Platinum-free interval affects efficacy of following treatment for platinum-refractory or -resistant ovarian cancer

  • Mayumi Kobayashi-Kato
  • Mayu YunokawaEmail author
  • Seiko Bun
  • Naoyuki Miyasaka
  • Tomoyasu Kato
  • Kenji Tamura
Original Article



Platinum-refractory or -resistant ovarian cancer (PRROC) is associated with poor prognosis and low response to further chemotherapy. We investigated predictors of effectiveness of following treatments for PRROC.

Patients and methods

We included 380 patients diagnosed with stage I–IV ovarian, fallopian tube, or primary peritoneal cancer, who were treated at the National Cancer Center Hospital in Japan from January 2007 to December 2014 and recurred after initial treatment, who had a platinum-refractory or -resistant relapses and received chemotherapy, in this single-center, retrospective study. We investigated factors related to response to following treatment, and to progression-free survival (PFS).


Among 183 patients (48%) who suffered recurrences, 62 (34%) developed PRROC after chemotherapy. In multivariate analysis, platinum-free interval (PFI) < 3 months was independently associated with progressive disease (odds ratio [OR] 6.043, 95% confidence interval [CI] 1.485–24.595, P = 0.012). Median PFS was 139 days (95% CI 19.4–258) among patients with PFI > 3 months, but was 57 days (95% CI 34.7–79.2) among those with PFI < 3 months. In multivariate analysis, two factors, performance status (PS) 1–2 (HR 1.915, 95% CI 1.074–3.415, P = 0.028) and PFI < 3 months (HR 1.943, 95% CI 1.109–3.403, P = 0.02), were independently associated with worse PFS.


PS 1–2 and PFI < 3 months were significant predictors of poor response to following treatment for PRROC. Risks and benefits of treatment should be frankly discussed with patients who have these characteristics.


Platinum-refractory ovarian cancer Platinum-resistant ovarian cancer Predictive marker Prognostic marker Chemotherapy Platinum free interval 



We thank Marla Brunker, from Edanz Group ( for editing a draft of this manuscript.

Compliance with ethical standards

Conflict of interest

There is no conflict of interest.


  1. 1.
    Parikh R, Kurosky SK, Udall M, Chang J, Cappelleri JC, Doherty JP, Kaye JA (2018) Treatment patterns and health outcomes in platinum-refractory or platinum-resistant ovarian cancer: a retrospective medical record review. Int J Gynecol Cancer 28(4):738–748. CrossRefGoogle Scholar
  2. 2.
    Slaughter K, Holman LL, Thomas EL, Gunderson CC, Lauer JK, Ding K, McMeekin DS, Moore KM (2016) Primary and acquired platinum-resistance among women with high grade serous ovarian cancer. Gynecol Oncol 142(2):225–230. CrossRefGoogle Scholar
  3. 3.
    Katsumata N, Yasuda M, Takahashi F, Isonishi S, Jobo T, Aoki D, Tsuda H, Sugiyama T, Kodama S, Kimura E, Ochiai K, Noda K, Japanese Gynecologic Oncology G (2009) Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial. Lancet 374(9698):1331–1338. CrossRefGoogle Scholar
  4. 4.
    Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, Mannel RS, Homesley HD, Fowler J, Greer BE, Boente M, Birrer MJ, Liang SX, Gynecologic Oncology G (2011) Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 365(26):2473–2483. CrossRefGoogle Scholar
  5. 5.
    Perren TJ, Swart AM, Pfisterer J, Ledermann JA, Pujade-Lauraine E, Kristensen G, Carey MS, Beale P, Cervantes A, Kurzeder C, du Bois A, Sehouli J, Kimmig R, Stahle A, Collinson F, Essapen S, Gourley C, Lortholary A, Selle F, Mirza MR, Leminen A, Plante M, Stark D, Qian W, Parmar MK, Oza AM, Investigators I (2011) A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 365(26):2484–2496. CrossRefGoogle Scholar
  6. 6.
    Pujade-Lauraine E, Wagner U, Aavall-Lundqvist E, Gebski V, Heywood M, Vasey PA, Volgger B, Vergote I, Pignata S, Ferrero A, Sehouli J, Lortholary A, Kristensen G, Jackisch C, Joly F, Brown C, Le Fur N, du Bois A (2010) Pegylated liposomal Doxorubicin and Carboplatin compared with Paclitaxel and Carboplatin for patients with platinum-sensitive ovarian cancer in late relapse. J Clin Oncol 28(20):3323–3329. CrossRefGoogle Scholar
  7. 7.
    Aghajanian C, Blank SV, Goff BA, Judson PL, Teneriello MG, Husain A, Sovak MA, Yi J, Nycum LR (2012) OCEANS: a randomized, double-blind, placebo-controlled 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 30(17):2039–2045. CrossRefGoogle Scholar
  8. 8.
    Davis A, Tinker AV, Friedlander M (2014) "Platinum resistant" ovarian cancer: what is it, who to treat and how to measure benefit? Gynecol Oncol 133(3):624–631. CrossRefGoogle Scholar
  9. 9.
    Tomao F, Marchetti C, Romito A, Di Pinto A, Di Donato V, Capri O, Palaia I, Monti M, Muzii L, Benedetti Panici P (2017) Overcoming platinum resistance in ovarian cancer treatment: from clinical practice to emerging chemical therapies. Expert Opin Pharmacother 18(14):1443–1455. CrossRefGoogle Scholar
  10. 10.
    Stuart GC, Kitchener H, Bacon M, duBois A, Friedlander M, Ledermann J, Marth C, Thigpen T, Trimble E, Participants of 4th Ovarian Cancer Consensus C, Gynecologic Cancer I (2011) 2010 Gynecologic Cancer InterGroup (GCIG) consensus statement on clinical trials in ovarian cancer: report from the Fourth Ovarian Cancer Consensus Conference. Int J Gynecol Cancer 21(4):750–755. CrossRefGoogle Scholar
  11. 11.
    Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247. CrossRefGoogle Scholar
  12. 12.
    Pujade-Lauraine E, Hilpert F, Weber B, Reuss A, Poveda A, Kristensen G, Sorio R, Vergote I, Witteveen P, Bamias A, Pereira D, Wimberger P, Oaknin A, Mirza MR, Follana P, Bollag D, Ray-Coquard I (2014) Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. J Clin Oncol 32(13):1302–1308. CrossRefGoogle Scholar
  13. 13.
    Champer M, Huang Y, Hou JY, Tergas AI, Burke WM, Hillyer GC, Ananth CV, Neugut AI, Hershman DL, Wright JD (2018) Adherence to treatment recommendations and outcomes for women with ovarian cancer at first recurrence. Gynecol Oncol 148(1):19–27. CrossRefGoogle Scholar
  14. 14.
    Lindemann K, Gao B, Mapagu C, Fereday S, Emmanuel C, Alsop K, Traficante N, Australian Ovarian Cancer Study G, Harnett PR, Bowtell DDL, deFazio A (2018) Response rates to second-line platinum-based therapy in ovarian cancer patients challenge the clinical definition of platinum resistance. Gynecol Oncol 150(2):239–246. CrossRefGoogle Scholar
  15. 15.
    Lacave ANGJTFDGDEPMEGAJ (2001) Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin. J Clin Oncol 15:20–28Google Scholar
  16. 16.
    Monk BJ, Poveda A, Vergote I, Raspagliesi F, Fujiwara K, Bae DS, Oaknin A, Ray-Coquard I, Provencher DM, Karlan BY, Lhomme C, Richardson G, Rincon DG, Coleman RL, Marth C, Brize A, Fabbro M, Redondo A, Bamias A, Ma H, Vogl FD, Bach BA, Oza AM (2016) Final results of a phase 3 study of trebananib plus weekly paclitaxel in recurrent ovarian cancer (TRINOVA-1): Long-term survival, impact of ascites, and progression-free survival-2. Gynecol Oncol 143(1):27–34. CrossRefGoogle Scholar
  17. 17.
    Meier W, du Bois A, Reuss A, Kuhn W, Olbricht S, Gropp M, Richter B, Luck HJ, Kimmig R, Pfisterer J (2009) Topotecan versus treosulfan, an alkylating agent, in patients with epithelial ovarian cancer and relapse within 12 months following 1st-line platinum/paclitaxel chemotherapy. A prospectively randomized phase III trial by the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group (AGOOVAR). Gynecol Oncol 114(2):199–205. CrossRefGoogle Scholar
  18. 18.
    Roncolato FT, Berton-Rigaud D, O'Connell R, Lanceley A, Sehouli J, Buizen L, Okamoto A, Aotani E, Lorusso D, Donnellan P, Oza A, Avall-Lundqvist E, Berek J, Hilpert F, Ledermann JA, Kaminsky MC, Stockler MR, King MT, Friedlander M (2018) Validation of the modified Glasgow Prognostic Score (mGPS) in recurrent ovarian cancer (ROC) - Analysis of patients enrolled in the GCIG Symptom Benefit Study (SBS). Gynecol Oncol 148(1):36–41. CrossRefGoogle Scholar
  19. 19.
    Trillsch F, Mahner S, Hilpert F, Davies L, Garcia-Martinez E, Kristensen G, Savarese A, Vuylsteke P, Los M, Zagouri F, Gladieff L, Sehouli J, Khoon Lee C, Gebski V, Pujade-Lauraine E (2016) Prognostic and predictive effects of primary versus secondary platinum resistance for bevacizumab treatment for platinum-resistant ovarian cancer in the AURELIA trial. Ann Oncol 27(9):1733–1739. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of GynecologyNational Cancer Center HospitalTokyoJapan
  2. 2.Breast and Medical OncologyNational Cancer Center HospitalTokyoJapan
  3. 3.Department of Medical Oncology/Gynecologic OncologyCancer Institute Hospital of Japanese Foundation for Cancer ResearchTokyoJapan
  4. 4.Department of PharmacyNational Cancer Center HospitalTokyoJapan
  5. 5.Department of Perinatal and Women’S MedicineTokyo Medical and Dental UniversityTokyoJapan

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