Abstract
Introduction
Metronomic chemotherapy combined with bevacizumab has proved to be effective in various tumour types. The aim of this study is to review our experience in recurrent ovarian carcinomas treated with low-dose cyclophosphamide and bevacizumab.
Materials and methods
Retrospective analysis of pre-treated ovarian cancer patients, i.e., ≥2 previous chemotherapy regimens who received treatment with oral cyclophosphamide 50 mg/day and bevacizumab 10 mg/kg IV every two weeks. Patients with a performance status 0–2 were included. The endpoints were response rates, progression-free disease and safety profile.
Results
Nine patients with advanced, measurable ovarian cancer were included. Of these, 8 were platinum-resistant and had received prior regimens with gemcitabine (88%), topotecan (77%) and liposomal doxorubicin (66%). There was a mean of 5 previous lines of chemotherapy, range 2–7. Applying RECIST criteria, the efficacy data were as follows: objective response (OR) 44%; 4/9 (CR 2/9 and PR 2/9), SD 2/9 and DP 3/9. At 6 months, 33% of patients were progression free. Response lasted for 12.5 months in three patients treated for 12 months; a further two patients who were re-treated achieved complete response. Mean time to progression was 5.5 months (95% CI 4.5–5.5). No severe adverse effects were reported. Only one patient had to delay several cycles due to G3 haematuria. Other toxicities observed include G3 abdominal pain (1 case); G2 mucositis and G2 dyspnoea in one patient.
Conclusions
Combined bevacizumab and metronomic oral cyclophosphamide is a safe and effective regimen for heavily pre-treated ovarian cancer patients. Further research is needed on predictive factors to screen for those patients who will benefit from anti-angiogenic therapy.
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References
Jemal A, Siegel R, Ward E et al (2007) Cancer statistics, 2007. CA Cancer J Clin 57:43–66
Ozols R, Bundy B, Creer B et al (2003) Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group Study. J Clin Oncol 17:3194–3200
Gordon AN, Fleagle JT, Guthrie D et al (2001) Recurrent epithelial ovarian carcinoma: a randomized phase III trial of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol 19:3312–3322
Ozols RF (2001) The current role of gemcitabine in ovarian cancer. Semin Oncol 28:18–24
Markman M, Hall J, Spitz D et al (2002) Phase II trial of weekly single agent paclitaxel in platinum/paclitaxel refractory ovarian cancer. J Clin Oncol 20:2365–2369
Burguer RA, DiSaia PJ, Roberts JA et al (1999) Phase II trial of vinorelbine in recurrent and progressive epithelial ovarian cancer. Gynecol Oncol 72:148–153
Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70
Brahimi-Horn C, Berra E, Pouysségur J (2001) Hypoxia: the tumor’s gateway to progression along the angiogenic pathway. Trends Cell Biol 11:S32–S36
Dvorak HF (2002) Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol 20:4368
Yamamoto S, Konishi I, Mandai M et al (1997) Expression of vascular endothelial growth factor (VEGF) in epithelial ovarian neoplasms: correlation with clinicopathology and patient survival, and analysis of serum VEGF levels. Br J Cancer 76:1221–1227
Hartenbach EM, Olson TA, Goswitz JJ et al (1997) Vascular endothelial growth factor (VEGF) expression and survival in human epithelial ovarian carcinomas. Cancer Lett 121:169–175
Shen GH, Ghazizadeh M, Kawanami O et al (2000) Prognostic significance of vascular endothelial growth factor expression in human ovarian carcinoma. Br J Cancer 83:196–203
Ferrara N, Hillan KJ, Novotny W et al (2005) Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. Biochem Biophys Res Commun 333:328–335
Hu L, Hofmann J, Holash J et al (2005) Vascular endothelial growth factor trap combined with paclitaxel strikingly inhibits tumor and ascites, prolonging survival in a human ovarian cancer model. Clin Cancer Res 11:6966–6971
Kerbel RS (1991) Inhibition of tumor angiogenesis as a strategy to circumvent acquired resistance to anti-cancer therapeutic agents. Bioessays 13:31–36
Kerbel RS, Viloria-Petit A, Klement G et al (2000) Accidental anti-angiogenic drugs: antioncogene directed signal transduction inhibitors and conventional chemotherapeutic agents as examples. Eur J Cancer 36:1248–1257
Bello L, Carrabba G, Giussani C et al (2001) Low-dose chemotherapy combined with an antiangiogenic drug reduces human glioma growth in vivo. Cancer Res 61:7501–7506
Man S, Bocci G, Francia G et al (2002) Antitumor effects in mice of low dose (metronomic) cyclophosphamide administered continuously through the drinking water. Cancer Res 62:2731–2735
Burstein HJ, Spiegel D, Kindsvogel K et al (2005) Metronomic chemotherapy with and without bevacizumab for advanced breast cancer: a randomized phase II study. Breast Cancer Res Treat 92:1s [suppl abstr 4]
Burguer RA, Sill M, Monk B et al (2007) Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer (EOC) or primary peritoneal cancer: a Gynecologic Oncology Group (GOG) study. J Clin Oncol 25:5165–5171
Cannistra SA, Matulonis UA, Penson RT et al (2007) Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol 25:5180–5186
Garcia AA, Hirte H, Fleming G et al (2008) Phase II clinical trial of bevacizumab (Bev) and low dose metronomic oral cyclophosphamide (mCTX) in recurrent ovarian cancer (OC): a Trial of the California, Chicago, and Princess Margaret Hospital Phase II Consortia. J Clin Oncol 26:76–82
Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216
Rustin GJ, Marples M, Nelstrop AE et al (2001) Use of CA-125 to define progression of ovarian cancer in patients with persistently elevated levels. J Clin Oncol 19:4054–4057
Rustin GJ (2003) Use of CA-125 to assess response to new agents in ovarian cancer trials. J Clin Oncol 21[10 Suppl]:187–193
Hurwitz H, Fehrenbacher L, Novotny W et al (2004) Bevacizumab plus irinotecan, fluoracil and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342
Wright JD, Hagemann A, Rader JS et al (2006) Bevacizumab combination therapy in recurrent, platinum-refractory epithelial ovarian carcinoma. Cancer 107:83–89
Koner JA, Fallon K, Pezulli S et al (2007) A phase II study of intravenous (IV) and intraperitoneal (IP) paclitaxel (Tax), IP cisplatin (Cis) and IV bevazicumab (Bev) as first-line chemotherapy for optimal stage II or III ovarian, primary peritoneal, and fallopian tube cancer. J Clin Oncol 25[Suppl] [Abstract 5523]
Burguer RA (2007) Experience with bevacizumab in the management of epithelial ovarian cancer. J Clin Oncol 25:2902–2908
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An erratum to this article is available at http://dx.doi.org/10.1007/s12094-008-0287-5.
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Jurado García, J.M., Sánchez, A., Pajares, B. et al. Combined oral cyclophosphamide and bevacizumab in heavily pre-treated ovarian cancer. Clin Transl Oncol 10, 583–586 (2008). https://doi.org/10.1007/s12094-008-0254-7
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DOI: https://doi.org/10.1007/s12094-008-0254-7