Cancer Chemotherapy and Pharmacology

, Volume 78, Issue 4, pp 785–790 | Cite as

Prognostic factors from a randomized phase III trial of paclitaxel and carboplatin versus paclitaxel and cisplatin in metastatic or recurrent cervical cancer: Japan Clinical Oncology Group (JCOG) trial: JCOG0505-S1

  • Shin Nishio
  • Ryo Kitagawa
  • Taro Shibata
  • Hiroyuki Yoshikawa
  • Ikuo Konishi
  • Kimio Ushijima
  • Toshiharu Kamura
Original Article



The Japan Clinical Oncology Group (JCOG) trial JCOG0505 demonstrated the statistically significant non-inferiority of paclitaxel plus carboplatin (TC) to paclitaxel plus cisplatin (TP) in terms of overall survival (OS) in metastatic or recurrent cervical cancer. In that trial, patients were randomly assigned, adjusting for institution and known prognostic factors. The objective of this ancillary study was to evaluate the appropriateness of the adjustment factors used to have randomly assigned treatments and to investigate new potentially useful prognostic factors of paclitaxel plus platinum for future randomized trials in metastatic or recurrent cervical cancer.


The study subjects comprised 244 eligible patients in the JCOG0505 who were merged to have received either TC or TP. The effects of the following factors on OS were investigated using a Cox regression model taking into consideration the adjustment factors used in randomization in this trial (e.g., performance status [PS]) and other baseline factors, including platinum-free interval (PFI), pretreatment hemoglobin levels (PHLs), and pretreatment platelet counts (PPCs).


The median follow-up was 17.6 months, and median OS was 18.0 months. The hazard ratio was 1.83 in patients with a PS of 1 or 2 (vs. 0; P = 0.0004; 95 % confidence interval [CI] 1.31–2.55), 2.92 in patients with a PFI of <6 months (vs. PFI of ≥12 months; P < 0.0001; 95 % CI 1.73–4.91), 2.09 in patients with a PFI of <12 months (vs. PFI of ≥12 months; P = 0.0034; 95 % CI 1.28–3.44), and 0.69 in patients with PHL higher than or equal to the median value (vs. less than the median; P = 0.016; 95 % CI 0.51–0.93). No significant differences were obtained for PPC or the other known factors.


In addition to the known prognostic factor of PS, which was used as an adjusting factor, a PFI of <12 months and lower PHL were newly demonstrated to be associated with poor outcomes in patients with metastatic or recurrent cervical cancer. These new prognostic factors should be validated in future prospective trials.

Clinical trial information

UMIN-CTR[] ID: C000000335.


Cervical cancer Metastatic Recurrent Platinum-free interval Pretreatment hemoglobin level 



This work was supported in part by the National Cancer Research and Development Fund (23-A-16, 23-A-17, 26-A-4). We are grateful to the members of the JCOG Data Center and JCOG Operations Office for their support in preparing the manuscript (Drs. Junko Eba, Tomonori Mizutani, Keisuke Kanato, Kenichi Nakamura, and Haruhiko Fukuda), statistical analysis (Mr. Junki Mizusawa), and data management (Ms. Kazumi Kubota).

Compliance with ethical standards

Conflict of interest

The authors have declared no conflict of interest.


  1. 1.
    Brader KR, Morris M, Levenback C, Levy L, Lucas KR, Gershenson DM (1998) Chemotherapy for cervical carcinoma: factors determining response and implications for clinical trial design. J Clin Oncol 16:1879–1884PubMedGoogle Scholar
  2. 2.
    Zanetta G, Torri W, Bocciolone L, Lucchini V, Mangioni C (1995) Factors predicting response to chemotherapy and survival in patients with metastatic or recurrent squamous cell cervical carcinoma: a multivariate analysis. Gynecol Oncol 58:58–63CrossRefPubMedGoogle Scholar
  3. 3.
    Moore DH, Tian C, Monk BJ et al (2010) Prognostic factors for response to cisplatin-based chemotherapy in advanced cervical carcinoma: a Gynecologic Oncology Group Study. Gynecol Oncol 116:44–49CrossRefPubMedGoogle Scholar
  4. 4.
    Potter ME, Hatch KD, Potter MY, Shingleton HM, Baker VV (1989) Factors affecting the response of recurrent squamous cell carcinoma of the cervix to cisplatin. Cancer 63:1283–1286CrossRefPubMedGoogle Scholar
  5. 5.
    Pectasides D, Fountzilas G, Papaxoinis G, Pectasides E, Xiros N, Sykiotis C et al (2009) Carboplatin and paclitaxel in metastatic or recurrent cervical cancer. Int J Gynecol Cancer 19:777–781CrossRefPubMedGoogle Scholar
  6. 6.
    Kitagawa R, Katsumata N, Shibata T, Kamura T, Kasamatsu T, Nakanishi T et al (2015) Paclitaxel plus carboplatin versus paclitaxel plus cisplatin in metastatic or recurrent cervical cancer: the open-label randomized phase III trial JCOG0505. J Clin Oncol 33:2129–2135CrossRefPubMedGoogle Scholar
  7. 7.
    Long HJ 3rd, Bundy BN, Grendys EC Jr, Benda JA, McMeekin DS, Sorosky J et al (2005) Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group Study. J Clin Oncol 23:4626–4633CrossRefPubMedGoogle Scholar
  8. 8.
    Hirte HW, Strychowsky JE, Oliver T, Fung-Kee-Fung M, Elit L, Oza AM (2007) Chemotherapy for recurrent, metastatic or persistent cervical cancer: a systematic review. Int J Gynecol Cancer 17:1194–1204CrossRefPubMedGoogle Scholar
  9. 9.
    Long HJ 3rd (2007) Management of metastatic cervical cancer: review of the literature. J Clin Oncol 25:2966–2974CrossRefPubMedGoogle Scholar
  10. 10.
    Tanioka M, Katsumata N, Yonemori K, Kouno T, Shimizu C, Tamura K et al (2011) Second platinum therapy in patients with uterine cervical cancer previously treated with platinum chemotherapy. Cancer Chemother Pharmacol 68:337–342CrossRefPubMedGoogle Scholar
  11. 11.
    Matoda M, Tanigawa T, Omatsu K, Ushioda N, Yamamoto A, Okamoto S et al (2013) Platinum-free interval in second-line chemotherapy for recurrent cervical cancer. Int J Gynecol Cancer 23:1670–1674CrossRefPubMedGoogle Scholar
  12. 12.
    Rodriguez GC, Clarke-Pearson DL, Soper JT, Berchuck A, Synan I, Dodge RK (1994) The negative prognostic implications of thrombocytosis in women with stage IB cervical cancer. Obstet Gynecol 83:445–448PubMedGoogle Scholar
  13. 13.
    De Jonge ET, Viljoen E, Lindeque BG, Amant F, Nesland JM, Holm R (1999) The prognostic significance of p53, mdm2, c-erbB-2, cathepsin D, and thrombocytosis in stage IB cervical cancer treated by primary radical hysterectomy. Int J Gynecol Cancer 9:198–205CrossRefPubMedGoogle Scholar
  14. 14.
    Hernandez E, Donohue KA, Anderson LL, Heller PB, Stehman FB (2000) The significance of thrombocytosis in patients with locally advanced cervical carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 78:137–142CrossRefPubMedGoogle Scholar
  15. 15.
    Dunst J, Kuhnt T, Strauss HG, Krause U, Pelz T, Koelbl H et al (2003) Anemia in cervical cancers: impact on survival, patterns of relapse, and association with hypoxia and angiogenesis. Int J Radiat Oncol Biol Phys 56:778–787CrossRefPubMedGoogle Scholar
  16. 16.
    Winter WE 3rd, Maxwell GL, Tian C, Sobel E, Rose GS, Thomas G et al (2004) Association of hemoglobin level with survival in cervical carcinoma patients treated with concurrent cisplatin and radiotherapy: a Gynecologic Oncology Group Study. Gynecol Oncol 94:495–501CrossRefPubMedGoogle Scholar
  17. 17.
    Fuso L, Mazzola S, Marocco F, Ferrero A, Dompè D, Carus AP et al (2005) Pretreatment serum hemoglobin level as a predictive factor of response to neoadjuvant chemotherapy in patients with locally advanced squamous cervical carcinoma: a preliminary report. Gynecol Oncol 99:S187–S191CrossRefPubMedGoogle Scholar
  18. 18.
    Serkies K, Badzio A, Jassem J (2006) Clinical relevance of hemoglobin level in cervical cancer patients administered definitive radiotherapy. Acta Oncol 45:695–701CrossRefPubMedGoogle Scholar
  19. 19.
    Van Belle SJ, Cocquyt V (2003) Impact of haemoglobin levels on the outcome of cancers treated with chemotherapy. Crit Rev Oncol Hematol 47:1–11CrossRefPubMedGoogle Scholar
  20. 20.
    Dabrow MB, Francesco MR, McBrearty FX, Caradonna S (1998) The effects of platelet-derived growth factor and receptor on normal and neoplastic human ovarian surface epithelium. Gynecol Oncol 71:29–37CrossRefPubMedGoogle Scholar
  21. 21.
    Anderberg C, Li H, Fredriksson L, Andrae J, Betsholtz C, Li X et al (2009) Paracrine signaling by platelet-derived growth factor-CC promotes tumor growth by recruitment of cancer-associated fibroblasts. Cancer Res 69:369–378CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481CrossRefGoogle Scholar
  23. 23.
    Royston P, Parmar MK (2002) Flexible parametric proportional-hazards and proportional-odds models for censored survival data, with application to prognostic modeling and estimation of treatment effects. Stat Med 21:2175–2197CrossRefPubMedGoogle Scholar
  24. 24.
    Benedet JL, Odicino F, Maisonneuve P et al (2003) Carcinoma of the cervix uteri. Int J Gynaecol Obstet 83:41–78CrossRefPubMedGoogle Scholar
  25. 25.
    Omura GA, Blessing JA, Vaccarello L, Berman ML, Clarke-Pearson DL, Mutch DG et al (1997) Randomized trial of cisplatin versus cisplatin plus mitolactol versus cisplatin plus ifosfamide in advanced squamous carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol 15:165–171PubMedGoogle Scholar
  26. 26.
    Vermorken JB, Zanetta G, De Oliveira CF, van der Burg ME, Lacave AJ, Teodorovic I et al (2001) Randomized phase III trial of bleomycin, vindesine, mitomycin-C, and cisplatin (BEMP) versus cisplatin (P) in disseminated squamous-cell carcinoma of the uterine cervix: an EORTC Gynecological Cancer Cooperative Group study. Ann Oncol 12:967–974CrossRefPubMedGoogle Scholar
  27. 27.
    Monk BJ, Sill MW, McMeekin DS, Cohn DE, Ramondetta LM, Boardman CH et al (2009) Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol 27:4649–4655CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Dicato M (2003) Anemia in cancer: some pathophysiological aspects. Oncologist 8:19–21CrossRefPubMedGoogle Scholar
  29. 29.
    Nashiltz JE, Yeshurun D, Eldar S, Lev LM (1996) Diagnosis of cancer-associated vascular disorder. Cancer 77:1759–1767CrossRefGoogle Scholar
  30. 30.
    Verheul HM, Jorna AS, Hoekman K, Broxterman HJ, Gebbink MF, Pinedo HM (2000) Vascular endothelial growth factor-stimulated endothelial cells promote adhesion and activation of platelets. Blood 96:4216–4221PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Shin Nishio
    • 1
  • Ryo Kitagawa
    • 2
  • Taro Shibata
    • 3
  • Hiroyuki Yoshikawa
    • 4
  • Ikuo Konishi
    • 5
  • Kimio Ushijima
    • 1
  • Toshiharu Kamura
    • 1
  1. 1.Department of Obstetrics and GynecologyKurume University School of MedicineKurumeJapan
  2. 2.Department of Obstetrics and GynecologyTohoku Medical and Pharmaceutical University HospitalSendaiJapan
  3. 3.JCOG Data Center, Center for Research Administration and SupportNational Cancer CenterChuo-kuJapan
  4. 4.Department of Obstetrics and Gynecology, Faculty of MedicineUniversity of TsukubaTsukubaJapan
  5. 5.Department of Gynecology and ObstetricsKyoto University HospitalKyotoJapan

Personalised recommendations