Are there candidates for high-dose chemotherapy in ovarian carcinoma?

Journal of Experimental & Clinical Cancer Research

Jean-Marc Extra³  Patrice Viens⁴  Christian Chabannon¹  Eric Lambaudie²  Frédérique Rousseau³  Maria-Antonietta Capiello³  François Bertucci⁴  Anthony Gonçalves⁴  Renaud Sabatier⁵ 

[1] Department of Hematology, Institut Paoli-Calmettes, Marseille, France;Department of Surgical Oncology, Institut Paoli-Calmettes, Marseille, France;Department of Medical Oncology, Institut Paoli-Calmettes, 232 Bd Ste-Marguerite, Marseille 13273, France;UFR Medicine, University of Mediterranean, Marseille, France;Department of Molecular Oncology, Centre de Recherche en Cancérologie de Marseille, UMR1068 INSERM, Marseille, France

关键词: Stem cell support;    High dose chemotherapy;    Prognosis;    Ovarian carcinomas;   

Others  :  1136201
DOI  :  10.1186/1756-9966-31-87

 received in 2012-08-20, accepted in 2012-10-10,  发布年份 2012

【 摘 要 】

Background

Prognosis of advanced ovarian carcinomas (AOC) remains poor with a 5-year survival of 30%. Benefit from high-dose chemotherapy (HDC) in this disease has not been demonstrated to date.

Methods

To evaluate the value of HDC as consolidation treatment after surgery and platinum/taxane-based therapy, we designed a monocentric retrospective comparative study. We used a subset approach to identify parameters associated with HDC efficacy.

Results

One hundred and three AOC patients treated with conventional chemotherapy alone (CCA) were compared to 60 patients receiving HDC plus hematopoietic stem cell support. After a median follow-up of 47.5 months there was no overall survival (OS) advantage for the HDC group in the whole population (p=0.29). Nevertheless, HDC was associated to a better outcome in young patients (≤50 years), both in term of progression-free survival (p=0.02, log-rank test) and OS (p=0.05, log-rank test). Median OS was 54.6 and 36 months in the HDC and CCA groups, respectively.

Conclusions

Although randomized trials failed to demonstrate any benefit for HDC in AOC patients, this study suggests that young patients may derive a substantial advantage from receiving it after the standard treatment. Further prospective studies are warranted to confirm this gain and to search for the biological processes associated with this improvement.

【 授权许可】

   
2012 Sabatier et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]National Cancer Institutehttp://www.cancer.gov/cancertopics/types/ovarian webcite
• [2]Cannistra SA: Cancer of the ovary. N Engl J Med 2006, 354:77-79.
• [3]du Bois A, Quinn M, Thigpen T, Vermorken J, Avall-Lundqvist E, Bookman M, et al.: 2004 consensus statements on the management of ovarian cancer: final document of the 3rd International gynecologic cancer intergroup ovarian cancer consensus conference (GCIG OCCC 2004). Ann Oncol 2005, 17:93-96.
• [4]Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL, Montz FJ: Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol 2002, 20:1248-1259.
• [5]International Collaborative Ovarian Neoplasm Group: Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: the ICON3 randomised trial. Lancet 2002, 360:505-515.
• [6]Ozols RF, Bundy BN, Greer BE, Fowler JM, Clarke-Pearson D, Burger RA, et al.: 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 2003, 21:3194-3200.
• [7]Young RC: Early-stage ovarian cancer: to treat or not to treat. J Natl Cancer Inst 2003, 95:94-95.
• [8]Holschneider CH, Berek JS: Ovarian cancer: epidemiology, biology, and prognostic factors. Semin Surg Oncol 2000, 19:3-10.
• [9]McGuire WP, Brady MF, Ozols RF: The gynecologic oncology group experience in ovarian cancer. Ann Oncol 1999, 10(Suppl 1):29-34.
• [10]McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY, et al.: Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996, 334:1-6.
• [11]Piccart MJ, Bertelsen K, James K, Cassidy J, Mangioni C, Simonsen E, et al.: Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results. J Natl Cancer Inst 2000, 92:699-708.
• [12]Behrens BC, Hamilton TC, Masuda H, Grotzinger KR, Whang-Peng J, Louie KG, et al.: Characterization of a cis-diamminedichloroplatinum(II)-resistant human ovarian cancer cell line and its use in evaluation of platinum analogues. Cancer Res 1987, 47:414-418.
• [13]Levin L, Hryniuk WM: Dose intensity analysis of chemotherapy regimens in ovarian carcinoma. J Clin Oncol 1987, 5:756-767.
• [14]Levin L, Simon R, Hryniuk W: Importance of multiagent chemotherapy regimens in ovarian carcinoma: dose intensity analysis. J Natl Cancer Inst 1993, 85:1732-1742.
• [15]Dauplat J, Legros M, Condat P, Ferriere JP, Ben Ahmed S, Plagne R: High-dose melphalan and autologous bone marrow support for treatment of ovarian carcinoma with positive second-look operation. Gynecol Oncol 1987, 34:294-298.
• [16]Viens P, Maraninchi D, Legros M, Oberling F, Philip T, Herve P, et al.: High dose melphalan and autologous marrow rescue in advanced epithelial ovarian carcinomas: a retrospective analysis of 35 patients treated in France. Bone Marrow Transplant 1990, 5:227-233.
• [17]Bertucci F, Viens P, Delpero JR, Bardou VJ, Faucher C, Houvenaeghel G, et al.: High-dose melphalan-based chemotherapy and autologous stem cell transplantation after second look laparotomy in patients with chemosensitive advanced ovarian carcinoma: long-term results. Bone Marrow Transplant 2000, 26:61-67.
• [18]Viret F, Bertucci F, Genre D, Gravis G, Chabannon C, Conte M, et al.: Intensive sequential dose chemotherapy with stem cell support as first-line treatment in advanced ovarian carcinoma: a phase II study. Bone Marrow Transplant 2000, 30:879-884.
• [19]Papadimitriou C, Dafni U, Anagnostopoulos A, Vlachos G, Voulgaris Z, Rodolakis A, et al.: High-dose melphalan and autologous stem cell transplantation as consolidation treatment in patients with chemosensitive ovarian cancer: results of a single-institution randomized trial. Bone Marrow Transplant 2008, 41:547-554.
• [20]Möbus V, Wandt H, Frickhofen N, Bengala C, Champion K, Kimmig R, et al.: Phase III trial of high-dose sequential chemotherapy with peripheral blood stem cell support compared with standard dose chemotherapy for first-line treatment of advanced ovarian cancer: intergroup trial of the AGO-Ovar/AIO and EBMT. J Clin Oncol 2007, 25:4187-4193.
• [21]Bertucci F, Tarpin C, Charafe-Jauffret E, Bardou VJ, Braud AC, Tallet A, et al.: Multivariate analysis of survival in inflammatory breast cancer: impact of intensity of chemotherapy in multimodality treatment. Bone Marrow Transplant 2004, 33:913-920.
• [22]Viens P, Tarpin C, Roche H, Bertucci F: Systemic therapy of inflammatory breast cancer from high-dose chemotherapy to targeted therapies: the French experience. Cancer 2010, 116(11 Suppl):2829-2836.
• [23]Zander AR, Schmoor C, Kröger N, Krüger W, Möbus V, Frickhofen N, et al.: Randomized trial of high-dose adjuvant chemotherapy with autologous hematopoietic stem-cell support versus standard-dose chemotherapy in breast cancer patients with 10 or more positive lymph nodes: overall survival after 6 years of follow-up. Ann Oncol 2008, 19:1082-1089.
• [24]Biron P, Durand M, Roché H, Delozier T, Battista C, Fargeot P, et al.: Pegase 03: a prospective randomized phase III trial of FEC with or without high-dose thiotepa, cyclophosphamide and autologous stem cell transplantation in first-line treatment of metastatic breast cancer. Bone Marrow Transplant 2008, 41:555-562.
• [25]Berry DA, Ueno NT, Johnson MM, Lei X, Caputo J, Rodenhuis S, et al.: High-dose chemotherapy with autologous stem-cell support as adjuvant therapy in breast cancer: overview of 15 randomized trials. J Clin Oncol 2011, 29:3214-3223.
• [26]Hartmann JT, Gauler T, Metzner B, Gerl A, Casper J, Rick O, et al.: Phase I/II study of sequential dose-intensified ifosfamide, cisplatin, and etoposide plus paclitaxel as induction chemotherapy for poor prognosis germ cell tumors by the German testicular cancer study group. J Clin Oncol 2007, 25:742-5747.
• [27]Gonçalves A, Delva R, Fabbro M, Gladieff L, Lotz JP, Ferrero JM, et al.: Post-operative sequential high-dose chemotherapy with haematopoietic stem cell support as front-line treatment in advanced ovarian cancer: a phase II multicentre study. Bone Marrow Transplant 2006, 37:651-659.
• [28]Viens P, Bertucci F, Gravis G, Camerlo J, Cowen D, Delpero JR, et al.: Intensive chemotherapy with autologous stem cell transplantation in ovarian cancers: analysis of 67 patients treated at the Paoli-Calmettes Institute and a review of the literature. Bull Cancer 1997, 9:869-876.
• [29]Cure H, Battista C, Guastalla JP, Fabbro M, Tubiana-Mathieu N, Bourgeois H, et al.: Phase III Randomized Trial of High-Dose Chemotherapy (HDC) and Peripheral Blood Stem Cell (PBSC) Support as Consolidation in Patients (pts) with Responsive Low-Burden Advanced Ovarian Cancer (AOC): Preliminary Results of a GINECO/ FNCLCC/ SFGM-TC Study. Proc Am Soc Clin Oncol 2001., 20(abstr 815)
• [30]Legros M, Dauplat J, Fleury J, Cure H, Suzanne F, Chassagne J, et al.: High-dose chemotherapy with hematopoietic rescue in patients with stage III to IV ovarian cancer: long-term results. J Clin Oncol 1997, 15:1302-1308.
• [31]Stiff PJ, Bayer R, Kerger C, Potkul RK, Malhotra D, Peace DJ, et al.: High-dose chemotherapy with autologous transplantation for persistent/relapsed ovarian cancer: a multivariate analysis of survival for 100 consecutively treated patients. J Clin Oncol 1997, 15:13092-1317.
• [32]Stiff PJ, Shpall EJ, Liu PY, Wilczynski SP, Callander NS, Scudder SA, et al.: Randomized Phase II trial of two high-dose chemotherapy regimens with stem cell transplantation for the treatment of advanced ovarian cancer in first remission or chemosensitive relapse: a Southwest Oncology Group study. Gynecol Oncol 2004, 94:98-106.
• [33]Pal T, Permuth-Wey J, Betts JA, Krischer JP, Fiorica J, Arango H, et al.: BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer 2005, 104:2807-2816.
• [34]Boyd J, Sonoda Y, Federici MG, Bogomolniy F, Rhei E, Maresco DL, et al.: Clinicopathologic features of BRCA-linked and sporadic ovarian cancer. JAMA 2000, 283:2260-2265.
• [35]Vencken PM, Kriege M, Hoogwerf D, Beugelink S, van der Burg ME, Hooning MJ, et al.: Chemosensitivity and outcome of BRCA1- and BRCA2-associated ovarian cancer patients after first-line chemotherapy compared with sporadic ovarian cancer patients. Ann Oncol 2011, 22:1346-1352.
• [36]Tan DS, Rothermundt C, Thomas K, Bancroft E, Eeles R, Shanley S, 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, 26:5530-5536.
• [37]Konstantinopoulos PA, Spentzos D, Karlan BY, Taniguchi T, Fountzilas E, Francoeur N, et al.: Gene expression profile of BRCAness that correlates with responsiveness to chemotherapy and with outcome in patients with epithelial ovarian cancer. J Clin Oncol 2010, 28:3555-3561.
• [38]Bast RC Jr, Mills GB: Personalizing therapy for ovarian cancer: BRCAness and beyond. J Clin Oncol 2010, 28:3545-3548.
• [39]Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, et al.: Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009, 361:123-134.
• [40]Fong PC, Yap TA, Boss DS, Carden CP, Mergui-Roelvink M, Gourley C, et al.: Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J Clin Oncol 2010, 28:2512-2519.
• [41]Audeh MW, Carmichael J, Penson RT, Friedlander M, Powell B, Bell-McGuinn KM, et al.: Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet 2010, 376:245-251.
• [42]Gelmon KA, Hirte HW, Robidoux A, Tonkin KS, Tischkowitz M, Swenerton K, 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, 12:852-861.
• [43]Piccart MJ, Floquet A, Scarfone G, Willemse PH, Emerich J, Vergote I, et al.: Intraperitoneal cisplatin versus no further treatment: 8-year results of EORTC 55875, a randomized phase III study in ovarian cancer patients with a pathologically complete remission after platinum-based intravenous chemotherapy. Int J Gynecol Cancer 2003, 13(Suppl 2):196-203.
• [44]Pecorelli S, Favalli G, Gadducci A, Katsaros D, Panici PB, Carpi A, et al.: Phase III trial of observation versus six courses of paclitaxel in patients with advanced epithelial ovarian cancer in complete response after six courses of paclitaxel/platinum-based chemotherapy: final results of the After-6 protocol 1. J Clin Oncol 2009, 27:4642-4648.
• [45]Perren TJ, Swart AM, Pfisterer J, Ledermann JA, Pujade-Lauraine E, Kristensen G, et al.: A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 2011, 365:2484-96.