 50% decrease in PSA level was 23 months, versus a median survival time of 7 months in patients without a PSA response (P = .02). Although 33% of cycles were associated with grade 4 neutropenia, febrile neutropenia occurred in only 7.8% of all cycles. Thrombocytopenia and anemia were rare. Nonhematologic toxicity was minimal. Patients who had received prior pelvic XRT had a lower Cy MTD, but their hematologic toxicity was not appreciably different.This is a well-tolerated, active regimen for the treatment of HRPC. Toxicity was not different in patients with prior pelvic XRT, although these patients had a lower MTD.

  View details for Web of Science ID A1996UJ40300029

  View details for PubMedID 8622080

• THE ANTIANDROGEN WITHDRAWAL SYNDROME - EXPERIENCE IN A LARGE COHORT OF UNSELECTED PATIENTS WITH ADVANCED PROSTRATE CANCER CANCER Small, E. J., Srinivas, S. 1995; 76 (8): 1428-1434

  Abstract

  Flutamide withdrawal has been reported to be therapeutically efficacious for patients with hormone-refractory prostate cancer, with a reported prostate specific antigen (PSA) response rate of 29%.to evaluate the results of flutamide withdrawal in a large group of unselected patients, the medical records of 107 consecutive patients with metastatic prostate cancer who developed progressive disease while receiving flutamide therapy were reviewed retrospectively. Flutamide withdrawal was undertaken at the time of disease progression.Eighty-two patients were evaluable. Of these, three had a > 80% fall in PSA value, and another nine had a > 50% decrease, for a response proportion of 14.6% (95% confidence interval 7.8%-24.2%). The median response duration was 3.5 months (range, 1-12+ months). Eight of patients treated with combined androgen blockade at the time of diagnosis of metastatic disease had a response (14%), whereas 4/25 responses (16%) were noted in patients in whom flutamide was added later, at the time of first progression. When patients who responded were compared with patients who did not respond, there was not a significant difference in age, pretreatment PSA level, type of gonadal androgen deprivation, or the likelihood of prior combined androgen blockade versus late addition of flutamide. The duration of prior therapy with flutamide was longer in patients who responded (21.5 vs. 12.0 months).These findings confirm the flutamide withdrawal phenomenon in a large group of unselected patients, although its frequency is not as high as previously reported. In contrast to earlier reports, whether patients have had initial hormonal therapy with combined androgen blockade or monotherapy does not appear to be predictive of the likelihood of response to antiandrogen withdrawal.

  View details for Web of Science ID A1995RY50600019

  View details for PubMedID 8620419

• THE WEIGHT-BASED HEPARIN DOSING NOMOGRAM COMPARED WITH A STANDARD CARE NOMOGRAM - A RANDOMIZED CONTROLLED TRIAL ANNALS OF INTERNAL MEDICINE Raschke, R. A., Reilly, B. M., Guidry, J. R., Fontana, J. R., Srinivas, S. 1993; 119 (9): 874-881

  Abstract

  To determine whether an intravenous heparin dosing nomogram based on body weight achieves therapeutic anticoagulation more rapidly than a "standard care" nomogram.Randomized controlled trial.Two community teaching hospitals in Phoenix, Arizona, and Rochester, New York.One hundred fifteen patients requiring intravenous heparin treatment for venous or arterial thromboembolism or for unstable angina.Patients were randomized to the weight-based nomogram (starting dose, 80 units/kg body weight bolus, 18 units/kg per hour infusion) or the standard care nomogram (starting dose, 5000-unit bolus, 1000 units per hour infusion). Activated partial thromboplastin time (APTT) values were monitored every 6 hours, and heparin dose adjustments were determined by the nomograms.Activated partial thromboplastin times were measured using a widely generalizable laboratory method. The primary outcomes were the time to exceed the therapeutic threshold (APTT > 1.5 times the control) and the time to achieve therapeutic range (APTT, 1.5 to 2.3 times the control). Bleeding complications and recurrent thromboembolism were also compared.Kaplan-Meier curves for the primary outcomes favored the weight-based nomogram (P < 0.001 for both). In the weight-based heparin group, 60 of 62 patients (97%) exceeded the therapeutic threshold within 24 hours, compared with 37 of 48 (77%) in the standard care group (P < 0.002). Only one major bleeding complication occurred (in a standard care patient). Recurrent thromboembolism was more frequent in the standard care group; relative risk, 5.0 (95% CI, 1.1 to 21.9).The weight-based heparin nomogram is widely generalizable and has proved to be effective, safe, and superior to one based on standard practice.

  View details for Web of Science ID A1993MD71100002

  View details for PubMedID 8214998

• INTRAVENOUS HEPARIN DOSING - PATTERNS AND VARIATIONS IN INTERNISTS PRACTICES JOURNAL OF GENERAL INTERNAL MEDICINE Reilly, B. M., Raschke, R., Srinivas, S., Nieman, T. 1993; 8 (10): 536-542

  Abstract

  To characterize internists' dosing practices when administering and adjusting intravenous heparin regimens.A survey administered by physician-investigators.Two community teaching hospitals and one Veterans Affairs Medical Center.Sixty-one attending physicians in internal medicine.Physicians' choices of therapeutic activated partial thromboplastin time (APTT) range, initial heparin bolus, initial infusion dose, and dose/infusion adjustments when APTT levels are < 1.2 x control (< 35 seconds), 1.2-1.5 x control (35-45 seconds), 1.5-2.3 x control (46-70 seconds), 2.3-3.0 x control (71-90 seconds), and > 3.0 x control (> 90 seconds).Physicians' dosing decisions and therapeutic ranges during heparin treatment varied widely. Responses to nontherapeutic APTT levels had especially high coefficients of variation (0.67-0.81). Two groups of physicians, together comprising a majority of all respondents, use mutually exclusive therapeutic ranges (mean 44-56 seconds and 60-83 seconds). These two groups differ significantly in several types of dosing decisions.In the absence of generalizable standard guidelines for intravenous heparin therapy, internists' dosing practices vary widely. Because such practices may impede timely, effective anticoagulation, experimental studies comparing standardized dosing protocols are needed.

  View details for Web of Science ID A1993MC43800003

  View details for PubMedID 8271085