Journal of Cancer Research and Clinical Oncology

, Volume 135, Issue 11, pp 1513–1520 | Cite as

In vitro extreme drug resistance assay to taxanes or platinum compounds for the prediction of clinical outcomes in epithelial ovarian cancer: a prospective cohort study

  • Hee Seung Kim
  • Tae Joong Kim
  • Hyun Hoon Chung
  • Jae Weon Kim
  • Byung Gie Kim
  • Noh Hyun Park
  • Yong Sang Song
  • Duk Soo Bae
  • Soon Beom KangEmail author
Original Paper



We sought to investigate the efficacy of in vitro extreme drug resistance (EDR) assay for the prediction of drug response, platinum-resistance (progression-free survival, PFS <6 months) and survival in patients with epithelial ovarian cancer (EOC) who received taxane- and platinum-based chemotherapy after surgery.


Between December 2005 and August 2007, 43 patients were enrolled prospectively. They underwent staging laparotomy followed by six or nine cycles of taxane- and platinum-based chemotherapy, and their tumors were submitted for in vitro EDR assay to taxanes (paclitaxel or docetaxel) and platinum compounds (carboplatin or cisplatin).


The rates of EDR to taxanes and platinum compounds were 20.9% (9/43) and 23.3% (10/43). Patients with EDR to platinum compounds showed a lower rate of overall response (60 vs. 100%), a higher rate of platinum-resistance (50 vs. 18.2%) and poor overall survival (OS) (median OS; 29.2 vs. 33.7 months) than those without EDR to platinum compounds (P < 0.05), whereas patients with EDR to taxanes showed poor PFS than those without EDR to taxanes (12.5 vs. 19 months, P < 0.01). Moreover, suboptimal debulking surgery and EDR to taxanes were poor prognostic factors for PFS (adjusted hazard ratio 3.215 and 3.984; 95% confidence interval 1.845–7.895 and 3.814–11.674, respectively) although there was no independent risk factor for poor OS by the multivariate Cox’s proportional hazard analysis.


In vitro EDR assay to taxanes and platinum compounds may be helpful for predicting drug response, platinum-resistance and survival in patients with EOC who received taxane- and platinum-based chemotherapy after staging laparotomy.


In vitro extreme drug resistance assay Taxanes Platinum compounds Epithelial ovarian cancer 



The authors in the current study wish to appreciate Innocell Company for taking charge of in vitro EDR assay to study successfully. Moreover, we deeply appreciate the committee of the International Symposium on Novel Strategies for Targeted Prevention and Treatment of Cancer for giving us the opportunity to present with young scientist award (December 19–20, 2008).

Conflict of interest statement

The authors declare that there are no conflicts of interest.


  1. Albrecht M, Simon WE, Hölzel F (1985) Individual chemosensitivity of in vitro proliferating mammary and ovarian carcinoma cells in comparison to clinical results of chemotherapy. J Cancer Res Clin Oncol 109:210–216. doi: 10.1007/BF00390360 PubMedCrossRefGoogle Scholar
  2. Berek JS (1992) Second-look versus second-nature. Gynecol Oncol 44:1–2. doi: 10.1016/0090-8258(92)90001-Y PubMedCrossRefGoogle Scholar
  3. Chen Y, He M, Wu Y, Li H, Yu D (2001) Investigation on marking method for phenomenon on regrowth drug resistance in relapsed acute myelogenous leukemia. J Tongji Med Univ 21:286–288PubMedGoogle Scholar
  4. Cortazar P, Johnson BE (1999) Review of the efficacy of individualized chemotherapy selected by in vitro drug sensitivity testing for patients with cancer. J Clin Oncol 17:1625–1631PubMedGoogle Scholar
  5. d’Amato TA, Landreneau RJ, McKenna RJ, Santos RS, Parker RJ (2006) Prevalence of in vitro extreme chemotherapy resistance in resected nonsmall-cell lung cancer. Ann Thorac Surg 81:440–446 (discussion 6–7)PubMedCrossRefGoogle Scholar
  6. Eitan R, Levine DA, Abu-Rustum N, Sonoda Y, Huh JN, Franklin CC, Stevens TA, Barakat RR, Chi DS (2005) The clinical significance of malignant pleural effusions in patients with optimally debulked ovarian carcinoma. Cancer 103:1397–1401PubMedCrossRefGoogle Scholar
  7. Eltabbakh GH (2000) Extreme drug resistance assay and response to chemotherapy in patients with primary peritoneal carcinoma. J Surg Oncol 73:148–152PubMedCrossRefGoogle Scholar
  8. Eltabbakh GH, Piver MS, Hempling RE, Recio FO, Lele SB, Marchetti DL, Baker TR, Blumenson LE (1998) Correlation between extreme drug resistance assay and response to primary paclitaxel and cisplatin in patients with epithelial ovarian cancer. Gynecol Oncol 70:392–397PubMedCrossRefGoogle Scholar
  9. Fan CW, Fan HA, Hsu SH, Chan CC, Chen SY, Hsu YH, Chan EC (2004) An in vitro short time-high dose drug exposure assay for predicting 5FU-resistance of colorectal cancer. Cancer Lett 214:181–188PubMedCrossRefGoogle Scholar
  10. Friedman JB, Weiss NS (1990) Second thoughts about second-look laparotomy in advanced ovarian cancer. N Engl J Med 322:1079–1082PubMedCrossRefGoogle Scholar
  11. Fruehauf JP (2002) In vitro assay-assisted treatment selection for women with breast or ovarian cancer. Endocr Relat Cancer 9:171–182PubMedCrossRefGoogle Scholar
  12. Geisler JP, Linnemeier GC, Thomas AJ, Manahan KJ (2007) Extreme drug resistance is common after prior exposure to paclitaxel. Gynecol Oncol 106:538–540PubMedCrossRefGoogle Scholar
  13. Hayward IP, Hurst T, Parsons PG, Khoo SK (1992) Combination chemotherapy tested in a short-term thymidine incorporation assay in primary cultures of ovarian adenocarcinomas. Int J Cell Cloning 10:182–189PubMedCrossRefGoogle Scholar
  14. Hillner BE (1987) Medical decision making: a Bayesian approach to laboratory testing. Med Sect Proc 2:7–37Google Scholar
  15. Holloway RW, Mehta RS, Finkler NJ, Li KT, McLaren CE, Parker RJ, Fruehauf JP (2002) Association between in vitro platinum resistance in the EDR assay and clinical outcomes for ovarian cancer patients. Gynecol Oncol 87:8–16PubMedCrossRefGoogle Scholar
  16. Kern DH, Weisenthal LM (1990) Highly specific prediction of antineoplastic drug resistance with an in vitro assay using suprapharmacologic drug exposures. J Natl Cancer Inst 82:582–588PubMedCrossRefGoogle Scholar
  17. Kim HS, Kim TH, Chung HH, Kim JW, Park NH, Song YS, Kang SB (2008) Clinical analysis for the prognostic factors in patients with recurrent epithelial ovarian cancer who underwent secondary cytoreductive surgery. J Gynecol Oncol 19:75–80CrossRefGoogle Scholar
  18. Loizzi V, Chan JK, Osann K, Cappuccini F, DiSaia PJ, Berman ML (2003) Survival outcomes in patients with recurrent ovarian cancer who were treated with chemoresistance assay-guided chemotherapy. Am J Obstet Gynecol 189:1301–1307PubMedCrossRefGoogle Scholar
  19. McAlpine JN, Eisenkop SM, Spirtos NM (2008) Tumor heterogeneity in ovarian cancer as demonstrated by in vitro chemoresistance assays. Gynecol Oncol 110:360–364PubMedCrossRefGoogle Scholar
  20. McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY, Clarke-Pearson DL, Davidson M (1996) Cyclophosphamide and cisplatin versus paclitaxel and cisplatin: a phase III randomized trial in patients with suboptimal stage III/IV ovarian cancer (from the Gynecologic Oncology Group). Semin Oncol 23:40–47PubMedGoogle Scholar
  21. Mehta RS, Bornstein R, Yu IR, Parker RJ, McLaren CE, Nguyen KP, Li KT, Fruehauf JP (2001) Breast cancer survival and in vitro tumor response in the extreme drug resistance assay. Breast Cancer Res Treat 66:225–237PubMedCrossRefGoogle Scholar
  22. Orr JW Jr, Orr P, Kern DH (1999) 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 Sci Am 5:174–178PubMedGoogle Scholar
  23. Ozols RF, Bundy BN, Greer BE, Fowler JM, Clarke-Pearson D, Burger RA, Mannel RS, DeGeest K, Hartenbach EM, Baergen R (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 21:3194–3200PubMedCrossRefGoogle Scholar
  24. Panici PB, Maggioni A, Hacker N, Landoni F, Ackermann S, Campagnutta E, Tamussino K, Winter R, Pellegrino A, Greggi S, Angioli R, Manci N, Scambia G, Dell’Anna T, Fossati R, Floriani I, Rossi RS, Grassi R, Favalli G, Raspagliesi F, Giannarelli D, Martella L, Mangioni C (2005) Systematic aortic and pelvic lymphadenectomy versus resection of bulky nodes only in optimally debulked advanced ovarian cancer: a randomized clinical trial. J Natl Cancer Inst 97:560–566PubMedGoogle Scholar
  25. Piver MS, Eltabbakh GH, Hempling RE, Recio FO, Blumenson LE (1998) Prospective sequential trials of induction weekly cisplatin followed by monthly cisplatin, doxorubicin, cyclophosphamide and paclitaxel and cisplatin in optimal (< or =1 cm) stage III and IV ovarian cancer. Eur J Gynaecol Oncol 19:5–10PubMedGoogle Scholar
  26. Schrag D, Garewal HS, Burstein HJ, Samson DJ, Von Hoff DD, Somerfield MR (2004) American Society of Clinical Oncology Technology Assessment: chemotherapy sensitivity and resistance assays. J Clin Oncol 22:3631–3638PubMedCrossRefGoogle Scholar
  27. Sondak VK, Bertelsen CA, Tanigawa N, Hildebrand-Zanki SU, Morton DL, Korn EL, Kern DH (1984) Clinical correlations with chemosensitivities measured in a rapid thymidine incorporation assay. Cancer Res 44:1725–1728PubMedGoogle Scholar
  28. Sondak VK, Korn EL, Morton DL, Kern DH (1988) Testing chemotherapeutic combinations in the human tumor colony—forming assay. J Surg Oncol 37:156–160PubMedCrossRefGoogle Scholar
  29. Tanigawa N, Kern DH, Hikasa Y, Morton DL (1982) Rapid assay for evaluating the chemosensitivity of human tumors in soft agar culture. Cancer Res 42:2159–2164PubMedGoogle Scholar
  30. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216PubMedCrossRefGoogle Scholar
  31. Vasey PA, Jayson GC, Gordon A, Gabra H, Coleman R, Atkinson R, Parkin D, Paul J, Hay A, Kaye SB (2004) Phase III randomized trial of docetaxel-carboplatin versus paclitaxel-carboplatin as first-line chemotherapy for ovarian carcinoma. J Natl Cancer Inst 96:1682–1691PubMedGoogle Scholar
  32. Villman K, Blomqvist C, Larsson R, Nygren P (2005) Predictive value of in vitro assessment of cytotoxic drug activity in advanced breast cancer. Anticancer Drugs 16:609–615PubMedCrossRefGoogle Scholar
  33. Yang L, Klint A, Lambe M, Bellocco R, Riman T, Bergfeldt K, Persson I, Weiderpass E (2008) Predictors of ovarian cancer survival: a population-based prospective study in Sweden. Int J Cancer 123:672–679PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Hee Seung Kim
    • 1
  • Tae Joong Kim
    • 2
  • Hyun Hoon Chung
    • 1
  • Jae Weon Kim
    • 1
  • Byung Gie Kim
    • 2
  • Noh Hyun Park
    • 1
  • Yong Sang Song
    • 1
  • Duk Soo Bae
    • 2
  • Soon Beom Kang
    • 1
    Email author
  1. 1.Department of Obstetrics and GynecologySeoul National University College of MedicineSeoulRepublic of Korea
  2. 2.Department of Obstetrics and Gynecology, Samsung Medical CenterSungkyunkwan University College of MedicineSeoulRepublic of Korea

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