Sandy Srinivas

All Publications

NCCN Guidelines Insights: Prostate Cancer, Version 1.2021. Journal of the National Comprehensive Cancer Network : JNCCN Schaeffer, E., Srinivas, S., Antonarakis, E. S., Armstrong, A. J., Bekelman, J. E., Cheng, H., D'Amico, A. V., Davis, B. J., Desai, N., Dorff, T., Eastham, J. A., Farrington, T. A., Gao, X., Horwitz, E. M., Ippolito, J. E., Kuettel, M. R., Lang, J. M., McKay, R., McKenney, J., Netto, G., Penson, D. F., Pow-Sang, J. M., Reiter, R., Richey, S., Roach Iii, M., Rosenfeld, S., Shabsigh, A., Spratt, D. E., Teply, B. A., Tward, J., Shead, D. A., Freedman-Cass, D. A. 2021; 19 (2): 134–43
Abstract

The NCCN Guidelines for Prostate Cancer address staging and risk assessment after a prostate cancer diagnosis and include management options for localized, regional, and metastatic disease. Recommendations for disease monitoring and treatment of recurrent disease are also included. The NCCN Prostate Cancer Panel meets annually to reevaluate and update their recommendations based on new clinical data and input from within NCCN Member Institutions and from external entities. This article summarizes the panel's discussions for the 2021 update of the guidelines with regard to systemic therapy for metastatic castration-resistant prostate cancer.

View details for DOI 10.6004/jnccn.2021.0008

View details for PubMedID 33545689
Treatment of Metastatic Urothelial Carcinoma After Previous Cisplatin-based Chemotherapy for Localized Disease: A Retrospective Comparison of Different Chemotherapy Regimens. Clinical genitourinary cancer Do, O. A., Ferris, L. A., Holt, S. K., Ramos, J. D., Harshman, L. C., Plimack, E. R., Crabb, S. J., Pal, S. K., De Giorgi, U., Ladoire, S., Baniel, J., Necchi, A., Vaishampayan, U. N., Bamias, A., Bellmunt, J., Srinivas, S., Dorff, T. B., Galsky, M. D., Yu, E. Y. 2020
Abstract

BACKGROUND: Optimal chemotherapy for patients who received cisplatin for localized urothelial carcinoma (UC) and develop metastatic disease is unclear. We compared the efficacy of platinum-based (PBC) versus non-platinum-based (NPBC) first-line chemotherapy for metastasis.PATIENTS AND METHODS: Data were collected from the Retrospective International Study of Cancers of the Urothelial Tract (RISC), a database of 3024 patients from 28 international academic centers from 2005 to 2012. Patient inclusion criteria included: (1) predominant UC; (2) any primary tumor site; (3) cT2-4, cN0-N2, cM0; (4) prior receipt of perioperative/radiation cisplatin-containing chemotherapy; and (5) receipt of cytotoxic chemotherapy in the first-line metastatic setting. Multivariate Cox proportional hazards models were used to show progression-free survival (PFS) and overall survival (OS) from the first day of chemotherapy for metastatic disease to date of censor.RESULTS: Eligibility criteria was met by 132 patients (n= 74 PBC; n= 58 NPBC). The median OS was 8.13 months (interquartile range, 4.87-16.64 months) and 8.77 months (interquartile range, 4.01-13.49 months) for PBC and NPBC, respectively. Neither OS (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.64-1.69; P= .87) nor PFS (HR, 0.86; 95% CI, 0.56-1.31; P= .48) differed for PBC versus NPBC. However, for patients who received chemotherapy more than a year after perioperative/radiation chemotherapy, OS was superior for PBC over NPBC (HR, 0.31; 95% CI, 0.10-0.92; P= .03).CONCLUSIONS: There is no significant outcome difference between PBC and NPBC in patients with metastatic UC who previously received cisplatin-based chemotherapy for localized disease. However, if over a year has elapsed, return to PBC is associated with superior OS.

View details for DOI 10.1016/j.clgc.2020.10.006

View details for PubMedID 33309564
Patient and caregiver benefit-risk preferences for nonmetastatic castration-resistant prostate cancer treatment. Cancer medicine Srinivas, S., Mohamed, A. F., Appukkuttan, S., Botteman, M., Ng, X., Joshi, N., Tsai, J., Fang, J., Waldeck, A. R., Simmons, S. J. 2020
Abstract

BACKGROUND: Recently approved second-generation androgen receptor inhibitors (SGARIs) for non-metastatic castration-resistant prostate cancer (nmCRPC) have similar efficacy but differ in safety profiles. We used a discrete choice experiment (DCE) to examine how nmCRPC patients and caregivers perceive the benefits versus risks of these new treatments.METHODS: An online DCE survey with 14 treatment choice questions was administered to nmCRPC patients and caregivers. Each choice question compared two hypothetical medication profiles varying in terms of 5 safety attributes (risk or severity of adverse events [AEs]: fatigue, skin rash, cognitive problems, serious fall, and serious fracture) and two efficacy attributes (duration of overall survival [OS] and time to pain progression). Random parameters logit models were used to estimate each attribute's relative importance. We also estimated the amounts of OS that respondents were willing to forego for a reduction in AEs.RESULTS: In total, 143 nmCRPC patients and 149 caregivers viewed the AEs in following order of importance (most to least): serious fracture, serious fall, cognitive problems, fatigue, and skin rash. On average, patients were willing to trade 5.8 and 4.0months of OS to reduce the risk of serious fracture and fall, respectively, from 3% to 0%; caregivers were willing to trade 6.6 and 5.4months of OS.CONCLUSIONS: nmCRPC patients and caregivers preferred treatments with lower AE burdens and were willing to forego OS to reduce the risk and severity of AEs. Our results highlight the importance of carefully balancing risks and benefits when selecting treatments in this relatively asymptomatic population.

View details for DOI 10.1002/cam4.3321

View details for PubMedID 32725755
Nivolumab versus everolimus in patients with advanced renal cell carcinoma: Updated results with long-term follow-up of the randomized, open-label, phase 3 CheckMate 025 trial. Cancer Motzer, R. J., Escudier, B., George, S., Hammers, H. J., Srinivas, S., Tykodi, S. S., Sosman, J. A., Plimack, E. R., Procopio, G., McDermott, D. F., Castellano, D., Choueiri, T. K., Donskov, F., Gurney, H., Oudard, S., Richardet, M., Peltola, K., Alva, A. S., Carducci, M., Wagstaff, J., Chevreau, C., Fukasawa, S., Tomita, Y., Gauler, T. C., Kollmannsberger, C. K., Schutz, F. A., Larkin, J., Cella, D., McHenry, M. B., Saggi, S. S., Tannir, N. M. 2020
Abstract

BACKGROUND: CheckMate 025 has shown superior efficacy for nivolumab over everolimus in patients with advanced renal cell carcinoma (aRCC) along with improved safety and tolerability. This analysis assesses the long-term clinical benefits of nivolumab versus everolimus.METHODS: The randomized, open-label, phase 3 CheckMate 025 trial (NCT01668784) included patients with clear cell aRCC previously treated with 1 or 2 antiangiogenic regimens. Patients were randomized to nivolumab (3 mg/kg every 2 weeks) or everolimus (10 mg once a day) until progression or unacceptable toxicity. The primary endpoint was overall survival (OS). The secondary endpoints were the confirmed objective response rate (ORR), progression-free survival (PFS), safety, and health-related quality of life (HRQOL).RESULTS: Eight hundred twenty-one patients were randomized to nivolumab (n=410) or everolimus (n=411); 803 patients were treated (406 with nivolumab and 397 with everolimus). With a minimum follow-up of 64 months (median, 72 months), nivolumab maintained an OS benefit in comparison with everolimus (median, 25.8 months [95% CI, 22.2-29.8 months] vs 19.7 months [95% CI, 17.6-22.1 months]; hazard ratio [HR], 0.73; 95% CI, 0.62-0.85) with 5-year OS probabilities of 26% and 18%, respectively. ORR was higher with nivolumab (94 of 410 [23%] vs 17 of 411 [4%]; P<.001). PFS also favored nivolumab (HR, 0.84; 95% CI, 0.72-0.99; P=.0331). The most common treatment-related adverse events of any grade were fatigue (34.7%) and pruritus (15.5%) with nivolumab and fatigue (34.5%) and stomatitis (29.5%) with everolimus. HRQOL improved from baseline with nivolumab but remained the same or deteriorated with everolimus.CONCLUSIONS: The superior efficacy of nivolumab over everolimus is maintained after extended follow-up with no new safety signals, and this supports the long-term benefits of nivolumab monotherapy in patients with previously treated aRCC.LAY SUMMARY: CheckMate 025 compared the effects of nivolumab (a novel immunotherapy) with those of everolimus (an older standard-of-care therapy) for the treatment of advanced kidney cancer in patients who had progressed on antiangiogenic therapy. After 5 years of study, nivolumab continues to be better than everolimus in extending the lives of patients, providing a long-lasting response to treatment, and improving quality of life with a manageable safety profile. The results demonstrate that the clinical benefits of nivolumab versus everolimus in previously treated patients with advanced kidney cancer continue in the long term.

View details for DOI 10.1002/cncr.33033

View details for PubMedID 32673417
Recent Developments in the Management of Advanced Prostate Cancer Srinivas, S. HARBORSIDE PRESS. 2020: 969–72
View details for DOI 10.6004/jnccn.2020.5021

View details for Web of Science ID 000577823100010
Development of robust artificial neural networks for prediction of 5-year survival in bladder cancer. Urologic oncology Bhambhvani, H. P., Zamora, A., Shkolyar, E., Prado, K., Greenberg, D. R., Kasman, A. M., Liao, J., Shah, S., Srinivas, S., Skinner, E. C., Shah, J. B. 2020
Abstract

PURPOSE: When exploring survival outcomes for patients with bladder cancer, most studies rely on conventional statistical methods such as proportional hazards models. Given the successful application of machine learning to handle big data in many disciplines outside of medicine, we sought to determine if machine learning could be used to improve our ability to predict survival in bladder cancer patients. We compare the performance of artificial neural networks (ANN), a type of machine learning algorithm, with that of multivariable Cox proportional hazards (CPH) models in the prediction of 5-year disease-specific survival (DSS) and overall survival (OS) in patients with bladder cancer.SUBJECTS AND METHODS: The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) 18 program database was queried to identify adult patients with bladder cancer diagnosed between 1995 and 2010, yielding 161,227 patients who met our inclusion criteria. ANNs were trained and tested on an 80/20 split of the dataset. Multivariable CPH models were developed in parallel. Variables used for prediction included age, sex, race, grade, SEER stage, tumor size, lymph node involvement, degree of extension, and surgery received. The primary outcomes were 5-year DSS and 5-year OS. Receiver operating characteristic curve analysis was conducted, and ANN models were tested for calibration.RESULTS: The area under the curve for the ANN models was 0.81 for the OS model and 0.80 for the DSS model. Area under the curve for the CPH models was 0.70 for OS and 0.81 for DSS. The ANN OS model achieved a calibration slope of 1.03 and a calibration intercept of -0.04, while the ANN DSS model achieved a calibration slope of 0.99 and a calibration intercept of -0.04.CONCLUSIONS: Machine learning algorithms can improve our ability to predict bladder cancer prognosis. Compared to CPH models, ANNs predicted OS more accurately and DSS with similar accuracy. Given the inherent limitations of administrative datasets, machine learning may allow for optimal interpretation of the complex data they contain.

View details for DOI 10.1016/j.urolonc.2020.05.009

View details for PubMedID 32593506
Physician preferences for non-metastatic castration-resistant prostate cancer treatment. BMC urology Srinivas, S., Mohamed, A. F., Appukkuttan, S., Botteman, M., Ng, X., Joshi, N., Horodniceanu, E., Waldeck, A. R., Simmons, S. J. 2020; 20 (1): 73
Abstract

BACKGROUND: Recent approvals of second-generation androgen receptor inhibitors (SGARIs) have changed the treatment landscape for non-metastatic castration-resistant prostate cancer (nmCRPC). These SGARIs have similar efficacy but differ in safety profiles. We used a discrete choice experiment to explore how United States physicians make treatment decisions between adverse events(AEs) and survival gains in nmCRPC, a largely asymptomatic disease.METHODS: Treating physicians (n=149) participated in an online survey that included 14 treatment choice questions, each comparing 2 hypothetical treatment profiles, which varied in terms of 5 safety and 2 efficacy attributes. We described safety attributes (fatigue, skin rash, cognitive problems, falls, and fractures) in terms of severity and frequency, and efficacy attributes (overall survival [OS] and time to pain progression) in terms of duration of effect. We used a random parameters logit model to estimate preference weights and importance scores for each attribute. We also estimated the amount of survival gain physicians were willing to trade for a reduction in specific AEs between treatment options.RESULTS: Physicians placed more importance on survival than on time to pain progression, and viewed a reduction in cognitive problems from severe to none, a reduction in risk of a serious fracture from 8% to none, and a reduction in fatigue from severe to none as the most important safety attributes. Physicians were willing to forego 9.1 and 6.6months of OS, respectively, to reduce cognitive problems and fatigue from severe to mild-to-moderate. To reduce the risk of a serious fracture from 8 to 5% and 5% to none, physicians were willing to trade 3.9 and 5.3months of OS, respectively.CONCLUSIONS: Physicians were willing to trade substantial amounts of survival to avoid AEs between hypothetical treatments. These results emphasize the importance of carefully balancing therapies' benefits and risks to ultimately optimize the overall quality of nmCRPC patients' survival. Nonetheless, it is noted that the results from the study sample of 149 physicans may not be representative of the viewpoints of all nmCRPC-treating physicians.

View details for DOI 10.1186/s12894-020-00631-4

View details for PubMedID 32571276
Prospective evaluation of F-18-DCFPyL PET/CT in biochemically recurrent prostate cancer: Analysis of lesion localization and distribution. Song, H., Duan, H., Harrison, C., Guja, K., Hatami, N., Franc, B., Moradi, F., Aparici, C., Davidzon, G., Srinivas, S., Iagaru, A. AMER SOC CLINICAL ONCOLOGY. 2020
View details for Web of Science ID 000560368302399
Study EV-103: Durability results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma. Rosenberg, J. E., Flaig, T. W., Friedlander, T. W., Milowsky, M., Srinivas, S., Petrylak, D., Merchan, J. R., Bilen, M., Carret, A., Yuan, N., Sasse, C., Hoimes, C. J. AMER SOC CLINICAL ONCOLOGY. 2020
View details for Web of Science ID 000560368302300
Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer: Results of cohort 6 of the COSMIC-021 study. Agarwal, N., Loriot, Y., McGregor, B., Dreicer, R., Dorff, T. B., Maughan, B., Kelly, W., Pagliaro, L. C., Srinivas, S., Squillante, C., Vaishampayan, U. N., Wang, E. W., Curran, D., Choueiri, T. K., Pal, S. K. AMER SOC CLINICAL ONCOLOGY. 2020
View details for Web of Science ID 000560368302407
Application of IMDC criteria across first-line (1L) and second-line (2L) therapies in metastatic renal-cell carcinoma (mRCC): New and updated benchmarks of clinical outcomes. Dudani, S., Gan, C., Wells, C., Bakouny, Z., Dizman, N., Pal, S. K., Wood, L., Kollmannsberger, C. K., Szabados, B., Powles, T., Beuselinck, B., Donskov, F., Hansen, A., Bjarnason, G. A., Canil, C. M., Srinivas, S., Agarwal, N., Liow, E., Choueiri, T. K., Heng, D. AMER SOC CLINICAL ONCOLOGY. 2020
View details for Web of Science ID 000560368302318
Deferred Cytoreductive Nephrectomy in Patients with Newly Diagnosed Metastatic Renal Cell Carcinoma. European urology Bhindi, B., Graham, J., Wells, J. C., Bakouny, Z., Donskov, F., Fraccon, A., Pasini, F., Lee, J. L., Basappa, N. S., Hansen, A., Kollmannsberger, C. K., Kanesvaran, R., Yuasa, T., Ernst, D. S., Srinivas, S., Rini, B. I., Bowman, I., Pal, S. K., Choueiri, T. K., Heng, D. Y. 2020
Abstract

BACKGROUND: The use of cytoreductive nephrectomy (CN) selectively for patients who show a favorable response to upfront systemic therapy may be an approach to select optimal candidates with metastatic renal cell carcinoma (mRCC) who are most likely to benefit.OBJECTIVE: We sought to characterize outcomes of deferred CN (dCN) after upfront sunitinib, outcomes relative to sunitinib alone, and outcomes of CN followed by sunitinib.DESIGN, SETTING, AND PARTICIPANTS: We used the prospectively maintained International mRCC Database Consortium (IMDC) database to identify patients with newly diagnosed mRCC (2006-2018).INTERVENTION: Sunitinib alone, upfront CN followed by sunitinib, sunitinib followed by dCN.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Outcomes were overall survival (OS) and time to sunitinib treatment failure (TTF). Kaplan-Meier and multivariable Cox regression analyses were performed; dCN was analyzed as a time-varying covariate to account for immortal time bias.RESULTS AND LIMITATIONS: We evaluated 1541 patients, of whom 651 (42%) received sunitinib alone, 805 (52%) underwent CN followed by sunitinib, and 85 (5.5%) received sunitinib followed by dCN, at a median of 7.8 mo from diagnosis. Median OS periods for patients treated with sunitinib alone, CN followed by sunitinib, and sunitinib followed by dCN were 10, 19, and 46 mo, respectively, while the median TTF values were 4, 8, and 13 mo, respectively. In multivariable regression analyses, sunitinib followed by dCN was significantly associated with improved OS (hazard ratio [HR]=0.45, 95% confidence interval [CI] 0.33-0.60, p<0.001) and TTF (HR=0.62, 95% CI 0.46-0.85, p=0.003) versus sunitinib alone. Among CN-treated patients, sunitinib followed by dCN was associated with improved OS (HR =0.52, 95% CI 0.39-0.70, p<0.001) and TTF (HR=0.71, 95% CI 0.56-0.90, p=0.005) compared with upfront CN followed by sunitinib. In various sensitivity analyses, dCN remained significantly associated with improved OS and TTF.CONCLUSIONS: Patients who received dCN were carefully selected and achieved long OS. With these benchmark outcomes, optimal selection criteria need to be identified and confirmation of the role of dCN in a clinical trial is warranted.PATIENT SUMMARY: We characterized benchmark survival outcomes for patients with metastatic kidney cancer treated with sunitinib alone, nephrectomy (kidney removal) followed by sunitinib, and sunitinib followed by nephrectomy. Patients who had their nephrectomy after an initial course of sunitinib had prolonged survival.

View details for DOI 10.1016/j.eururo.2020.04.038

View details for PubMedID 32362493
Prostate Cancer Brain Metastases: A Single-Institution Experience. World neurosurgery Bhambhvani, H. P., Greenberg, D. R., Srinivas, S., Gephart, M. H. 2020
Abstract

BACKGROUND: Brain metastases from prostate cancer are rare and poorly described. We sought to assess the proportion of brain metastases arising from prostate cancer and to detail clinical characteristics, treatment modalities, and survival outcomes.METHODS: We retrospectively identified and reviewed the charts of 31 patients with intraparenchymal brain metastases from prostate adenocarcinoma seen at our institution from 2008 to 2018.RESULTS: Among all patients with brain metastases, the proportion originating from prostate adenocarcinoma was 0.86%. The median age at the time of brain metastasis diagnosis was 69 (range, 57 - 90). The median original Gleason score was 8 (range, 6 - 10), and the median PSA at the time of brain metastasis was 60 ng/ml (range, 0.34 - 4600). The median months from initial cancer diagnosis to brain metastasis was 81 (range, 3 - 195). The median number of brain metastases was 2 (range, 1 - 5). Patients had concurrent metastases to bone (100%), lung (48%), and liver (35%). Median overall survival was 3 months (range, 0.4 - 25.0). Treatment of the brain metastases was correlated with an increase in median survival from 1.2 months to 4.6 months with radiosurgery (HR = 0.11, p = 0.001) and surgical resection plus radiotherapy to 13 months (HR = 0.05, p < 0.001). All patients died of advanced, systemic disease and not of their intracranial disease.CONCLUSIONS: Brain metastasis from prostate cancer constitutes a small fraction of total brain metastases, but is associated with poor prognosis and is seen in the setting of advanced, castrate resistant disease. These data enable treating physicians to appropriately counsel their patients with prostate adenocarcinoma brain metastasis.

View details for DOI 10.1016/j.wneu.2020.02.152

View details for PubMedID 32147556
Study EV-103: Preliminary durability results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma Rosenberg, J. E., Flaig, T. W., Friedlander, T. W., Milowsky, M. I., Srinivas, S., Petrylak, D., Merchan, J. R., Bilen, M., Carret, A., Yuan, N., Sasse, C., Hoimes, C. J. AMER SOC CLINICAL ONCOLOGY. 2020
View details for Web of Science ID 000529525900470
Cabozantinib (C) in combination with atezolizumab (A) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Results of Cohort 6 of the COSMIC-021 Study Agarwal, N., Loriot, Y., McGregor, B., Dreicer, R., Dorff, T. B., Maughan, B., Kelly, W., Pagliaro, L. C., Srinivas, S., Squillante, C., Vaishampayan, U. N., Liu, Y., Curran, D., Choueiri, T. K., Pal, S. K. AMER SOC CLINICAL ONCOLOGY. 2020
View details for Web of Science ID 000529525900208
Final analysis of the CheckMate 025 trial comparing nivolumab (NIVO) versus everolimus (EVE) with > 5 years of follow-up in patients with advanced renal cell carcinoma (aRCC) Motzer, R. J., Tykodi, S. S., Escudier, B., Oudard, S., Hammers, H. J., McDermott, D. F., George, S., Castellano, D., Choueiri, T. K., Alva, A., Richardet, M., Plimack, E. R., Srinivas, S., Procopio, G., Donskov, F., Gurney, H., Tomita, Y., McHenry, M., Saggi, S., Tannir, N. M. AMER SOC CLINICAL ONCOLOGY. 2020
View details for Web of Science ID 000529525900620
Rucaparib for recurrent, locally advanced, or metastatic urothelial carcinoma (mUC): Results from ATLAS, a phase II open-label trial Grivas, P., Loriot, Y., Feyerabend, S., Morales-Barrera, R., Teo, M., Vogelzang, N. J., Grande, E., Zakharia, Y., Adra, N., Alva, A., Necchi, A., Gupta, S., Josephs, D., Rodriguez-Vida, A., Srinivas, S., Wride, K., Thomas, D., Dusek, R., Nepert, D. L., Chowdhury, S. AMER SOC CLINICAL ONCOLOGY. 2020
View details for Web of Science ID 000529525900469
EV-101: A Phase I Study of Single-Agent Enfortumab Vedotin in Patients With Nectin-4-Positive Solid Tumors, Including Metastatic Urothelial Carcinoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Rosenberg, J., Sridhar, S. S., Zhang, J., Smith, D., Ruether, D., Flaig, T. W., Baranda, J., Lang, J., Plimack, E. R., Sangha, R., Heath, E. I., Merchan, J., Quinn, D. I., Srinivas, S., Milowsky, M., Wu, C., Gartner, E. M., Zuo, P., Melhem-Bertrandt, A., Petrylak, D. P. 2020: JCO1902044
Abstract

To assess the safety/tolerability and antitumor activity of enfortumab vedotin (EV), a novel investigational antibody-drug conjugate that delivers the microtubule-disrupting agent, monomethyl auristatin E, to cells that express Nectin-4.EV-101 is a phase I dose escalation/expansion study that enrolled patients with Nectin-4-expressing solid tumors (eg, metastatic urothelial carcinoma [mUC]) who progressed on ≥ 1 prior chemotherapy regimen and/or programmed death-1 receptor/programmed death ligand-1 [PD-(L)1] inhibitor, including a cohort of patients with mUC who received prior anti-PD-(L)1 therapy. Patients received escalating doses of EV up to 1.25 mg/kg on days 1, 8, and 15 of every 28-day cycle. Primary objectives were evaluation of safety/tolerability and pharmacokinetics; antitumor activity was a secondary objective.Enrolled patients with mUC (n = 155) were heavily pretreated, with 96% having prior platinum-based chemotherapy and 29% receiving ≥ 3 lines of prior treatment. Maximum tolerated dose of EV was not established; however, the recommended phase II dose was identified as 1.25 mg/kg. Rash, peripheral neuropathy, fatigue, alopecia, and nausea were the most common treatment-related adverse events (TRAEs); the most common TRAEs were grade 1-2 in severity. Among the 112 patients with mUC treated with single-agent EV 1.25 mg/kg, the investigator-assessed confirmed objective response rate (ORR) was 43%, and duration of response was 7.4 months. Median overall survival (OS) was 12.3 months, and the OS rate at 1 year was 51.8%. Similar ORR and estimated median OS were observed in patients ≥ 75 years of age with and without prior anti-PD-(L)1 treatment, liver metastases, or upper-tract disease.Single-agent EV was generally well tolerated and provided clinically meaningful and durable responses in patients with mUC; survival data are encouraging. A pivotal phase II and a confirmatory phase III study are ongoing.

View details for DOI 10.1200/JCO.19.02044

View details for PubMedID 32031899
Dual Blockade of c-MET and the Androgen Receptor in Metastatic Castration-Resistant Prostate Cancer: A Phase 1 Study of Concurrent Enzalutamide and Crizotinib. Clinical cancer research : an official journal of the American Association for Cancer Research Tripathi, A., Supko, J. G., Gray, K. P., Melnick, Z., Regan, M. M., Taplin, M. E., Choudhury, A. D., Pomerantz, M. M., Bellmunt, J., Yu, C., Sun, Z., Srinivas, S., Kantoff, P. W., Sweeney, C. J., Harshman, L. C. 2020
Abstract

Androgen-receptor (AR) inhibition can upregulate c-MET expression, which may be a resistance mechanism driving progression of castration-resistant prostate cancer (CRPC). We conducted a phase 1 trial investigating the safety and pharmacokinetics of a potent c-MET inhibitor crizotinib with the AR antagonist enzalutamide in CRPC.Employing a 3+3 dose-escalation design, we tested 3 dose levels of crizotinib (250mg daily, 200mg BID, 250mg BID) with standard dose enzalutamide (160mg daily). The primary endpoint was rate of dose-limiting toxicities (DLTs). Tolerability and pharmacokinetic profile were secondary endpoints.24 patients were enrolled in the dose-escalation (n=16) and dose-expansion (n=8) phases. Two DLTs occurred in dose-escalation (grade 3 ALT elevation). The maximum tolerated dose (MTD) of crizotinib was 250mg BID. Most frequent treatment-related adverse events were fatigue (50%), transaminitis (38%), nausea (33%), and vomiting, constipation and diarrhea (21% each). Grade ≥3 events (25%) included: transaminitis (n=2), fatigue (n=1), hypertension (n=1), pulmonary embolism (n=1), and a cardiac event encompassing QTc prolongation/ventricular arrhythmia/cardiac arrest. Median progression-free survival was 5.5 months (95%CI: 2.8-21.2). Pharmacokinetic analysis at the MTD (n=12) revealed a mean Cmaxss of 104±45 ng/mL and AUCτss of 1,000±476 ng•h/mL, representing a 74% decrease in crizotinib systemic exposure relative to historical data (Cmaxss: 315 ng/mL, AUCτss: 3,817 ng•h/mL).Concurrent administration of enzalutamide and crizotinib resulted in a clinically significant 74% decrease in systemic crizotinib exposure. Further investigation of this combination in CRPC is not planned. Our results highlight the importance of evaluating pharmacokinetic interactions when evaluating novel combination strategies in CRPC.

View details for DOI 10.1158/1078-0432.CCR-20-2306

View details for PubMedID 32943461
Clinicopathologic characterization of enfortumab vedotin-associated cutaneous toxicity in patients with urothelial carcinoma. Journal of the American Academy of Dermatology Hirotsu, K. E., Rana, J., Wang, J. Y., Raghavan, S. S., Rieger, K. E., Srinivas, S., Fan, A. C., Kwong, B. Y., Novoa, R. A., Zaba, L. 2020
View details for DOI 10.1016/j.jaad.2020.11.067

View details for PubMedID 33301805
Five-Factor Prognostic Model for Survival of Post-Platinum Patients with Metastatic Urothelial Carcinoma Receiving PD-L1 Inhibitors. The Journal of urology Sonpavde, G., Manitz, J., Gao, C., Tayama, D., Kaiser, C., Hennessy, D., Makari, D., Gupta, A., Abdullah, S. E., Niegisch, G., Rosenberg, J. E., Bajorin, D. F., Grivas, P., Apolo, A. B., Dreicer, R., Hahn, N. M., Galsky, M. D., Necchi, A., Srinivas, S., Powles, T., Choueiri, T. K., Pond, G. R. 2020: 101097JU0000000000001199
Abstract

A prognostic model for overall survival (OS) of post-platinum patients with metastatic urothelial carcinoma (mUC) receiving PD-1/PD-L1 inhibitors is necessary since existing models were constructed in the chemotherapy setting.Patient level data were used from phase I/II trials evaluating PD-L1 inhibitors following platinum-based chemotherapy for mUC. The derivation dataset consisted of 2 phase I/II trials evaluating atezolizumab (n=405). Two phase I/II trials that evaluated avelumab (n=242) and durvalumab (n=198) comprised the validation datasets. Cox regression analyses evaluated the association of candidate prognostic factors with OS. Stepwise selection was employed to select an optimal model using the derivation dataset. Discrimination and calibration were assessed in the avelumab and durvalumab datasets.The 5 prognostic factors identified in the optimal model employing the atezolizumab derivation dataset were ECOG-PS (1 vs. 0; HR 1.80; 95% CI [1.36-2.36]), liver metastasis (HR 1.55; 95% CI [1.20-2.00]), platelet count (HR 2.22; 95% CI [1.54-3.18]), neutrophil-lymphocyte ratio (HR 1.94; 95% CI [1.57-2.40]) and lactate dehydrogenase (HR 1.60; 95% CI [1.28-1.99]). There was robust discrimination of survival between low, intermediate and high-risk groups. The c-statistic was 0.692 in the derivation and 0.671 and 0.773 in the avelumab and durvalumab validation datasets, respectively. A web-based interactive tool was developed to calculate the expected survival probabilities based on risk factors.A validated 5-factor model has satisfactory prognostic performance for survival across 3 PD-L1 inhibitors to treat mUC post-platinum and may assist in stratification, interpreting and designing trials incorporating PD-1/PD-L1 inhibitors in the post-platinum setting.

View details for DOI 10.1097/JU.0000000000001199

View details for PubMedID 32552295
Impact of mortality reviews on supportive care utilization, end-of-life care, and inpatient mortality. Karimi, Y., Divi, V., Srinivas, S., Smith, A., Hansen, J., Tokareva, I., Tulu, Z., Hedlin, H., Fronk, J., Rosenthal, E., Blayney, D. W. AMER SOC CLINICAL ONCOLOGY. 2019
View details for DOI 10.1200/JCO.2019.37.31_suppl.45

View details for Web of Science ID 000518224200044
The Impact of Cisplatin- or Non-Cisplatin-Containing Chemotherapy on Long-Term and Conditional Survival of Patients with Advanced Urinary Tract Cancer ONCOLOGIST Bamias, A., Tzannis, K., Bamia, C., Harshman, L. C., Crabb, S., Plimack, E. R., Pal, S., De Giorgi, U., Ladoire, S., Theodore, C., Agarwal, N., Yu, E. Y., Niegisch, G., Sternberg, C. N., Srinivas, S., Vaishampayan, U., Necchi, A., Liontos, M., Rosenberg, J. E., Powles, T., Bellmunt, J., Galsky, M. D. 2019; 24 (10): 1348–55
View details for DOI 10.1634/theoncologist.2018-0739

View details for Web of Science ID 000490365300013
Feasibility and design of a cloud-based digital platform in patients with advanced cancer. Roy, M., Hall, E., Velazquez, B., Shah, S., Fardeen, T., Cunanan, K., San Pedro-Salcedo, M., Wakelee, H. A., Neal, J. W., Padda, S., Das, M., Fan, A. C., Srinivas, S., Fisher, G. A., Haraldsdottir, S., Johnson, T., Chu, G., McMillan, A., Ramchandran, K. AMER SOC CLINICAL ONCOLOGY. 2019
View details for DOI 10.1200/JCO.2019.37.27_suppl.211

View details for Web of Science ID 000518223100208
Patient and caregiver benefit-risk preferences for non metastatic castration-resistant prostate cancer treatment (nmCRPC). Srinivas, S., Mohamed, A. F., Appukkuttan, S., Botteman, M., Ng, X., Joshi, N., Tsai, J., Fang, J., Waldeck, A., Simmons, S. J. AMER SOC CLINICAL ONCOLOGY. 2019
View details for DOI 10.1200/JCO.2019.37.27_suppl.196

View details for Web of Science ID 000518223100193
ATLAS: A Phase II, open-label study of rucaparib in patients with locally advanced or metastatic urothelial carcinoma Grivas, P., Teo, M., Vogelzang, N., Alva, A., Zakharia, Y., Adra, N., Drakaki, A., Hussain, A., Morales-Barrera, R., Necchi, A., Rodriguez-Vida, A., Feyerabend, S., Gupta, S., Josephs, D. H., Loriot, Y., Srinivas, S., Wride, K., Thomas, D., Dusek, R., Simmons, A. D., Nepert, D., Chowdhury, S. AMER ASSOC CANCER RESEARCH. 2019
View details for DOI 10.1158/1538-7445.AM2019-CT179

View details for Web of Science ID 000488129900161
Safety and effectiveness of classical and alternative sunitinib dosing schedules for metastatic renal cell carcinoma: a meta-analysis FUTURE ONCOLOGY Abogunrin, S., Ashaye, A. O., Cappelleri, J. C., Clair, A. G., Fahrbach, K., Ramaswamy, K., Serfass, L., Srinivas, S., Thomaidou, D., Zanotti, G. 2019; 15 (18): 2175–90
View details for DOI 10.2217/fon-2018-0858

View details for Web of Science ID 000485097700011
Biomarkers of outcomes in a randomized phase II trial of first-line paclitaxel, ifosfamide, and cisplatin (TIP) versus bleomycin, etoposide, and cisplatin (BEP) for intermediate- and poor-risk germ cell tumors (GCT). Feldman, D. R., Hu, J. S., Patil, S., Reuter, V. E., Srinivas, S., Stadler, W., Costello, B., Milowsky, M. I., Appleman, L., Dorff, T. B., Bromberg, M., Joseph, G., Funt, S., Bajorin, D. F., Bosl, G. J., Quinn, D. I., Motzer, R. J. AMER SOC CLINICAL ONCOLOGY. 2019
View details for DOI 10.1200/JCO.2019.37.15_suppl.4563

View details for Web of Science ID 000487345805385
5-factor prognostic model for survival of patients with metastatic urothelial carcinoma receiving three different post-platinum PD-L1 inhibitors. Sonpavde, G., Manitz, J., Gao, C., Hennessy, D., Makari, D., Niegisch, G., Rosenberg, J. E., Bajorin, D. F., Grivas, P., Apolo, A. B., Dreicer, R., Hahn, N. M., Galsky, M. D., Necchi, A., Srinivas, S., Powles, T., Gupta, A., Abdullah, S., Pond, G. AMER SOC CLINICAL ONCOLOGY. 2019
View details for DOI 10.1200/JCO.2019.37.15_suppl.4552

View details for Web of Science ID 000487345805375
Deferred cytoreductive nephrectomy among patients with newly diagnosed metastatic renal cell carcinoma treated initially with sunitinib. Bhindi, B., Graham, J., Wells, C., Donskov, F., Pasini, F., Lee, J., Basappa, N. S., Hansen, A., Wood, L., Kollmannsberger, C. K., Kanesvaran, R., Yuasa, T., Ernst, D., Srinivas, S., Rini, B. I., Bowman, I., Pal, S. K., Choueiri, T. K., Heng, D. AMER SOC CLINICAL ONCOLOGY. 2019
View details for DOI 10.1200/JCO.2019.37.15_suppl.4578

View details for Web of Science ID 000487345805400
Physician benefit-risk preferences for non-metastatic castration-resistant prostate cancer treatment (nmCRPC). Srinivas, S., Mohamed, A. F., Appukkuttan, S., Botteman, M., Ng, X., Joshi, N., Horodniceanu, E., Waldeck, R., Simmons, S. J. AMER SOC CLINICAL ONCOLOGY. 2019
View details for DOI 10.1200/JCO.2019.37.15_suppl.e16610

View details for Web of Science ID 000487345801626
Prostate Cancer, Version 2.2019 JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Mohler, J. L., Antonarakis, E. S., Armstrong, A. J., D'Amico, A., Davis, B. J., Dorff, T., Eastham, J. A., Enke, C. A., Farrington, T. A., Higano, C. S., Horwitz, E., Hurwitz, M., Ippolito, J. E., Kane, C. J., Kuettel, M. R., Lang, J. M., McKenney, J., Netto, G., Penson, D. F., Plimack, E. R., Pow-Sang, J. M., Pugh, T. J., Richey, S., Roach, M., Rosenfeld, S., Schaeffer, E., Shabsigh, A., Small, E. J., Spratt, D. E., Srinivas, S., Tward, J., Shead, D. A., Freedman-Cass, D. A. 2019; 17 (5): 479–505
Abstract

The NCCN Guidelines for Prostate Cancer include recommendations regarding diagnosis, risk stratification and workup, treatment options for localized disease, and management of recurrent and advanced disease for clinicians who treat patients with prostate cancer. The portions of the guidelines included herein focus on the roles of germline and somatic genetic testing, risk stratification with nomograms and tumor multigene molecular testing, androgen deprivation therapy, secondary hormonal therapy, chemotherapy, and immunotherapy in patients with prostate cancer.

View details for DOI 10.6004/jnccn.2019.0023

View details for Web of Science ID 000468989400010

View details for PubMedID 31085757
Safety and effectiveness of classical and alternative sunitinib dosing schedules for metastatic renal cell carcinoma: a meta-analysis. Future oncology (London, England) Abogunrin, S., Ashaye, A. O., Cappelleri, J. C., Clair, A. G., Fahrbach, K., Ramaswamy, K., Serfass, L., Srinivas, S., Thomaidou, D., Zanotti, G. 2019
Abstract

The optimal dosing schedule to maintain the effectiveness of sunitinib for metastatic renal cell carcinoma -while reducing toxicity-remains an important clinical question. A meta-analysis of randomized trials and observational studies assessed the relative treatment effects of 4/2, 2/1and transitional-2/1 schedules on outcomes and adverse events using Bayesian network meta-analysis methods. Treatment with 2/1 reduced the risk of disease progression or death by 25% and had lower odds of hand-and-foot syndrome compared with the 4/2. A numerical but not 'statistical' benefit in progression-free survival was observed with the transitional-2/1 compared with 4/2. Alternative schedules with the 2/1 and transitional-2/1 may be more clinically beneficial in metastatic renal cell carcinoma than the 4/2 schedule.

View details for PubMedID 31010323
Predicting Response to Immunotherapy by Evaluating Tumors, Lymphoid Cell-Rich Organs, and Immune-Related Adverse Events Using FDG-PET/CT CLINICAL NUCLEAR MEDICINE Nobashi, T., Baratto, L., Reddy, S. A., Srinivas, S., Toriihara, A., Hatami, N., Yohannan, T. K., Mittra, E. 2019; 44 (4): E272–E279
View details for DOI 10.1097/RLU.0000000000002453

View details for Web of Science ID 000461451300003
Cabozantinib in advanced non-clear-cell renal cell carcinoma: a multicentre, retrospective, cohort study LANCET ONCOLOGY Changa, N., Xie, W., Bilen, M., Dzimitrowicz, H., Burkart, J., Geynisman, D. M., Balakrishnan, A., Bowman, I., Jain, R., Stadler, W., Zakharia, Y., Narayan, V., Beuselinck, B., McKay, R. R., Tripathi, A., Pachynski, R., Hahn, A. W., Hsu, J., Shah, S. A., Lam, E. T., Rose, T. L., Mega, A. E., Vogelzang, N., Harrison, M. R., Mortazavi, A., Plimack, E. R., Vaishampayan, U., Hammers, H., George, S., Haas, N., Agarwal, N., Pal, S. K., Srinivas, S., Carneiro, B. A., Heng, D. C., Bosse, D., Choueiri, T. K., Harshman, L. C. 2019; 20 (4): 581–90
View details for DOI 10.1016/S1470-2045(18)30907-0

View details for Web of Science ID 000463009600039
The Impact of Cisplatin- or Non-Cisplatin-Containing Chemotherapy on Long-Term and Conditional Survival of Patients with Advanced Urinary Tract Cancer. The oncologist Bamias, A., Tzannis, K., Bamia, C., Harshman, L. C., Crabb, S., Plimack, E. R., Pal, S., De Giorgi, U., Ladoire, S., Theodore, C., Agarwal, N., Yu, E. Y., Niegisch, G., Sternberg, C. N., Srinivas, S., Vaishampayan, U., Necchi, A., Liontos, M., Rosenberg, J. E., Powles, T., Bellmunt, J., Galsky, M. D. 2019
Abstract

BACKGROUND: The impact of cisplatin use on long-term survival of unselected patients with advanced urinary tract cancer (aUTC) has not been adequately investigated. We used a multinational database to study long-term survival and the impact of treatment type in unselected patients with aUTC.MATERIALS AND METHODS: A total of 1,333 patients with aUTC (cT4bN0M0, cTanyN+M0, cTanyNanyM+), transitional-cell, squamous, or adenocarcinoma histology who received systemic chemotherapy and had available survival data were selected. Long-term survival was defined as alive at 3 years following initiation of first-line chemotherapy. Conditional overall survival (COS) analysis was employed to study change in prognosis given time survived from initiation of first-line chemotherapy.RESULTS: Median follow-up was 31.7 months. The combination of cisplatin use and cisplatin eligibility accurately predicted long-term survival. Eligible patients treated with cisplatin conferred a 31.6% probability of 3-year survival (95% confidence interval [CI]: 25.1-38.3), and 2-year COS for patients surviving 3 years after initiation of cisplatin-based chemotherapy was 83% (95% CI: 59.7-93.5). The respective probabilities for patients who were ineligible for cisplatin or not treated with cisplatin despite eligibility were 14% (95% CI: 10.8-17.6) and 49.3% (95% CI: 28.2-67.4). Two-year COS remained significantly different between these two groups up to 3 years after chemotherapy initiation.CONCLUSION: Cisplatin-based therapy was associated with the highest likelihood of long-term survival in patients with aUTC and should be used in patients who fulfill the established eligibility criteria. Novel therapies are necessary to increase long-term survival in cisplatin-ineligible patients.IMPLICATIONS FOR PRACTICE: Long-term, disease-free survival is possible in one in four eligible-for-cisplatin patients with advanced urinary tract cancer (aUTC) treated with cisplatin-based combination chemotherapy. Therefore, deviations from eligibility criteria should be avoided. Consolidation surgery should be considered in responders. These data provide benchmarks for the study of novel therapies in aUTC.

View details for PubMedID 30936379
Application of pharmacoeconomics to formulary management in a health system setting AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY Studdert, A. L., Gong, C. L., Srinivas, S., Chin, A. L., Deresinski, S. 2019; 76 (6): 381–86
View details for DOI 10.1093/ajhp/zxy010

View details for Web of Science ID 000459287500011
Alliance A031501: Phase III randomized adjuvant study of MK-3475 (pembrolizumab) in muscle-invasive and locally advanced urothelial carcinoma (MIBC) (AMBASSADOR) versus observation. Apolo, A. B., Rosenberg, J. E., Kim, W. Y., Chen, R. C., Sonpavde, G., Srinivas, S., Mortazavi, A., Watt, C., Mallek, M., Graap, K., Diaz, C., Odegaard, M., Ballman, K. V., Morris, M. J. AMER SOC CLINICAL ONCOLOGY. 2019
View details for DOI 10.1200/JCO.2019.37.7_suppl.TPS504

View details for Web of Science ID 000489108800037
Lack of Effectiveness of Postchemotherapy Lymphadenectomy in Bladder Cancer Patients with Clinical Evidence of Metastatic Pelvic or Retroperitoneal Lymph Nodes Only: A Propensity Score-based Analysis EUROPEAN UROLOGY FOCUS Necchi, A., Mariani, L., Lo Vullo, S., Yu, E. Y., Woods, M. E., Wong, Y., Harshman, L. C., Alva, A., Sternberg, C. N., Bamias, A., Grivas, P., Koshkin, V. S., Roghmann, F., Dobruch, J., Eigl, B. J., Nappi, L., Milowsky, M., Niegisch, G., Pal, S. K., De Giorgi, U., Recine, F., Vaishampayan, U., Berthold, D. D., Bowles, D. W., Baniel, J., Theodore, C., Ladoire, S., Srinivas, S., Agarwal, N., Crabb, S., Sridhar, S., Golshayan, A., Ohlmann, C., Xylinas, E., Powles, T., Rosenberg, J. E., Bellmunt, J., van Rhijn, B., Galsky, M. D., Hendricksen, K., Young Acad Urologists-Urothelial C, European Assoc Urology, Retrospective Int Study Invasive A 2019; 5 (2): 242–49
View details for DOI 10.1016/j.euf.2017.05.006

View details for Web of Science ID 000486153200024
Mature results from EV-101: A phase I study of enfortumab vedotin in patients with metastatic urothelial cancer (mUC). Rosenberg, J. E., Sridhar, S. S., Zhang, J., Smith, D. C., Ruether, J. D., Flaig, T. W., Baranda, J., Lang, J., Plimack, E. R., Sangha, R. S., Heath, E. I., Merchan, J. R., Quinn, D. I., Srinivas, S., Milowsky, M. I., Wu, C., Gartner, E. M., Melhem-Bertrandt, A., Petrylak, D. AMER SOC CLINICAL ONCOLOGY. 2019
View details for DOI 10.1200/JCO.2019.37.7_suppl.377

View details for Web of Science ID 000489108800394
ATLAS: A phase II open-label study of rucaparib in patients with locally advanced or metastatic urothelial carcinoma (mUC). Grivas, P., Vogelzang, N. J., Alva, A., Feyerabend, S., Loriot, Y., Necchi, A., Gupta, S., Josephs, D., Rodriguez-Vida, A., Srinivas, S., Zakharia, Y., Wride, K., Thomas, D., Dusek, R., Simmons, A., Nepert, D. L., Chowdhury, S. AMER SOC CLINICAL ONCOLOGY. 2019
View details for DOI 10.1200/JCO.2019.37.7_suppl.TPS496

View details for Web of Science ID 000489108800029
Cabozantinib in advanced non-clear-cell renal cell carcinoma: a multicentre, retrospective, cohort study. The Lancet. Oncology Martinez Chanza, N., Xie, W., Asim Bilen, M., Dzimitrowicz, H., Burkart, J., Geynisman, D. M., Balakrishnan, A., Bowman, I. A., Jain, R., Stadler, W., Zakharia, Y., Narayan, V., Beuselinck, B., McKay, R. R., Tripathi, A., Pachynski, R., Hahn, A. W., Hsu, J., Shah, S. A., Lam, E. T., Rose, T. L., Mega, A. E., Vogelzang, N., Harrison, M. R., Mortazavi, A., Plimack, E. R., Vaishampayan, U., Hammers, H., George, S., Haas, N., Agarwal, N., Pal, S. K., Srinivas, S., Carneiro, B. A., Heng, D. Y., Bosse, D., Choueiri, T. K., Harshman, L. C. 2019
Abstract

BACKGROUND: Cabozantinib is approved for patients with metastatic renal cell carcinoma on the basis of studies done in clear-cell histology. The activity of cabozantinib in patients with non-clear-cell renal cell carcinoma is poorly characterised. We sought to analyse the antitumour activity and toxicity of cabozantinib in advanced non-clear-cell renal cell carcinoma.METHODS: We did a multicentre, international, retrospective cohort study of patients with metastatic non-clear-cell renal cell carcinoma treated with oral cabozantinib during any treatment line at 22 centres: 21 in the USA and one in Belgium. Eligibility required patients with histologically confirmed non-clear-cell renal cell carcinoma who received cabozantinib for metastatic disease during any treatment line roughly between 2015 and 2018. Mixed tumours with a clear-cell histology component were excluded. No other restrictive inclusion criteria were applied. Data were obtained from retrospective chart review by investigators at each institution. Demographic, surgical, pathological, and systemic therapy data were captured with uniform database templates to ensure consistent data collection. The main objectives were to estimate the proportion of patients who achieved an objective response, time to treatment failure, and overall survival after treatment.FINDINGS: Of 112 identified patients with non-clear-cell renal cell carcinoma treated at the participating centres, 66 (59%) had papillary histology, 17 (15%) had Xp11.2 translocation histology, 15 (13%) had unclassified histology, ten (9%) had chromophobe histology, and four (4%) had collecting duct histology. The proportion of patients who achieved an objective response across all histologies was 30 (27%, 95% CI 19-36) of 112 patients. At a median follow-up of 11 months (IQR 6-18), median time to treatment failure was 6·7 months (95% CI 5·5-8·6), median progression-free survival was 7·0 months (5·7-9·0), and median overall survival was 12·0 months (9·2-17·0). The most common adverse events of any grade were fatigue (58 [52%]), and diarrhoea (38 [34%]). The most common grade 3 events were skin toxicity (rash and palmar-plantar erythrodysesthesia; five [4%]) and hypertension (four [4%]). No treatment-related deaths were observed. Across 54 patients with available next-generation sequencing data, the most frequently altered somatic genes were CDKN2A (12 [22%]) and MET (11 [20%]) with responses seen irrespective of mutational status.INTERPRETATION: While we await results from prospective studies, this real-world study provides evidence supporting the antitumour activity and safety of cabozantinib across non-clear-cell renal cell carcinomas. Continued support of international collaborations and prospective ongoing studies targeting non-clear-cell renal cell carcinoma subtypes and specific molecular alterations are warranted to improve outcomes across these rare diseases with few evidence-based treatment options.FUNDING: None.

View details for PubMedID 30827746
Predicting Response to Immunotherapy by Evaluating Tumors, Lymphoid Cell-Rich Organs, and Immune-Related Adverse Events Using FDG-PET/CT. Clinical nuclear medicine Nobashi, T., Baratto, L., Reddy, S. A., Srinivas, S., Toriihara, A., Hatami, N., Yohannan, T. K., Mittra, E. 2019
Abstract

PURPOSE: To investigate whether the evaluation of tumors, lymphoid cell-rich organs, and immune-related adverse events (IRAE) with F-FDG PET/CT can predict the efficacy and outcome of immunotherapy.METHODS: Forty patients who underwent F-FDG-PET/CT scans before and after therapy with immune checkpoint inhibitors from December 2013 to December 2016 were retrospectively enrolled (malignant melanoma, n = 21; malignant lymphoma, n = 11; renal cell carcinoma, n = 8). SUVmax of the baseline and first restaging scans were evaluated in tumors, spleen, bone marrow, thyroid and pituitary glands, and were correlated to best overall response in the first year after therapy; IRAE-affected areas were also evaluated.RESULTS: Interval change between the baseline and first restaging scans showed that patients with a clinical benefit had a significant decrease in tumor parameters (P < 0.001). All patients with an increase of SUVmax in the thyroid of more than 1.5 (n = 5) on the first restaging scan had a complete response (CR) in 1 year. Patients with CR within 1 year (n = 22) were significantly associated with a favorable long-term outcome (P = 0.002). Nine patients with IRAE findings had CR at final evaluation. Among IRAE, thyroiditis was seen significantly earlier than arthritis (P = 0.040).CONCLUSIONS: The decrease of tumor parameters at early time-point PET scans was seen in patients with immunotherapy who had clinical benefit within 1 year. PET-detectable IRAE was useful for prediction of a favorable outcome. Early development of thyroiditis may particularly represent an early response indicator to immunotherapy.

View details for PubMedID 30688730
Time on Therapy for at Least Three Months Correlates with Overall Survival in Metastatic Renal Cell Carcinoma. Cancers Chen, V. J., Hernandez-Meza, G., Agrawal, P., Zhang, C. A., Xie, L., Gong, C. L., Hoerner, C. R., Srinivas, S., Oermann, E. K., Fan, A. C. 2019; 11 (7)
Abstract

With 15 drugs currently approved for the treatment of metastatic renal cell carcinoma (mRCC) and even more combination regimens with immunotherapy on the horizon, there remains a distinct lack of molecular biomarkers for therapeutic efficacy. Our study reports on real-world clinical outcomes of mRCC patients from a tertiary academic medical center treated with empirically selected standard-of-care therapy. We utilized the Stanford Renal Cell Carcinoma Database (RCCD) to report on various outcome measures, including overall survival (OS) and the median number of lines of targeted therapies received from the time of metastatic diagnosis. We found that most metastatic patients did not survive long enough to attempt even half of the available targeted therapies. We also noted that patients who failed to receive a clinical benefit within the first two lines of therapy could still go on to experience clinical benefit in later lines of therapy. The term, "clinical benefit" was assigned to a line of therapy if a patient remained on drug treatment for three months or longer. Moreover, patients with clinical benefit in at least one line of therapy experienced significantly longer OS compared to those who did not have clinical benefit in at least one line of therapy. Developing biomarkers that identify patients who will receive clinical benefit in individual lines of therapy is one potential strategy for achieving rational drug sequencing in mRCC.

View details for DOI 10.3390/cancers11071000

View details for PubMedID 31319594
Application of pharmacoeconomics to formulary management in a health system setting. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists Studdert, A. L., Gong, C. L., Srinivas, S., Chin, A. L., Deresinski, S. 2019; 76 (6): 381–86
Abstract

A novel value-based approach to evaluate costly specialty drugs for formulary addition was developed.In February 2016, Stanford Health Care launched the specialty drug subcommittee (SDSC), a subcommittee of the pharmacy and therapeutics committee, responsible for the formulary review of specialty pharmaceuticals. A process was developed for value-based review that includes not only consideration of clinical trial data and institutional acquisition costs but also internal patient outcomes and a cost-effectiveness model using internal financial data. A Markov model was developed to assess the value of trabectedin, which was approved for formulary addition in April 2016, relative to the addition of dacarbazine. The economic model and internal patient outcome analysis were presented to the prescribing oncologist and the SDSC for review. Internal data revealed that fewer patients than had been estimated received trabectedin, with outcomes significantly worse than those observed in the clinical trial leading to Food and Drug Administration approval. In the cost-effectiveness model, trabectedin had higher costs and poorer outcomes compared with dacarbazine. Based on the economic model, low utilization, and real-world outcomes, trabectedin was removed from formulary and a restrictive treatment pathway for nonformulary use, developed by the primary prescriber, was implemented. This process has since been applied to 11 more specialty drugs.Internal cost-effectiveness models in combination with real-world patient outcomes data can be effective formulary management tools. Engagement and collaboration with the requesting provider are key to developing thoughtful treatment pathways.

View details for DOI 10.1093/ajhp/zxy010

View details for PubMedID 31361838
Real-world chart review study of adverse events management in patients taking tyrosine kinase inhibitors to treat metastatic renal cell carcinoma JOURNAL OF ONCOLOGY PHARMACY PRACTICE Srinivas, S., Stein, D., Teltsch, D. Y., Tao, S., Cisar, L., Ramaswamy, K. 2018; 24 (8): 574–83
Abstract

The purpose is to describe management of adverse events of special interest across tyrosine kinase inhibitors approved for metastatic renal cell carcinoma.We conducted a retrospective chart review in metastatic renal cell carcinoma patients initiating tyrosine kinase inhibitor monotherapy between 15 November 2010 and 15 November 2013, and experiencing ≥ 1 adverse events of special interest (diarrhea, fatigue, hand-foot syndrome, hypertension, or stomatitis/mucositis) within 3 months of initiation. Demographics, medical history, treatment regimens, and adverse events of special interest management data for 3.5 months postonset were collected.In 220 charts from 27 centers, tyrosine kinase inhibitors prescribed included sunitinib (55%), pazopanib (27%), axitinib (9%), and sorafenib (8%). During the study period, patients experienced 376 adverse events of special interest (13% serious). Fatigue was most common (62% of patients), followed by hypertension (37%), diarrhea (30%), stomatitis/mucositis (29%), and hand-foot syndrome (12%). Over half (56%) the adverse events of special interest were resolved or resolving. Treatment discontinuation due to adverse events of special interest occurred in 15% of patients. Prophylaxis was rarely provided (8%), whereas 59% of patients received adverse events of special interest treatment (pharmacologic (55%) and/or nonpharmacologic (7%)), 27% received tyrosine kinase inhibitor dose management, 23% received both adverse events of special interest treatment and dose management, and 31% received neither. Hypertension was the most treated (72% of all events), and fatigue was the least treated (9%); only 4% of patients received pharmacologic treatment for fatigue.Most adverse events of special interest were nonserious and more than half of the patients received pharmacologic and/or nonpharmacologic treatment. Fatigue was the most common yet least frequently treated adverse event of special interest, and few patients received prophylaxis or nonpharmacologic treatment. More emphasis on treatment and prophylaxis options for bothersome adverse events is warranted.

View details for PubMedID 28732453
Impact of the Number of Cycles of Platinum Based First Line Chemotherapy for Advanced Urothelial Carcinoma JOURNAL OF UROLOGY Sonpavde, G. P., Mariani, L., Lo Vullo, S., Raggi, D., Giannatempo, P., Bamias, A., Crabb, S. J., Bellmunt, J., Yu, E. Y., Niegisch, G., Vaishampayan, U. N., Theodore, C., Berthold, D. R., Srinivas, S., Sridhar, S. S., Plimack, E. R., Rosenberg, J. E., Powles, T., Galsky, M. D., Necchi, A. 2018; 200 (6): 1207–14
Abstract

We evaluated the impact of the number of cycles of platinum based, first line chemotherapy (fewer than 6 cycles vs the conventional 6 cycles or more) on the survival of patients with metastatic urothelial carcinoma.We used the RISC (Retrospective International Study of Invasive/Advanced Cancer of the Urothelium) database. The association of the number of cycles of chemotherapy with overall survival was investigated by Cox multiple regression analysis after controlling for recognized prognostic factors. We excluded patients who received fewer than 3 or more than 9 platinum chemotherapy cycles to reduce confounding factors. The primary analysis was a comparison of overall survival for 3 to 5 vs 6 to 9 cycles using 6-month landmark analysis when 281 death events were observed.Of the 1,020 patients in the RISC 472 received cisplatin or carboplatin, of whom 338 and 134, respectively, were evaluable. A total of 157 patients received 3 to 5 cycles (median 4) and 315 received 6 to 9 cycles (median 6). There was no significant difference in overall survival between 3 to 5 and 6 to 9 cycles (HR 1.02, 95% CI 0.78-1.33, p = 0.91). No significant interactions were observed for the type of platinum (p = 0.09) and completed planned chemotherapy (p = 0.56). The limitations of a hypothesis generating, retrospective analysis applied.Four cycles of platinum based, first line chemotherapy appeared adequate and did not significantly compromise the survival of patients with advanced urothelial carcinoma. The omission of excessive cycles may avoid unnecessary cumulative toxicity and facilitate a better transition to second line therapy and investigational switch maintenance therapy strategies. These results require prospective validation but they may impact practice in select patients.

View details for PubMedID 30012366
Robot-assisted Versus Open Radical Cystectomy in Patients Receiving Perioperative Chemotherapy for Muscle-invasive Bladder Cancer: The Oncologist's Perspective from a Multicentre Study EUROPEAN UROLOGY FOCUS Necchi, A., Pond, G. R., Smaldone, M. C., Pal, S. K., Chan, K., Wong, Y., Viterbo, R., Sonpavde, G., Harshman, L. C., Crabb, S., Alva, A., Chowdhury, S., De Giorgi, U., Srinivas, S., Agarwal, N., Bamias, A., Baniel, J., Golshayan, A., Ladoire, S., Sternberg, C. N., Cerbone, L., Yu, E. Y., Bellmunt, J., Vaishampayan, U., Niegisch, G., Hussain, S., Bowles, D. W., Morales-Barrera, R., Milowsky, M. I., Theodore, C., Berthold, D. R., Sridhar, S. S., Powles, T., Rosenberg, J. E., Galsky, M. D., Retrospective Int Study Invasive 2018; 4 (6): 937–45
View details for DOI 10.1016/j.euf.2017.03.011

View details for Web of Science ID 000486148900019
Checkpoint Inhibitors in Patients With Metastatic Renal Cell Carcinoma: Results From the International Metastatic Renal Cell Carcinoma Database Consortium CANCER Yip, S. M., Wells, C., Moreira, R., Wong, A., Srinivas, S., Beuselinck, B., Porta, C., Sim, H., Ernst, D., Rini, B. I., Yuasa, T., Basappa, N. S., Kanesvaran, R., Wood, L. A., Canil, C., Kapoor, A., Fu, S. F., Choueiri, T. K., Heng, D. C. 2018; 124 (18): 3677–83
Abstract

To the authors' knowledge, outcomes and prognostic tools have yet to be clearly defined in patients with metastatic renal cell carcinoma (mRCC) who are treated with immuno-oncology (IO) checkpoint inhibitors (programmed death-ligand 1 [PD-L1] inhibitors). In the current study, the authors aimed to establish IO efficacy benchmarks in patients with mRCC and update patient outcomes in each International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic class.A retrospective analysis was performed using the IMDC database with data from 38 centers. It included patients with mRCC who were treated with ≥1 line of IO. Overall response rates (ORRs), duration of treatment (DOT), and overall survival (OS) were calculated. Patients were stratified using IMDC prognostic factors.A total of 687 patients (90% with clear cell and 10% with non-clear cell) were included. The ORR was 27% in evaluable patients (461 patients). In patients treated with first-line nivolumab and ipilimumab (49 patients), the combination of PD-L1 inhibitor and vascular endothelial growth factor inhibitor (72 patients), and PD-L1 inhibitor (51 patients), the ORR was 31%, 39%, and 40%, respectively, and the median DOT was 8.3 months, 14.7 months, and 8.3 months, respectively. The ORR for second-line, third-line, and fourth-line nivolumab was 22%, 24%, and 26%, respectively. The median DOT was 5.7 months, 6.2 months, and 8.3 months, respectively, in the second-line, third-line, and fourth-line settings. When segregated into IMDC favorable-risk, intermediate-risk, and poor-risk groups, the median OS rates for the first-line, second-line, third-line, and fourth-line treatment settings were not reached (NR), NR, and NR, respectively (P = .163); NR, 26.7 months, and 7.4 months, respectively (P < 0. 0001); 36.1 months, 28.2 months, and 11.1 months, respectively (P = .016); and NR, NR, and 6.7 months, respectively (P = .047).The ORR was not found to deteriorate from the first-line to the fourth-line of IO therapy. In the second line through fourth line, the IMDC criteria appropriately stratified patients into favorable-risk, intermediate-risk, and poor-risk groups for OS.

View details for PubMedID 30307610
Systemic Therapy for Advanced Urothelial Carcinoma: Current Standards and Treatment Considerations. American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting Dietrich, B., Siefker-Radtke, A. O., Srinivas, S., Yu, E. Y. 2018: 342–53
Abstract

Urothelial carcinoma is the sixth most common malignancy in the United States. Although most are diagnosed with non-muscle-invasive malignancy, many patients will develop recurrent disease within 5 years, with 10% to 20% developing advanced muscle-invasive or more distant incurable disease. For such patients, clinical outcomes have remained suboptimal, although recent therapeutic advances have brought new hope to the field. Here, we discuss the main systemic treatment options available for the treatment of patients with advanced disease. This review begins with traditional chemotherapy, which remains a first-line treatment option for many patients. The second section focuses on the evolving landscape of immunotherapy, specifically on approved checkpoint inhibitors and future challenges. Last, we address advances in targeted treatments, including angiogenesis and fibroblast growth factor receptor (FGFR) inhibitors as well as antibody-drug conjugates. As the number of available treatment options continues to expand, ongoing trials to investigate the best sequence and combination strategies to incorporate these drugs into clinical practice will help delineate the future.

View details for PubMedID 30231356
Therapeutic benefit of empiric drug sequencing in metastatic renal cell carcinoma Chen, V., Gong, C., Hoerner, C. R., Zhang, C. A., Srinivas, S., Fan, A. C. AMER SOC CLINICAL ONCOLOGY. 2018
View details for DOI 10.1200/JCO.2018.36.15_suppl.e16569

View details for Web of Science ID 000442916005425
Multicenter randomized phase 2 trial of paclitaxel, ifosfamide, and cisplatin (TIP) versus bleomycin, etoposide, and cisplatin (BEP) for first-line treatment of patients (pts) with intermediate- or poor-risk germ cell tumors (GCT). Feldman, D. R., Hu, J., Srinivas, S., Stadler, W., Costello, B., Appleman, L., Milowsky, M. I., Patil, S., Bromberg, M., Nolan, P., Dorff, T. B., Reuter, V. E., Al-Ahmadie, H., Funt, S., Bajorin, D. F., Bosl, G. J., Quinn, D. I., Motzer, R. J. AMER SOC CLINICAL ONCOLOGY. 2018
View details for DOI 10.1200/JCO.2018.36.15_suppl.4508

View details for Web of Science ID 000442916002035
Updated results from the enfortumab vedotin phase 1 (EV-101) study in patients with metastatic urothelial cancer (mUC). Rosenberg, J. E., Sridhar, S. S., Zhang, J., Smith, D. C., Ruether, J. D., Flaig, T. W., Baranda, J., Lang, J., Plimack, E. R., Sangha, R. S., Heath, E. I., Merchan, J. R., Quinn, D. I., Srinivas, S., Milowsky, M. I., Wu, C., Gartner, E. M., Melhem-Bertrandt, A., Petrylak, D. AMER SOC CLINICAL ONCOLOGY. 2018
View details for DOI 10.1200/JCO.2018.36.15_suppl.4504

View details for Web of Science ID 000442916002031
Combined "One Stop Shop" NaF/FDG PET/MRI Evaluation of Response to Xofigo (R) in mCRPC Patients Song, H., Yohannan, T., Srinivas, S., Vasanawala, S., Iagaru, A. SOC NUCLEAR MEDICINE INC. 2018
View details for Web of Science ID 000467489902151
CheckMate 025 Randomized Phase 3 Study: Outcomes by Key Baseline Factors and Prior Therapy for Nivolumab Versus Everolimus in Advanced Renal Cell Carcinoma (vol 72, pg 962, 2017) 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., CheckMate 025 Investigators 2018; 73 (4): E116–E118
View details for PubMedID 29306512
Bone Metastases as the Only Metastatic Site in Patients With Urothelial Carcinoma: Focus on a Special Patient Population CLINICAL GENITOURINARY CANCER Necchi, A., Pond, G. R., Pal, S. K., Agarwal, N., Bowles, D. W., Plimack, E. R., Yu, E. Y., Ladoire, S., Baniel, J., Crabb, S., Niegisch, G., Srinivas, S., Berthold, D. R., Rosenberg, J. E., Powles, T., Bamias, A., Harshman, L. C., Bellmunt, J., Galsky, M. D., Retrospective Int Study Invasive A 2018; 16 (2): E483–E490
Abstract

Patients with exclusive bone metastatic spread from urothelial carcinoma (UC) throughout their disease course represent a rare subgroup with unique clinical features. These patients deserved special consideration in a retrospective multicenter study.Analyses were made from a pool of 1911 patients with a diagnosis of metastatic UC, from 23 centers. Baseline characteristics, access to treatment, and outcomes were analyzed according to metastatic spread. Univariable and multivariable Cox analyses were performed.A total of 128 evaluable patients (6.7%), diagnosed between February 1997 and April 2013, were identified. Eastern Cooperative Oncology Group performance status (PS) was ≥ 2 in 33.3% versus 17.7% of the remaining patients. Seventy-three (57%) received first-line chemotherapy, that was platinum-based in 50 patients (69%). Twenty-eight (21.9%) received second-line chemotherapy (vs. 75.9% and 32.2%, respectively, of the remaining patients). In multivariable analyses, no clinical factor was significantly associated with overall survival (OS). Among platinum chemotherapy-treated patients (total evaluable n = 972), significantly different relapse-free survival (RFS) and OS were observed according to bone metastases status (no bone metastases vs. bone metastases only vs. bone and other sites, P < .001). In these groups, 2-year RFS was 37.4%, 28.8%, and 25.9%, respectively. Two-year OS was 35.5%, 15.8%, and 23%, respectively.Patients with metastatic UC and bone-only metastases are less likely to receive systemic therapy than those with other metastases, likely because of their lower PS. The prognostic effect of having exclusive bone metastases or additional sites seems to be equally poor. These patients deserve new effective and tolerable agents, and improvements in the knowledge of their disease.

View details for PubMedID 29158079
Serum miR371a Quantitation for Assessing Tumor Burden in Testicular Germ Cell Tumors Kunder, C., Imae, Y., Srinivas, S., Fan, A. C. NATURE PUBLISHING GROUP. 2018: 703
View details for Web of Science ID 000429308604323
Serum miR371a Quantitation for Assessing Tumor Burden in Testicular Germ Cell Tumors Kunder, C., Imae, Y., Srinivas, S., Fan, A. C. NATURE PUBLISHING GROUP. 2018: 703
View details for Web of Science ID 000459341003276
Nomogram-based risk prediction of local and distant relapse after radical cystectomy, and role of perioperative chemotherapy, in patients with muscle-invasive bladder cancer (MIBC): A multicenter study Necchi, A., Pond, G., Plimack, E. R., Niegisch, G., Yu, E. Y., Pal, S. K., Bamias, A., Agarwal, N., Alva, A., Srinivas, S., Crabb, S. J., Vaishampayan, U. N., Bowles, D. W., Berthold, D. R., Theodore, C., Sridhar, S. S., Powles, T., Rosenberg, J. E., Bellmunt, J., Galsky, M. D. AMER SOC CLINICAL ONCOLOGY. 2018
View details for DOI 10.1200/JCO.2018.36.6_suppl.448

View details for Web of Science ID 000436179500442
Enfortumab vedotin (EV) in patients (Pts) with metastatic urothelial carcinoma (mUC) with prior checkpoint inhibitor (CPI) failure: A prospective cohort of an ongoing phase 1 study. Petrylak, D., Smith, D. C., Flaig, T. W., Zhang, J., Sridhar, S. S., Ruether, J. D., Plimack, E. R., Merchan, J. R., Quinn, D. I., Kilari, D., Srinivas, S., Baranda, J., Lang, J., Milowsky, M. I., Galsky, M. D., Spira, A. I., Gartner, E. M., Wu, C., Melhem-Bertrandt, A., Rosenberg, J. E. AMER SOC CLINICAL ONCOLOGY. 2018
View details for DOI 10.1200/JCO.2018.36.6_suppl.431

View details for Web of Science ID 000436179500425
Real world outcomes of nivolumab and cabozantinib in metastatic renal cell carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). Stukalin, I., Wells, J., Graham, J., Yuasa, T., Beuselinck, B., Kollmannsberger, C. K., Ernst, D., Agarwal, N., Le, T., Donskov, F., Hansen, A., Bjarnason, G. A., Srinivas, S., Wood, L., Alva, A., Kanesvaran, R., Fu, S., Davis, I. D., Choueiri, T. K., Heng, D. AMER SOC CLINICAL ONCOLOGY. 2018
View details for DOI 10.1200/JCO.2018.36.6_suppl.615

View details for Web of Science ID 000436179500609
Impact of tumor size on survival outcome in metastatic renal cell carcinoma patients (mRCC) treated with targeted therapy. Xie, W., DiNatale, R., Hakimi, A., Donskov, F., Porta, C., Reaume, M., Basappa, N. S., Hansen, A., Rini, B. I., Beuselinck, B., Bjarnason, G. A., Srinivas, S., Brugarolas, J., Rha, S., Wood, L., Lalani, A. A., Bosse, D., Duquette, A., Heng, D., Choueiri, T. K. AMER SOC CLINICAL ONCOLOGY. 2018
View details for DOI 10.1200/JCO.2018.36.6_suppl.667

View details for Web of Science ID 000436179500661
Impact of number of cycles of platinum-based first-line chemotherapy for advanced urothelial carcinoma. Necchi, A., Mariani, L., Lo Vullo, S., Raggi, D., Giannatempo, P., Bamias, A., Crabb, S. J., Bellmunt, J., Yu, E. Y., Niegisch, G., Vaishampayan, U. N., Theodore, C., Berthold, D. R., Srinivas, S., Sridhar, S. S., Plimack, E. R., Rosenberg, J. E., Powles, T., Galsky, M., Sonpavde, G. AMER SOC CLINICAL ONCOLOGY. 2018
View details for DOI 10.1200/JCO.2018.36.6_suppl.426

View details for Web of Science ID 000436179500420
New 6-factor prognostic model for patients (pts) with advanced urothelial carcinoma (UC) receiving post-platinum atezolizumab. Pond, G., Niegisch, G., Rosenberg, J. E., Dreicer, R., Powles, T., Necchi, A., Wei, X. X., Grivas, P., Balar, A., Galsky, M. D., Srinivas, S., Choueiri, T. K., Bellmunt, J., Bajorin, D. F., Sonpavde, G. AMER SOC CLINICAL ONCOLOGY. 2018
View details for DOI 10.1200/JCO.2018.36.6_suppl.413

View details for Web of Science ID 000436179500407
Robot-assisted Versus Open Radical Cystectomy in Patients Receiving Perioperative Chemotherapy for Muscle-invasive Bladder Cancer: The Oncologist's Perspective from a Multicentre Study. European urology focus Necchi, A., Pond, G. R., Smaldone, M. C., Pal, S. K., Chan, K., Wong, Y., Viterbo, R., Sonpavde, G., Harshman, L. C., Crabb, S., Alva, A., Chowdhury, S., De Giorgi, U., Srinivas, S., Agarwal, N., Bamias, A., Baniel, J., Golshayan, A., Ladoire, S., Sternberg, C. N., Cerbone, L., Yu, E. Y., Bellmunt, J., Vaishampayan, U., Niegisch, G., Hussain, S., Bowles, D. W., Morales-Barrera, R., Milowsky, M. I., Theodore, C., Berthold, D. R., Sridhar, S. S., Powles, T., Rosenberg, J. E., Galsky, M. D., Retrospective International Study of Invasive/Advanced Cancer of the Urothelium (RISC) 2018; 4 (6): 937–45
Abstract

BACKGROUND: Little is known about the outcomes of robot-assisted radical cystectomy (RARC) compared to open radical cystectomy (ORC) combined with perioperative chemotherapy for muscle-invasive urothelial bladder cancer (UBC).OBJECTIVE: To evaluate surgical and oncological outcomes for RARC and ORC in multimodal treatment.DESIGN, SETTING, AND PARTICIPANTS: Data from 28 centres were collected for cystectomies performed between January 2000 and July 2013.INTERVENTION: RARC or ORC combined with perioperative chemotherapy for UBC.OUTCOME MEASURES AND STATISTICAL ANALYSIS: Fisher's exact tests, chi2 tests, and Wilcoxon rank-sum tests were used to compare the RARC and ORC groups. Logistic and Cox regression analyses were performed to evaluate potential prognostic factors.RESULTS AND LIMITATIONS: A total of 688 patients (n=603 ORC and n=85 RARC) were analysed; 60.6% received neoadjuvant chemotherapy, and 45.1% adjuvant chemotherapy. No significant differences in baseline characteristics were found between the groups. The median time from surgery to adjuvant chemotherapy was 1.9 mo for both RARC and ORC groups. The median number of lymph nodes removed was 21 (interquartile range [IQR] 14-35) for RARC and 13 (IQR 8-21) for ORC (p<0.001); the results were confirmed in subgroup analyses. Multivariable analyses revealed no difference in the rate of positive surgical margins (p=0.54 and p=0.78), rate of neobladder diversion (p=0.33 and p=0.51), relapse-free survival (p=0.31 and p=0.23), and overall survival (p=0.63 and p=0.69). The retrospective nature of the data is the major limitation.CONCLUSIONS: In this study, no differences in efficacy outcomes or ability to deliver adjuvant chemotherapy were observed between RARC and ORC. The increasing use of RARC is justifiable from an oncological viewpoint.PATIENT SUMMARY: In a retrospective study of patients who received perioperative chemotherapy for urothelial bladder cancer, we found no difference in key outcomes between robot-assisted radical cystectomy (RARC) and open radical cystectomy. Performing RARC seems to be justifiable in the multidisciplinary setting.

View details for PubMedID 28753879
Urothelial carcinoma: the evolving landscape of immunotherapy for patients with advanced disease RESEARCH AND REPORTS IN UROLOGY Dietrich, B., Srinivas, S. 2018; 10: 7–16
Abstract

Urothelial carcinoma is the sixth most common malignancy in the US. While most patients present with non-muscle-invasive disease, many will develop recurrent disease including some progressing to muscle invasive metastatic cancer. Treatment outcomes have remained poor and stagnant for those with more advanced illness, with typical 5-year survival rates in the range of ≤15%. While first-line, platinum-based chemotherapy remains the current standard for those eligible, the recent incorporation of checkpoint inhibitors into the management of advanced bladder cancer has resulted in an expansion of treatment options for a difficult-to-treat disease. This review will discuss the historic standard treatment options, followed by the more recent evolving role immune therapy has in the management of bladder cancer.

View details for PubMedID 29417045
Recommendations for the Management of Rare Kidney Cancers EUROPEAN UROLOGY Giles, R. H., Choueiri, T. K., Heng, D. Y., Albiges, L., Hsieh, J. J., Linehan, W., Pal, S., Maskens, D., Paseman, B., Jonasch, E., Malouf, G., Molina, A. M., Pickering, L., Shuch, B., Srinivas, S., Srinivasan, R., Tannir, N. M., Bex, A. 2017; 72 (6): 974–83
Abstract

The European Association of Urology Renal Cell Carcinoma Guideline Panel recently conducted a systematic review of treatment options for patients with advanced non-clear-cell renal cell carcinomas (RCCs), which showed a substantial lack of evidence for management recommendations.To improve the outcomes of patients with rare kidney cancers (RKCs), we performed a subsequent unstructured review to determine current treatment strategies and druggable pathways, involving key stakeholders with a global perspective to generate recommendations.Based on the systematic review, literature was queried in Pubmed, Medline, and abstracts from proceedings of European Society for Medical Oncology and American Society of Clinical Oncology, in addition to consulting key opinion leaders and stakeholders. A conventional narrative review strategy was adopted to summarize the data.The systematic review showed an absence of evidence for treating RKCs, with data only supporting sunitinib or MET inhibitors for some specific subtypes. However, a growing body of evidence implicates druggable pathways in specific RKC subtypes. To test hypotheses, the small patient numbers in each subtype require coordinated multicenter efforts. Many RKC patients are currently excluded from studies or are not analyzed using subtype-specific parameters, despite their unmet medical need.We recognize the need for additional multicenter studies and subtype-specific analyses; however, we present management recommendations based on the data available. Web-based tools facilitating subtype-specific global registries and shared translational research resources will help generate sufficient data to formulate evidence-based recommendations for guidelines.Patients confronted with rare kidney cancers are often treated the same way as clear-cell renal cell carcinoma patients, despite little evidence from randomized trials. Molecular characterization of tumors to stratify patients may improve outcomes. Availability of potential agents and trials remain a problem. Collaboration among medical centers is important to pool scarce data.

View details for PubMedID 28720391
Practice Makes Perfect: The Rest of the Story in Testicular Cancer as a Model Curable Neoplasm JOURNAL OF CLINICAL ONCOLOGY Tandstad, T., Kollmannsberger, C. K., Roth, B. J., Jeldres, C., Gillessen, S., Fizazi, K., Daneshmand, S., Lowrance, W. T., Hanna, N. H., Albany, C., Foster, R., Cedermark, G., Feldman, D. R., Powles, T., Lewis, M. A., Grimison, P., Bank, D., Porter, C., Albers, P., De Santis, M., Srinivas, S., Bosl, G. J., Nichols, C. R. 2017; 35 (31): 3525-+
View details for PubMedID 28854068
Evolution of Circulating Tumor DNA Profile from First-line to Subsequent Therapy in Metastatic Renal Cell Carcinoma EUROPEAN UROLOGY Pal, S. K., Sonpavde, G., Agarwal, N., Vogelzang, N. J., Srinivas, S., Haas, N. B., Signoretti, S., McGregor, B. A., Jones, J., Lanman, R. B., Banks, K. C., Choueiri, T. K. 2017; 72 (4): 557–64
Abstract

Treatment of metastatic renal cell carcinoma (mRCC) typically entails mechanistically distinct agents across the first- and second-line setting. Activity of these agents may be predicated on selective pressure that modulates RCC biology. Circulating tumor DNA (ctDNA) is a platform to noninvasively ascertain temporal changes in genomic profile.To assess the ctDNA profile in a large cohort of mRCC patients, and to assess changes across patients receiving first-line and later lines of therapy.We obtained the ctDNA profile in mRCC patients who received ctDNA profiling as part of routine clinical care at progression using a 73-gene Clinical Laboratory Improvement Amendments-certified ctDNA platform.Genomic alterations (GAs) were pooled for the entire cohort. A comparison of first- and postfirst-line was performed with grouping based on conventional practice patterns (first-line regimens included sunitinib, pazopanib, and bevacizumab, and postfirst-line regimens included everolimus, axitinib, cabozantinib, and nivolumab).ctDNA clinical results from a nationwide cohort of 220 consecutive patients with mRCC were assessed (145 men, 75 women; median age: 63 yr, interquartile range: 57-70). GAs were detected in 78.6% of patients. The most frequent GAs in the overall cohort included TP53 (35%), VHL (23%), EGFR (17%), NF1 (16%), and ARID1A (12%). Thirty-eight and 64 patients were coded as receiving first-line and later line agents, respectively. The highest disparity in GA frequencies in postfirst-line versus first-line were in TP53 (49% vs 24%), VHL (29% vs 18%), NF1 (20% vs 3%), EGFR (15% vs 8%), and PIK3CA (17% vs 8%) while ARID1A was equivalent (13% vs 11%). Restricting the analysis to later lines versus first-line vascular endothelial growth factor inhibitors, these differences were even more prominent, particularly for TP53 (64% vs 31%) and NF1 (29% vs 4%).In the largest assessment of ctDNA-detected GAs prevalence in mRCC to date, the majority of patients demonstrated clinically and biologically relevant GAs. Increasing p53 and mechanistic target of rapamycin pathway (eg, NF1, PIK3CA) alterations in postfirst-line patients with first-line vascular endothelial growth factor-directed therapy may underlie mechanisms of resistance. Routine ctDNA assessment during the clinical course of mRCC patients may have therapeutic implications.Collection of circulating tumor DNA is feasible in patients with metastatic renal cell carcinoma, and analysis of a large cohort demonstrates significant changes in circulating tumor DNA profile across patients' clinical course which may have therapeutic implications.

View details for PubMedID 28413127
Efficacy and Safety of Durvalumab in Locally Advanced or Metastatic Urothelial Carcinoma Updated Results From a Phase 1/2 Open-label Study JAMA ONCOLOGY Powles, T., O'Donnell, P. H., Massard, C., Arkenau, H., Friedlander, T., Hoimes, C. J., Lee, J., Ong, M., Sridhar, S. S., Vogelzang, N. J., Fishman, M. N., Zhang, J., Srinivas, S., Parikh, J., Antal, J., Jin, X., Gupta, A. K., Ben, Y., Hahn, N. M. 2017; 3 (9): e172411
Abstract

The data reported herein were accepted for assessment by the US Food and Drug Administration for Biologics License Application under priority review to establish the clinical benefit of durvalumab as second-line therapy for locally advanced or metastatic urothelial carcinoma (UC), resulting in its recent US approval.To report a planned update of the safety and efficacy of durvalumab in patients with locally advanced/metastatic UC.This is an ongoing phase 1/2 open-label study of 191 adult patients with histologically or cytologically confirmed locally advanced/metastatic UC whose disease had progressed on, were ineligible for, or refused prior chemotherapy from 60 sites in 9 countries as reported herein.Patients were administered durvalumab intravenous infusion, 10 mg/kg every 2 weeks, for up to 12 months or until progression, starting another anticancer therapy, or unacceptable toxic effects.Primary end points were safety and confirmed objective response rate (ORR) per blinded independent central review (Response Evaluation Criteria In Solid Tumors [RECIST], version 1.1).A total of 191 patients with UC had received treatment. As of October 24, 2016 (90-day update), the median follow-up was 5.78 months (range, 0.4-25.9 months). The median age of patients was 67.0 years and most were male (136 [71.2%]) and white (123 [71.1%]). All patients had stage 4 disease, and 190 (99.5%) had prior anticancer therapy (182 [95.3%] postplatinum). The ORR was 17.8% (34 of 191; 95% CI, 12.7%-24.0%), including 7 complete responses. Responses were early (median time to response, 1.41 months), durable (median duration of response not reached), and observed regardless of programmed cell death ligand-1 (PD-L1) expression (ORR, 27.6% [n = 27; 95% CI, 19.0%-37.5%] and 5.1% [n = 4; 95% CI, 1.4%-12.5%] in patients with high and low or negative expression of PD-L1, respectively). Median progression-free survival and overall survival were 1.5 months (95% CI, 1.4-1.9 months) and 18.2 months (95% CI, 8.1 months to not estimable), respectively; the 1-year overall survival rate was 55% (95% CI, 44%-65%), as estimated by Kaplan-Meier method. Grade 3/4 treatment-related adverse events (AEs) occurred in 13 patients (6.8%); grade 3/4 immune-mediated AEs occurred in 4 patients (2.1%); and treatment-related AEs led to discontinuation of 3 patients (1.6%), 2 of whom had immune-mediated AEs that led to death (autoimmune hepatitis and pneumonitis).Durvalumab, 10 mg/kg every 2 weeks, demonstrates favorable clinical activity and an encouraging and manageable safety profile in patients with locally advanced/metastatic UC.clinicaltrials.gov Identifier: NCT01693562.

View details for PubMedID 28817753

View details for PubMedCentralID PMC5824288
Lack of Effectiveness of Postchemotherapy Lymphadenectomy in Bladder Cancer Patients with Clinical Evidence of Metastatic Pelvic or Retroperitoneal Lymph Nodes Only: A Propensity Score-based Analysis. European urology focus Necchi, A., Mariani, L., Lo Vullo, S., Yu, E. Y., Woods, M. E., Wong, Y., Harshman, L. C., Alva, A., Sternberg, C. N., Bamias, A., Grivas, P., Koshkin, V. S., Roghmann, F., Dobruch, J., Eigl, B. J., Nappi, L., Milowsky, M. I., Niegisch, G., Pal, S. K., De Giorgi, U., Recine, F., Vaishampayan, U., Berthold, D. D., Bowles, D. W., Baniel, J., Theodore, C., Ladoire, S., Srinivas, S., Agarwal, N., Crabb, S., Sridhar, S., Golshayan, A., Ohlmann, C., Xylinas, E., Powles, T., Rosenberg, J. E., Bellmunt, J., van Rhijn, B., Galsky, M. D., Hendricksen, K., Young Academic Urologists-Urothelial Carcinoma Group-European Association of Urology and the Retrospective International Study of Invasive/Advanced Cancer of the Urothelium group 2017
Abstract

BACKGROUND: Limited data is available on the role, and extent of, postchemotherapy lymphadenectomy (PC-LND) in patients with clinical evidence of pelvic (cN1-3) or retroperitoneal (RP) lymph node spread from urothelial bladder carcinoma.OBJECTIVE: To compare the outcomes of operated versus nonoperated patients after first-line chemotherapy.DESIGN, SETTING, AND PARTICIPANTS: Data from 34 centers was collected, totaling 522 patients, treated between January 2000 and June 2015. Criteria for patient selection were the following: bladder primary tumor, lymph node metastases (pelvic±RP) only, first-line platinum-based chemotherapy given.INTERVENTION: LND (with cystectomy) versus observation after first-line chemotherapy for metastatic urothelial bladder carcinoma.OUTCOME MEASURES AND STATISTICAL ANALYSIS: Overall survival (OS) was the primary endpoint. Multiple propensity score techniques were adopted, including 1:1 propensity score matching and inverse probability of treatment weighting. Additionally, the inverse probability of treatment weighting analysis was performed with the inclusion of the covariates, that is, with doubly robust estimation.RESULTS AND LIMITATIONS: Overall, 242 (46.4%) patients received PC-LND and 280 (53.6%) observation after chemotherapy. There were 177 (33.9%) and 345 (66.1%) patients with either RP or pelvic LND only, respectively. Doubly robust estimation-adjusted comparison was not significant for improved OS for PC-LND (hazard ratio [HR]: 0.86, 95% confidence interval [CI]: 0.56-1.31, p=0.479), confirmed by matched analysis (HR: 0.91, 95% CI: 0.60-1.36, p=0.628). This was also observed in the RP subgroup (HR: 1.12, 95% CI: 0.68-1.84). The retrospective nature of the data and the heterogeneous patient population were the major limitations.CONCLUSIONS: Although there were substantial differences between the two groups, after accounting for major confounders we report a nonsignificant OS difference with PC-LND compared with observation only. These findings may be hypothesis-generating for future prospective trials.PATIENT SUMMARY: We found no differences in survival by adding postchemotherapy lymphadenectomy in patients with pelvic or retroperitoneal lymph node metastatic bladder cancer. The indication to perform postchemotherapy lymphadenectomy in the most suitable patients requires additional studies.

View details for PubMedID 28753897
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
Abstract

We hypothesized that changes in International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic category at start of second-line therapy (2L) for metastatic renal cell carcinoma (mRCC) might predict response.To assess outcomes of 2L according to type of therapy and change in IMDC prognostic category.We performed a retrospective review of the IMDC database for mRCC patients who received first-line (1L) VEGF inhibitors (VEGFi) and then 2L with VEGFi or mTOR inhibitors (mTORi). IMDC prognostic categories were defined before each line of therapy (favorable, F; intermediate, I; poor, P). Data were analyzed for 1516 patients, of whom 89% had clear cell histology.All included patients received targeted therapy for mRCC.Overall survival (OS), time to treatment failure, and response to 2L were analyzed using Cox or logistic regression.At start of 2L, 60% of patients remained in the same prognostic category; 9.0% improved (3% I → F; 6% P → I); 31% deteriorated (15% F → I or P; 16% I → P). Patients with the same or better IMDC prognostic category had a longer time to treatment failure if they remained on VEGFi compared to those who switched to mTORi (adjusted hazard ratio [AHR] ranging from 0.33 to 0.78, adjusted p<0.05). Patients who deteriorated from F to I appeared more likely to benefit from switching to mTORi (median OS 16.5 mo, 95% confidence interval [CI] 12.0-19.0 for VEGFi; 20.2 mo, 95% CI 14.3-26.1 for mTORi; AHR 1.53, 95% CI 1.04-2.24; adjusted p=0.03).Changes in IMDC prognostic category predict the subsequent clinical course for patients with mRCC and provide a rational basis for selection of subsequent therapy.The pattern of treatment failure might help to predict what the next treatment should be for patients with metastatic renal cell carcinoma.

View details for DOI 10.1016/j.eururo.2016.09.047

View details for Web of Science ID 000400050300031
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
Abstract

We hypothesized that changes in International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic category at start of second-line therapy (2L) for metastatic renal cell carcinoma (mRCC) might predict response.To assess outcomes of 2L according to type of therapy and change in IMDC prognostic category.We performed a retrospective review of the IMDC database for mRCC patients who received first-line (1L) VEGF inhibitors (VEGFi) and then 2L with VEGFi or mTOR inhibitors (mTORi). IMDC prognostic categories were defined before each line of therapy (favorable, F; intermediate, I; poor, P). Data were analyzed for 1516 patients, of whom 89% had clear cell histology.All included patients received targeted therapy for mRCC.Overall survival (OS), time to treatment failure, and response to 2L were analyzed using Cox or logistic regression.At start of 2L, 60% of patients remained in the same prognostic category; 9.0% improved (3% I → F; 6% P → I); 31% deteriorated (15% F → I or P; 16% I → P). Patients with the same or better IMDC prognostic category had a longer time to treatment failure if they remained on VEGFi compared to those who switched to mTORi (adjusted hazard ratio [AHR] ranging from 0.33 to 0.78, adjusted p<0.05). Patients who deteriorated from F to I appeared more likely to benefit from switching to mTORi (median OS 16.5 mo, 95% confidence interval [CI] 12.0-19.0 for VEGFi; 20.2 mo, 95% CI 14.3-26.1 for mTORi; AHR 1.53, 95% CI 1.04-2.24; adjusted p=0.03).Changes in IMDC prognostic category predict the subsequent clinical course for patients with mRCC and provide a rational basis for selection of subsequent therapy.The pattern of treatment failure might help to predict what the next treatment should be for patients with metastatic renal cell carcinoma.

View details for DOI 10.1016/j.eururo.2016.09.047

View details for PubMedID 27771126
Economic burden of empiric drug utilization in metastatic renal cell carcinoma emphasizes the need for early biomarkers of response. Chen, V., Gong, C., Zhang, C. A., Srinivas, S., Lee, H. E., Fan, A. C. AMER SOC CLINICAL ONCOLOGY. 2017
View details for DOI 10.1200/JCO.2017.35.15_suppl.e16072

View details for Web of Science ID 000411931702162
Updated efficacy and tolerability of durvalumab in locally advanced or metastatic urothelial carcinoma (UC). Hahn, N. M., Powles, T., Massard, C., Arkenau, H., Friedlander, T. W., Holmes, C. J., Lee, J., Ong, M., Sridhar, S. S., Vogelzang, N. J., Fishman, M. N., Zhang, J., Srinivas, S., Parikh, J., Antal, J., Jin, X., Ben, Y., Gupta, A., O'Donnell, P. H. AMER SOC CLINICAL ONCOLOGY. 2017
View details for DOI 10.1200/JCO.2017.35.15_suppl.4525

View details for Web of Science ID 000411931702025
Clinical outcomes according to ethnicity in patients with metastatic renal cell carcinoma (mRCC) treated with VEGF-targeted therapy (TT). Bosse, D., Xie, W., Wells, C., Lalani, A. A., Donskov, F., Bent, A., Sim, H., Beuselinck, B., Bamias, A., Porta, C., Vaishampayan, U. N., Pal, S. K., Agarwal, N., Srinivas, S., Rini, B. I., Alva, A., Wood, L., Kapoor, A., Choueiri, T. K., Heng, D. AMER SOC CLINICAL ONCOLOGY. 2017
View details for DOI 10.1200/JCO.2017.35.15_suppl.e16065

View details for Web of Science ID 000411931702156
Checkpoint inhibitors in metastatic renal cell carcinoma patients including elderly subgroups: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). Yip, S., Wells, C., Moreira, R., Wong, A., Srinivas, S., Beuselinck, B., Porta, C., Sim, H., Ernst, D., Rini, B. I., Yuasa, T., Basappa, N. S., Kanesvaran, R., Wood, L., Canil, C. M., Kapoor, A., Fu, S., Choueiri, T. K., Heng, D. AMER SOC CLINICAL ONCOLOGY. 2017
View details for DOI 10.1200/JCO.2017.35.15_suppl.4580

View details for Web of Science ID 000411931702080
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 PubMedID 28414866
Automated bone scan index as a prognostic tool in prostate cancer patients with bone metastasis Park, S., Srinivas, S., Mittra, E. SOC NUCLEAR MEDICINE INC. 2017
View details for Web of Science ID 000404949903120
Bone scan index as a new imaging biomarker in response assessment of prostate cancer patients with bone metastasis Park, S., Srinivas, S., Mittra, E. SOC NUCLEAR MEDICINE INC. 2017
View details for Web of Science ID 000404949903158
Consolidative Radiotherapy in Metastatic Urothelial Cancer. Clinical genitourinary cancer Shah, S., Zhang, C. A., Hancock, S., Fan, A., Skinner, E., Srinivas, S. 2017
Abstract

We report outcomes of a retrospective, single-institution experience with consolidative radiation after chemotherapy in metastatic urothelial cancer (MUC).From our single-institution database of 2597 patients with urothelial carcinoma treated since 1997, we identified 22 patients with MUC who underwent consolidative radiotherapy after a partial response to chemotherapy with the intent of rendering them disease-free. All patients had undergone primary surgical therapy with either cystectomy or nephroureterectomy. Progression-free survival (PFS) was defined as time from completion of radiation therapy to relapse or last follow-up. Overall survival (OS) was defined as time from start of chemotherapy to death or last follow-up.In the selected group of patients with MUC, the median age was 67 years; 59% had received previous cisplatin-based chemotherapy. The most common sites radiated were the regional lymph nodes (64%). Other radiated sites included the lung, adrenal glands, and omental metastases. Median survival from diagnosis to cystectomy was 48 months. Median PFS was 13 months and median OS was 29 months. Eight patients (36%) were alive and disease-free 6 years after radiation therapy. Patients who were rendered disease-free were those with nodal metastases and delivery of radiation to a single site of metastasis.In this highly selective cohort of patients with MUC treated with consolidative radiation after chemotherapy, 36% were rendered disease-free. This suggests that radiation is feasible and might contribute to long-term disease control. Further prospective studies are needed to better characterize the benefit of combined modality treatment.

View details for DOI 10.1016/j.clgc.2017.04.007

View details for PubMedID 28465049
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
Updated efficacy and tolerability of durvalumab in locally advanced or metastatic urothelial carcinoma. Powles, T., O'Donnell, P. H., Massard, C., Arkenau, H., Friedlander, T. W., Hoimes, C., Lee, J., Ong, M., Sridhar, S. S., Vogelzang, N. J., Fishman, M. N., Zhang, J., Srinivas, S., Parikh, J., Antal, J., Jin, X., Gupta, A., Hahn, N. M. AMER SOC CLINICAL ONCOLOGY. 2017
View details for DOI 10.1200/JCO.2017.35.6_suppl.286

View details for Web of Science ID 000443269500348
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
Abstract

The available prognostic models for overall survival (OS) in patients with metastatic urothelial carcinoma (UC) have been derived from clinical trial populations of cisplatin-treated patients.To develop a new model based on real-world patients.Individual patient-level data from 29 centers were collected, including metastatic UC and first-line cisplatin- or carboplatin-based chemotherapy administered between January 2006 and January 2011.First-line, platinum-based, combination chemotherapy.The population was randomly split into a development and a validation cohort. Generalized boosted regression modelling was used to screen out irrelevant variables and address multivariable analyses. Two nomograms were built to estimate OS probability, the first based on baseline factors and platinum agent, the second incorporating objective response (OR). The performance of the above nomograms and that of other available models was assessed. We plotted decision curves to evaluate the clinical usefulness of the two nomograms.A total of 1020 patients were analyzed (development: 687, validation: 333). In a platinum-stratified Cox model, significant variables for OS were performance status (p<0.001), white blood cell count (p=0.013), body mass index (p=0.003), ethnicity (p=0.012), lung, liver, or bone metastases (p<0.001), and prior perioperative chemotherapy (p=0.012). The c-index was 0.660. The distribution of the nomogram scores was associated with OR (p<0.001), and incorporating OR into the model further improved the c-index in the validation cohort (0.670).We developed and validated two nomograms for OS to be used before and after completion of first-line chemotherapy for metastatic UC.We proposed two models for estimating overall survival of patients with metastatic urothelial carcinoma receiving first-line, platinum-based chemotherapy. These nomograms have been developed on real-world patients who were treated outside of clinical trials and may be used irrespective of the chemotherapeutic platinum agent used.

View details for DOI 10.1016/j.eururo.2016.09.042

View details for Web of Science ID 000390565700047
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 PubMedID 27318422
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
Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial LANCET Balar, A. V., Galsky, M. D., Rosenberg, J. E., Powles, T., Petrylak, D. P., Bellmunt, J., Loriot, Y., Necchi, A., Hoffman-Censits, J., Perez-Gracia, J. L., Dawson, N. A., van der Heijden, M. S., Dreicer, R., Srinivas, S., Retz, M. M., Joseph, R. W., Drakaki, A., Vaishampayan, U. N., Sridhar, S. S., Quinn, D. I., Duran, I., Shaffer, D. R., Eigl, B. J., Grivas, P. D., Yu, E. Y., Li, S., Kadel, E. E., Boyd, Z., Bourgon, R., Hegde, P. S., Mariathasan, S., Thastrom, A., Abidoye, O. O., Fine, G. D., Bajorin, D. F. 2017; 389 (10064): 67-76
Abstract

First-line chemotherapy for patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma is associated with short response duration, poor survival, and high toxicity. This study assessed atezolizumab (anti-programmed death-ligand 1 [PD-L1]) as treatment for metastatic urothelial cancer in cisplatin-ineligible patients.For this single-arm, multicentre, phase 2 study, in 47 academic medical centres and community oncology practices in seven countries in North America and Europe, we recruited previously untreated patients with locally advanced or metastatic urothelial cancer who were cisplatin ineligible. Patients were given 1200 mg intravenous atezolizumab every 21 days until progression. The primary endpoint was independently confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (central review), assessed in prespecified subgroups based on PD-L1 expression and in all patients. All participants who received one or more doses of atezolizumab were included in the primary and safety analyses. This study was registered with ClinicalTrials.gov, number NCT02108652.Between June 9, 2014, and March 30, 2015, we enrolled 123 patients, of whom 119 received one or more doses of atezolizumab. At 17·2 months' median follow-up, the objective response rate was 23% (95% CI 16 to 31), the complete response rate was 9% (n=11), and 19 of 27 responses were ongoing. Median response duration was not reached. Responses occurred across all PD-L1 and poor prognostic factor subgroups. Median progression-free survival was 2·7 months (2·1 to 4·2). Median overall survival was 15·9 months (10·4 to not estimable). Tumour mutation load was associated with response. Treatment-related adverse events that occurred in 10% or more of patients were fatigue (36 [30%] patients), diarrhoea (14 [12%] patients), and pruritus (13 [11%] patients). One treatment-related death (sepsis) occurred. Nine (8%) patients had an adverse event leading to treatment discontinuation. Immune-mediated events occurred in 14 (12%) patients.Atezolizumab showed encouraging durable response rates, survival, and tolerability, supporting its therapeutic use in untreated metastatic urothelial cancer.F Hoffmann-La Roche, Genentech.

View details for DOI 10.1016/S0140-6736(16)32455-2

View details for PubMedID 27939400
Incorporating VEGF-targeted therapy in advanced urothelial cancer THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY Narayanan, S., Srinivas, S. 2017; 9 (1): 33-45
Abstract

Patients with relapsed or refractory urothelial carcinoma (UC) have poor prognosis coupled with few options for systemic treatment. The role of angiogenesis in the evolution of cancers has been established, and studies have shown that it plays a key role in the pathogenesis of UC. Many targeted agents have been used in phase I-II trials for the treatment of UC, with encouraging but modest results. Recently, studies combining angiogenesis inhibitors with other chemotherapeutic agents were able to achieve objective responses higher than most commonly used second-line therapies in UC. Future efforts in investigating these therapies in UC rely on identification of biomarkers and other predictors of response to anti-VEGF therapy.

View details for DOI 10.1177/1758834016667179

View details for Web of Science ID 000391771800004

View details for PubMedID 28203296

View details for PubMedCentralID PMC5298449
Second-line Chemotherapy in Older Patients With Metastatic Urothelial Carcinoma: Pooled Analysis of 10 Second-line Studies. Clinical genitourinary cancer Salah, S., Lee, J., Rozzi, A., Kitamura, H., Matsumoto, K., Vis, D. J., Srinivas, S., Morales-Barrera, R., Carles, J., Al-Rimawi, D., Lee, S., Kim, K. H., Izumi, K., Lewin, J. 2016
Abstract

Older patients with metastatic urothelial carcinoma (UC) are under-represented in clinical trials, and data regarding outcomes for second-line therapy is limited.Individual data for patients with metastatic UC, aged ≥ 70 years, were pooled from 10 second-line studies. The influence of potential prognostic factors on overall survival (OS) was assessed via univariate and multivariate Cox regression analysis.In total, 102 patients were included; the median age was 74.0 years (range, 70-88 years). Second-line chemotherapy was single-agent in 42 (41%) patients and combination regimens in 60 (59%) patients. Median progression-free and OS were 4.3 and 9.7 months, respectively. In multivariate analysis, age > 75 years, Eastern Cooperative Oncology Group performance status ≥ 1, serum hemoglobin < 10 g/dL, and non-lymph node only metastasis predicted inferior OS. Median OS for patients with 0, 1, 2, and ≥ 3 adverse factors was unreached, 15.5, 9.8, and 4.8 months, respectively (P < .001). There was no difference in OS between patients treated with single-agent or combination chemotherapy. Combination regimens were associated with higher occurrences of any ≥ grade 2 toxicity (80% vs. 38%; P < .001), ≥ grade 2 hematologic (78% vs. 12%; P < .001), and ≥ grade 2 gastrointestinal toxicity (36% vs. 7%; P < .001).In this pooled analysis of older patients with metastatic UC, combination chemotherapy for second-line treatment was associated with greater toxicity without improvement in OS. Eastern Cooperative Oncology Group performance status ≥1, serum hemoglobin < 10 g/dL, and age > 75 years predicted worse survival, whereas isolated lymph node metastasis predicted a favorable outcome.

View details for DOI 10.1016/j.clgc.2016.12.014

View details for PubMedID 28065418
The effect of information on preferences for treatments of metastatic renal cell carcinoma. Current medical research and opinion Mansfield, C., Srinivas, S., Chen, C., Hauber, A. B., Hariharan, S., Matczak, E., Sandin, R. 2016; 32 (11): 1827-1838
Abstract

Limited information exists regarding the effect of uncertainty in outcomes on patient preferences for metastatic renal cell carcinoma (mRCC) treatments. This study tested the effect on patients' preferences and willingness to tolerate toxicities when patients were provided with information about possible correlations between treatment-related toxicities and efficacy.Patients with self-reported RCC diagnosis completed an online survey. Respondents were randomly assigned to the information treatment (i.e. information about the possible correlation). Medicines were defined by progression-free survival (PFS), three toxicities potentially correlated with PFS, and one toxicity uncorrelated with PFS. Direct-elicitation questions measured willingness to tolerate the toxicities, preferences for medicines with higher toxicity but a higher chance of longer PFS, and preferences for medicines with higher toxicity during treatment and a 2 week dosing schedule break. A discrete-choice experiment (DCE) tested the effect of information on relative preferences for medication attributes.A total of 378 RCC patients completed the survey. Respondents who received the information reported greater willingness to accept more severe toxicities and preferred treatment with a higher chance of longer PFS but more severe toxicities. The DCE results were consistent with the hypothesis that the information increased willingness to tolerate toxicities; however, the results were only statistically significant for changes in fatigue (none to severe; p < 0.05) and hypertension (none to manageable; p < 0.05).Online recruitment through patient support groups may limit generalizability to the population of patients with mRCC who would be candidates for the targeted therapies.The findings suggest that RCC patients have diverse preferences but may be willing to continue targeted therapies, even in the presence of severe toxicities, if there is a chance of improved clinical benefit. Physicians should provide patients with comprehensive information about medication features, including toxicities and efficacy (and their potential correlation), to improve compliance and optimize outcomes.

View details for PubMedID 27404275
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

View details for PubMedCentralID PMC5065111
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. 2016
Abstract

The available prognostic models for overall survival (OS) in patients with metastatic urothelial carcinoma (UC) have been derived from clinical trial populations of cisplatin-treated patients.To develop a new model based on real-world patients.Individual patient-level data from 29 centers were collected, including metastatic UC and first-line cisplatin- or carboplatin-based chemotherapy administered between January 2006 and January 2011.First-line, platinum-based, combination chemotherapy.The population was randomly split into a development and a validation cohort. Generalized boosted regression modelling was used to screen out irrelevant variables and address multivariable analyses. Two nomograms were built to estimate OS probability, the first based on baseline factors and platinum agent, the second incorporating objective response (OR). The performance of the above nomograms and that of other available models was assessed. We plotted decision curves to evaluate the clinical usefulness of the two nomograms.A total of 1020 patients were analyzed (development: 687, validation: 333). In a platinum-stratified Cox model, significant variables for OS were performance status (p<0.001), white blood cell count (p=0.013), body mass index (p=0.003), ethnicity (p=0.012), lung, liver, or bone metastases (p<0.001), and prior perioperative chemotherapy (p=0.012). The c-index was 0.660. The distribution of the nomogram scores was associated with OR (p<0.001), and incorporating OR into the model further improved the c-index in the validation cohort (0.670).We developed and validated two nomograms for OS to be used before and after completion of first-line chemotherapy for metastatic UC.We proposed two models for estimating overall survival of patients with metastatic urothelial carcinoma receiving first-line, platinum-based chemotherapy. These nomograms have been developed on real-world patients who were treated outside of clinical trials and may be used irrespective of the chemotherapeutic platinum agent used.

View details for DOI 10.1016/j.eururo.2016.09.042

View details for PubMedID 27726966
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 PubMedID 26948397
Atezolizumab (atezo) as first-line (1L) therapy in cisplatin-ineligible locally advanced/metastatic urothelial carcinoma (mUC): Primary analysis of IMvigor210 cohort 1. Balar, A., Galsky, M. D., Loriot, Y., Dawson, N., Necchi, A., Srinivas, S., Joseph, R., Vaishampayan, U. N., Sridhar, S. S., Quinn, D. I., Drakaki, A., Duran, I., Rosenberg, J. E., Powles, T., Hoffman-Censits, J. H., Cui, N., Mariathasan, S., Thastrom, A., Abidoye, O. O., Bajorin, D. F. AMER SOC CLINICAL ONCOLOGY. 2016
View details for Web of Science ID 000443264100015
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
Second-line chemotherapy in older patients with metastatic urothelial carcinoma: Pooled analysis of 10 second-line studies. Salah, S., Lee, J., Rozzi, A., Lewin, J., Kitamura, H., Matsumoto, K., Vis, D. J., Wessels, L. A., Srinivas, S., Morales, R., Carles, J., Toubasi, S., Lee, S., Kim, K., Izumi, K. AMER SOC CLINICAL ONCOLOGY. 2016
View details for DOI 10.1200/JCO.2016.34.15_suppl.e16038

View details for Web of Science ID 000404711500020
Prognostic factors for pancreatic metastases in renal cell cancer. Chung, A., Li, S., Shah, S., Fan, A. C., Srinivas, S. AMER SOC CLINICAL ONCOLOGY. 2016
View details for DOI 10.1200/JCO.2016.34.15_suppl.e16106

View details for Web of Science ID 000404711500073
An investigator-initiated phase I study of crizotinib in combination with enzalutamide in metastatic castration-resistant prostate cancer (mCRPC) before or after progression on docetaxel. Harshman, L., Gray, K. P., Polacek, L., Taplin, M., Choudhury, A., Pomerantz, M. M., Bellmunt, J., Yu, C., Sun, Z., Srinivas, S., Kantoff, P. W., Sweeney, C. AMER SOC CLINICAL ONCOLOGY. 2016
View details for DOI 10.1200/JCO.2016.34.15_suppl.e16509

View details for Web of Science ID 000404711501078
Characterizing the outcomes of metastatic papillary renal cell carcinoma (papRCC) Wells, J., Donskov, F., Fraccon, A., Pasini, F., Bjarnason, G. A., Knox, J. J., Beuselinck, B., Rha, S., Agarwal, N., Brugarolas, J., Lee, J., Pal, S. K., Srinivas, S., Ernst, D., Vaishampayan, U. N., Wood, L., Simpson, R., de Velasco, G., Choueiri, T. K., Heng, D. AMER SOC CLINICAL ONCOLOGY. 2016
View details for DOI 10.1200/JCO.2016.34.15_suppl.4554

View details for Web of Science ID 000404665407127
Correlation of response with overall survival (OS) for nivolumab vs everolimus in advanced renal cell carcinoma (aRCC): Results from the phase III CheckMate 025 study Motzer, R. J., Sharma, P., Escudier, B. J., McDermott, D. F., George, S., Srinivas, S., Tykodi, S. S., Sosman, J., Plimack, E. R., Nathan, P. D., Gruenwald, V., Tomita, Y., Zhao, H., Waxman, I. M., Hammers, H. J. AMER SOC CLINICAL ONCOLOGY. 2016
View details for DOI 10.1200/JCO.2016.34.15_suppl.4552

View details for Web of Science ID 000404665407125
Platinum retreatment in second line chemotherapy for metastatic urothelial carcinoma (UC): Assessing the concept of platinum sensitivity and predictors of survival. Ma'koseh, M., Kitamura, H., Srinivas, S., Lewin, J., Salah, S. AMER SOC CLINICAL ONCOLOGY. 2016
View details for DOI 10.1200/JCO.2016.34.15_suppl.e16024

View details for Web of Science ID 000404711500008
The RISC nomogram (RN) to predict overall survival (OS) of patients (pts) with metastatic urothelial carcinoma (mUC) receiving first-line platinum-based combination chemotherapy (CT). Necchi, A., Sonpavde, G., Lo Vullo, S., Bamias, A., Crabb, S. J., Harshman, L., Bellmunt, J., De Giorgi, U., Sternberg, C. N., Ladoire, S., Wong, Y., Yu, E. Y., Chowdhury, S., Niegisch, G., Srinivas, S., Vaishampayan, U. N., Pal, S. K., Rosenberg, J. E., Galsky, M. D., Mariani, L. AMER SOC CLINICAL ONCOLOGY. 2016
View details for DOI 10.1200/JCO.2016.34.15_suppl.e16026

View details for Web of Science ID 000404711500010
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 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 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
Disparities in Adolescent and Young Adult Survival After Testicular Cancer Vary by Histologic Subtype: A Population-Based Study in California 1988-2010. Journal of adolescent and young adult oncology DeRouen, M. C., Mujahid, M., Srinivas, S., Keegan, T. H. 2016; 5 (1): 31-40
Abstract

Testicular cancer is the most common cancer among adolescent and young adult (AYA) men 15-39 years of age. This study aims to determine whether race/ethnicity and/or neighborhood socioeconomic status (SES) contribute independently to survival of AYAs with testicular cancer.Data on 14,249 eligible AYAs with testicular cancer diagnosed in California between 1988 and 2010 were obtained from the population-based California Cancer Registry. Multivariable Cox proportional hazards regression was used to examine overall and testicular cancer-specific survival and survival for the seminoma and nonseminoma histologic subtypes according to race/ethnicity, census-tract level neighborhood SES, and other patient and clinical characteristics.Compared with White AYAs, Hispanic AYAs had worse overall and testicular cancer-specific survival (hazard ratio [HR], 1.21; 95% confidence interval [CI], 1.07-1.37) and Black AYAs had worse overall survival (HR, 1.41; 95% CI, 1.01-1.97), independent of neighborhood SES and other demographic and clinical factors. Racial/ethnic disparities in survival were more pronounced for nonseminoma than for seminoma. AYAs residing in middle and low SES neighborhoods experienced worse survival across both histologic subtypes independent of race/ethnicity and other factors, while improvements in survival over time were more pronounced for seminoma. Longer time to treatment was also associated with worse survival, particularly for AYAs with nonseminoma.Among AYAs, race/ethnicity, and neighborhood SES are independently associated with survival after testicular cancer. Variation in disparities by histologic type according to demographic factors, year of diagnosis, and time to treatment may reflect differences in prognosis and extent of treatment for the two histologies.

View details for DOI 10.1089/jayao.2015.0041

View details for PubMedID 26812451

View details for PubMedCentralID PMC4779289
Consolidative radiotherapy in metastatic urothelial cancer (MUC) Srinivas, S., Narayanan, S., Fan, A. C., Hancock, S., Skinner, E. C. AMER SOC CLINICAL ONCOLOGY. 2016
View details for DOI 10.1200/jco.2016.34.2_suppl.406

View details for Web of Science ID 000378109100400
Real world chart review of adverse event management in patients taking tyrosine kinase inhibitors (TKIs) for metastatic renal cell carcinoma (mRCC) by line of therapy (LoT). Srinivas, S., Stein, D., Teltsch, D. Y., Tao, S., Ramaswamy, K. AMER SOC CLINICAL ONCOLOGY. 2016
View details for DOI 10.1200/jco.2016.34.2_suppl.521

View details for Web of Science ID 000378109100514
CheckMate 025 phase III trial: Outcomes by key baseline factors and prior therapy for nivolumab (NIVO) versus everolimus (EVE) in advanced renal cell carcinoma (RCC). Motzer, R. J., Sharma, P., McDermott, D. F., George, S., Hammers, H. J., Srinivas, S., Tykodi, S. S., Sosman, J., Procopio, G., Plimack, E. R., Castellano, D. E., Gurney, H., Donskov, F., Bono, P., Wagstaff, J., Gauler, T., Ueda, T., Zhao, H., Waxman, I. M., Escudier, B. AMER SOC CLINICAL ONCOLOGY. 2016
View details for DOI 10.1200/jco.2016.34.2_suppl.498

View details for Web of Science ID 000378109100491
First-line sunitinib versus pazopanib in metastatic renal cell carcinoma (mRCC): Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). Morales, J., Wells, J., Donskov, F., Bjarnason, G. A., Lee, J., Knox, J. J., Beuselinck, B., Vaishampayan, U. N., Brugarolas, J., Broom, R., Bamias, A., Yuasa, T., Srinivas, S., Ernst, D., Pezaro, C., Wood, L., Kollmannsberger, C. K., Rini, B. I., Choueiri, T. K., Heng, D. AMER SOC CLINICAL ONCOLOGY. 2016
View details for Web of Science ID 000378109100537
Discontinuing VEGF-targeted therapy (VEGF-TT) for progression versus toxicity impacts outcomes of second-line therapies in metastatic renal cell carcinoma (mRCC). de Velasco, G., Xie, W., Donskov, F., Albiges, L., Beuselinck, B., Srinivas, S., Agarwal, N., Lee, J., Brugarolas, J., Wood, L., Kollmannsberger, C. K., Rha, S., North, S. A., Kanesvaran, R., Rini, B. I., Broom, R., Yamamoto, H., Kaymakcalan, M., Heng, D., Choueiri, T. K. AMER SOC CLINICAL ONCOLOGY. 2016
View details for DOI 10.1200/jco.2016.34.2_suppl.503

View details for Web of Science ID 000378109100496
Change in International mRCC Database Consortium (IMDC) prognostic category and implications for efficacy of second-line targeted therapy. Davis, I. D., Xie, W., Pezaro, C., Donskov, F., Wells, C., Agarwal, N., Srinivas, S., Yuasa, T., Beuselinck, B., Wood, L., Ernst, D., Kanesvaran, R., Knox, J. J., Pantuck, A. J., Saleem, S., Alva, A., Rini, B. I., Lee, J., Choueiri, T. K., Heng, D. AMER SOC CLINICAL ONCOLOGY. 2016
View details for DOI 10.1200/jco.2016.34.2_suppl.534

View details for Web of Science ID 000378109100527
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
Abstract

The NCCN Guidelines for Prostate Cancer address staging and risk assessment after an initial diagnosis of prostate cancer and management options for localized, regional, and metastatic disease. Recommendations for disease monitoring, treatment of recurrent disease, and systemic therapy for metastatic castration-recurrent prostate cancer also are included. This article summarizes the NCCN Prostate Cancer Panel's most significant discussions for the 2016 update of the guidelines, which include refinement of risk stratification methods and new options for the treatment of men with high-risk and very-high-risk disease and progressive castration-naïve disease.

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
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 Web of Science ID 000367655300006
Real world chart review study of adverse events of special interest (AESI) Management in patients taking tyrosine kinase inhibitors (TKis) to treat metastatic renal cell carcinoma (mRCC) Srinivas, S., Stein, D., Teltsch, D., Tao, S., Chen, C., Cisar, L., Ramaswamy, K. WILEY-BLACKWELL. 2015: 20–21
View details for Web of Science ID 000366284900041
CheckMate 025: a randomized, open-label, phase Ill study of nivolumab versus everolimus in advanced renal cell carcinoma (RCC) 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., Gurney, H., Donskov, F., Bono, P., Wagstaff, J., Gauler, T. C., Ueda, T., Xu, L., Waxman, I. M., Sharma, P., Checkmate 025 Invest WILEY-BLACKWELL. 2015: 17
View details for Web of Science ID 000366284900033
First line sunitinib versus pazopanib in metastatic renal cell carcinoma: results from the international metastatic renal cell carcinoma database consortium Morales, J., Wells, J., Donskov, F., Bjarnason, G. A., Lee, J., Knox, J. J., Beuselinck, B., Vasihampayan, U., Brugarolas, J., Broom, R., Koutsoukos, K., Yuasa, T., Srinivas, S., Ernst, D., Pezaro, C., Wood, L. A., Kollmannsberger, C., Rini, B. I., Choueiri, T. K., Heng, D. C. WILEY-BLACKWELL. 2015: 20
View details for Web of Science ID 000366284900040
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 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
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 Web of Science ID 000360572300035
Third-line therapy in metastatic renal cell carcinoma (mRCC): Results from the International mRCC Database Consortium (IMDC) Heng, D., Stukalin, I., Wells, C., Donskov, F., Rini, B. I., Lee, J., Bjarnason, G. A., Beuselinck, B., Smoragiewicz, M., Alva, A., Srinivas, S., Wood, L., Brugarolas, J., Pal, S., Yuasa, T., Broom, R., Kanesvaran, R., Bamias, A., Knox, J. J., Choueiri, T. K. AMER SOC CLINICAL ONCOLOGY. 2015
View details for Web of Science ID 000358036903121
Prognostic features for testicular cancers (TCs): Can this be gleaned from pathology reports? Srinivas, S., Eisenberg, M., Skinner, E. C. AMER SOC CLINICAL ONCOLOGY. 2015
View details for Web of Science ID 000358036903097
Evaluation of FDG PET/CT measurement parameters for prediction of the prognosis after Sunitinib Therapy in Renal Cell Carcinoma Minamimoto, R., Barkhodari, A., Harshman, L., Quon, A., Srinivas, S. SOC NUCLEAR MEDICINE INC. 2015
View details for Web of Science ID 000358738803049
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
Phase II study of pazopanib with weekly paclitaxel in refractory urothelial cancer. Srinivas, S., Narayanan, S., Harshman, L., Pachynski, R., Lam, A. P., Fan, A. C., Poushnejad, S., Haas, D., Vaishampayan, U. N. AMER SOC CLINICAL ONCOLOGY. 2015
View details for DOI 10.1200/jco.2015.33.7_suppl.294

View details for Web of Science ID 000356886700294
Second-line chemotherapy for metastatic urothelial cell carcinoma: Pooled analysis and construction of a prognostic model. Salah, S., Lee, J., Rozzi, A., Kitamura, H., Matsumoto, K., Srinivas, S., Morales, R., Carles, J., Al-Wardat, R., Maakoseh, M. AMER SOC CLINICAL ONCOLOGY. 2015
View details for DOI 10.1200/jco.2015.33.7_suppl.309

View details for Web of Science ID 000356886700309
Third-line therapy in metastatic renal cell carcinoma: Results from the International mRCC Database Consortium. Heng, D., Wells, C., Donskov, F., Rini, B. I., Lee, J., Bjarnason, G. A., Beuselinck, B., Smoragiewicz, M., Alva, A., Srinivas, S., Wood, L., Yamamoto, H., Ernst, D., Pal, S., Yuasa, T., Broom, R., Kanesvaran, R., Bamias, A., Knox, J. J., Choueiri, T. K. AMER SOC CLINICAL ONCOLOGY. 2015
View details for DOI 10.1200/jco.2015.33.7_suppl.430

View details for Web of Science ID 000356886700427
Exploring the effect of medication features in renal cell carcinoma: A patient preference study Srinivas, S., Mansfield, C., Sandin, R., Hauber, A., Hariharan, S., Matczak, E., Pugh, A., Chen, C. AMER SOC CLINICAL ONCOLOGY. 2015
View details for DOI 10.1200/jco.2015.33.7_suppl.463

View details for Web of Science ID 000356886700460
New therapeutic options in metastatic castration-resistant prostate cancer: Can cost-effectiveness analysis help in treatment decisions? Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners Wilson, L., Tang, J., Zhong, L., Balani, G., Gipson, G., Xiang, P., Yu, D., Srinivas, S. 2014; 20 (6): 417-425
Abstract

To evaluate the cost-effectiveness of abiraterone, cabazitaxel, and enzalutamide compared to placebo for treatment of metastatic castration-resistant prostate cancer.A decision-tree model compared three treatment options for metastatic castration-resistant prostate cancer patients over 18 months from a societal perspective in 2012 USD. Chance nodes included baseline pain as a severity indicator, significant adverse effects (neutropenia, cardiac events, or seizures), and survival. Probabilities, survival rates, and health utilities were from clinical trials (COU-AA, TROPIC, and AFFIRM) and other published studies. Survival of enzalutamide was adjusted to match placebo groups across trials. Probabilistic sensitivity analyses, acceptability curves and net benefit calculations were performed.Abiraterone was the most cost-effective of the treatments ($123.4 K/quality-adjusted life year) compared to placebo, enzalutamide was $437.6 K/quality-adjusted life year compared to abiraterone, and cabazitaxel was $351.9 K/quality-adjusted life year compared to enzalutamide. Enzalutamide and cabazitaxel were not cost-effective compared to placebo at $154.3 K/quality-adjusted life year and $163.2 K/quality-adjusted life year, respectively. Acceptability curves showed abiraterone was cost-effective 29.3% of the time with a willingness to pay threshold of $100 K. The model was sensitive to changes in cost of the drugs, life expectancy, and survival rate. Sensitivity analysis shows that enzalutamide can become the most cost-effective option if the price of the medication decreased by 26% and other drug costs remained the same.Based on the cost-effective analysis, and survival adjustments necessary to match placebo groups, we would recommend abiraterone for treatment of metastatic castration-resistant prostate cancer despite not quite falling under the usually accepted willingness to pay threshold. Further analysis should examine comparative survival across the three drugs.

View details for DOI 10.1177/1078155213509505

View details for PubMedID 24243919
New therapeutic options in metastatic castration-resistant prostate cancer: Can cost-effectiveness analysis help in treatment decisions? JOURNAL OF ONCOLOGY PHARMACY PRACTICE Wilson, L., Tang, J., Zhong, L., Balani, G., Gipson, G., Xiang, P., Yu, D., Srinivas, S. 2014; 20 (6): 417-425
Abstract

To evaluate the cost-effectiveness of abiraterone, cabazitaxel, and enzalutamide compared to placebo for treatment of metastatic castration-resistant prostate cancer.A decision-tree model compared three treatment options for metastatic castration-resistant prostate cancer patients over 18 months from a societal perspective in 2012 USD. Chance nodes included baseline pain as a severity indicator, significant adverse effects (neutropenia, cardiac events, or seizures), and survival. Probabilities, survival rates, and health utilities were from clinical trials (COU-AA, TROPIC, and AFFIRM) and other published studies. Survival of enzalutamide was adjusted to match placebo groups across trials. Probabilistic sensitivity analyses, acceptability curves and net benefit calculations were performed.Abiraterone was the most cost-effective of the treatments ($123.4 K/quality-adjusted life year) compared to placebo, enzalutamide was $437.6 K/quality-adjusted life year compared to abiraterone, and cabazitaxel was $351.9 K/quality-adjusted life year compared to enzalutamide. Enzalutamide and cabazitaxel were not cost-effective compared to placebo at $154.3 K/quality-adjusted life year and $163.2 K/quality-adjusted life year, respectively. Acceptability curves showed abiraterone was cost-effective 29.3% of the time with a willingness to pay threshold of $100 K. The model was sensitive to changes in cost of the drugs, life expectancy, and survival rate. Sensitivity analysis shows that enzalutamide can become the most cost-effective option if the price of the medication decreased by 26% and other drug costs remained the same.Based on the cost-effective analysis, and survival adjustments necessary to match placebo groups, we would recommend abiraterone for treatment of metastatic castration-resistant prostate cancer despite not quite falling under the usually accepted willingness to pay threshold. Further analysis should examine comparative survival across the three drugs.

View details for DOI 10.1177/1078155213509505

View details for Web of Science ID 000344851800003
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
Abstract

Approval of the mTOR inhibitors for the treatment of mRCC was based on efficacy in poor-risk patients in the first-line setting for temsirolimus and in vascular endothelial growth factor inhibitor-refractory patients for everolimus. We strove to characterize temsirolimus and everolimus use and effectiveness in the first-line setting.We performed a retrospective database analysis of mRCC patients who received mTOR inhibitors as first-line targeted therapy. The Kaplan-Meier product-limit method was used to estimate the distribution of progression-free survival (PFS) and overall survival (OS).We identified 127 mRCC patients who had received a first-line mTOR inhibitor. Temsirolimus was administered in 93 patients (73%) and everolimus in 34 patients (27%). The main reasons for choice of temsirolimus were poor-risk disease (38%), non-clear cell histology (27%), and clinical trial availability (15%), whereas clinical trial (82%) and non-clear cell histology (6%) drove everolimus selection. Of the temsirolimus and everolimus patients, 58% and 32% were poor-risk according to the International mRCC Database Consortium criteria, respectively. The median PFS and OS were 3.4 and 12.5 months and 4.8 and 15.9 months with temsirolimus and everolimus, respectively. Although limited by small numbers, this study characterizes a real-world, international experience with the use of mTOR inhibition in treatment-naive mRCC patients.Poor-risk RCC, non-clear cell histology, and clinical trials were the predominant reasons for mTOR inhibitor selection in the front-line setting. Because of the different patient populations in which they were administered, direct comparisons of the front-line efficacy of temsirolimus and everolimus cannot be made.

View details for DOI 10.1016/j.clgc.2014.03.003

View details for Web of Science ID 000342152800017

View details for PubMedCentralID PMC4164603
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
Abstract

The benefit of cytoreductive nephrectomy (CN) for overall survival (OS) is unclear in patients with synchronous metastatic renal cell carcinoma (mRCC) in the era of targeted therapy.To determine OS benefit of CN compared with no CN in mRCC patients treated with targeted therapies.Retrospective data from patients with synchronous mRCC (n=1658) from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) were used to compare 982 mRCC patients who had a CN with 676 mRCC patients who did not.OS was compared and hazard ratios (HRs) adjusted for IMDC poor prognostic criteria.Patients who had CN had better IMDC prognostic profiles versus those without (favorable, intermediate, or poor in 9%, 63%, and 28% vs 1%, 45%, and 54%, respectively). The median OS of patients with CN versus without CN was 20.6 versus 9.5 mo (p<0.0001). When adjusted for IMDC criteria to correct for imbalances, the HR of death was 0.60 (95% confidence interval, 0.52-0.69; p<0.0001). Patients estimated to survive <12 mo may receive marginal benefit from CN. Patients who have four or more of the IMDC prognostic criteria did not benefit from CN. Data were collected retrospectively.CN is beneficial in synchronous mRCC patients treated with targeted therapy, even after adjusting for prognostic factors. Patients with estimated survival times <12 mo or four or more IMDC prognostic factors may not benefit from CN. This information may aid in patient selection as we await results from randomized controlled trials.We looked at the survival outcomes of metastatic renal cell carcinoma patients who did or did not have the primary tumor removed. We found that most patients benefited from tumor removal, except for those with four or more IMDC risk factors.

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

View details for PubMedCentralID PMC4142676
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
The impact of body mass index (BMI) on treatment outcome of targeted therapy in metastatic renal cell carcinoma (mRCC): Results from the International Metastatic Renal Cell Cancer Database Consortium Albiges, L., Xie, W., Lee, J., Rini, B. I., Srinivas, S., Bjarnason, G. A., Ernst, D., Wood, L., Vaishamayan, U. N., Rha, S., Agarwal, N., Yuasa, T., Pal, S., Koutsoukos, K., Fay, A., Preston, M. A., Cho, E., Heng, D., Choueiri, T. K., Int mRCC Database Consortium AMER SOC CLINICAL ONCOLOGY. 2014
View details for Web of Science ID 000358613203381
Timing of angiotensin system inhibitor use and overall survival in patients on tyrosine kinase inhibitors for renal cell carcinoma Lam, A. P., Allen, J., Srinivas, S. AMER SOC CLINICAL ONCOLOGY. 2014
View details for DOI 10.1200/jco.2014.32.15_suppl.e15587

View details for Web of Science ID 000358613200728
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
Combined NaF/FDG PET/CT evaluation of prostate cancer patients Iagaru, A., Mosci, C., Keu, K., Mittra, E., Hancock, S., Pachynski, R., Srinivas, S., Gambhir, S. SOC NUCLEAR MEDICINE INC. 2014
View details for Web of Science ID 000361438102320
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

View details for PubMedCentralID PMC3992507
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 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 Web of Science ID 000333984000027
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
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
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
Cytoreductive nephrectomy (CN) in patients with synchronous metastases from renal cell carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) Heng, D., Rini, B. I., Beuselinck, B., Lee, J., Knox, J. J., Bjarnason, G. A., Pal, S., Kollmannsberger, C. K., Yuasa, T., Srinivas, S., Donskov, F., Bamias, A., Wood, L., Ernst, D., Agarwal, N., Vaishampayan, U. N., Rha, S., Kim, J. J., Kanesvaran, R., Choueiri, T. K. AMER SOC CLINICAL ONCOLOGY. 2014
View details for DOI 10.1200/jco.2014.32.4_suppl.396

View details for Web of Science ID 000335318100396
Phase II trial of pazopanib and weekly paclitaxel in metastatic urothelial cancer (UC). Srinivas, S., Narayanan, S., Harshman, L., Lam, A. P., Vaishampayan, U. N., Haas, D., Poushnejad, S., Pachynski, R. AMER SOC CLINICAL ONCOLOGY. 2014
View details for DOI 10.1200/jco.2014.32.4_suppl.299

View details for Web of Science ID 000335318100300
Neutrophil to lymphocyte ratio (NLR) and its effect on the prognostic value of the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model for patients treated with targeted therapy (TT) Templeton, A. J., Heng, D., Choueiri, T. K., McDermott, D. F., Fay, A. P., Srinivas, S., Harshman, L., Beuselinck, B., Smoragiewicz, M., Kim, J. J., Knox, J. J. AMER SOC CLINICAL ONCOLOGY. 2014
View details for DOI 10.1200/jco.2014.32.4_suppl.470

View details for Web of Science ID 000335318100468
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
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 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
Therapeutic Options in Docetaxel-Refractory Metastatic Castration-Resistant Prostate Cancer: A Cost-Effectiveness Analysis PLOS ONE Zhong, L., Pon, V., Srinivas, S., Nguyen, N., Frear, M., Kwon, S., Gong, C., Malmstrom, R., Wilson, L. 2013; 8 (5)
Abstract

Docetaxel is an established first-line therapy to treat metastatic castration-resistant prostate cancer (mCRPC). Recently, abiraterone and cabazitaxel were approved for use after docetaxel failure, with improved survival. National Institute for Health and Clinical Excellence (NICE) preliminary recommendations were negative for both abiraterone (now positive in final recommendation) and cabazitaxel (negative in final recommendation).To evaluate the cost-effectiveness of abiraterone, cabazitaxel, mitoxantrone and prednisone for mCRPC treatment in US.A decision-tree model was constructed to compare the two mCRPC treatments versus two placebos over 18 months from a societal perspective. Chance nodes include baseline pain as a severity indicator, grade III/IV side-effects, and survival at 18 months. Probabilities, survival and health utilities were from published studies. Model cost inputs included drug treatment, side-effect management and prevention, radiation for pain, and death associated costs in 2010 US dollars.Abiraterone is a cost-effective choice at $94K/QALY (quality adjusted life years) compared to placebo in our base-case analysis. Cabazitaxel and abiraterone are the most effective, yet also most expensive agents. The incremental cost-effectiveness ratios (ICER) at base-case are $101K/QALY (extended dominated) for mitoxantrone vs. placebo, $91K/QALY for abiraterone vs. mitoxantrone, $956K/QALY for cabazitaxel vs. abiraterone. Abiraterone becomes less cost-effective as its AWP increases, or if the cost of mitoxantrone side-effect management decreases. Increases in the percentage of patients with baseline pain leads to an increased ICER for both mitoxantrone and abiraterone, but mitoxantrone does relatively better. Cabazitaxel remains not cost-effective.Our base case model suggests that abiraterone is a cost-effective option in docetaxel-refractory mCRPC patients. Newer treatments will also need a CEA assessment compared to abiraterone.

View details for DOI 10.1371/journal.pone.0064275

View details for Web of Science ID 000320362700127

View details for PubMedID 23717582

View details for PubMedCentralID PMC3661482
First-, second-, third-line therapy for metastatic renal cell carcinoma (mRCC): Benchmarks for trials design from the International mRCC Database Consortium (IMDC) Heng, D., Rini, B. I., Lee, J., Kroeger, N., Srinivas, S., Harshman, L., Knox, J. J., Bjarnason, G. A., MacKenzie, M. J., Wood, L., Vaishampayan, U. N., Agarwal, N., Pal, S., Tan, M., Rha, S., Yuasa, T., Donskov, F., Bamias, A., North, S. A., Choueiri, T. K. AMER SOC CLINICAL ONCOLOGY. 2013
View details for Web of Science ID 000335419601600
First-line mTOR inhibition in metastatic renal cell carcinoma (mRCC): An updated analysis from the International mRCC Database Consortium (IMDC). Harshman, L., Kroeger, N., Rha, S., Donskov, F., Wood, L., Tantravahi, S., Vaishampayan, U. N., Rini, B. I., Knox, J. J., North, S. A., MacKenzie, M. J., Yuasa, T., Srinivas, S., Pal, S., Heng, D., Choueiri, T. K. AMER SOC CLINICAL ONCOLOGY. 2013
View details for Web of Science ID 000335419604094
Outcome of metastatic sarcomatoid renal cell carcinoma (sRCC): Results from the International mRCC Database Consortium Chittoria, N., Zhu, H., Choueiri, T. K., Kroeger, N., Lee, J., Srinivas, S., Knox, J., Bjarnason, G. A., MacKenzie, M. J., Wood, L., Vaishamayan, U. N., Agarwal, N., Pal, S., Tan, M., Rha, S., Yuasa, T., Donskov, F., North, S. A., Rini, B. I., Heng, D. AMER SOC CLINICAL ONCOLOGY. 2013
View details for Web of Science ID 000335419601579
Treatment response and survival outcome of patients with late relapse (LR) from renal cell carcinoma (RCC) in the era of targeted therapy Kroeger, N., Lee, J., Bjarnason, G. A., Knox, J. J., MacKenzie, M. J., Vaishamayan, U. N., Wood, L., Srinivas, S., Rha, S., Pal, S., Yuasa, T., Donskov, F., Agarwal, N., Tan, M., Bamias, A., Kollmannsberger, C. K., North, S. A., Rini, B. I., Choueiri, T. K., Heng, D. AMER SOC CLINICAL ONCOLOGY. 2013
View details for Web of Science ID 000335419601592
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 PubMedID 21353796
TEMPORAL TRENDS IN UTILIZATION OF CYTOREDUCTIVE NEPHRECTOMY AND PATIENT SURVIVAL IN THE TARGETED THERAPY ERA Annual Meeting of the American-Urological-Association (AUA) Conti, S. L., Hagedorn, J., Chung, B. I., Srinivas, S., Leppert, J. ELSEVIER SCIENCE INC. 2013: E753–E753
View details for Web of Science ID 000320281602402
NANO-SCALE PROTEOMIC PROFILING TO DEFINE DIAGNOSTIC SIGNATURES AND BIOMARKERS OF THERAPEUTIC ACTIVITY IN RCC Leppert, J., Fan, A., Liliental, J., Xu, L., Thong, A., Yost, C., Yaghi, A., Metzner, T., Brooks, J., Harshman, L., Sabatti, C., Srinivas, S., Felsher, D. ELSEVIER SCIENCE INC. 2013: E246–E247
View details for DOI 10.1016/j.juro.2013.02.154

View details for Web of Science ID 000320281600603
Impact of bone and liver metastases (BM, LM) in patients with metastatic renal cell carcinoma (mRCC) treated with molecularly targeted agents (MTAs): Results from the International mRCC Database Consortium (IMDC) 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., Donskov, F., Tantravahi, S., Rini, B. I., Heng, D., Choueiri, T. K. AMER SOC CLINICAL ONCOLOGY. 2013
View details for DOI 10.1200/jco.2013.31.6_suppl.394

View details for Web of Science ID 000333679600391
First-line mTOR inhibition in metastatic renal cell carcinoma (mRCC): An analysis from the International mRCC Database Consortium Harshman, L., Wood, L., Srinivas, S., Heng, D., Choueiri, T. K. AMER SOC CLINICAL ONCOLOGY. 2013
View details for DOI 10.1200/jco.2013.31.6_suppl.430

View details for Web of Science ID 000333679600427
Nanoscale proteomic profiling to define diagnostic signatures and biomarkers of therapeutic activity in patients with RCC Fan, A. C., Leppert, J., Liliental, J. E., Xu, L., Thong, A. E., Yost, C., Yaghi, A., Brooks, J. D., Harshman, L., Sabatti, C., Srinivas, S., Felsher, D. W. AMER SOC CLINICAL ONCOLOGY. 2013
View details for DOI 10.1200/jco.2013.31.6_suppl.432

View details for Web of Science ID 000333679600429
Metastatic non-clear cell renal cell carcinoma (nccRCC) treated with targeted therapy agents: Applying the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic model to predict outcomes 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., Donskov, F., Agarwal, N., Kollmannsberger, C. K., Tan, M., North, S. A., Rini, B. I., Choueiri, T. K., Heng, D. AMER SOC CLINICAL ONCOLOGY. 2013
View details for DOI 10.1200/jco.2013.31.6_suppl.396

View details for Web of Science ID 000333679600393
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
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 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

View details for PubMedCentralID PMC3532390
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 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
Therapeutic options in metastatic castration-resistant prostate cancer (mCRPC): A cost-effectiveness analysis. 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Zhong, L., Srinivas, S., Pon, V., Nicole Nguyen, N., Frear, M., Kwan, S., Gong, C., Malmstrom, R., Loucks, A., Wilson, L. AMER SOC CLINICAL ONCOLOGY. 2012
View details for Web of Science ID 000318009802737
Randomized phase II trial of gemcitabine/cisplatin (GC) with or without cetuximab (CET) in patients (pts) with advanced urothelial carcinoma (UC). Grivas, P., Agarwal, N., Siefker-Radtke, A. O., Daignault, S., Puzanov, I., MacVicar, G. R., Levine, E., Srinivas, S., Twardowski, P., Eisenberger, M. A., Quinn, D. I., Vaishampayan, U. N., Yu, E. Y., Dawsey, S., Day, K. C., Day, M. L., Smith, D. C., Hussain, M. AMER SOC CLINICAL ONCOLOGY. 2012
View details for Web of Science ID 000318009803162
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
Correlation of germline MET mutation with response to the dual Met/VEGFR-2 inhibitor foretinib in patients with sporadic and hereditary papillary renal cell carcinoma: Results from a multicenter phase II study (MET111644). Srinivasan, R., Bottaro, D. P., Choueiri, T. K., Vaishampayan, U. N., Rosenberg, J. E., Logan, T., Harzstark, A., Rini, B. I., Srinivas, S., Adams, L. M., Laubscher, K., Ottesen, L., McDermott, D. F., Linehan, W. AMER SOC CLINICAL ONCOLOGY. 2012
View details for DOI 10.1200/jco.2012.30.5_suppl.372

View details for Web of Science ID 000208892400371
A phase II and biomarker study (MET111644) of the dual Met/VEGFR-2 inhibitor foretinib in patients with sporadic and hereditary papillary renal cell carcinoma: Final efficacy, safety, and PD results. Choueiri, T. K., Vaishampayan, U. N., Rosenberg, J. E., Logan, T., Harzstark, A., Rini, B. I., Srinivas, S., Adams, L. M., Sherman, L., Ottesen, L., McDermott, D. F., Bottaro, D. P., Linehan, W., Srinivasan, R. AMER SOC CLINICAL ONCOLOGY. 2012
View details for Web of Science ID 000208892400354
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

View details for PubMedCentralID PMC3166448
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 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
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
Formulating the Question and Objectives ONCOLOGY CLINICAL TRIALS Harshman, L. C., Srinivas, S., Symanowski, J., Vogelzang, N. J., Kelly, W. K., Halabi, S. 2010: 29–34
View details for Web of Science ID 000273577900005
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
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 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 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

View details for PubMedCentralID PMC3047404
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
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
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

View details for PubMedCentralID PMC2814022
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 PubMedID 19603304
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
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
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
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
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 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 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 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 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 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
Continuous daily administration of sunitinib malate (SU11248) - A phase II study in patients (PTS) with cytokine-refractory metastatic renal cell carcinoma (MRCC) Escudier, B., Roigas, J., Gillessen, S., Srinivas, S., Pisa, P., Vogelzang, N., Fountzilas, G., Peschel, C., Baum, C. M., De Mulder, P. OXFORD UNIV PRESS. 2006: 144
View details for Web of Science ID 000248078900448
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
Case 3. Photo therapy recall with gemcitabine following ultraviolet B treatment JOURNAL OF CLINICAL ONCOLOGY Badger, J., Uzieblo, A., Srinivas, S., Kang, S. W. 2005; 23 (28): 7224-7225
View details for DOI 10.1200/JCO.2005.09.092

View details for Web of Science ID 000232232000053
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 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

Professor of Medicine (Oncology) and, by courtesy, of Urology at the Stanford University Medical Center

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