Regular Article| Volume 87, ISSUE 1, P8-16, October 2002

Download started.


Association between in Vitro Platinum Resistance in the EDR Assay and Clinical Outcomes for Ovarian Cancer Patients

      This paper is only available as a PDF. To read, Please Download here.


      Objective. The initial clinical response to platinum is a major determinant of outcome for patients with ovarian cancer. This retrospective study was undertaken to correlate the response and survival of newly diagnosed advanced ovarian cancer patients who received platinum-based therapy with in vitro drug response to cisplatin or carboplatin measured as percentage cell inhibition (PCI) in the in vitro Extreme Drug Resistance (EDR) assay.
      Methods. Outcomes for newly diagnosed ovarian cancer patients with tumor specimens submitted in a serial fashion for the EDR assay were studied. EDR assay results for cisplatin and carboplatin were correlated with clinical outcome for 79 evaluable chemotherapy naı̈ve cases who presented with advanced (stages IIC, III, and IV) ovarian cancer. Stage IV and suboptimally debulked stage IIIc accounted for 16 cases, while 63 cases were optimally debulked Stage III/IIc. All patients were treated with platinum-based combination chemotherapy at a single institution. In vitro results for patient tumors were classified as low drug resistance (PCI > median), intermediate drug resistance [PCI between the median and 1 standard deviation (SD) below the median], or extreme drug resistance (PCI more than 1 SD below the median). For the purpose of this analysis, in vitro EDR to either cisplatin or carboplatin was considered to represent extreme resistance to platinum (EDRP), while the absence of EDR to either cisplatin or carboplatin was considered to represent low resistance to platinum (LDRP). Patients demonstrating relative in vitro resistance to paclitaxel and non-cross-resistance to cyclophosphamide and/or doxorubicin received cyclophosphamide plus platinum (CP); cyclophosphamide, doxorubicin, and platinum (CAP); or platinum alone in place of paclitaxel plus platinum (TP). Progression-free survival (PFS) and overall survival (OS) were correlated with EDR assay results.
      Results. Median PFS was 6 months for the 17 cases exhibiting EDRP, compared to 24 months for the 62 cases exhibiting LDRP in vitro [relative risk (RR) 3.78, confidence intervals (CI) 1.82–7.83], adjusted for stage, debulking status, in vitro response to 3-OH-cyclophosphamide, and histological grade. Estimated overall 5-year survival was 19% for patients with tumors showing EDRP, compared to 68% for patients with tumors showing LDRP (RR 2.32, CI 1.06–5.07). Patients treated with CP (n = 20) showed no significant difference in OS compared to patients treated with TP (n = 54), CAP (n = 4), or cisplatin (n = 1) alone. In vitro platinum response remained an independent predictor of PFS and OS in multivariate analyses adjusted for CP versus TP, CAP, or platinum administration, and adjusted for debulking status. Median PFS for all 79 patients was 22 months, with an estimated 5-year survival of 57%.
      Conclusions. Patients with tumors demonstrating in vitro EDR to platinum were at significantly increased risk for progression and death when treated with standard platinum-based regimens. Such patients may therefore benefit from entry onto trials with novel agents or combinations.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Gynecologic Oncology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect



        • Fruehauf JP
        • Bosanquet A
        In vitro determination of drug response: a discussion of clinical applications.
        PPO Updates. 1993; 7: 1-16
        • Chu E
        • DeVita V
        Principles of cancer management: Chemotherapy.
        in: DeVita V Hellman S Rosenberg S Cancer: Principles and Practice of Oncology. Lippincott Williams & Wilkins, 2001
        • Kern DH
        • Weisenthal ML
        Highly specific prediction of antineoplastic drug resistance with an in vitro assay utilizing suprapharmacological drug exposures.
        J Natl Cancer Inst. 1990; 82: 582-588
        • Fruehauf JP
        • Manetta A
        Use of the extreme drug resistance assay to evaluate mechanisms of resistance in ovarian cancer: taxol resistance and MDR-1 expression.
        Contrib Gynecol Obstet. 1994; 19: 39-52
        • Mehta RS
        • Bornstein R
        • Yu I-R
        • Parker RJ
        • McLaren CE
        • Nguyen P
        • Fruehauf JP
        Association between in vitro extreme drug resistance assay scores and breast cancer patient survival after chemotherapy.
        Breast Cancer Res Treat. 2001; 66: 225-237
        • Colombo N
        Randomized trial of paclitaxel (PTX) and carboplatin (CBDCA) versus a control arm of carboplatin or CAP (Cyclophosphamide, Doxorubicin & Cisplatin): the third International Collaborative Ovarian Neoplasm study (ICON3).
        Proc Am Soc Clin Oncol. 2000; 19
        • McGuire WP
        • Hoskins WJ
        • Brady MF
        • Kucera PR
        • Partridge EE
        • Look KY
        • Clarke-Pearson DL
        • Davidson M
        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
        • Aabo K
        • Adams M
        • Adnitt P
        • Alberts DS
        • Athanazziou A
        • Barley V
        • Bell DR
        • Bianchi U
        • Bolis G
        • Brady MF
        • Brodovsky HS
        • Bruckner H
        • Buyse M
        • Canetta R
        • Chylak V
        • Cohen CJ
        • Colombo N
        • Conte PF
        • Crowther D
        • Edmonson JH
        • Gennatas C
        • Gilbey E
        • Gore M
        • Guthrie D
        • Yeap BY
        Chemotherapy in advanced ovarian cancer: four systematic meta-analyses of individual patient data from 37 randomized trials.
        Br J Cancer. 1998; 78: 1479-1487
        • Go RS
        • Adjei AA
        Review of the comparative pharmacology and clinical activity of Cisplatin and carboplatin.
        J Clin Oncol. 1999; 17: 409-411
        • ten Bokkel Huinink WW
        • van der Burg ME
        • van Oosterom AT
        • Neijt JP
        • George M
        • Guastalla JP
        • Veenhof CH
        • Rotmensz N
        • Dalesio O
        • Vermorken JB
        Carboplatin in combination chemotherapy for ovarian cancer.
        Cancer Treat Rev. 1988; 15: 9-13
        • Alberts DS
        • Green S
        • Hannigan EV
        • O'Toole R
        • Stock-Novack D
        • Anderson P
        • Surwit EA
        • Malvlya VK
        • Nahhas WA
        • Jolles CJ
        Improved therapeutic index of carboplatin plus cyclophosphamide versus Cisplatin plus cyclophosphamide: final report by the Southwest Oncology Group of a phase III randomized trial in stages III and IV ovarian cancer.
        J Clin Oncol. 1992; 10: 706-710
        • Hacker NF
        • Berek JS
        • Lagasse LD
        • Nieberg RK
        • Elashoff RM
        Primary cytoreductive surgery for epithelial ovarian cancer.
        Obstet Gynecol. 1983; 61: 413-420
        • Kurbacher CM
        • Janát MM
        • Brenne U
        • Cree IA
        • Andreotti PE
        • Bruckner HW
        Optimized use of paclitaxel and platinum for primary ovarian cancer guided by an ex vivo chemosensitivity assay.
        Proc Am Assoc Clin Oncol. 2000; 19
        • Eltabbakh GH
        • Piver MS
        • Hempling RE
        • Recio FO
        • Lele SB
        • Marchetti DL
        • Baker TR
        • Blumenson LE
        Correlation between extreme drug resistance assay and response to primary paclitaxel and cisplatin in patients with epithelial ovarian cancer.
        Gynecol Oncol. 1998; 70: 392-397
        • DiSaia PJ
        Letter to the editor.
        Gynecol Oncol. 1999; 74: 148-149
        • Andreotti PE
        • Cree IA
        • Kurbacher CM
        • Hartmann DM
        • Linder D
        • Harel G
        • Gleiberman I
        • Caruso PA
        • Ricks SH
        • Untch M
        Chemosensitivity testing of human tumors using a microplate adenosine triphosphate luminescence assay: clinical correlation for cisplatin resistance of ovarian carcinoma.
        Cancer Res. 1995; 15: 5276-5282
        • Taylor CG
        • Sargent JM
        • Elgie AW
        • Reid FD
        • Alton PA
        • Hill JG
        • Taylor CG
        • Path F RC
        • Sargent JM
        The clinical relevance of chemosensitivity testing in ovarian cancer.
        Cancer Det Prev. 1998; 22: 305-312
        • Muggia FM
        • Braly PS
        • Brady MF
        • Sutton G
        • Niemann TH
        • Lentz SL
        • Alvarez RD
        • Kucera PR
        • Small JM
        Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: a Gynecologic Oncology Group study.
        J Clin Oncol. 2000; 18: 106-115
        • Orr JM
        • Orr P
        • Kern DH
        Cost-effective treatment of women with advanced ovarian cancer by cytoreductive surgery and chemotherapy directed by an in vitro assay for drug resistance.
        Cancer J. 1999; 5: 174-178
        • Markman M
        • Bookman MA
        Second-line treatment of ovarian cancer.
        Oncologist. 2000; 5: 26-35
        • Cortazar P
        • Johnson B
        Review of efficacy of individualized chemotherapy selected by in vitro drug sensitivity testing for patients with cancer.
        J Clin Oncol. 1999; 17: 1625-1631
        • Dottino P
        • Evans SS
        • Segna R
        • Beddoe AM
        • Sommers B
        • Nagourney R
        EVA-Assay-directed therapy of advanced ovarian cancer.
        Proc Am Assoc Clin Oncol. 2000; 19
        • Kurbacher CM
        • Steir U
        • Janat MM
        • Cree I
        • Bruckner HW
        ATP-assay-directed chemotherapy for recurrent ovarian cancer: mature results of an ISCO clinical study group trial.
        Proc Am Soc Clin Oncol. 2001; 20
        • Csoka K
        • Tholander B
        • Gerdin E
        • de la Torre M
        • Larsson R
        • Nygren P
        In vitro determination of cytotoxic drug response in ovarian carcinoma using the fluorometric microculture cytotoxicity assay (FMCA).
        Int J Cancer. 1997; 72: 1008-1012
        • Konecny G
        • Crohns C
        • Pegram M
        • Felber M
        • Lude S
        • Kurbacher C
        • Cree IA
        • Hepp H
        • Untch M
        Correlation of drug response with the ATP tumor chemosensitivity assay in primary FIGO stage III ovarian cancer.
        Gynecol Oncol. 2000; 77: 258-263