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Anti-angiogenics in Kidney Cancer Therapy

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Tumor Angiogenesis

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Abstract

Metastatic renal cell carcinoma (RCC) remains largely incurable. Up to 30% of patients show metastasis at the time of the initial diagnosis. Prognostic criteria developed by the IMDC (International Metastatic Renal Cell Carcinoma Database Consortium) and MSKCC (Memorial Sloan Kettering Cancer Center) are used to classify patients based on certain pretreatment factors. The prognosis of patients with metastatic disease varies depending on these risk factors. Anti-angiogenic agents targeting the vascular endothelial growth factor (VEGF) and its receptors are standard treatments based on improved clinical outcomes in randomized phase III trials. Standard of care therapies now include multitargeted tyrosine kinase inhibitors (TKIs) such as sunitinib, axitinib, pazopanib, and cabozantinib, as well as the mTOR inhibitors temsirolimus and everolimus.

Tumor-associated PD-L1 expression has been detected in RCC and is associated with a worse prognosis. Immune checkpoint inhibitors such as the PD-1 inhibitor nivolumab have shown promising results in treatment of the metastatic disease. Future developments including novel combinations and attempts to find the optimal position of immunotherapy in the disease pathway are subject of ongoing clinical trials.

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References

  • Adams RH, Alitalo K (2007) Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol 8:464–478

    Article  CAS  PubMed  Google Scholar 

  • Atsushi T, Sasald I, Sun JK, Ken-ichi T, Tadao K, Yoshiaki K et al (1994) Markedly increased amounts of messenger RNAs for vascular endothelial growth factor and placenta growth factor in renal cell carcinoma associated with angiogenesis. Cancer Res 54:4233–4237

    Google Scholar 

  • Bard RH, Mydlo JH, Freed SZ (1986) Detection of tumor angiogenesis factor in adenocarcinoma of kidney. Urology 27:447–450

    Article  CAS  PubMed  Google Scholar 

  • Bergström A, Hsieh CC, Lindblad P, Lu CM, Cook NR, Wolk A (2001) Obesity and renal cell cancer – a quantitative review. Br J Cancer 85(7):984–990

    Article  PubMed  PubMed Central  Google Scholar 

  • Bianconi M, Scartozzi M, Faloppi L et al (2012) Angiogenetic pathway as a therapeutic target in renal cell carcinoma. Anal Quant Cytol Histol 34(1):15–22

    PubMed  Google Scholar 

  • Calvo E, Escudier B, Motzer RJ, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Ravaud A, Kim D, Panneerselvam A, Anak O, Figlin RA (2012) Everolimus in metastatic renal cell carcinoma: subgroup analysis of patients with 1 or 2 previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapies enrolled in the phase III RECORD-1 study. Eur J Cancer 48(3):333–339

    Article  CAS  PubMed  Google Scholar 

  • Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, Hammers H, Hutson TE, Lee JL, Peltola K, Roth BJ, Bjarnason GA, Géczi L, Keam B, Maroto P, Heng DY, Schmidinger M, Kantoff PW, Borgman-Hagey A, Hessel C, Scheffold C, Schwab GM, Tannir NM, Motzer RJ, METEOR Investigators (2015) Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med 373(19):1814–1823

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Choueiri TK, Halabi S, Sanford BL, Hahn O, Michaelson MD, Walsh MK, Feldman DR, Olencki T, Picus J, Small EJ, Dakhil S, George DJ, Morris MJ (2017) Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the alliance A031203 CABOSUN trial. J Clin Oncol 35(6):591–597

    Article  CAS  PubMed  Google Scholar 

  • Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM, TARGET Study Group (2007a) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356(2):125–134

    Article  CAS  PubMed  Google Scholar 

  • Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N, AVOREN Trial Investigators (2007b) Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 370(9605):2103–2111

    Article  PubMed  Google Scholar 

  • Escudier B, Porta C, Schmidinger M, Rioux-Leclercq N, Bex A, Khoo V, Gruenvald V, Horwich A (2017) Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 28(suppl_4):iv167–iv168

    Google Scholar 

  • Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H, Forman D, Bray F (2013) Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer 49(6):1374–1403

    Article  CAS  PubMed  Google Scholar 

  • Fischer A, Wu S, Ho AL, Lacouture ME (2013) The risk of hand-foot skin reaction to axitinib, a novel VEGF inhibitor: a systematic review of literature and meta-analysis. Investig New Drugs 31:787–797

    Article  CAS  Google Scholar 

  • Greenblatt M, Shubik P (1968) Tumor angiogenesis: trans filter diffusion studies by the transparent chamber technique. J Natl Cancer Inst 41:111–124

    CAS  PubMed  Google Scholar 

  • Haas NB, Lin X, Manola J, Pins M, Liu G, McDermott D, Nanus D, Heath E, Wilding G, Dutcher J (2012) A phase II trial of doxorubicin and gemcitabine in renal cell carcinoma with sarcomatoid features: ECOG 8802. Med Oncol 29(2):761–767

    Article  CAS  PubMed  Google Scholar 

  • Hanahan D, Christofori G, Naik P, Arbeit J (1996) Transgenic mouse models of tumour angiogenesis: the angiogenic switch, its molecular controls, and prospects for preclinical therapeutic models. Eur J Cancer 32A:2386–2393

    Article  CAS  PubMed  Google Scholar 

  • Hutson TE, Lesovoy V, Al-Shukri S, Stus VP, Lipatov ON, Bair AH, Rosbrook B, Chen C, Kim S, Vogelzang NJ (2013) Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial. Lancet Oncol 14(13):1287–1294

    Article  CAS  PubMed  Google Scholar 

  • Hutson TE, Escudier B, Esteban E, Bjarnason GA, Lim HY, Pittman KB, Senico P, Niethammer A, Lu DR, Hariharan S, Motzer RJ (2014) 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(8):760–767

    Article  CAS  PubMed  Google Scholar 

  • Itsumi M, Tatsugami K (2010) Immunotherapy for renal cell carcinoma. Clin Dev Immunol 2010:284581

    Article  PubMed  CAS  Google Scholar 

  • Janusch M, Fischer M, Marsch WC, Holzhausen HJ, Kegel T, Helmbold P (2006) The hand-foot syndrome – a frequent secondary manifestation in antineoplastic chemotherapy. Eur J Dermatol 16:494–499

    CAS  PubMed  Google Scholar 

  • Kamba T, McDonald DM (2007) Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J Cancer 96:1788–1795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim WY, Kaelin WG (2004) Role of VHL gene mutation in human cancer. J Clin Oncol 22:4991–5004

    Article  CAS  PubMed  Google Scholar 

  • Lacouture ME, Wu S, Robert C, Atkins MB, Kong HH, Guitart J, Garbe C, Hauschild A, Puzanov I, Alexandrescu DT, Anderson RT, Wood L, Dutcher JP (2008) Evolving strategies for the management of hand-foot skin reaction associated with the multitargeted kinase inhibitors sorafenib and sunitinib. Oncologist 13:1001–1011

    Article  CAS  PubMed  Google Scholar 

  • Lipworth AD, Robert C, Zhu AX (2009) Hand-foot syndrome (hand-foot skin reaction, palmar-plantar erythrodysesthesia): focus on sorafenib and sunitinib. Oncology 77:257–271

    Article  CAS  PubMed  Google Scholar 

  • Maglione D, Guerriero V, Viglieno O, Ferraro MG, Aprelikova O, Alitalo IL et al (1993) Two alternative mRNAs coding for the angiogenic factor, placenta growth factor (PIGF), are transcribed from a single gene of chromosome 14. Oncogene 8:925–931

    CAS  PubMed  Google Scholar 

  • McDermott DF, Regan MM, Clark JI, Flaherty LE, Weiss GR, Logan TF, Kirkwood JM, Gordon MS, Sosman JA, Ernstoff MS, Tretter CP, Urba WJ, Smith JW, Margolin KA, Mier JW, Gollob JA, Dutcher JP, Atkins MB (2005) Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol 23(1):133–141

    Article  CAS  PubMed  Google Scholar 

  • Moch H, Cubilla AL, Humphrey PA, Reuter VE, Ulbright TM (2016) The 2016 WHO classification of tumours of the urinary system and male genital organs-part a: renal, penile, and testicular tumours. Eur Urol 70(1):93–105

    Article  PubMed  Google Scholar 

  • Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M (2002) Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol 20(1):289–296

    Article  CAS  PubMed  Google Scholar 

  • Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA, Ginsberg MS, Kim ST, Baum CM, DePrimo SE, Li JZ, Bello CL, Theuer CP, George DJ, Rini BI (2006) Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 24(1):16–24

    Article  CAS  PubMed  Google Scholar 

  • Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, Garcia-del-Muro X, Sosman JA, Solska E, Wilding G, Thompson JA, Kim ST, Chen I, Huang X, Figlin RA (2009) Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 27(22):3584–3590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N, Kay A, Ravaud A, RECORD-1 Study Group (2010) Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer 116(18):4256–4265

    Article  CAS  PubMed  Google Scholar 

  • Motzer RJ, Hutson TE, Olsen MR, Hudes GR, Burke JM, Edenfield WJ, Wilding G, Agarwal N, Thompson JA, Cella D, Bello A, Korytowsky B, Yuan J, Valota O, Martell B, Hariharan S, Figlin RA (2012) Randomized phase II trial of sunitinib on an intermittent versus continuous dosing schedule as first-line therapy for advanced renal cell carcinoma. J Clin Oncol 30(12):1371–1377

    Article  CAS  PubMed  Google Scholar 

  • Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, Nathan P, Staehler M, de Souza P, Merchan JR, Boleti E, Fife K, ** J, Jones R, Uemura H, De Giorgi U, Harmenberg U, Wang J, Sternberg CN, Deen K, McCann L, Hackshaw MD, Crescenzo R, Pandite LN, Choueiri TK (2013a) Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 369(8):722–731

    Article  CAS  PubMed  Google Scholar 

  • Motzer RJ, Nosov D, Eisen T, Bondarenko I, Lesovoy V, Lipatov O, Tomczak P, Lyulko O, Alyasova A, Harza M, Kogan M, Alekseev BY, Sternberg CN, Szczylik C, Cella D, Ivanescu C, Krivoshik A, Strahs A, Esteves B, Berkenblit A, Hutson TE (2013b) Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. J Clin Oncol 31(30):3791–3799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Choueiri TK, Gurney H, Donskov F, Bono P, Wagstaff J, Gauler TC, Ueda T, Tomita Y, Schutz FA, Kollmannsberger C, Larkin J, Ravaud A, Simon JS, Xu LA, Waxman IM, Sharma P, CheckMate 025 Investigators (2015) Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 373(19):1803–1813

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Negrier S, Perol D, Ravaud A, Chevreau C, Bay JO, Delva R, Sevin E, Caty A, Escudier B, French Immunotherapy Intergroup (2007) Medroxyprogesterone, interferon alfa-2a, interleukin 2, or combination of both cytokines in patients with metastatic renal carcinoma of intermediate prognosis: results of a randomized controlled trial. Cancer 110(11):2468–2477

    Article  CAS  PubMed  Google Scholar 

  • Pages G, Puyssegur J (2005) Transcriptional regulation of the vascular endothelial growth factor gene – a concert of activating factors. Cardiovasc Res 65:564–573

    Article  CAS  PubMed  Google Scholar 

  • Porta C, Paglino C, Imarisio I, Bonomi L (2007) Uncovering Pandora’s vase: the growing problem of new toxicities from novel anticancer agents. The case of sorafenib and sunitinib. Clin Exp Med 7:127–134

    Article  CAS  PubMed  Google Scholar 

  • Prasad V, Massey PR, Fojo T (2014) Oral anticancer drugs: how limited dosing options and dose reductions may affect outcomes in comparative trials and efficacy in patients. J Clin Oncol 32(15):1620–1629

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ribas A (2012) Tumor immunotherapy directed at PD-1. N Engl J Med 366(26):2517–2519

    Article  CAS  PubMed  Google Scholar 

  • Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ (2010) 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(13):2137–2143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, Michaelson MD, Gorbunova VA, Gore ME, Rusakov IG, Negrier S, Ou YC, Castellano D, Lim HY, Uemura H, Tarazi J, Cella D, Chen C, Rosbrook B, Kim S, Motzer RJ (2011) Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 378(9807):1931–1939

    Article  CAS  PubMed  Google Scholar 

  • Scartozzi M, Faloppi L, Svegliati Baroni G, Loretelli C, Piscaglia F, Iavarone M, Toniutto P, Fava G, De Minicis S, Mandolesi A, Bianconi M, Giampieri R, Granito A, Facchetti F, Bitetto D, Marinelli S, Venerandi L, Vavassori S, Gemini S, D'Errico A, Colombo M, Bolondi L, Bearzi I, Benedetti A, Cascinu F (2014) VEGF and VEGFR genoty** in the prediction of clinical outcome for hcc patients receiving sorafenib: the alice-1 study. Int J Cancer 135(5):1247–1256

    Article  CAS  PubMed  Google Scholar 

  • Stadler WM, Huo D, George C, Yang X, Ryan CW, Karrison T, Zimmerman TM, Vogelzang NJ (2003) Prognostic factors for survival with gemcitabine plus 5-fluorouracil based regimens for metastatic renal cancer. J Urol 170(4 Pt 1):1141–1145

    Article  CAS  PubMed  Google Scholar 

  • Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman P, Gladkov OA, Kavina A, Zarbá JJ, Chen M, McCann L, Pandite L, Roychowdhury DF, Hawkins RE (2010) Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 28(6):1061–1068

    Article  CAS  PubMed  Google Scholar 

  • Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205–216

    Article  CAS  PubMed  Google Scholar 

  • Tsui KH, Shvarts O, Smith RB, Figlin R, de Kernion JB, Belldegrun A (2000) Renal cell carcinoma: prognostic significance of incidentally detected tumors. J Urol 163(2):426–430

    Article  CAS  PubMed  Google Scholar 

  • Yang JC, Sherry RM, Steinberg SM, Topalian SL, Schwartzentruber DJ, Hwu P, Seipp CA, Rogers-Freezer L, Morton KE, White DE, Liewehr DJ, Merino MJ, Rosenberg SA (2003) Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol 21(16):3127–3132

    Article  CAS  PubMed  Google Scholar 

  • Yang CH, Lin WC, Chuang CK, Chang YC, Pang ST, Lin YC, Kuo TT, Hsieh JJ, Chang JW (2008) Hand-foot skin reaction in patients treated with sorafenib: a clinicopathological study of cutaneous manifestations due to multitargeted kinase inhibitor therapy. Br J Dermatol 158:592–596

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Urology, University Hospital Essen, Essen, Germany

    Herbert Rübben & Andrej Panic

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  1. Herbert Rübben
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  2. Andrej Panic
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Correspondence to Herbert Rübben .

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  1. Tumor Biology Center, Freiburg, Baden-Württemberg, Germany

    Dieter Marmé

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Rübben, H., Panic, A. (2019). Anti-angiogenics in Kidney Cancer Therapy. In: Marmé, D. (eds) Tumor Angiogenesis. Springer, Cham. https://doi.org/10.1007/978-3-319-31215-6_27-1

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  • DOI: https://doi.org/10.1007/978-3-319-31215-6_27-1

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