, Volume 27, Issue 4, pp 375–392

Bevacizumab Combination Therapy: A Review of its Use in Patients with Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Adis Drug Evaluation


Bevacizumab (Avastin®) is a recombinant, humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody that neutralizes the biological activity of VEGF and inhibits tumor angiogenesis. In the EU, in adult patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer, bevacizumab (in combination with carboplatin and paclitaxel) is approved for the first-line treatment of advanced disease and (in combination with carboplatin and gemcitabine) is approved for the treatment of patients with first recurrence of platinum-sensitive disease who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor-targeted agents. This article summarizes the pharmacology of bevacizumab and reviews the efficacy and tolerability of bevacizumab combination therapy in well-designed clinical studies in these indications. The addition of bevacizumab to first-line carboplatin plus paclitaxel, followed by bevacizumab maintenance therapy significantly prolonged progression-free survival in women with newly-diagnosed advanced disease (GOG-0218 and ICON7 studies). Progression-free survival was also significantly prolonged after second-line treatment with bevacizumab in combination with carboplatin and gemcitabine, followed by maintenance treatment with bevacizumab alone in women with recurrence (≥6 months after front-line platinum-based therapy) of platinum-sensitive disease (OCEANS study). Bevacizumab combination therapy had a generally acceptable tolerability profile in these studies, with the nature of adverse events generally similar to that observed in previous clinical trials in patients with other solid tumors. Although several unanswered questions remain, such as the optimal dosage and duration of treatment, current evidence suggests that bevacizumab combination therapy extends the treatment options available for patients with ovarian cancer.


  1. 1.
    Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.PubMedCrossRefGoogle Scholar
  2. 2.
    Colombo N, Peiretti M, Parma G, et al. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21 Suppl 5:v23–30.PubMedCrossRefGoogle Scholar
  3. 3.
    Vaughan S, Coward JI, Bast RC Jr, et al. Rethinking ovarian cancer: recommendations for improving outcomes. Nat Rev Cancer. 2011;11(10):719–25.PubMedCrossRefGoogle Scholar
  4. 4.
    Burger RA. Experience with bevacizumab in the management of epithelial ovarian cancer. J Clin Oncol. 2007;25(20):2902–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Ledermann JA, Marth C, Carey MS, et al. Role of molecular agents and targeted therapy in clinical trials for women with ovarian cancer. Int J Gynecol Cancer. 2011;21(4):763–70.PubMedCrossRefGoogle Scholar
  6. 6.
    Teoh DG, Secord AA. Antiangiogenic therapies in epithelial ovarian cancer. Cancer Control. 2011;18(1):31–43.PubMedGoogle Scholar
  7. 7.
    Kerbel RS. Tumor angiogenesis. N Engl J Med. 2008;358(19):2039–49.PubMedCrossRefGoogle Scholar
  8. 8.
    Kraft A, Weindel K, Ochs A, et al. Vascular endothelial growth factor in the sera and effusions of patients with malignant and nonmalignant disease. Cancer. 1999;85(1):178–87.PubMedCrossRefGoogle Scholar
  9. 9.
    Brustmann H. Vascular endothelial growth factor expression in serous ovarian carcinoma: relationship with topoisomerase II alpha and prognosis. Gynecol Oncol. 2004;95(1):16–22.PubMedCrossRefGoogle Scholar
  10. 10.
    Manenti L, Paganoni P, Floriani I, et al. Expression levels of vascular endothelial growth factor, matrix metalloproteinases 2 and 9 and tissue inhibitor of metalloproteinases 1 and 2 in the plasma of patients with ovarian carcinoma. Eur J Cancer. 2003;39(13):1948–56.PubMedCrossRefGoogle Scholar
  11. 11.
    Wong C, Wellman TL, Lounsbury KM. VEGF and HIF-1alpha expression are increased in advanced stages of epithelial ovarian cancer. Gynecol Oncol. 2003;91(3):513–7.PubMedCrossRefGoogle Scholar
  12. 12.
    European Medicines Agency. Avastin: summary of product characteristics. 2013. Accessed 17 May 2013.
  13. 13.
    Lyseng-Williamson KA, Robinson DM. Bevacizumab: a review of its use in advanced colorectal cancer, breast cancer, and NSCLC. Am J Cancer. 2006;5(1):43–60.CrossRefGoogle Scholar
  14. 14.
    Scott LJ. Bevacizumab: in first-line treatment of metastatic breast cancer. Drugs. 2007;67(12):1793–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Croom KF, Dhillon S. Bevacizumab: a review of its use in combination with paclitaxel or capecitabine as first-line therapy for HER2-negative metastatic breast cancer. Drugs. 2011;71(16):2213–29.PubMedCrossRefGoogle Scholar
  16. 16.
    Gerber HP, Ferrara N. Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in preclinical studies. Cancer Res. 2005;65(3):671–80.PubMedGoogle Scholar
  17. 17.
    Wang Y, Fei D, Vanderlaan M, et al. Biological activity of bevacizumab, a humanized anti-VEGF antibody in vitro. Angiogenesis. 2004;7(4):335–45.PubMedCrossRefGoogle Scholar
  18. 18.
    Mabuchi S, Terai Y, Morishige K, et al. Maintenance treatment with bevacizumab prolongs survival in an in vivo ovarian cancer model. Clin Cancer Res. 2008;14(23):7781–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Wedam SB, Low JA, Yang SX, et al. Antiangiogenic and antitumor effects of bevacizumab in patients with inflammatory and locally advanced breast cancer. J Clin Oncol. 2006;24(5):769–77.PubMedCrossRefGoogle Scholar
  20. 20.
    Gordon MS, Margolin K, Talpaz M, et al. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol. 2001;19(3):843–50.PubMedGoogle Scholar
  21. 21.
    Margolin K, Gordon MS, Holmgren E, et al. Phase Ib trial of intravenous recombinant humanized monoclonal antibody to vascular endothelial growth factor in combination with chemotherapy in patients with advanced cancer: pharmacologic and long-term safety data. J Clin Oncol. 2001;19(3):851–6.PubMedGoogle Scholar
  22. 22.
    Hsei V, DeGuzman GG, Nixon A, et al. Complexation of VEGF with bevacizumab decreases VEGF clearance in rats. Pharm Res. 2002;19(11):1753–6.PubMedCrossRefGoogle Scholar
  23. 23.
    Mabuchi S, Kawase C, Altomare DA, et al. Vascular endothelial growth factor is a promising therapeutic target for the treatment of clear cell carcinoma of the ovary. Mol Cancer Ther. 2010;9(8):2411–22.PubMedCrossRefGoogle Scholar
  24. 24.
    Presta LG, Chen H, O’Connor SJ, et al. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res. 1997;57(20):4593–9.PubMedGoogle Scholar
  25. 25.
    Yanagisawa M, Yorozu K, Kurasawa M, et al. Bevacizumab improves the delivery and efficacy of paclitaxel. Anticancer Drugs. 2010;21(7):687–94.PubMedGoogle Scholar
  26. 26.
    Hu L, Hofmann J, Zaloudek C, et al. Vascular endothelial growth factor immunoneutralization plus paclitaxel markedly reduces tumor burden and ascites in athymic mouse model of ovarian cancer. Am J Pathol. 2002;161(5):1917–24.PubMedCrossRefGoogle Scholar
  27. 27.
    Oliva P, Decio A, Castiglioni V, et al. Cisplatin plus paclitaxel and maintenance of bevacizumab on tumour progression, dissemination, and survival of ovarian carcinoma xenograft models. Br J Cancer. 2012;107(2):360–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Belotti D, Calcagno C, Garofalo A, et al. Vascular endothelial growth factor stimulates organ-specific host matrix metalloproteinase-9 expression and ovarian cancer invasion. Mol Cancer Res. 2008;6(4):525–34.PubMedCrossRefGoogle Scholar
  29. 29.
    Smerdel MP, Steffensen KD, Waldstrom M, et al. The predictive value of serum VEGF in multiresistant ovarian cancer patients treated with bevacizumab. Gynecol Oncol. 2010;118(2):167–71.PubMedCrossRefGoogle Scholar
  30. 30.
    Han ES, Burger RA, Darcy KM, et al. Predictive and prognostic angiogenic markers in a gynecologic oncology group phase II trial of bevacizumab in recurrent and persistent ovarian or peritoneal cancer. Gynecol Oncol. 2010;119(3):484–90.PubMedCrossRefGoogle Scholar
  31. 31.
    Fuh K, Kiet T, Amanam I, et al. Immunoregulatory gene expression and response to bevacizumab in ovarian cancer: an analysis of the cancer genome atlas [abstract]. Gynecol Oncol. 2012;127(1):S15.CrossRefGoogle Scholar
  32. 32.
    Alvarez-Secord A, Huh W, Tillmanns T, et al. Prognostic factors predictive of response to bevacizumab combined with chemotherapy in recurrent ovarian cancer: a multi-institutional study [abstract no. 234]. Gynecol Oncol. 2012;125 Suppl 1:S98–9.CrossRefGoogle Scholar
  33. 33.
    Chase DM, Sill MW, Monk BJ, et al. Changes in tumor blood flow as measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) may predict activity of single agent bevacizumab in recurrent epithelial ovarian (EOC) and primary peritoneal cancer (PPC) patients: an exploratory analysis of a Gynecologic Oncology Group Phase II study. Gynecol Oncol. 2012;126(3):375–80.PubMedCrossRefGoogle Scholar
  34. 34.
    Nick A, Stone R, Soliman P, et al. Pressure to respond: hypertension predicts clinical benefit from bevacizumab in recurrent ovarian cancer [abstract no. 84]. Gynecol Oncol. 2011;120 Suppl 1:S37.CrossRefGoogle Scholar
  35. 35.
    Randall LM, Monk BJ. Bevacizumab toxicities and their management in ovarian cancer. Gynecol Oncol. 2010;117(3):497–504.PubMedCrossRefGoogle Scholar
  36. 36.
    Stone RL, Sood AK, Coleman RL. Collateral damage: toxic effects of targeted antiangiogenic therapies in ovarian cancer. Lancet Oncol. 2010;11(5):465–75.PubMedCrossRefGoogle Scholar
  37. 37.
    Gressett SM, Shah SR. Intricacies of bevacizumab-induced toxicities and their management. Ann Pharmacother. 2009;43(3):490–501.PubMedCrossRefGoogle Scholar
  38. 38.
    Wu JY, Wu XN, Ding L, et al. Phase I safety and pharmacokinetic study of bevacizumab in Chinese patients with advanced cancer. Chin Med J (Engl). 2010;123(7):901–6.Google Scholar
  39. 39.
    European Medicines Agency. Avastin: European public assessment report: scientific discussion. 2005. Accessed 1 Feb 2013.
  40. 40.
    European Medicines Agency. Avastin: European public assessment report variation (H-C-582-II-41). 2011. Accessed 21 Jan 2013.
  41. 41.
    European Medicines Agency. Avastin: European public assessment report (H-C-582-II-46). 2012. Accessed 22 Jan 2013.
  42. 42.
    Micha JP, Goldstein BH, Rettenmaier MA, et al. A phase II study of outpatient first-line paclitaxel, carboplatin, and bevacizumab for advanced-stage epithelial ovarian, peritoneal, and fallopian tube cancer. Int J Gynecol Cancer. 2007;17(4):771–6.PubMedCrossRefGoogle Scholar
  43. 43.
    Penson RT, Dizon DS, Cannistra SA, et al. Phase II study of carboplatin, paclitaxel, and bevacizumab with maintenance bevacizumab as first-line chemotherapy for advanced mullerian tumors. J Clin Oncol. 2010;28(1):154–9.PubMedCrossRefGoogle Scholar
  44. 44.
    Burger RA, Brady MF, Bookman MA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365(26):2473–83.PubMedCrossRefGoogle Scholar
  45. 45.
    Perren TJ, Swart AM, Pfisterer J, et al. A phase 3 trial of bevacizumab in ovarian cancer [erratum appears in N Engl J Med. 2012;366(3):284]. N Engl J Med. 2011;365(26):2484–96.PubMedCrossRefGoogle Scholar
  46. 46.
    Monk BJ, Huang HQ, Burger RA, et al. Patient reported outcomes of a randomized, placebo-controlled trial of bevacizumab in the front-line treatment of ovarian cancer: a Gynecologic Oncology Group Study. Gynecol Oncol. 2013;128(3):573–8.PubMedCrossRefGoogle Scholar
  47. 47.
    Stark D, Nankivell M, Pujade-Lauraine E, et al. Standard chemotherapy with or without bevacizumab in advanced ovarian cancer: quality-of-life outcomes from the International Collaboration on Ovarian Neoplasms (ICON7) phase 3 randomised trial. Lancet Oncol. 2013;14(3):236–43.PubMedCrossRefGoogle Scholar
  48. 48.
    Pfisterer J, Plante M, Vergote I, et al. Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol. 2006;24(29):4699–707.PubMedCrossRefGoogle Scholar
  49. 49.
    Cannistra SA, Matulonis UA, Penson RT, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer [erratum appears in J Clin Oncol. 2008;26(10):1773]. J Clin Oncol. 2007;25(33):5180–6.PubMedCrossRefGoogle Scholar
  50. 50.
    Burger RA, Sill MW, Monk BJ, et al. Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group Study. J Clin Oncol. 2007;25(33):5165–71.PubMedCrossRefGoogle Scholar
  51. 51.
    Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012;30(17):2039–45.PubMedCrossRefGoogle Scholar
  52. 52.
    Aghajanian C, Nycum LR, Goff B, et al. Updated overall survival analysis in OCEANS, a randomized phase 3 trial of gemcitabine (G) + carboplatin (C) and bevacizumab (Bv) or placebo (Pl) followed by Bv or Pl in platinum-sensitive recurrent epithelial ovarian (Roc), primary peritoneal (PPC) or fallopian tube cancer (FTC) [abstract no. 9670]. Ann Oncol. 2012;23(Suppl 9).Google Scholar
  53. 53.
    Burger R, Brady M, Bookman M, et al. Prospective investigation of risk factors for gastrointestinal adverse events in a phase III randomized trial of bevacizumab in first-line therapy of advanced epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer: a Gynecologic Oncology Group study [abstract no. 7]. Gynecol Oncol. 2011;120:S5.CrossRefGoogle Scholar
  54. 54.
    Aghajanian C, Blank SV, Goff BA, et al. An updated safety analysis of OCEANS, a randomized, double-blind, phase III trial of gemcitabine (G) and carboplatin (C) with bevacizumab (BV) or placebo (PL) followed by BV or PL to disease progression (PD) in patients with platinum-sensitive (Plat-S) recurrent ovarian cancer [abstract no. 5054]. J Clin Oncol. 2012;30(15 Suppl).Google Scholar
  55. 55.
    Thigpen T. A rational approach to the management of recurrent or persistent ovarian carcinoma. Clin Obstet Gynecol. 2012;55(1):114–30.PubMedCrossRefGoogle Scholar
  56. 56.
    Sato S, Itamochi H. Bevacizumab and ovarian cancer. Curr Opin Obstet Gynecol. 2012;24(1):8–13.PubMedCrossRefGoogle Scholar
  57. 57.
    Bookman MA. The addition of new drugs to standard therapy in the first-line treatment of ovarian cancer. Ann Oncol. 2010;21 Suppl 7:vii211–7.PubMedCrossRefGoogle Scholar
  58. 58.
    Thigpen T, duBois A, McAlpine J, et al. First-line therapy in ovarian cancer trials. Int J Gynecol Cancer. 2011;21(4):756–62.PubMedCrossRefGoogle Scholar
  59. 59.
    Bookman MA, Brady MF, McGuire WP, et al. Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer: a phase III trial of the Gynecologic Cancer Intergroup [erratum appears in J Clin Oncol. 2009;27(13):2305]. J Clin Oncol. 2009;27(9):1419–25.PubMedCrossRefGoogle Scholar
  60. 60.
    Collinson FJ, Seligmann J, Perren TJ. Ovarian cancer: advances in first-line treatment strategies with a particular focus on anti-angiogenic agents. Curr Oncol Rep. 2012;14(6):509–18.PubMedCrossRefGoogle Scholar
  61. 61.
    Hall M, Gourley C, McNeish I, et al. Targeted anti-vascular therapies for ovarian cancer: current evidence. Br J Cancer. 2013;108(2):250–8.PubMedCrossRefGoogle Scholar
  62. 62.
    Heitz F, Harter P, Barinoff J, et al. Bevacizumab in the treatment of ovarian cancer. Adv Ther. 2012;29(9):723–35.PubMedCrossRefGoogle Scholar
  63. 63.
    Chan J, Huh W, McClung C, et al. Factors predictive of toxicity associated with bevacizumab and chemotherapy in recurrent ovarian cancer: a multi-institutional study [abstract no. 163]. Gynecol Oncol. 2012;125 Suppl 1:S69.CrossRefGoogle Scholar
  64. 64.
    Tanyi JL, McCann G, Hagemann AR, et al. Clinical predictors of bevacizumab-associated gastrointestinal perforation. Gynecol Oncol. 2011;120(3):464–9.PubMedCrossRefGoogle Scholar
  65. 65.
    Richardson DL, Backes FJ, Hurt JD, et al. Which factors predict bowel complications in patients with recurrent epithelial ovarian cancer being treated with bevacizumab? Gynecol Oncol. 2010;118(1):47–51.PubMedCrossRefGoogle Scholar
  66. 66.
    Diaz JP, Tew WP, Zivanovic O, et al. Incidence and management of bevacizumab-associated gastrointestinal perforations in patients with recurrent ovarian carcinoma. Gynecol Oncol. 2010;116(3):335–9.PubMedCrossRefGoogle Scholar
  67. 67.
    Ranpura V, Hapani S, Wu S. Treatment-related mortality with bevacizumab in cancer patients: a meta-analysis. JAMA. 2011;305(5):487–94.PubMedCrossRefGoogle Scholar
  68. 68.
    Cohn D, Kim K, Resnick K, et al. At what cost does a potential survival advantage of bevacizumab make sense for the primary treatment of ovarian cancer? A cost-effectiveness analysis. Gynecol Oncol. 2010;1:S12–3.Google Scholar
  69. 69.
    Cooper K, Pickett K, Frampton G, et al. Bevacizumab in combination with paclitaxel and carboplatin for the first-line treatment of ovarian cancer: evidence review group report. On behalf of the National Institute of Health and Clinical Excellence 2012. Accessed 30 Jan 2013.
  70. 70.
    Chan J, Monk B, Fuh K, et al. An economic analysis of bevacizumab in recurrent treatment of ovarian cancer [abstract no. 66]. Gynecol Oncol. 2011;120 Suppl 1:S29–30.CrossRefGoogle Scholar
  71. 71.
    Walter A, Geisler J, Manahan K. Annual cost of bevacizumab in the adjuvant treatment of ovarian cancer to the U.S. Medicare system [abstract no. 263]. Gynecol Oncol. 2012;125 Suppl 1:S110–1.CrossRefGoogle Scholar
  72. 72.
    Lesnock JL, Farris C, Krivak TC, et al. Consolidation paclitaxel is more cost-effective than bevacizumab following upfront treatment of advanced epithelial ovarian cancer. Gynecol Oncol. 2011;122(3):473–8.PubMedCrossRefGoogle Scholar
  73. 73.
    London Cancer New Drugs Group. Rapid review: bevacizumab for the first-line treatment of advanced ovarian cancer in combination with paclitaxel and carboplatin. 2012. Accessed 30 Apr 2013.
  74. 74.
    Scottish Medicines Consortium. Bevacizumab: detailed advice. 2012. Accessed 3 May 2013.
  75. 75.
    Kroep JR, Nortier JWR. The role of bevacizumab in advanced epithelial ovarian cancer. Curr Pharm Des. 2012;18(25):3775–83.PubMedCrossRefGoogle Scholar
  76. 76.
    Jubb AM, Harris AL. Biomarkers to predict the clinical efficacy of bevacizumab in cancer. Lancet Oncol. 2010;11(12):1172–83.PubMedCrossRefGoogle Scholar
  77. 77.
    Jayson GC, De Haas S, Delmar P, et al. Evaluation of plasma VEGFA as potential predictive pan-tumour biomarker for bevaizumab [abstract no. 804]. The European Multidisciplinary Cancer Congress; 23–27 Sep 2011; Stockholm.Google Scholar
  78. 78.
    Muggia F. Bevacizumab in ovarian cancer: unanswered questions. Drugs. 2012;72(7):931–6.PubMedCrossRefGoogle Scholar
  79. 79.
    Raja FA, Chopra N, Ledermann JA. Optimal first-line treatment in ovarian cancer. Ann Oncol. 2012;23 Suppl 10:x118–27.PubMedCrossRefGoogle Scholar
  80. 80.
    AGO Study Group. Evaluation of optimal initial treatment duration of bevacizumab in combination with standard chemotherapy in patients with ovarian cancer (BOOST) [ identifier NCT01462890]. US National Institutes of Health, 2012. Accessed 24 Jan 2013.
  81. 81.
    European Society of Gynaecological Oncology. ENGOT-ov17/MITO 16: phase III trial with second line chemotherapy +/− bevacizumab in patients with platinum sensitive ovarian cancer recurrence after bevacizumab and chemotherapy in the first line. 2011. Accessed 25 Jan 2013.
  82. 82.
    Paez-Ribes M, Allen E, Hudock J, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell. 2009;15(3):220–31.PubMedCrossRefGoogle Scholar
  83. 83.
    Ebos JM, Lee CR, Cruz-Munoz W, et al. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell. 2009;15(3):232–9.PubMedCrossRefGoogle Scholar
  84. 84.
    Miles D, Harbeck N, Escudier B, et al. Disease course patterns after discontinuation of bevacizumab: pooled analysis of randomized phase III trials. J Clin Oncol. 2011;29(1):83–8.PubMedCrossRefGoogle Scholar
  85. 85.
    Pujade-Lauraine E, Hilpert F, Weber B, et al. AURELIA: a randomized phase III trial evaluating bevacizumab (BEV) plus chemotherapy (CT) for platinum (PT)-resistant recurrent ovarian cancer (OC) [abstract no. LBA5002]. 48th Annual Meeting of the American Society of Clinical Oncology; 1–5 Jun 2012; Chicago (IL).Google Scholar
  86. 86.
    US National Institutes of Health. 2013. Accessed 25 Mar 2013.

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© Springer International Publishing Switzerland 2013

Authors and Affiliations

  1. 1.AdisAucklandNew Zealand

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