Management of Poor-Risk Metastatic Renal Cell Carcinoma: Current Approaches, the Role of Temsirolimus and Future Directions

References

• Cohen HT , McGovernFJ. Renal-cell carcinoma. N. Engl. J. Med.353, 2477–2490 (2005).
   PubMed Web of Science ®Google Scholar
• Janzen NK , KimHL, FiglinRAet al. Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and management of recurrent disease. Urol. Clin. North Am.30, 843–852 (2003).
   PubMed Web of Science ®Google Scholar
• Heng DYC , XieW, ReganMMet al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J. Clin. Oncol.27, 5794–5799 (2009).
   PubMed Web of Science ®Google Scholar
• Motzer RJ , BacikJ, MurphyBAet al. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J. Clin. Oncol.20, 289–296 (2002).
   PubMed Web of Science ®Google Scholar
• Heng DY , XieW, ReganMMet al. External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol.14, 141–148 (2013).
   PubMed Web of Science ®Google Scholar
• Motzer RJ , BacikJ, SchwartzLHet al. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J. Clin. Oncol.22, 454–463 (2004).
   PubMed Web of Science ®Google Scholar
• de Reijke TM , BellmuntJ, van PoppelHet al. EORTC-GU group expert opinion on metastatic renal cell cancer. Eur. J. Cancer45, 765–773 (2009).
   PubMed Web of Science ®Google Scholar
• Escudier B , PortaC, SchmidingerMet al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol.25(Suppl. 3), iii49–iii56 (2014).
   PubMed Web of Science ®Google Scholar
• Ljungberg B , BensalahK, BexAet al. Guidelines on renal cell carcinoma. European Association of Urology (2015). http://uroweb.org/wp-content/uploads/10-Renal-Cell-Carcinoma_LR-LV2–2015.pdf.
   Google Scholar
• Ryan C , JonaschE, LaraPNJr. Evolving Standards of Care for Advanced Renal Cell Cancer. 2010 Educational Book. ASCO University (2010).
   Google Scholar
• Hudes G , CarducciM, TomczakPet al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N. Engl. J. Med.356, 2271–2281 (2007).
   PubMed Web of Science ®Google Scholar
• Motzer RJ , EscudierB, OudardSet al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled Phase III trial. Lancet372, 449–456 (2008).
   PubMed Web of Science ®Google Scholar
• Rini BI , EscudierB, TomczakPet al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised Phase 3 trial. Lancet378, 1931–1939 (2011).
   PubMed Web of Science ®Google Scholar
• Escudier B , EisenT, StadlerWMet al. Sorafenib in advanced clear-cell renal-cell carcinoma. N. Engl. J. Med.356, 125–134 (2007).
   PubMed Web of Science ®Google Scholar
• Escudier B , PluzanskaA, KoralewskiPet al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind Phase III trial. Lancet370, 2103–2111 (2007).
   PubMed Web of Science ®Google Scholar
• Motzer RJ , HutsonTE, TomczakPet al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N. Engl. J. Med.356, 115–124 (2007).
   PubMed Web of Science ®Google Scholar
• Sternberg CN , HawkinsRE, WagstaffJet al. A randomised, double-blind Phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur. J. Cancer49, 1287–1296 (2013).
   PubMed Web of Science ®Google Scholar
• Pfizer . Torisel® (temsirolimus) summary of product characteristics (2014). www.medicines.org.uk/EMC/medicine/21260/SPC/TORISEL+25+mg+ml+concentrate+and+diluent+for+solution+for+infusion/.
   Google Scholar
• Stenner-Liewen F , GrünwaldV, GreilR, PortaC. Expert Rev. Anticancer Ther.13, 1021–1033 (2013).
   PubMed Web of Science ®Google Scholar
• Choueiri TK , XieW, KollmannsbergerCet al. The impact of cytoreductive nephrectomy on survival of patients with metastatic renal cell carcinoma receiving vascular endothelial growth factor targeted therapy. J. Urol.185, 60–66 (2011).
   PubMed Web of Science ®Google Scholar
• National Comprehensive Cancer Network (NCCN) . National comprehensive cancer network clinical practice guidelines in oncology: kidney cancer. version 3.2015. NCCN Guidelines, Fort Washington, PA, USA.
   Google Scholar
• Powles T , StaehlerM, LjungbergBet al. Updated EAU guidelines for clear cell renal cancer patients who fail VEGF targeted therapy. Eur. Urol. doi: 10.1016/j.eururo.2015.10.017 (2015) ( Epub ahead of print).
   Google Scholar
• Fingar DC , RichardsonCJ, TeeARet al. mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E. Mol. Cell Biol.24, 200–216 (2004).
   PubMed Web of Science ®Google Scholar
• Hudson CC , LiuM, ChiangGGet al. Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol. Cell Biol.22, 7004–7014 (2002).
   PubMed Web of Science ®Google Scholar
• Schmelzle T , HallMN. TOR, a central controller of cell growth. Cell103, 253–262 (2000).
   PubMed Web of Science ®Google Scholar
• Pantuck AJ , SeligsonDB, KlatteTet al. Prognostic relevance of the mTOR pathway in renal cell carcinoma: implications for molecular patient selection for targeted therapy. Cancer109, 2257–2267 (2007).
   PubMed Web of Science ®Google Scholar
• Harding MW . Immunophilins, mTOR, and pharmacodynamic strategies for a targeted cancer therapy. Clin. Cancer Res.9, 2882–2886 (2003).
   PubMed Web of Science ®Google Scholar
• Hidalgo M , RowinskyEK. The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene19, 6680–6686 (2000).
   PubMed Web of Science ®Google Scholar
• Loewith R , JacintoE, WullschlegerSet al. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol. Cell10, 457–468 (2002).
   PubMed Web of Science ®Google Scholar
• Sarbassov DD , AliSM, SenguptaSet al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol. Cell22, 159–168 (2006).
   PubMed Web of Science ®Google Scholar
• Zeng Z , Sarbassov dosD, SamudioIJet al. Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood109, 3509–3512 (2007).
   PubMed Web of Science ®Google Scholar
• Atkins MB , HidalgoM, StadlerWMet al. Randomized Phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J. Clin. Oncol.22, 909–918 (2004).
   PubMed Web of Science ®Google Scholar
• Coppin C , PorzsoltF, AwaAet al. Immunotherapy for advanced renal cell cancer. Cochrane Database Syst. Rev. (1), CD001425 (2005).
   PubMed Web of Science ®Google Scholar
• Zbrozek AS , HudesG, LevyDet al. Q-TWiST analysis of patients receiving temsirolimus or interferon alpha for treatment of advanced renal cell carcinoma. Pharmacoeconomics28, 577–584 (2010).
   PubMed Web of Science ®Google Scholar
• Dutcher JP , de SouzaP, McDermottDet al. Effect of temsirolimus versus interferon-alpha on outcome of patients with advanced renal cell carcinoma of different tumor histologies. Med. Oncol.26, 202–209 (2009).
   PubMed Web of Science ®Google Scholar
• Bellmunt J , DutcherJ. Targeted therapies and the treatment of non-clear cell renal cell carcinoma. Ann. Oncol.24, 1730–1740 (2013).
   PubMed Web of Science ®Google Scholar
• Logan T , McDermottD, DutcherJet al. Exploratory analysis of the influence of nephrectomy status on temsirolimus efficacy in patients with advanced renal cell carcinoma and poor-risk features. Presented at: The 2009 Genitourinary Cancers Symposium. Orlando, FL, USA, 26–29 February 2009 ( Abstract 281).
   Google Scholar
• Mallick R , ChenJ. Predictors of survival in patients with advanced renal cell carcinoma who received first line treatment with temsirolimus, interferon-alpha or combination temsirolimus/interferon alpha. Ann. Oncol.19(Suppl. 8), Abstract 591P (2008).
   Google Scholar
• Hutson TE , EscudierB, EstebanEet al. Randomized Phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J. Clin. Oncol.32, 760–767 (2014).
   PubMed Web of Science ®Google Scholar
• Woike M , BergmannL, SteinerTet al. Evaluation of safety, tolerability and activity of temsirolimus in patients (pts) with advanced or metastatic renal cell carcinoma (a/mRCC) in routine clinical practice. Poster presented at: The 2014 European Society for Medical Oncology (ESMO) Congress. Madrid, Spain, 26–30 September 2014 ( Abstract 850P).
   Google Scholar
• Guida F , SantoniM, De GiorgiMet al. Poor risk metastatic Renal Cell Carcinoma (mRCC) patients are not a homogeneous group: a new stratificating model in the era of targeted therapy. Ann. Oncol.25(Suppl. 4), iv280–iv304 (2014).
   Google Scholar
• Bellmunt J , SzczylikC, FeingoldJet al. Temsirolimus safety profile and management of toxic effects in patients with advanced renal cell carcinoma and poor prognostic features. Ann. Oncol.19, 1387–1392 (2008).
   PubMed Web of Science ®Google Scholar
• Hutson TE , FiglinRA, KuhnJGet al. Targeted therapies for metastatic renal cell carcinoma: an overview of toxicity and dosing strategies. Oncologist13, 1084–1096 (2008).
   PubMed Web of Science ®Google Scholar
• Negrier S , GravisG, PerolDet al. Temsirolimus and bevacizumab, or sunitinib, or interferon alfa and bevacizumab for patients with advanced renal cell carcinoma (TORAVA): a randomised Phase 2 trial. Lancet Oncol.12, 673–680 (2011).
   PubMed Web of Science ®Google Scholar
• Hainsworth JD , SpigelDR, BurrisHAet al. Phase II trial of bevacizumab and everolimus in patients with advanced renal cell carcinoma. J. Clin. Oncol.28, 2131–2136 (2010).
   PubMed Web of Science ®Google Scholar
• Ravaud A , BarriosCH, AlekseevBet al. RECORD-2: Phase II randomized study of everolimus and bevacizumab versus interferon α-2a and bevacizumab as first-line therapy in patients with metastatic renal cell carcinoma. Ann. Oncol.26(7), 1378–1384 (2015).
   PubMed Web of Science ®Google Scholar
• Rini BI , BellmuntJ, ClancyJet al. Randomized Phase III trial of temsirolimus and bevacizumab versus interferon alfa and bevacizumab in metastatic renal cell carcinoma: INTORACT trial. J. Clin. Oncol.32, 752–759 (2014).
   PubMed Web of Science ®Google Scholar
• Flaherty KT , ManolaJB, PinsMet al. BEST: a randomized Phase II study of vascular endothelial growth factor, RAF kinase, and mammalian target of rapamycin combination targeted therapy with bevacizumab, sorafenib, and temsirolimus in advanced renal cell carcinoma-a trial of the ECOG-ACRIN Cancer Research Group (E2804). J. Clin. Oncol.33(21), 2384–2391 (2015).
   PubMed Web of Science ®Google Scholar
• Clinical Trials database: NCT00782275. https://clinicaltrials.gov/ct2/show/NCT00782275.
   Google Scholar
• Clinical Trials database: NCT01264341. https://clinicaltrials.gov/ct2/show/NCT01264341.
   Google Scholar
• Novartis . Novartis Europharm Limited. Afinitor® (everolimus) Summary of Product Characteristics (2014). www.medicines.org.uk/emc/medicine/22281/SPC/Afinitor+Tablets.
   Google Scholar
• Escudier BJ , Abadie-LacourtoisieS, BlancEet al. Efficacy of everolimus in poor risk patients: result of the POORTOR study. J. Clin. Oncol.33(Suppl. 7), Abstract 488 (2015).
   Web of Science ®Google Scholar
• Motzer RJ , HutsonTE, TomczakPet al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J. Clin. Oncol.27, 3584–3590 (2009).
   PubMed Web of Science ®Google Scholar
• Gore ME , SzczylikC, PortaCet al. Final results from the large sunitinib global expanded-access trial in metastatic renal cell carcinoma. Br. J. Cancer113(1), 12–19 (2015).
   PubMed Web of Science ®Google Scholar
• Heng DY , ElsonP, GolshayanARet al. A retrospective multicenter study of MSKCC poor-prognosis patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib. J. Clin. Oncol.26(15 Suppl.), Abstract 16057 (2008).
   Web of Science ®Google Scholar
• Bamias A , TzannisK, BeuselinckBet al. Development and validation of a prognostic model in patients with metastatic renal cell carcinoma treated with sunitinib: a European collaboration. Br. J. Cancer109, 332–341 (2013).
   PubMed Web of Science ®Google Scholar
• Michaelson MD , ZhuAX, RyanDPet al. Sunitinib in combination with gemcitabine for advanced solid tumours: a Phase I dose-finding study. Br. J. Cancer108, 1393–1401 (2013).
   PubMed Web of Science ®Google Scholar
• McKay RR , ChoueiriTK, WernerLet al. A Phase II trial of sunitinib and gemcitabine in sarcomatoid and/or poor-risk patients with metastatic renal cell carcinoma. J. Clin. Oncol.33(Suppl. 7), Abstract 408 (2015).
   Web of Science ®Google Scholar
• Motzer RJ , EscudierB, TomczakPet al. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised Phase 3 trial. Lancet Oncol.14, 552–562 (2013).
   PubMed Web of Science ®Google Scholar
• Escudier B , BellmuntJ, NegrierSet al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J. Clin. Oncol.28, 2144–2150 (2010).
   PubMed Web of Science ®Google Scholar
• Rini BI , HalabiS, RosenbergJEet al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J. Clin. Oncol.26, 5422–5428 (2008).
   PubMed Web of Science ®Google Scholar
• Rini BI , HalabiS, RosenbergJEet al. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206. J. Clin. Oncol.28, 2137–2143 (2010).
   PubMed Web of Science ®Google Scholar
• Motzer RJ , NosovD, EisenTet al. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a Phase III trial. J. Clin. Oncol.31, 3791–3799 (2013).
   PubMed Web of Science ®Google Scholar
• Choueiri TK , EscudierB, PowlesTet al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med.373(19), 1814–1823 (2015).
   PubMed Web of Science ®Google Scholar
• Clinical Trials databse: NCT01392183. http://clinicaltrials.gov/show/NCT01392183.
   Google Scholar
• Amin A , DudekA, LoganTet al. Prolonged survival with personalized immunotherapy (AGS-003) in combination with sunitinib in unfavorable risk metastatic RCC (mRCC). J. Clin. Oncol.31(Suppl. 6), Abstract 357 (2013).
   Web of Science ®Google Scholar
• Clinical Trials database: NCT01582672. http://clinicaltrials.gov/show/NCT01582672.
   Google Scholar
• Bailey A , McDermottDF. Immune checkpoint inhibitors as novel targets for renal cell carcinoma therapeutics. Cancer J.19, 348–352 (2013).
   PubMed Web of Science ®Google Scholar
• Escudier B , AlbigesL, SonpavdeG. Optimal management of metastatic renal cell carcinoma: current status. Drugs73, 427–438 (2013).
   PubMed Web of Science ®Google Scholar
• Motzer RJ , RiniBI, McDermotDFet al. Nivolumab for metastatic renal cell carcinoma (mRCC): Results of a randomized, dose-ranging Phase II trial. Presented at: The 50th Annual Meeting of the American Society of Clinical Oncology (ASCO). Chicago, IL, USA, 30 May–3 June 2014 ( Abstract 5009).
   Google Scholar
• Motzer RJ , RiniBI, McDermotDFet al. Nivolumab for metastatic renal cell carcinoma: results of a randomized Phase II trial. J. Clin. Oncol.33, 1430–1437 (2015).
   PubMed Web of Science ®Google Scholar
• Motzer RJ , EscudierB, McDermottDFet al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med.373(19), 1803–1813 (2015).
   PubMed Web of Science ®Google Scholar
• Motzer RJ , HutsonTE, CellaDet al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N. Engl. J. Med.369, 722–731 (2013).
   PubMed Web of Science ®Google Scholar
• Choueiri TK , FigueroaDJ, FayAPet al. Correlation of PD-L1 tumor expression and treatment outcomes in patients with renal cell carcinoma receiving sunitinib or pazopanib: results from COMPARZ, a randomized controlled trial. Clin. Cancer Res.21, 1071–1077 (2015).
   PubMed Web of Science ®Google Scholar
• Clinical Trials databse: NCT01521715. http://clinicaltrials.gov/show/NCT01521715.
   Google Scholar
• Sanchez A , DomínguezRG, De VelascoGet al. Pazopanib in metastatic renal carcinoma (mRC): Experience of 31 centers in Spain in first, second, third, or subsequent lines in daily clinical practice. J. Clin. Oncol.31(Suppl.), Abstract e15609 (2013).
   Google Scholar
• Figlin RA , KaufmannI, BrechbielJ. Targeting PI3K and mTORC2 in metastatic renal cell carcinoma: new strategies for overcoming resistance to VEGFR and mTORC1 inhibitors. Int. J. Cancer133, 788–796 (2013).
   PubMed Web of Science ®Google Scholar
• Bendell JC , RodonJ, BurrisHAet al. Phase I, dose-escalation study of BKM120, an oral panclass I PI3K inhibitor, in patients with advanced solid tumors. J. Clin. Oncol.30, 282–290 (2012).
   PubMed Web of Science ®Google Scholar
• Grana B , BurrisHA, Rodon AhnertJet al. Oral PI3 kinase inhibitor BKM120 monotherapy in patients (pts) with advanced solid tumors: an update on safety and efficacy. 2011 ASCO Annual Meeting. J. Clin. Oncol.29(Suppl.), Abstract 3043 (2011).
   Google Scholar
• Burris H , RodonJ, SharmaSet al. First-in-man Phase I study of the oral dual PI3K and mTORC1/2 inhibitor BEZ235 in patients with advanced solid tumors. J. Clin. Oncol.28, Abstract 3005 (2010).
   Google Scholar
• Powles T , OudardS, EscudierBJet al. A randomized Phase II study of GDC-0980 versus everolimus in metastatic renal cell carcinoma (mRCC) patients (pts) after VEGF-targeted therapy (VEGF-TT). J. Clin. Oncol.32, Abstract 4525 (2014).
   Google Scholar
• Powles T , WheaterM, DinOet al. A randomised Phase 2 study of AZD2014 versus everolimus in patients with VEGF-refractory metastatic clear cell renal cancer. Eur. Urol. doi: 10.1016/j.eururo.2015.08.035 (2015) ( Epub ahead of print).
   Google Scholar
• Flanigan RC , SalmonSE, BlumensteinBAet al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N. Engl. J. Med.345, 1655–1659 (2001).
   PubMed Web of Science ®Google Scholar
• Mickisch GH , GarinA, van PoppelHet al. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet358, 966–970 (2001).
   PubMed Web of Science ®Google Scholar
• Warren M , VennerPM, NorthSet al. A population-based study examining the effect of tyrosine kinase inhibitors on survival in metastatic renal cell carcinoma in Alberta and the role of nephrectomy prior to treatment. Can. Urol. Assoc. J.3, 281–289 (2009).
   PubMed Web of Science ®Google Scholar
• Kutikov A , UzzoRG, CarawayAet al. Use of systemic therapy and factors affecting survival for patients undergoing cytoreductive nephrectomy. BJU. Int.106, 218–223 (2010).
   PubMed Web of Science ®Google Scholar
• Jonasch E , WoodCG, MatinSFet al. Phase II presurgical feasibility study of bevacizumab in untreated patients with metastatic renal cell carcinoma. J. Clin. Oncol.27, 4076–4081 (2009).
   PubMed Web of Science ®Google Scholar
• Abel EJ , CulpSH, TannirNMet al. Primary tumor response to targeted agents in patients with metastatic renal cell carcinoma. Eur. Urol.59, 10–15 (2011).
   PubMed Web of Science ®Google Scholar
• Clinical Trials database: NCT00930033. http://clinicaltrials.gov/show/NCT00930033.
   Google Scholar
• Clinical Trials database: NCT01099423. http://clinicaltrials.gov/show/NCT01099423.
   Google Scholar
• Cho D , SignorettiS, DaboraSet al. Potential histologic and molecular predictors of response to temsirolimus in patients with advanced renal cell carcinoma. Clin. Genitourin. Cancer5, 379–385 (2007).
   PubMed Web of Science ®Google Scholar
• Fay AP , KwiatkowskiDJ, GrayKPet al. Activating genomic mutations in the mTOR pathway to predict responses to everolimus and temsirolimus in patients with metastatic renal cell carcinoma (mRCC): results from a large multi-institutional cohort. J. Clin. Oncol.33(Suppl.), Abstract 4519 (2015).
   Google Scholar
• Figlin RA , de SouzaP, McDermottDet al. Analysis of PTEN and HIF-1alpha and correlation with efficacy in patients with advanced renal cell carcinoma treated with temsirolimus versus interferon-alpha. Cancer115, 3651–3660 (2009).
   PubMed Web of Science ®Google Scholar
• Di Napoli A , SignorettiS. Tissue biomarkers in renal cell carcinoma: issues and solutions. Cancer115(10 Suppl.), 2290–2297 (2009).
   PubMed Web of Science ®Google Scholar
• Armstrong AJ , GeorgeDJ, HalabiS. Serum lactate dehydrogenase predicts for overall survival benefit in patients with metastatic renal cell carcinoma treated with inhibition of mammalian target of rapamycin. J. Clin. Oncol.30, 3402–3407 (2012).
   PubMed Web of Science ®Google Scholar
• Nallari A , KarrisonT, RosnerGLet al. Fasting glucose and triglycerides as biomarkers of mTOR inhibition, evidence of a categorical response. J. Clin. Oncol.28(Suppl. 15s), Abstract 3091 (2010).
   Google Scholar
• Lee CK , MarschnerIC, SimesRJet al. Increase in cholesterol predicts survival advantage in renal cell carcinoma patients treated with temsirolimus. Clin. Cancer. Res.18, 3188–3196 (2012).
   PubMed Web of Science ®Google Scholar
• Dienstmann R , BranaI, RodonJet al. Toxicity as a biomarker of efficacy of molecular targeted therapies: focus on EGFR and VEGF inhibiting anticancer drugs. Oncologist16, 1729–1740 (2011).
   PubMed Web of Science ®Google Scholar
• White DA , CamusP, EndoMet al. Noninfectious pneumonitis after everolimus therapy for advanced renal cell carcinoma. Am. J. Respir. Crit. Care Med.182, 396–403 (2010).
   PubMed Web of Science ®Google Scholar
• Maroto JP , HudesG, DutcherJPet al. Drug-related pneumonitis in patients with advanced renal cell carcinoma treated with temsirolimus. J. Clin. Oncol.29, 1750–1756 (2011).
   PubMed Web of Science ®Google Scholar
• Dabydeen DA , JagannathanJP, RamaiyaNet al. Pneumonitis associated with mTOR inhibitors therapy in patients with metastatic renal cell carcinoma: incidence, radiographic findings and correlation with clinical outcome. Eur. J. Cancer48, 1519–1524 (2012).
   PubMed Web of Science ®Google Scholar