Platinum-Gemcitabine-Avastin (PGA) for platinum-resistant/refractory ovarian cancer

Objectives: Synergism between gemcitabine and platinum is known clinically. Bevacizumab in combination with single-agent chemotherapy has demonstrated significant clinical activity in platinum-resistant recurrent ovarian cancer in AURELIA study. However, the efficacy of platinum-gemcitabine-bevacizumab (PGA) has not been investigated in the platinum-resistant population. Materials and Methods: A retrospective chart review was conducted in all patients with platinum-resistant/refractory ovarian cancer treated with triplet combination therapy containing a platinum agent, gemcitabine, and bevacizumab between July 2011 and December 2013. Results: In total, 13 patients met the selection criteria, including ten patients with resistant disease (10/13, 77%) and three patients with refractory disease (3/13, 23%). Most of the patients were heavily pre-treated, having received over three lines of prior chemotherapy regimens on average (range 1-11). All patients had previously received taxane therapy; four patients received gemcitabine, seven patients failed combination regimens including bevacizumab, and three patients progressed on chemotherapy including both gemcitabine and bevacizumab. Ten patients responded biochemically to the therapy (defined by CA-125 declined by at least 50%). Of ten responders, one patient achieved CR for 24 months (8%), six patients achieved PR for 6.8 months (46%), three had stable disease for 6.7 months (23%), and three patients had PD (23%) by RECIST 1.1 criteria. The regimen was well-tolerated. One patient (8%) developed grade 3 neutropenia and neutropenic fever, requiring hospitalization, two patients developed grade 3 thrombocytopenia, two patients (15%) developed thrombosis in internal jugular vein, requiring discontinuation of bevacizumab, one patient (8%) experienced skin ulcer, and two patients developed thrombosis in internal jugular vein, requiring discontinuation of bevacizumab. Conclusions: Combination of PGA appears to be safe and very active against platinum-resistant/refractory ovarian cancer and merits further evaluation prospectively. A randomized phase II study (NCT01936974) is currently under way to confirm this important finding.

Ovarian cancer; Resistant; Refractory; Chemotherapy; Platinum; Gemcitabine; Bevacizumab.

[1] Siegel R.L., Miller K.D., Jemal A.: “Cancer statistics, 2015”. CA Cancer J. Clin., 2015, 65, 5.

[2] Pinato D.J., Graham J., Gabra H., Sharma R.: “Evolving concepts in the management of drug resistant ovarian cancer: dose dense chemotherapy and the reversal of clinical platinum resistance”. Cancer Treat. Rev., 2013, 39, 153.

[3] Gore M.E., Fryatt I., Wiltshaw E., Dawson T.: “Treatment of relapsed carcinoma of the ovary with cisplatin or carboplatin following initial treatment with these compounds”. Gynecol. Oncol., 1990, 36, 207.

[4] Naumann R.W., Coleman R.L.: “Management strategies for recurrent platinum-resistant ovarian cancer”. Drugs, 2011, 71, 1397.

[5] Markman M., Blessing J., Rubin S.C., 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.

[6] Fracasso P.M., Blessing J.A., Morgan M.A., Sood A.K., Hoffman J.S.: “Phase II study of oxaliplatin in platinum-resistant and refractory ovarian cancer: a gynecologic group study”. J. Clin. Oncol., 2003, 21, 2856.

[7] Pujade-Lauraine E., Hilpert F., Weber B., Reuss A., Poveda A., Kristensen G., et al.: “Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA openlabel randomized phase III trial”. J. Clin. Oncol., 2014, 32, 1302.

[8] Aghajanian C., Blank S.V., Goff B.A., Judson P.L., Teneriello M.G., Husain A., et al.: “OCEANS: a randomized, double-blind, placebocontrolled 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.

[9] Matsuo K., Lin Y.G., Roman L.D., Sood A.K.: “Overcoming platinum resistance in ovarian carcinoma”. Expert Opin. Investig. Drugs, 2010, 19, 1339.

[10] See H.T., Freedman R.S., Kudelka A.P., Burke T.W., Gershenson D.M., Tangjitgamol S., et al.: “Retrospective review: re-treatment of patients with ovarian cancer with carboplatin after platinum resistance”. Int. J. Gynecol. Cancer, 2005, 15, 209.

[11] Piccart M.J., Green J.A., Lacave A.J., Reed N., Vergote I., Benedetti- Panici P., et al.: “Oxaliplatin or paclitaxel in patients with platinumpretreated advanced ovarian cancer: A randomized phase II study of the European Organization for Research and Treatment of Cancer Gynecology Group”. J. Clin. Oncol., 2000, 18, 1193.

[12] Mutch D.G., Orlando M., Goss T., Teneriello M.G., Gordon A.N., McMeekin S.D., et al.: “Randomized phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer”. J. Clin. Oncol., 2007, 25, 2811.

[13] Peters G.J., Van Moorsel C.J., Lakerveld B., Smid K., Noordhuis P., Comijn E.C., et al.: “Effects of gemcitabine on cis-platinum-DNA adduct formation and repair in a panel of gemcitabine and cisplatinsensitive or -resistant human ovarian cancer cell lines”. Int. J. Oncol., 2006, 28, 237.

[14] Wynne P., Newton C., Ledermann J.A., Olaitan A., Mould T.A., Hartley J.A.: “Enhanced repair of DNA interstrand crosslinking in ovarian cancer cells from patients following treatment with platinumbased chemotherapy”. Br. J Cancer, 2007, 97, 927.

[15] van Moorsel C.J., Pinedo H.M., Veerman G., Bergman A.M., Kuiper C.M., Vermorken J.B., et al.: “Mechanisms of synergism between cisplatin and gemcitabine in ovarian and non-small-cell lung cancer cell lines”. Br J. Cancer, 1999, 80, 981.

[16] Bozas G., Bamias A., Koutsoukou V., Efstathiou E., Gika D., Papadimitriou C.A., et al.: “Biweekly gemcitabine and cisplatin in platinum- resistant/refractory, paclitaxel-pretreated, ovarian and peritoneal carcinoma”. Gynecol. Oncol., 2007, 104, 580.

[17] Kalykaki A., Papakotoulas P., Tsousis S., Boukovinas I., Kalbakis K., Vamvakas L., et al.: “Gemcitabine plus oxaliplatin (GEMOX) in pretreated patients with advanced ovarian cancer: a multicenter phase II study of the Hellenic Oncology Research Group (HORG)”. Anticancer Res., 2008, 28, 495.

[18] Pujade-Lauraine E., Hilpert F., Weber B., Reuss A., Poveda A., Kristensen G., 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, abstr LBA5002.

[19] Tabernero J., Yoshino T., Cohn A.L., 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, 499.

[20] 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, 29.