Advertisement

Drugs

, Volume 79, Issue 1, pp 63–74 | Cite as

Targeting Angiogenesis in Colorectal Carcinoma

  • Anthony Lopez
  • Kazuto Harada
  • Maria Vasilakopoulou
  • Namita Shanbhag
  • Jaffer A. AjaniEmail author
Review Article
  • 91 Downloads

Abstract

Neo-angiogenesis plays a key role in colorectal cancer, with the vascular endothelial growth factor family proteins and their receptors in particular triggering multiple signaling networks that result in endothelial cell survival, migration, mitogenesis, differentiation, and vascular permeability. Anti-angiogenic therapies have improved colorectal cancer prognosis within the past 15 years. Bevacizumab demonstrated efficacy in combination with chemotherapy under different conditions, including as first- and second-line therapies, and also as a maintenance treatment strategy. Other drugs targeting angiogenesis effectors (e.g., ramucirumab and aflibercept) were approved after bevacizumab failure, confirming the concept of “continuous anti-angiogenic blocking”. Recently, a number of new orally available multiple receptor tyrosine kinase inhibitors have been tested in late-stage clinical trials, with modest efficacy. Due to the availability of several anti-angiogenic agents, we need well-designed prospective randomized trials to optimize therapeutic sequencing. The place of biosimilars in the therapeutic armamentarium remains unclear at the moment. Further research is warranted to identify robust predictive biomarkers of efficacy and innovative clinically meaningful anti-angiogenic drugs that are cost-efficient.

Notes

Compliance with Ethical Standards

Funding

No external funding was used in the preparation of this manuscript.

Conflict of interest

Anthony Lopez has received research funding from Roche, has served as consultant for Amgen, received lecture fees from Vifor Pharma, and received travel accommodation expenses (not for this work) from Abbvie, Amgen, MSD, Vifor-Pharma. Jaffer A. Ajani has received honoraria from Lilly, Bayer, Novartis, Five Prime Therapeutics, Taiho Pharmaceutical, Genentech, and Roche, received research funding from Novartis, Bristol-Myers Squibb, Taiho Pharmaceutical, Roche/Genentech, MedImmune, Amgen, Lilly/ImClone, Merck, Delta-Fly Pharma, Gilead Sciences, and Takeda, and received travel accommodation expenses (not for this work) from Novartis, Bayer, and Five Prime Therapeutics. Kazuto Harada, Maria Vasilakopoulou, and Namita Shanbhag declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.

References

  1. 1.
    Siegel RL, Fedewa SA, Anderson WF, Miller KD, Ma J, Rosenberg PS, et al. Colorectal Cancer Incidence Patterns in the United States, 1974–2013. Journal of the National Cancer Institute. 2017;109(8) (Epub 2017/04/05).Google Scholar
  2. 2.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30.CrossRefGoogle Scholar
  3. 3.
    Kerr J, Anderson C, Lippman SM. Physical activity, sedentary behaviour, diet, and cancer: an update and emerging new evidence. Lancet Oncol. 2017;18(8):e457–71 (Epub 2017/08/02).CrossRefGoogle Scholar
  4. 4.
    Brenner H, Kloor M, Pox CP. Colorectal cancer. Lancet. 2014;383(9927):1490–502 (Epub 2013/11/15).CrossRefGoogle Scholar
  5. 5.
    Guinney J, Dienstmann R, Wang X, de Reynies A, Schlicker A, Soneson C, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21(11):1350–6 (Epub 2015/10/13).CrossRefGoogle Scholar
  6. 6.
    Liu Y, Sethi NS, Hinoue T, Schneider BG, Cherniack AD, Sanchez-Vega F, et al. Comparative molecular analysis of gastrointestinal adenocarcinomas. Cancer Cell. 2018;33(4):721–735 e8 (Epub 2018/04/07).CrossRefGoogle Scholar
  7. 7.
    Zubeldia IG, Bleau AM, Redrado M, Serrano D, Agliano A, Gil-Puig C, et al. Epithelial to mesenchymal transition and cancer stem cell phenotypes leading to liver metastasis are abrogated by the novel TGFbeta1-targeting peptides P17 and P144. Exp Cell Res. 2013;319(3):12–22 (Epub 2012/11/17).CrossRefGoogle Scholar
  8. 8.
    Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285(21):1182–6 (Epub 1971/11/18).CrossRefGoogle Scholar
  9. 9.
    Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335–42 (Epub 2004/06/04).CrossRefGoogle Scholar
  10. 10.
    Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev. 1997;18(1):4–25 (Epub 1997/02/01).CrossRefGoogle Scholar
  11. 11.
    Prat A, Casado E, Cortes J. New approaches in angiogenic targeting for colorectal cancer. World J Gastroenterol. 2007;13(44):5857–66 (Epub 2007/11/09).CrossRefGoogle Scholar
  12. 12.
    Divella R, Daniele A, De Luca R, Simone M, Naglieri E, Savino E, et al. Circulating levels of VEGF and CXCL1 are predictive of metastatic organotropismin in patients with colorectal cancer. Anticancer Res. 2017;37(9):4867–71 (Epub 2017/09/06).PubMedGoogle Scholar
  13. 13.
    Liu Z, Zhang Y, Niu Y, Li K, Liu X, Chen H, et al. A systematic review and meta-analysis of diagnostic and prognostic serum biomarkers of colorectal cancer. PLoS One. 2014;9(8):e103910 (Epub 2014/08/12).CrossRefGoogle Scholar
  14. 14.
    Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov. 2004;3(5):391–400 (Epub 2004/05/12).CrossRefGoogle Scholar
  15. 15.
    Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26(12):2013–9 (Epub 2008/04/19).CrossRefGoogle Scholar
  16. 16.
    Passardi A, Nanni O, Tassinari D, Turci D, Cavanna L, Fontana A, et al. Effectiveness of bevacizumab added to standard chemotherapy in metastatic colorectal cancer: final results for first-line treatment from the ITACa randomized clinical trial. Ann Oncol. 2015;26(6):1201–7 (Epub 2015/03/05).CrossRefGoogle Scholar
  17. 17.
    Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016;27(8):1386–422 (Epub 2016/07/07).CrossRefGoogle Scholar
  18. 18.
    Jang HJ, Kim BJ, Kim JH, Kim HS. The addition of bevacizumab in the first-line treatment for metastatic colorectal cancer: an updated meta-analysis of randomized trials. Oncotarget. 2017;8(42):73009–16 (Epub 2017/10/27).CrossRefGoogle Scholar
  19. 19.
    Loupakis F, Cremolini C, Masi G, Lonardi S, Zagonel V, Salvatore L, et al. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med. 2014;371(17):1609–18 (Epub 2014/10/23).CrossRefGoogle Scholar
  20. 20.
    Gruenberger T, Bridgewater J, Chau I, Garcia Alfonso P, Rivoire M, Mudan S, et al. Bevacizumab plus mFOLFOX-6 or FOLFOXIRI in patients with initially unresectable liver metastases from colorectal cancer: the OLIVIA multinational randomised phase II trial. Ann Oncol. 2015;26(4):702–8 (Epub 2014/12/30).CrossRefGoogle Scholar
  21. 21.
    Tomasello G, Petrelli F, Ghidini M, Russo A, Passalacqua R, Barni S. FOLFOXIRI plus bevacizumab as conversion therapy for patients with initially unresectable metastatic colorectal cancer: a systematic review and pooled analysis. JAMA Oncol. 2017;3(7):e170278 (Epub 2017/05/26).CrossRefGoogle Scholar
  22. 22.
    Cunningham D, Lang I, Marcuello E, Lorusso V, Ocvirk J, Shin DB, et al. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial. Lancet Oncol. 2013;14(11):1077–85 (Epub 2013/09/14).CrossRefGoogle Scholar
  23. 23.
    Aparicio T, Bouche O, Taieb J, Maillard E, Kirscher S, Etienne PL, et al. Bevacizumab + chemotherapy versus chemotherapy alone in elderly patients with untreated metastatic colorectal cancer: a randomized phase II trial-PRODIGE 20 study results. Ann Oncol. 2018;29:133–8 (Epub 2018/05/03).CrossRefGoogle Scholar
  24. 24.
    de Gramont A, Van Cutsem E, Schmoll HJ, Tabernero J, Clarke S, Moore MJ, et al. Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial. Lancet Oncol. 2012;13(12):1225–33 (Epub 2012/11/22).CrossRefGoogle Scholar
  25. 25.
    Allegra CJ, Yothers G, O’Connell MJ, Sharif S, Petrelli NJ, Colangelo LH, et al. Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08. J Clin Oncol. 2011;29(1):11–6 (Epub 2010/10/14).CrossRefGoogle Scholar
  26. 26.
    Simkens LH, van Tinteren H, May A, ten Tije AJ, Creemers GJ, Loosveld OJ, et al. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet. 2015;385(9980):1843–52 (Epub 2015/04/12).CrossRefGoogle Scholar
  27. 27.
    Hegewisch-Becker S, Graeven U, Lerchenmuller CA, Killing B, Depenbusch R, Steffens CC, et al. Maintenance strategies after first-line oxaliplatin plus fluoropyrimidine plus bevacizumab for patients with metastatic colorectal cancer (AIO 0207): a randomised, non-inferiority, open-label, phase 3 trial. Lancet Oncol. 2015;16(13):1355–69 (Epub 2015/09/13).CrossRefGoogle Scholar
  28. 28.
    Goey KKH, Elias SG, van Tinteren H, Lacle MM, Willems SM, Offerhaus GJA, et al. Maintenance treatment with capecitabine and bevacizumab versus observation in metastatic colorectal cancer: updated results and molecular subgroup analyses of the phase 3 CAIRO3 study. Ann Oncol. 2017;28(9):2128–34 (Epub 2017/09/16).CrossRefGoogle Scholar
  29. 29.
    Goey KKH, Elias SG, Hinke A, Oijen MGH, Punt CJA, Hegewisch-Becker S, et al. Clinicopathological factors influencing outcome in metastatic colorectal cancer patients treated with fluoropyrimidine and bevacizumab maintenance treatment vs. observation: an individual patient data meta-analysis of two phase 3 trials. Br J Cancer. 2017;117(12):1768–76 (Epub 2017/11/11).CrossRefGoogle Scholar
  30. 30.
    Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007;25(12):1539–44 (Epub 2007/04/20).CrossRefGoogle Scholar
  31. 31.
    Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer. 2003;3(6):401–10 (Epub 2003/06/05).CrossRefGoogle Scholar
  32. 32.
    Grothey A, Sugrue MM, Purdie DM, Dong W, Sargent D, Hedrick E, et al. Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: results from a large observational cohort study (BRiTE). J Clin Oncol. 2008;26(33):5326–34 (Epub 2008/10/16).CrossRefGoogle Scholar
  33. 33.
    Bendell JC, Bekaii-Saab TS, Cohn AL, Hurwitz HI, Kozloff M, Tezcan H, et al. Treatment patterns and clinical outcomes in patients with metastatic colorectal cancer initially treated with FOLFOX-bevacizumab or FOLFIRI-bevacizumab: results from ARIES, a bevacizumab observational cohort study. Oncologist. 2012;17(12):1486–95 (Epub 2012/09/28).CrossRefGoogle Scholar
  34. 34.
    Bennouna J, Sastre J, Arnold D, Osterlund P, Greil R, Van Cutsem E, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013;14(1):29–37 (Epub 2012/11/22).CrossRefGoogle Scholar
  35. 35.
    Masi G, Salvatore L, Boni L, Loupakis F, Cremolini C, Fornaro L, et al. Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial. Ann Oncol. 2015;26(4):724–30 (Epub 2015/01/21).CrossRefGoogle Scholar
  36. 36.
    Fontanella C, Ongaro E, Bolzonello S, Guardascione M, Fasola G, Aprile G. Clinical advances in the development of novel VEGFR2 inhibitors. Ann Transl Med. 2014;2(12):123 (Epub 2015/01/09).PubMedPubMedCentralGoogle Scholar
  37. 37.
    Spratlin JL, Cohen RB, Eadens M, Gore L, Camidge DR, Diab S, et al. Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2. J Clin Oncol. 2010;28(5):780–7 (Epub 2010/01/06).CrossRefGoogle Scholar
  38. 38.
    Tabernero J, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015;16(5):499–508 (Epub 2015/04/17).CrossRefGoogle Scholar
  39. 39.
    Arnold D, Fuchs CS, Tabernero J, Ohtsu A, Zhu AX, Garon EB, et al. Meta-analysis of individual patient safety data from six randomized, placebo-controlled trials with the antiangiogenic VEGFR2-binding monoclonal antibody ramucirumab. Ann Oncol. 2017;28(12):2932–42 (Epub 2017/09/28).CrossRefGoogle Scholar
  40. 40.
    Tabernero J, Hozak RR, Yoshino T, Cohn AL, Obermannova R, Bodoky G, et al. Analysis of angiogenesis biomarkers for ramucirumab efficacy in patients with metastatic colorectal cancer from RAISE, a global, randomized, double-blind, phase III study. Ann Oncol. 2018;29:602–9 (Epub 2017/12/12).CrossRefGoogle Scholar
  41. 41.
    Moore M, Gill S, Asmis T, Berry S, Burkes R, Zbuk K, et al. Randomized phase II study of modified FOLFOX-6 in combination with ramucirumab or icrucumab as second-line therapy in patients with metastatic colorectal cancer after disease progression on first-line irinotecan-based therapy. Ann Oncol. 2016;27(12):2216–24 (Epub 2016/10/14).CrossRefGoogle Scholar
  42. 42.
    Bridgewater Ns-aUSL. Zaltrap (ziv-aflibercept)—drug development technology. ZALTRAP Prescribing Information; 2016. http://www.drugdevelopment-technology.com. Accessed 10 Apr 2018.
  43. 43.
    Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausova J, Macarulla T, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012;30(28):3499–506 (Epub 2012/09/06).CrossRefGoogle Scholar
  44. 44.
    Wilhelm SM, Dumas J, Adnane L, Lynch M, Carter CA, Schutz G, et al. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer. 2011;129(1):245–55 (Epub 2010/12/21).CrossRefGoogle Scholar
  45. 45.
    Huynh H, Ong R, Zopf D. Antitumor activity of the multikinase inhibitor regorafenib in patient-derived xenograft models of gastric cancer. J Exp Clin Cancer Res. 2015;34:132 (Epub 2015/10/31).CrossRefGoogle Scholar
  46. 46.
    Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303–12 (Epub 2012/11/28).CrossRefGoogle Scholar
  47. 47.
    Van Cutsem ECF, Seitz J-F, et al. Results from the large, open-label phase 3b CONSIGN study of regorafenib in patients with previously treated metastatic colorectal cancer. Ann Oncol. 2015;26(suppl_4):LBA-05.Google Scholar
  48. 48.
    Li J, Qin S, Xu R, Yau TC, Ma B, Pan H, et al. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015;16(6):619–29 (Epub 2015/05/20).CrossRefGoogle Scholar
  49. 49.
    Bekaii-Saab TSOF, Anderson DM, et al. Regorafenib dose optimization study (ReDOS): Randomized phase II trial to evaluate dosing strategies for regorafenib in refractory metastatic colorectal cancer (mCRC): an ACCRU Network study. J Clin Oncol. 2018;36(4_suppl):611.CrossRefGoogle Scholar
  50. 50.
    Shitara KYT, Denda T, et al. Reverce: randomized phase II study of regorafenib followed by cetuximab versus the reverse sequence for metastatic colorectal cancer patients previously treated with fluoropyrimidine, oxaliplatin, and irinotecan. J Clin Oncol. 2018;36(4_suppl):557.CrossRefGoogle Scholar
  51. 51.
    Reck M, Kaiser R, Mellemgaard A, Douillard JY, Orlov S, Krzakowski M, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014;15(2):143–55 (Epub 2014/01/15).CrossRefGoogle Scholar
  52. 52.
    Van Cutsem E, Yoshino T, Lenz HJ, Lonardi S, Falcone A, Limon ML, et al. Nintedanib for the treatment of patients with refractory metastatic colorectal cancer (LUME-Colon 1): a phase III, international, randomized, placebo-controlled study. Ann Oncol. 2018;29(9):1955–63 (Epub 2018/07/17).CrossRefGoogle Scholar
  53. 53.
    Sun Q, Zhou J, Zhang Z, Guo M, Liang J, Zhou F, et al. Discovery of fruquintinib, a potent and highly selective small molecule inhibitor of VEGFR 1, 2, 3 tyrosine kinases for cancer therapy. Cancer Biol Ther. 2014;15(12):1635–45 (Epub 2014/12/09).CrossRefGoogle Scholar
  54. 54.
    Gu Y, Wang J, Li K, Zhang L, Ren H, Guo L, et al. Preclinical pharmacokinetics and disposition of a novel selective VEGFR inhibitor fruquintinib (HMPL-013) and the prediction of its human pharmacokinetics. Cancer Chemother Pharmacol. 2014;74(1):95–115 (Epub 2014/05/13).CrossRefGoogle Scholar
  55. 55.
    Li JCJ, Xu R-H, et al. A phase 1b study of VEGFR inhibitor fruquintinib in patients with pretreated advanced colorectal cancer. J Clin Oncol. 2014;32(15_suppl):3548.CrossRefGoogle Scholar
  56. 56.
    Xu RH, Li J, Bai Y, Xu J, Liu T, Shen L, et al. Safety and efficacy of fruquintinib in patients with previously treated metastatic colorectal cancer: a phase Ib study and a randomized double-blind phase II study. J Hematol Oncol. 2017;10(1):22 (Epub 2017/01/21).CrossRefGoogle Scholar
  57. 57.
    Cao J, Zhang J, Peng W, Chen Z, Fan S, Su W, et al. A Phase I study of safety and pharmacokinetics of fruquintinib, a novel selective inhibitor of vascular endothelial growth factor receptor-1, -2, and -3 tyrosine kinases in Chinese patients with advanced solid tumors. Cancer Chemother Pharmacol. 2016;78(2):259–69 (Epub 2016/06/15).CrossRefGoogle Scholar
  58. 58.
    Hiret SBC, Bertaut A, et al. Bevacizumab or cetuximab plus chemotherapy after progression with bevacizumab plus chemotherapy in patients with wtKRAS metastatic colorectal cancer: a randomized phase II study (Prodige 18–UNICANCER GI). J Clin Oncol. 2016;34(15_suppl):3514.CrossRefGoogle Scholar
  59. 59.
    Cascinu S, Rosati G, Nasti G, Lonardi S, Zaniboni A, Marchetti P, et al. Treatment sequence with either irinotecan/cetuximab followed by FOLFOX-4 or the reverse strategy in metastatic colorectal cancer patients progressing after first-line FOLFIRI/bevacizumab: an Italian Group for the Study of Gastrointestinal Cancer phase III, randomised trial comparing two sequences of therapy in colorectal metastatic patients. Eur J Cancer. 2017;83:106–15 (Epub 2017/07/25).CrossRefGoogle Scholar
  60. 60.
    Hecht JR, Cohn A, Dakhil S, Saleh M, Piperdi B, Cline-Burkhardt M, et al. SPIRITT: a randomized, multicenter, phase II study of panitumumab with FOLFIRI and bevacizumab with FOLFIRI as second-line treatment in patients with unresectable wild type KRAS metastatic colorectal cancer. Clin Colorectal Cancer. 2015;14(2):72–80 (Epub 2015/05/20).CrossRefGoogle Scholar
  61. 61.
    Kopetz S, Hoff PM, Morris JS, Wolff RA, Eng C, Glover KY, et al. Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J Clin Oncol. 2010;28(3):453–9 (Epub 2009/12/17).CrossRefGoogle Scholar
  62. 62.
    FDA approves first biosimilar to treat cancer. Cancer Discov. 2017;7(11):1206 (Epub 2017/10/07).Google Scholar
  63. 63.
    IMS Health. The impact of biosimilar competition. 2016. http://ec.europa.eu/DocsRoom/documents/17325/attachments/1/translations/en/renditions/native42. Accessed 10 Apr 2018.
  64. 64.
    Thatcher NTM, Paz-Ares L, et al. Randomized, double-blind, phase 3 study evaluating efficacy and safety of ABP 215 compared with bevacizumab in patients with non-squamous NSCLC. J Clin Oncol. 2016;34(15_suppl):9095.CrossRefGoogle Scholar
  65. 65.
    Monk BJ, Lammers PE, Cartwright T, Jacobs I. Barriers to the access of bevacizumab in patients with solid tumors and the potential impact of biosimilars: a physician survey. Pharmaceuticals (Basel). 2017;10(1) (Epub 2017/01/31).Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Anthony Lopez
    • 1
    • 2
  • Kazuto Harada
    • 1
  • Maria Vasilakopoulou
    • 1
  • Namita Shanbhag
    • 1
  • Jaffer A. Ajani
    • 1
    Email author
  1. 1.Department of Gastrointestinal Medical OncologyUniversity of Texas MD Anderson Cancer CenterHoustonUSA
  2. 2.Department of Gastroenterology and Hepatology and Inserm U954, Nancy University HospitalLorraine UniversityVandoeuvre-lès-NancyFrance

Personalised recommendations