Current Oncology Reports

, Volume 14, Issue 6, pp 509–518

Ovarian Cancer: Advances in First-Line Treatment Strategies with a Particular Focus on Anti-Angiogenic Agents

  • Fiona J. Collinson
  • Jenny Seligmann
  • Timothy J. Perren
Gynecologic Cancers (NS Reed, Section Editor)

Abstract

Ovarian cancer is an important health concern worldwide. The majority of patients present with advanced disease, and despite initial chemosensitivity, most relapse and die from their disease. Better therapeutic options are urgently required. Maximal surgical debulking in combination with platinum/taxane chemotherapy has been the standard of care in advanced ovarian cancer since the mid-1990s. Trials investigating the addition of a third chemotherapeutic agent have disappointingly failed to demonstrate benefit. Intra-peritoneal therapy demonstrated improvements in outcomes in some trials, but at the cost of increased toxicity and inconvenience. Encouragingly, prospective data has now demonstrated benefits with bevacizumab in both the first-line and relapsed settings; however, interpretation is complex, particularly considering recent data demonstrating non-inferiority of neo-adjuvant chemotherapy with delayed primary surgery, and other data demonstrating a substantial improvement in outcome as a result of first-line paclitaxel dose fractionation. This article reviews the recent advances in ovarian cancer treatment and discusses current management and key areas for future research.

Keywords

Ovarian cancer Anti-angiogenic VEGF inhibitors Bevacizumab Intra-peritoneal therapy Dose-fractionation Dose-density Neo-adjuvant chemotherapy Interval debulking therapy Parp inhibitors Olaparib 

References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. 1.
    Jemal A, Siegel R, Xu J, Ward E. Cancer statistics. CA Cancer J Clin. 2010;60:277–300.PubMedCrossRefGoogle Scholar
  2. 2.
    Altekruse SF, Kosary CL, Krapcho M, et al. SEER Cancer Statistics Review, 1975–2007. 2010 http://seercancergov/csr/1975_2007/.
  3. 3.
    Proceedings of the 4th Ovarian Cancer Consensus Meeting. In; 2010.Google Scholar
  4. 4.
    Allen DG, Baak J, Belpomme D, et al. Advanced epithelial ovarian cancer: 1993 consensus statements. Ann Oncol. 1993;4 Suppl 4:83–8.PubMedGoogle Scholar
  5. 5.
    du Bois A, Weber B, Rochon J, et al. Addition of epirubicin as a third drug to carboplatin-paclitaxel in first-line treatment of advanced ovarian cancer: a prospectively randomized gynecologic cancer intergroup trial by the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group and the Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens. J Clin Oncol. 2006;24:1127–35.PubMedCrossRefGoogle Scholar
  6. 6.
    du Bois A, Herrstedt J, Hardy-Bessard AC, et al. Phase III trial of carboplatin plus paclitaxel with or without gemcitabine in first-line treatment of epithelial ovarian cancer. J Clin Oncol. 2010;28:4162–9.PubMedCrossRefGoogle Scholar
  7. 7.
    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. J Clin Oncol. 2009;27:1419–25.PubMedCrossRefGoogle Scholar
  8. 8.
    Kristensen GB, Vergote I, Stuart G, et al. First-line treatment of ovarian cancer FIGO stages IIb-IV with paclitaxel/epirubicin/carboplatin versus paclitaxel/carboplatin. Int J Gynecol Cancer. 2003;13 Suppl 2:172–7.PubMedCrossRefGoogle Scholar
  9. 9.
    Hoskins P, Vergote I, Cervantes A, et al. Advanced ovarian cancer: phase III randomized study of sequential cisplatin-topotecan and carboplatin-paclitaxel vs. carboplatin-paclitaxel. J Natl Cancer Inst. 2010;102:1547–56.PubMedCrossRefGoogle Scholar
  10. 10.
    Bolis G, Scarfone G, Raspagliesi F, et al. Paclitaxel/carboplatin versus topotecan/paclitaxel/carboplatin in patients with FIGO suboptimally resected stage III-IV epithelial ovarian cancer a multicenter, randomized study. Eur J Cancer. 2010;46:2905–12.PubMedCrossRefGoogle Scholar
  11. 11.
    Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med. 2001;7:987–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Ramakrishnan S, Subramanian IV, Yokoyama Y, Geller M. Angiogenesis in normal and neoplastic ovaries. Angiogenesis. 2005;8:169–82.PubMedCrossRefGoogle Scholar
  13. 13.
    Brown MR, Blanchette JO, Kohn EC. Angiogenesis in ovarian cancer. Baillieres Best Pract Res Clin Obstet Gynaecol. 2000;14:901–18.PubMedCrossRefGoogle Scholar
  14. 14.
    Byrne AT, Ross L, Holash J, et al. Vascular endothelial growth factor-trap decreases tumor burden, inhibits ascites, and causes dramatic vascular remodeling in an ovarian cancer model. Clin Cancer Res. 2003;9:5721–8.PubMedGoogle Scholar
  15. 15.
    Cannistra SA, Matulonis UA, Penson RT, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol. 2007;25:5180–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Garcia AA, Hirte H, Fleming G, et al. Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital Phase II consortia. J Clin Oncol. 2008;26:76–82.PubMedCrossRefGoogle Scholar
  17. 17.
    Tillmanns TD, Lowe MP, Schwartzberg LS, Walker MS, Stepanski EJ. A Phase II study of bevacizumab with nab-paclitaxel in patients with recurrent, platinum-resistant primary epithelial ovarian cancer or primary peritoneal cancer. In: American Society of Clinical Oncology Annual Meeting; 2010; 2010. p. 5009 (Abs).Google Scholar
  18. 18.
    Burger RA, Sill MW, Monk BJ, Greer BE, Sorosky JI. 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;25:5165–71.PubMedCrossRefGoogle Scholar
  19. 19.
    Rose PG, Drake R, Braly PS, al. e. Preliminary results of a Phase II study of oxaliplatin, docetaxel and bevacizumab as first-line therapy for advanced cancer of the ovary, peritoneaum and fallopian tube. In: American Society of Clinical Oncology Annual Meeting; 2009; 2009. p. 5546 (abs).Google Scholar
  20. 20.
    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. 2009;28:154–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Hu L, Hofmann J, Zaloudek C, Ferrara N, Hamilton T, Jaffe RB. Vascular endothelial growth factor immunoneutralization plus Paclitaxel markedly reduces tumor burden and ascites in athymic mouse model of ovarian cancer. Am J Pathol. 2002;161:1917–24.PubMedCrossRefGoogle Scholar
  22. 22.
    •• Perren TJ, Swart AM, Pfisterer J, et al. A Phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011;365:2484–96. This trial is one of the first trials to demonstrate benefit in the addition of a new drug to the standard chemothrapy backbone of carboplatin and pacltiaxel.PubMedCrossRefGoogle Scholar
  23. 23.
    •• Burger RA, Brady MF, Bookman MA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365:2473–83. This trial is one of the first trials to demonstrate benefit in the addition of a new drug to the standard chemothrapy backbone of carboplatin and pacltiaxel.PubMedCrossRefGoogle Scholar
  24. 24.
    Han ES, Monk BJ. What is the risk of bowel perforation associated with bevacizumab therapy in ovarian cancer? Gynecol Oncol. 2007;105:3–6.PubMedCrossRefGoogle Scholar
  25. 25.
    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;30:2039–45.PubMedCrossRefGoogle Scholar
  26. 26.
    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). J Clin Oncol. 2012;30:LBA5002.Google Scholar
  27. 27.
    Griffiths CT. Surgical resection of tumor bulk in the primary treatment of ovarian carcinoma. Natl Cancer Inst Monogr. 1975;42:101–4.PubMedGoogle Scholar
  28. 28.
    Bristow RE, Eisenhauer EL, Santillan A, Chi DS. Delaying the primary surgical effort for advanced ovarian cancer: a systematic review of neoadjuvant chemotherapy and interval cytoreduction. Gynecol Oncol. 2007;104:480–90.PubMedCrossRefGoogle Scholar
  29. 29.
    Vasudev NS, Trigonis I, Cairns DA, et al. The prognostic and predictive value of CA-125 regression during neoadjuvant chemotherapy for advanced ovarian or primary peritoneal carcinoma. Arch Gynecol Obstet. 2011;284:221–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Markman M. Intraperitoneal paclitaxel in the management of ovarian cancer. Semin Oncol. 1995;22:86–7.PubMedGoogle Scholar
  31. 31.
    Howell SB, Pfeifle CL, Wung WE, et al. Intraperitoneal cisplatin with systemic thiosulfate protection. Ann Intern Med. 1982;97:845–51.PubMedGoogle Scholar
  32. 32.
    Miyagi Y, Fujiwara K, Kigawa J, et al. Intraperitoneal carboplatin infusion may be a pharmacologically more reasonable route than intravenous administration as a systemic chemotherapy. A comparative pharmacokinetic analysis of platinum using a new mathematical model after intraperitoneal vs. intravenous infusion of carboplatin—a Sankai Gynecology Study Group (SGSG) study. Gynecol Oncol. 2005;99:591–6.PubMedCrossRefGoogle Scholar
  33. 33.
    Alberts DS, Liu PY, Hannigan EV, et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med. 1996;335:1950–5.PubMedCrossRefGoogle Scholar
  34. 34.
    Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354:34–43.PubMedCrossRefGoogle Scholar
  35. 35.
    Markman M, Bundy BN, Alberts DS, et al. Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol. 2001;19:1001–7.PubMedGoogle Scholar
  36. 36.
    Polyzos A, Tsavaris N, Kosmas C, et al. A comparative study of intraperitoneal carboplatin versus intravenous carboplatin with intravenous cyclophosphamide in both arms as initial chemotherapy for stage III ovarian cancer. Oncology. 1999;56:291–6.PubMedCrossRefGoogle Scholar
  37. 37.
    Kirmani S, Braly PS, McClay EF, et al. A comparison of intravenous versus intraperitoneal chemotherapy for the initial treatment of ovarian cancer. Gynecol Oncol. 1994;54:338–44.PubMedCrossRefGoogle Scholar
  38. 38.
    Gadducci A, Carnino F, Chiara S, et al. Intraperitoneal versus intravenous cisplatin in combination with intravenous cyclophosphamide and epidoxorubicin in optimally cytoreduced advanced epithelial ovarian cancer: a randomized trial of the Gruppo Oncologico Nord-Ovest. Gynecol Oncol. 2000;76:157–62.PubMedCrossRefGoogle Scholar
  39. 39.
    Jaaback K, Johnson N. Intraperitoneal chemotherapy for the initial management of primary epithelial ovarian cancer. Cochrane database of systematic reviews 2006:CD005340.Google Scholar
  40. 40.
    Kyrgiou M, Salanti G, Pavlidis N, Paraskevaidis E, Ioannidis JP. Survival benefits with diverse chemotherapy regimens for ovarian cancer: meta-analysis of multiple treatments. J Natl Cancer Inst. 2006;98:1655–63.PubMedCrossRefGoogle Scholar
  41. 41.
    Hess LM, Benham-Hutchins M, Herzog TJ, et al. A meta-analysis of the efficacy of intraperitoneal cisplatin for the front-line treatment of ovarian cancer. Int J Gynecol Cancer. 2007;17:561–70.PubMedCrossRefGoogle Scholar
  42. 42.
    Wenzel LB, Huang HQ, Armstrong DK, Walker JL, Cella D. Health-related quality of life during and after intraperitoneal versus intravenous chemotherapy for optimally debulked ovarian cancer: a Gynecologic Oncology Group Study. J Clin Oncol. 2007;25:437–43.PubMedCrossRefGoogle Scholar
  43. 43.
    Ozols RF, Bookman MA, du Bois A, Pfisterer J, Reuss A, Young RC. Intraperitoneal cisplatin therapy in ovarian cancer: comparison with standard intravenous carboplatin and paclitaxel. Gynecol Oncol. 2006;103:1–6.PubMedCrossRefGoogle Scholar
  44. 44.
    Katsumata N, Yasuda M, Takahashi F, et al. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a Phase 3, open-label, randomised controlled trial. Lancet. 2009;374:1331–8.PubMedCrossRefGoogle Scholar
  45. 45.
    Seidman AD, Berry D, Cirrincione C, et al. Randomized Phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol. 2008;26:1642–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Belotti D, Vergani V, Drudis T, et al. The microtubule-affecting drug paclitaxel has antiangiogenic activity. Clin Cancer Res: J Am Assoc Cancer Res. 1996;2:1843–9.Google Scholar
  47. 47.
    Linch M, Stavridi F, Hook J, Barbachano Y, Gore M, Kaye SB. Experience in a UK cancer centre of weekly paclitaxel in the treatment of relapsed ovarian and primary peritoneal cancer. Gynecol Oncol. 2008;109:27–32.PubMedCrossRefGoogle Scholar
  48. 48.
    Markman M, Hall J, Spitz D, et al. Phase II trial of weekly single-agent paclitaxel in platinum/paclitaxel-refractory ovarian cancer. J Clin Oncol. 2002;20:2365–9.PubMedCrossRefGoogle Scholar
  49. 49.
    Fennelly D, Aghajanian C, Shapiro F, et al. Phase I and pharmacologic study of paclitaxel administered weekly in patients with relapsed ovarian cancer. J Clin Oncol. 1997;15:187–92.PubMedGoogle Scholar
  50. 50.
    Markman M, Blessing J, Rubin SC, Connor J, Hanjani P, Waggoner S. Phase II trial of weekly paclitaxel (80 mg/m2) in platinum and paclitaxel-resistant ovarian and primary peritoneal cancers: a Gynecologic Oncology Group study. Gynecol Oncol. 2006;101:436–40.PubMedCrossRefGoogle Scholar
  51. 51.
    Katsumata N, Yasuda M, Isonishi S, et al. Long-term follow-up of a randomized trial comparing conventional paclitaxel and carboplatin with dose-dense weekly paclitaxel and carboplatin in women with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer: JGOG 3016 trial. Journal of Clinical Oncology. 2012;30:suppl; abstr 5003.Google Scholar
  52. 52.
    Fruscio R, Garbi A, Parma G, et al. Randomized Phase III Clinical Trial Evaluating Weekly Cisplatin for Advanced Epithelial Ovarian Cancer. J Natl Cancer Inst 2011.Google Scholar
  53. 53.
    Arnold D, Andre T, Bennouna J, et al. Bevacizumab (BEV) plus chemotherapy (CT) continued beyond first progression in patients with metastatic colorectal cancer (mCRC) previously treated with BEV plus CT: Results of a randomized Phase III intergroup study (TML study). J Clin Oncol. 2012;30:CRA3503.Google Scholar
  54. 54.
    Relf M, LeJeune S, Scott PA, et al. Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res. 1997;57:963–9.PubMedGoogle Scholar
  55. 55.
    Casanovas O, Hicklin DJ, Bergers G, Hanahan D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell. 2005;8:299–309.PubMedCrossRefGoogle Scholar
  56. 56.
    Laschke MW, Elitzsch A, Vollmar B, Vajkoczy P, Menger MD. Combined inhibition of vascular endothelial growth factor (VEGF), fibroblast growth factor and platelet-derived growth factor, but not inhibition of VEGF alone, effectively suppresses angiogenesis and vessel maturation in endometriotic lesions. Hum Reprod. 2006;21:262–8.PubMedCrossRefGoogle Scholar
  57. 57.
    Matei D, Sill M, DeGeest K, Bristow R. Phase II trial of sorafenib in persistent or recurrent epithelial ovarain cancer or primary peritoneal cancer: A GOG study. JCO 2008;20s:5537.Google Scholar
  58. 58.
    Biagi JJ, Oza AM, Chalchal HI, et al. A Phase II study of sunitinib in patients with recurrent epithelial ovarian and primary peritoneal carcinoma: an NCIC Clinical Trials Group Study. Ann Oncol. 2008;22:335–40.CrossRefGoogle Scholar
  59. 59.
    Azad NS, Posadas EM, Kwitkowski VE, et al. Combination targeted therapy with sorafenib and bevacizumab results in enhanced toxicity and antitumor activity. J Clin Oncol. 2008;26:3709–14.PubMedCrossRefGoogle Scholar
  60. 60.
    Ledermann JA, Hackshaw A, Kaye S, et al. Randomized Phase II placebo-controlled trial of maintenance therapy using the oral triple angiokinase inhibitor BIBF 1120 after chemotherapy for relapsed ovarian cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2011;29:3798–804.CrossRefGoogle Scholar
  61. 61.
    Ashworth A. A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. J Clin Oncol Off J Am Soc Clin Oncol. 2008;26:3785–90.CrossRefGoogle Scholar
  62. 62.
    Kaye SB, Lubinski J, Matulonis U, et al. Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer. J Clin Oncol. 2012;30:372–9.PubMedCrossRefGoogle Scholar
  63. 63.
    Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a Phase 2, multicentre, open-label, non-randomised study. Lancet Oncol. 2011;12:852–61.PubMedCrossRefGoogle Scholar
  64. 64.
    Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, Lacave AJ. Recurrent epithelial ovarian carcinoma: a randomized Phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol. 2001;19:3312–22.PubMedGoogle Scholar
  65. 65.
    Konstantinopoulos PA, Cannistra SA. Comparing poly (ADP-ribose) polymerase inhibitors with standard chemotherapy in BRCA-mutated, recurrent ovarian cancer: lessons learned from a negative trial. J Clin Oncol. 2012;30:347–50.PubMedCrossRefGoogle Scholar
  66. 66.
    Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366:1382–92.PubMedCrossRefGoogle Scholar
  67. 67.
    Calabrese CR, Almassy R, Barton S, et al. Anticancer chemosensitization and radiosensitization by the novel poly(ADP-ribose) polymerase-1 inhibitor AG14361. J Natl Cancer Inst. 2004;96:56–67.PubMedCrossRefGoogle Scholar
  68. 68.
    Donawho CK, Luo Y, Luo Y, et al. ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res. 2007;13:2728–37.PubMedCrossRefGoogle Scholar
  69. 69.
    Delaney CA, Wang LZ, Kyle S, et al. Potentiation of temozolomide and topotecan growth inhibition and cytotoxicity by novel poly(adenosine diphosphoribose) polymerase inhibitors in a panel of human tumor cell lines. Clin Cancer Res. 2000;6:2860–7.PubMedGoogle Scholar
  70. 70.
    Tan DS, Rothermundt C, Thomas K, et al. “BRCAness” syndrome in ovarian cancer: a case-control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations. J Clin Oncol. 2008;26:5530–6.PubMedCrossRefGoogle Scholar
  71. 71.
    Gourley C, Michie CO, Roxburgh P, et al. Increased incidence of visceral metastases in scottish patients with BRCA1/2-defective ovarian cancer: an extension of the ovarian BRCAness phenotype. J Clin Oncol. 2010;28:2505–11.PubMedCrossRefGoogle Scholar
  72. 72.
    Moller P, Hagen AI, Apold J, et al. Genetic epidemiology of BRCA mutations—family history detects less than 50 % of the mutation carriers. Eur J Cancer. 2007;43:1713–7.PubMedCrossRefGoogle Scholar
  73. 73.
    Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129–39.PubMedCrossRefGoogle Scholar
  74. 74.
    Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2008;26:1626–34.CrossRefGoogle Scholar
  75. 75.
    Chambers SK, Clouser MC, Baker AF, et al. Overexpression of tumor vascular endothelial growth factor A may portend an increased likelihood of progression in a Phase II trial of bevacizumab and erlotinib in resistant ovarian cancer. Clin Cancer Res J Am Assoc Cancer Res. 2010;16:5320–8.CrossRefGoogle Scholar
  76. 76.
    Schultheis AM, Lurje G, Rhodes KE, et al. Polymorphisms and clinical outcome in recurrent ovarian cancer treated with cyclophosphamide and bevacizumab. Clin Cancer Res J Am Assoc Cancer Res. 2008;14:7554–63.CrossRefGoogle Scholar
  77. 77.
    Smerdel MP, Steffensen KD, Waldstrom M, Brandslund I, Jakobsen A. The predictive value of serum VEGF in multiresistant ovarian cancer patients treated with bevacizumab. Gynecol Oncol. 2010;118:167–71.PubMedCrossRefGoogle Scholar
  78. 78.
    Spannuth WA, Nick AM, Jennings NB, et al. Functional significance of VEGFR-2 on ovarian cancer cells. Int J Cancer J Int Cancer. 2009;124:1045–53.Google Scholar
  79. 79.
    Pohl G, Ho CL, Kurman RJ, Bristow R, Wang TL, Shih Ie M. Inactivation of the mitogen-activated protein kinase pathway as a potential target-based therapy in ovarian serous tumors with KRAS or BRAF mutations. Cancer Res. 2005;65:1994–2000.PubMedCrossRefGoogle Scholar
  80. 80.
    Singer G, Stohr R, Cope L, et al. Patterns of p53 mutations separate ovarian serous borderline tumors and low- and high-grade carcinomas and provide support for a new model of ovarian carcinogenesis: a mutational analysis with immunohistochemical correlation. Am J Surg Pathol. 2005;29:218–24.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Fiona J. Collinson
    • 1
  • Jenny Seligmann
    • 2
  • Timothy J. Perren
    • 3
  1. 1.Clinical Trials Research UnitUniversity of LeedsLeedsUK
  2. 2.Leeds Institute of Molecular MedicineUniversity of LeedsLeedsUK
  3. 3.St James’s Institute of Oncology, Bexley WingSt James’s University HospitalLeedsUK

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