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Dose-dense paclitaxel/carboplatin as neo-adjuvant chemotherapy followed by radical surgery in locally advanced cervical cancer: a prospective phase II study

  • Gabriella Ferrandina
  • Giacomo Corrado
  • Giuseppe Vitrano
  • Valerio Gallotta
  • Eleonora Palluzzi
  • Mariagrazia Distefano
  • Giovanni Scambia
Original Article

Abstract

Purpose

The role of dose-dense schedules in the neo-adjuvant treatment (NACT) of locally advanced cervical cancer (LACC) has been reported. This phase II study investigated activity of dose-dense paclitaxel/platinum before radical surgery (RS) in LACC patients.

Methods

The primary end-point was the rate of optimal pathological response (OPR: pathological complete/microscopic response). NACT (paclitaxel: 80 mg/m2) and carboplatin (AUC 2) were administered for 6 weeks. Overall response rate (ORR) to NACT was assessed by the RECIST criteria. Patients amenable to surgery were triaged to RS. The null hypothesis was that the OPR rate would improve from 30.0 to 45.0% (α error: 0.05, β error: 0.2). The regimen would be considered active if > 25 OPRs were found.

Results

36 patients were enrolled; 19 patients were stage IIB (52.8%) and 16 (44.4%) patients had pelvic lymph-node involvement at imaging. All patients completed neo-adjuvant chemotherapy; ORR was of 75.0%. RS was performed in 29 (93.5%) patients. Since the OPR was 16.1%, we evaluated the real chances to achieve the number of OPR required by the Simon design and decided to close the study. Grade 3/4 hematological toxicity occurred in 5 patients; surgical morbidity occurred in 14 patients. The 2-year PFS rate was 69.0%.

Conclusion

Dose-dense neo-adjuvant paclitaxel/carboplatin is feasible and safe in LACC patients; however, failure to achieve the primary end-point has to be recognized. Given the heterogeneity of the available studies, robust data from an adequately sized prospective study focused on more homogeneous series are required.

Keywords

Locally advanced cervical cancer Neo-adjuvant chemotherapy Dose density Radical hysterectomy Personalized medicine 

Notes

Compliance with ethical standards

Conflict of interest

The authors report no conflicts of interest. The authors are responsible for the content and writing of the paper.

Supplementary material

280_2018_3742_MOESM1_ESM.doc (33 kb)
Supplementary material 1 (DOC 33 KB)
280_2018_3742_MOESM2_ESM.doc (48 kb)
Supplementary material 2 (DOC 47 KB)

References

  1. 1.
    McNeil C (1999) New standard of care for cervical cancer sets stage for next questions. J Natl Cancer Inst 91:500–501CrossRefPubMedGoogle Scholar
  2. 2.
    Chemoradiotherapy for Cervical Cancer Meta-analysis Collaboration (CCCMAC) (2010) Reducing uncertainties about the effect of chemoradiotherapy for cervical cancer: individual patients data meta-analysis. Cochrane Database Syst Rev 1:CD008285Google Scholar
  3. 3.
    Shrivastava S, Mahantshetty U, Engineer R, Gynecologic Disease Management Group et al (2018) Cisplatin chemoradiotherapy vs radiotherapy in FIGO stage IIIB squamous cell carcinoma of the uterine cervix: a randomized clinical trial. JAMA Oncol 4(4):506–513CrossRefPubMedGoogle Scholar
  4. 4.
    Benedetti-Panici P, Greggi S, Colombo A et al (2002) Neoadjuvant chemotherapy and radical surgery versus exclusive radiotherapy in locally advanced squamous cell cervical cancer: results from the Italian multicenter randomized study. J Clin Oncol 20(1):179–188CrossRefPubMedGoogle Scholar
  5. 5.
    Neoadjuvant Chemotherapy for Cervical Cancer Meta-analysis Collaboration (2003) Neoadjuvant chemotherapy locally advanced cervical cancer: a systematic review and meta-analysis of individual patient data from 21 randomised trials. Eur J Cancer 39:2470–2486CrossRefGoogle Scholar
  6. 6.
    Buda A, Fossati R, Colombo N et al (2005) Randomized trial of neoadjuvant chemotherapy comparing paclitaxel, fosfamide, and cisplatin with ifosfamide and cisplatin followed by radical surgery in patients with locally advanced squamous cell cervical carcinoma: the SNAP01 (Studio Neo-Adjuvante Portio) Italian Collaborative Study. J Clin Oncol 23(18):4137–4145CrossRefPubMedGoogle Scholar
  7. 7.
    Lissoni AA, Colombo N, Pellegrino A et al (2009) A phase II, randomized trial of neo-adjuvant chemotherapy comparing a three-drug combination of paclitaxel, ifosfamide, and cisplatin (TIP) versus paclitaxel and cisplatin (TP) followed by radical surgery in patients with locally advanced squamous cell cervical carcinoma: the Snap-02 Italian Collaborative Study. Ann Oncol 20(4):660–665CrossRefPubMedGoogle Scholar
  8. 8.
    He D, Duan C, Chen J et al (2015) The safety and efficacy of the preoperative neoadjuvant chemotherapy for patients with cervical cancer: a systematic review and meta analysis. Int J Clin Exp Med 8(9):14693–14700PubMedPubMedCentralGoogle Scholar
  9. 9.
    Kokka F, Bryant A, Brockbank E et al (2015) Hysterectomy with radiotherapy or chemotherapy or both for women with locally advanced cervical cancer. Cochrane Database Syst Rev 4:CD010260Google Scholar
  10. 10.
    Gupta S, Maheshwari A, Parab P et al (2018) Neoadjuvant chemotherapy followed by radical surgery versus concomitant chemotherapy and radiotherapy in patients with stage IB2, IIA, or IIB squamous cervical cancer: a randomized controlled trial. J Clin Oncol 36(16):1548–1555CrossRefPubMedGoogle Scholar
  11. 11.
    Monk BJ, Sill MW, McMeekin DS 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(28):4649–4655CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Kitagawa R, Katsumata N, Shibata 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(19):2129–2135CrossRefPubMedGoogle Scholar
  13. 13.
    Norton L (2001) Theoretical concepts and the emerging role of taxanes in adjuvant therapy. Oncologist 6(Suppl 3):30–35CrossRefPubMedGoogle Scholar
  14. 14.
    Seidman AD, Berry D, Cirrincione C et al (2008) Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol 26:1642–1649CrossRefPubMedGoogle Scholar
  15. 15.
    Bonilla L, Ben-Aharon I, Vidal L et al (2010) Dose-dense chemotherapy in nonmetastatic breast cancer: a systematic review and meta-analysis of randomized controlled trials. J Natl Cancer Inst 102:1845–1854CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Katsumata N, Yasuda M, Takahashi F et al (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):1331–1338CrossRefPubMedGoogle Scholar
  17. 17.
    Mori T, Hosokawa K, Sawada M et al (2010) Neoadjuvant weekly carboplatin and paclitaxel followed by radical hysterectomy for locally advanced cervical cancer: long-term results. Int J Gynecol Cancer 20(4):611–616CrossRefPubMedGoogle Scholar
  18. 18.
    Benedetti Panici P, Palaia I, Marchetti C et al (2015) Dose-dense neoadjuvant chemotherapy plus radical surgery in locally advanced cervical cancer: a phase II study. Oncology 89(2):103–110CrossRefGoogle Scholar
  19. 19.
    Vergote I, Debruyne P, Kridelka F et al (2015) Phase II study of weekly paclitaxel/carboplatin in combination with prophylactic G-CSF in the treatment of gynecologic cancers: a study in 108 patients by the Belgian Gynaecological Oncology Group. Gynecol Oncol 138(2):278–284CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Zanaboni F, Grijuela B, Giudici S et al (2013) Weekly topotecan and cisplatin (TOPOCIS) as neo-adjuvant chemotherapy for locally-advanced squamous cervical carcinoma: results of a phase II multicentric study. Eur J Cancer 49(5):1065–1072CrossRefPubMedGoogle Scholar
  21. 21.
    Salihi R, Leunen K, Moerman P et al (2017) Neoadjuvant weekly paclitaxel-carboplatin is effective in Stage I–II cervical cancer. Int J Gynecol Cancer 27(6):1256–1260CrossRefPubMedGoogle Scholar
  22. 22.
    Tanioka M, Yamaguchi S, Shimada M et al (2017) Cisplatin with dose-dense paclitaxel before and after radical hysterectomy for locally advanced cervical cancer: a prospective multicenter phase II trial with a dose-finding study. Med Oncol 34(8):134CrossRefPubMedGoogle Scholar
  23. 23.
    Gadducci A, Barsotti C, Laliscia C et al (2017) Dose-dense paclitaxel- and carboplatin-based neoadjuvant chemotherapy followed by surgery or concurrent chemo-radiotherapy in cervical cancer: a preliminary analysis. Anticancer Res 37(3):1249–1255CrossRefPubMedGoogle Scholar
  24. 24.
    Torfs S, Cadron I, Amant F et al (2012) Evaluation of paclitaxel/carboplatin in a dose dense or weekly regimen in 66 patients with recurrent or primary metastatic cervical cancer. Eur J Cancer 48(9):1332–1340CrossRefPubMedGoogle Scholar
  25. 25.
    McCormack M, Kadalayil L, Hackshaw A et al (2013) A phase II study of weekly neoadjuvant chemotherapy followed by radical chemoradiation for locally advanced cervical cancer. Br J Cancer 108(12):2464–2469CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    de Azevedo CRAS, Thuler LCS, de Mello MJG et al (2017) Phase II trial of neoadjuvant chemotherapy followed by chemoradiation in locally advanced cervical cancer. Gynecol Oncol 146(3):560–565CrossRefPubMedGoogle Scholar
  27. 27.
    Ferrandina G, Palluzzi E, Gallotta V et al (2018) Neo-adjuvant platinum-based chemotherapy followed by chemoradiation and radical surgery in locally advanced cervical cancer (Lacc) patients: a phase II study. Eur J Surg Oncol 44(7):1062–1068CrossRefPubMedGoogle Scholar
  28. 28.
    Therasse P, Arbuck SG, Eisenhauer EA et al (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(3):205–216CrossRefPubMedGoogle Scholar
  29. 29.
    Querleu D, Morrow CP (2009) Classification of radical hysterectomy. Gynecol Oncol 115(2):314–315CrossRefPubMedGoogle Scholar
  30. 30.
    Chassagne D, Sismondi P, Horiot JC et al (1993) A glossary for reporting complications of treatment in gynecological cancers. Radiother Oncol 26(3):195–202CrossRefPubMedGoogle Scholar
  31. 31.
    Simon R (1989) Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10(1):1–10CrossRefPubMedGoogle Scholar
  32. 32.
    Kaplan FL, Meier P (1958) Non parametric estimation from incomplete observations. Am J Stat Assoc 53:457–481CrossRefGoogle Scholar
  33. 33.
    Mantel N (1966) Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163–170PubMedGoogle Scholar
  34. 34.
    Clamp AR, McNeish I, Dean A et al (2017) ICON8: a GCIG phase III randomised trial evaluating weekly dose-dense chemotherapy integration in first-line epithelial ovarian/fallopian tube/primary peritoneal carcinoma (EOC) treatment: results of primary progression-free survival (PFS) analysis. Ann Oncol 28(suppl_5):v605–v649CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Gynecologic Oncology Unit, Department of Women and Children Health, Fondazione Policlinico Universitario A. Gemelli IRCCSUniversità Cattolica del Sacro CuoreRomeItaly
  2. 2.Department of Obstetrics and GynecologyHospital “Paolo Giaccone”PalermoItaly

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