Skip to main content
SpringerLink
Log in

Cisplatin–epirubicin–paclitaxel weekly administration in advanced breast cancer: A phase I study of the Southern Italy Cooperative Oncology Group

  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose: Both cisplatin and epirubicin have been shown to enhance the antitumor activity of paclitaxel in vitro. Weekly administration could result in a substantial improvement in the therapeutic index of cisplatin and paclitaxel. This study was aimed at determining the MTDs of epirubicin and paclitaxel given weekly with a fixed dose of cisplatin.

Patientsandmethods: Sixty–three breast cancer patients with advanced disease (24 locally advanced and 39 metastatic), who had not received prior chemotherapy (except adjuvant), received weekly cisplatin (CDDP) doses of 30 mg/m2 together with escalating doses of paclitaxel (PTX) and epirubicin (EPI) for a minimum of six cycles. The dose escalation was stopped if DLT occurred during the first six treatment cycles in >33% of patients of a given cohort.

Results: Nine different dose levels were tested, for a total of 506 weekly cycles delivered. G–CSF support on days 3–5 of each week was also given in the last four cohorts (24 patients). An overall 11 patients showed DLT in the first six cycles. EPI and PTX doses up to 40 and 85 mg/m2/week, respectively, were safely delivered without G–CSF support. However, the actually delivered mean dose intensity was only 64 in this cohort. Therefore, the dose escalation continued with the addition of filgrastim from day 3 to day 5 each week. Doses of EPI and PTX up to 50 and 120 mg/m2/week were administered without observing DLT in the first six cycles in more than one third of the patients enrolled. No toxic deaths were observed. Only two patients had to be hospitalized because of sepsis. Grade 3–4 neutropenia, thrombocytopenia, and anemia occurred in 25, 9, and 16 patients, respectively. Alopecia was almost universal. Other nonhematologic toxicities were generally mild, being of grade 3–4 in only eight patients (fatigue and loss of appetite in two cases, diarrhoea in four cases, peripheral neuropathy and mucositis in one case).abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Early Breast Cancer Trialists' Collaborative Group: Systemic treatment of early breast cancer: hormonal, cytotoxic and immunotherapy. Lancet 330: 1–15, 1992

    Google Scholar 

  2. A'Hern R, Smith I, Ebbs S: Chemotherapy and survival in advanced breast cancer: the inclusion of doxorubicin in cooper type regimens. Br J Cancer 67: 801–805, 1993

    Google Scholar 

  3. Greenberg PA, Hortobagyi GN, Smith TL, Ziegler LD, Frye DK, Buzdar AU: Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer. J Clin Oncol 14: 2197–2205, 1996

    Google Scholar 

  4. Holmes FA, Walters RS, Theriault RL, Forman AD, Newton LK, Raber MN, Budzar AU, Frye DK, Hortobagyi GN: Phase II trial of Taxol: an active drug in the treatment of metastatic breast cancer. J Natl Cancer Inst 83: 1797–1805, 1991

    Google Scholar 

  5. Seidman AD, Reichman BS, Crown JP, Yao TJ, Currie V, Hakes TB, Hudis CA, Gilewski TA, Baselga J, Forsythe P, Lepore J, Marks L, Fain K, Souhrada M, Onetto N, Arbuck S, Norton L: Paclitaxel as second and subsequent therapy for metastatic breast cancer: activity independent of prior anthracycline response. J Clin Oncol 13: 1152–1159, 1995

    Google Scholar 

  6. Chevallier B, Fumoleau P, Kerbrat P, Azli N, Bayssas M, Lentz MA, van Glabbeke M, Dieras V, Roche H, Krakowski I: Docetaxel is a major cytotoxic drug for the treatment of advanced breast cancer: a phase II trial of the Clinical Screening Cooperative Group of the European Organization for Research and Treatment of Cancer. J Clin Oncol 13: 314–324, 1995

    Google Scholar 

  7. Sikov W, Akerley W, Strenger R, Cummings F: Weekly highdose paclitaxel demonstrates significant activity in advanced breast cancer (Abstract). Proc Am Soc Clin Oncol 17: 112a, 1998

    Google Scholar 

  8. Seidman AD, Hudis C, Albanel J, Tong W, Tepler I, Currie V, Moynahan M, Theodoulou M, Gollub M, Baselga J, Norton L: Dose-dense therapy with weekly 1-h paclitaxel infusion in the treatment of metastatic breast cancer. J Clin Oncol 16: 3353–3361, 1998

    Google Scholar 

  9. Gianni L, Munzone E, Capri G, Fulfaro F, Tarenzi E, Villani F, Spreafico C, Laffranchi A, Caraceni A, Martini C, Stefanelli M, Valagussa P, Bonadonna G: Paclitaxel by 3-h infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: high antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study. J Clin Oncol 13: 2688–2699, 1995

    Google Scholar 

  10. Frassineti GL, Zoli W, Tienghi A, Ravaioli A, Milandri C, Gentile A, Onetto N, Amadori D: Phase I/II study of sequential combination of paclitaxel and doxorubicin in the treatment of advanced breast cancer (Abstract) Proc Am Soc Clin Oncol 15: 109, 1996

    Google Scholar 

  11. Schwartsmann G, Menke CH, Caleffi M, Xavier N, Ferreira Filho AF, Schunemann H, Koya R, Stroda PR, Pohlmann P, Vengas LF, Kalakun L: Phase II trial of taxol, doxorubicin plus G-CSF in patients with metastatic breast cancer (Abstract). Proc Am Soc Clin Oncol 15: 126, 1996

    Google Scholar 

  12. Conte PF, Baldini E, Gennari A, Salvadori B, Gennari A, Da Prato M, Tibaldi C, Salzano E, Gentile A: Dose-finding study and pharmacokinetics of epirubicin and paclitaxel over 3 h, a regimen with high activity and low cardiotoxicity in advanced breast cancer. J Clin Oncol 15: 2510–2517, 1997

    Google Scholar 

  13. Sledge CW, Neuberg D, Ingle J, Martino S, Wood W: Phase III trial of doxorubicin (A) vs. paclitaxel (T) vs doxorubicinpaclitaxel (A+T), as first-line therapy for metastatic breast cancer (MBC): an intergroup trial (Abstract). Proc Am Soc Clin Oncol 16: 1a, 1997

    Google Scholar 

  14. Sledge GW, Loehrer P3, Roth BK, Einhom LH: Cisplatin as first-line therapy for metastatic breast cancer: J Clin Oncol 6: 1811–1814, 1988

    Google Scholar 

  15. Smith IF, Talbot DC: Cisplatin and its analogues in the treatment of advanced breast cancer: a review. Br J Cancer 65: 787–793, 1992

    Google Scholar 

  16. Dogliotti L, Danese S, Berruti A, Zola P, Bottini A, Buniva T, Richiardi G, Moro G, Farrris A, Porcile G, Zaffaroni N: Epirubicin, cisplatin and lonidarnine in advanced breast cancer: a phase II study (Abstract). Proc Am Soc Clin Oncol 15: 140, 1996

    Google Scholar 

  17. Roy SN, Horwitz SB: A phosphoglycoprotein associated with with Taxol-resistance in J774.2 cells. Cancer Res 45: 3856–3863, 1985

    Google Scholar 

  18. Parker RJ, Eastman A, Bostick-Bruton F, Reed E: Acquired cisplatin resistance in human ovarian cancer cells is associated with enhanced repair of cisplatin-DNA lesions and reduced drug accumulation. J Clin Invest 87: 772–777, 1991

    Google Scholar 

  19. Frasci G, Comella P, D'Aiuto G, Budillon A, Barbarulo D, Thomas R, Capasso I, Casaretti R, Daponte A, Caponigro F, Gravina A, Carteni' G, Gentile A, Comella G: Weekly paclitaxel-cisplatin administration with G-CSF support in advanced breast cancer: a phase II study. Breast Cancer Res Treat 49: 13–26, 1998

    Google Scholar 

  20. Gelmon KA, O'Reilly SE, Tolcher AW, Zola P, Bottini A, Buniva T, Richiardi G, Moro G, Farrris A, Porcile G, Zaffaroni N: Phase I/II study of biweekly paclitaxel and cisplatin in the treatment of metastatic breast cancer. J Clin Oncol 14: 1185–1191, 1996

    Google Scholar 

  21. McCaskill-Stevens W, Ansari R, Fisher W, Penningion K, Dobbs C, Gonin R, Schaefer S, Loesch D, Sledge G: Phase II study of biweekly cisplatin and paclitaxel in the treatment of metastatic breast cancer (Abstract). Proc Am Soc Clin Oncol 15: 120, 1996

    Google Scholar 

  22. Sparano JA, Neuberg D, Glick JH, Robert NJ, Goldstein LJ, Sledge GW, Wood W: A phase II trial of biweekly paclitaxel and cisplatin in patients with advanced breast carcinoma: an Eastern Cooperative Oncology Group trial (Abstract). Proc Am Soc Clin Oncol 15: 114, 1996

    Google Scholar 

  23. Miller AB, Hoogstraten B, Staquet M: Reporting results of cancer treatment. Cancer 47: 207–214, 1981

    Google Scholar 

  24. Kaplan ES, Meier P: Non parametric estimation for incomplete observations. J Am Stat Assoc 53: 557–580, 1958

    Google Scholar 

  25. Frasci G, Comella P, Panza N, Pacilio C, Nicolella GP, Natale M, Manzione L, Gravina A, Cioffi R, Maiorino L, Comella G: Cisplatin-gemcitabine-paclitaxel in advanced non-small cell lung cancer: A dose-finding study (Abstract 1850). Proc Am Soc Clin Oncol 17: 481a, 1998

    Google Scholar 

  26. Gianni L, Kearns C, Giani A, Capri G, Vigano L, Locatelli A, Bonadonna G, Egorin MJ: Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/ pharmacodynamic relationships in humans. J Clin Oncol 13: 180–190, 1995

    Google Scholar 

  27. Lissoni A, Sessa C, Gabriele A, Bonazzi C, Pittelli MR, Marzola M, Mangioni C: Cisplatin, epirubicin and paclitaxel in uterine adenocarcinoma (Abstract). Proc. Am Soc Clin Oncol 16: 373a, 1997

    Google Scholar 

  28. Dimopoulos MA, Papadimitriou CA, Akrivos T, Vlahos G, Georgoulias N, Voulgaris Z, Diacomanolis E, Papadimitris C, Athanassiades P, Mihalas S: Paclitaxel, cisplatin and epirubicin with G-CSF for newly diagnosed patients with epithelial ovarian cancer (Abstract). Proc Am Soc Clin Oncol 16: 369a, 1997

    Google Scholar 

  29. Naumann RW, Alvarez RD, Omura GA, Segars ET, Roland PY, Kilgore LC, Partridge EE: A phase I study of paclitaxel and cisplatin with escalating doses of doxorubicin in patients with previously untreated epithelial ovarian cancer (Abstract). Proc Am Soc Clin Oncol 16: 374a, 1997

    Google Scholar 

  30. Luck HJ, Thomssen C, du Bois A, Untch M, Lisboa B, Kohler G, Diergarten K: Phase II study of paclitaxel and epirubicin as first-line therapy in patients with metastatic breast cancer. Semin Oncol 24 (Suppl 17): 35–39, 1997

    Google Scholar 

  31. Kohler U, Olbricht SS, Fuechsel G, Kettner E, Richter B, Ridwelski K: Weekly paclitaxel with epirubicin as second-line therapy of metastatic breast cancer. Results of a clinical phase II study. Semin Oncol 24 (Suppl 17): 40–43, 1997

    Google Scholar 

  32. Lalisang R, Nortier J, Wils J, Erdkamp F, Wals J, Hillen H, Blijiam G: Dose dense epirubicin and paclitaxel with G-CSF in metastatic breast cancer: a weekly schedule? (Abstract). Proc Am Soc Clin Oncol 16: 178a, 1997

    Google Scholar 

  33. van der Burgh MEL, de Wit R, Stoter G, Verweij J: Phase I study of weekly cisplatin and weekly or 4-weekly taxol: a highly active regimen in advanced epithelial ovarian cancer (Abstract). Proc Am Soc Clin Oncol 17: 355a, 1998

    Google Scholar 

  34. Fisher B, Brown A, Mamounas E, Wieand S, Robidoux A, Margolese RG, Cruz AB, Fisher ER, Wickerman DL, Wolmark N, DeCillis A, Hoehn JL, Lees AW, Dimitrov NV: Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol 15: 2483–2494, 1997

    Google Scholar 

  35. Moliterni A, Tarenzi E, Capri G, Terenziani M, Bertuzzi A, Grasselli G, Agresti R, Piotti P, Greco M, Salvadori B, Pilotti S, Lombardi F, Valagussa P, Bonadonna G, Gianni L: Pilot study of primary chemotherapy with doxorubicin plus paclitaxel in women with locally advanced or operable breast cancer. Semin Oncol 24 (Suppl 17): 10–14, 1997

    Google Scholar 

  36. Perez EA, Suman VJ, Krook JE, Stella PJ, Hartmann LC, Hat-field AK, Fitch T, Ingle JN: Phase II study of paclitaxel plus carboplatin as first-line chemotherapy for women with metastatic breast cancer: a North Central Cancer Treatment Group trial (Abstract). Proc Am Soc Clin Oncol 17: 165a, 1998

    Google Scholar 

  37. Estevez LG, Andrade J, Robles L, Casado V, Ageitos AG, Domine M, Vicente J, Lobo F: Taxol-cisplatinum in patients with breast cancer previously treated with an anthracycline containing regimen (Abstract 530). Proc Am Soc Clin Oncol17: 139a, 1998

    Google Scholar 

  38. Ezzat A, Rahal M, Raja MA, Raginwala M, Bazarbashi S: Pathologic response to paclitaxel-cisplatin versus fluorouracildoxorubicin-cyclophosphamide primary chemotherapy in locally advanced breast cancer (Abstract). Proc Am Soc Clin Oncol 17: 139a, 1998

    Google Scholar 

  39. Sola C, Lluch A, Garcia-Conde J, Ojeda B, Hornedo J, Benavides M, Solano C, Garcia T, Salazar R, Alonso S, Cortes-Funes H, Lopez JJ: Phase II study of weekly paclitaxel in recurrent breast cancer after high-dose chemotherapy (Abstract). Proc Am Soc Clin Oncol 17: 174a, 1998

    Google Scholar 

  40. Alvarez A, Mickiewicz E, Brosio C, Giglio R, Cinat G, Suarez A: Weekly taxol in patients who had relapsed or remained stable with taxol in a 21 day schedule (Abstract). Proc Am Soc Clin Oncol 17: l88a, 1998

    Google Scholar 

  41. Gamucci T, Piccart M, Bruning P, Klijn J, Biganzoli L, Houston S, Coleman R, Van Vreckem A, Cleall S, Curran D, Awada A, Paridaens R: Single agent taxol versus doxorubicin as firstline chemotherapy in advanced breast cancer. Final results of an EORTC randomized study with crossover (Abstract). Proc Am Soc Clin Oncol 17: 111a, 1998

    Google Scholar 

  42. Winer E, Berry D, Duggan D, Henderson IC, Cirrincione C, Cooper R, Norton L: Failure of higher dose paclitaxel to improve outcome in patients with metastatic breast cancer. Results from CALGB 9342 (Abstract). Proc Am Soc Clin Oncol 17: 101a, 1998

    Google Scholar 

  43. Holmes FA, Valero V, Budzar AU, Booser DJ, Winn R, Tolcker A, Seidman A, Goodwin W, Bearden I, Baysinger L, Hortobagyi GN, Arbuck SA: Final results: randomized phase III trial of paclitaxel by 3-h versus 96-h infusion in patients with breast cancer. The long and short of it (Abstract). Proc Am Soc Clin Oncol 17: 110a, 1998

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Divisions of Medical Oncology A and Surgical Oncology A, Services of Pathology, Diagnostic Imaging, Cardiology and Clinical Pharmacology, National Tumor Institute, Naples

    Giuseppe Frasci, Giuseppe D'Aiuto, Pasquale Comella, Anna Apicella, Renato Thomas, Immacolata Capasso, Maurizio Di Bonito, Giacomo Cartenì, Maria Biglietto, Luigi De Lucia, Luigii Maiorino, Sergio Piccolo, Ugo Bianchi, Roberta D'Aniello, Liliana Lapenta & Giuseppe Comella

  2. Division of Medical Oncology, Cardarelli Hospital, Naples

    Giuseppe Frasci, Giuseppe D'Aiuto, Pasquale Comella, Anna Apicella, Renato Thomas, Immacolata Capasso, Maurizio Di Bonito, Giacomo Cartenì, Maria Biglietto, Luigi De Lucia, Luigii Maiorino, Sergio Piccolo, Ugo Bianchi, Roberta D'Aniello, Liliana Lapenta & Giuseppe Comella

  3. Medical Oncology Unit, S. Gennaro Hospital, Naples

    Giuseppe Frasci, Giuseppe D'Aiuto, Pasquale Comella, Anna Apicella, Renato Thomas, Immacolata Capasso, Maurizio Di Bonito, Giacomo Cartenì, Maria Biglietto, Luigi De Lucia, Luigii Maiorino, Sergio Piccolo, Ugo Bianchi, Roberta D'Aniello, Liliana Lapenta & Giuseppe Comella

  4. Medical Oncology Unit, City Hospital, Caserta, Italy

    Giuseppe Frasci, Giuseppe D'Aiuto, Pasquale Comella, Anna Apicella, Renato Thomas, Immacolata Capasso, Maurizio Di Bonito, Giacomo Cartenì, Maria Biglietto, Luigi De Lucia, Luigii Maiorino, Sergio Piccolo, Ugo Bianchi, Roberta D'Aniello, Liliana Lapenta & Giuseppe Comella

Authors
  1. Giuseppe Frasci
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Giuseppe D'Aiuto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pasquale Comella
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anna Apicella
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Renato Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Immacolata Capasso
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Maurizio Di Bonito
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Giacomo Cartenì
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Maria Biglietto
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Luigi De Lucia
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Luigii Maiorino
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Sergio Piccolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ugo Bianchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Roberta D'Aniello
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Liliana Lapenta
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Giuseppe Comella
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Frasci, G., D'Aiuto, G., Comella, P. et al. Cisplatin–epirubicin–paclitaxel weekly administration in advanced breast cancer: A phase I study of the Southern Italy Cooperative Oncology Group. Breast Cancer Res Treat 56, 237–250 (1999). https://doi.org/10.1023/A:1006263226099

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1006263226099

Search

Navigation