A randomized phase II non-comparative study of pemetrexed‑carboplatin and gemcitabine‑vinorelbine in anthracycline- and taxane-pretreated advanced breast cancer patients

Amadori,Dino; Carrasco,Eva; Roesel,Siegfried; Labianca,Roberto; Uziely,Beatrice; Soldatenkova,Victoria; Moreau,Valerie; Desaiah,Durisala; Bauknecht,Thomas; Martin,Miguel

doi:10.3892/ijo.2013.1869

A randomized phase II non-comparative study of pemetrexed‑carboplatin and gemcitabine‑vinorelbine in anthracycline- and taxane-pretreated advanced breast cancer patients

Authors:
- Dino Amadori
- Eva Carrasco
- Siegfried Roesel
- Roberto Labianca
- Beatrice Uziely
- Victoria Soldatenkova
- Valerie Moreau
- Durisala Desaiah
- Thomas Bauknecht
- Miguel Martin
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Affiliations: Romagnolo Scientific Institute for the Study and Treatment of Cancer, Meldola, Italy, Spanish Breast Cancer Research Group (GEICAM), Madrid, Spain, Gütersloh Oncology Practice, Gütersloh, Germany, Riuniti Hospital, Bergamo, Italy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel, Lilly Deutschland, Bad Homburg, Germany, Lilly France, Paris, France, Eli Lilly and Company, Indianapolis, IN, USA, Gregorio Marañón University Hospital Research Institute, Complutense University, Madrid, Spain
Published online on: March 28, 2013 https://doi.org/10.3892/ijo.2013.1869
Pages: 1778-1785

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Abstract

Pemetrexed-carboplatin and gemcitabine‑vinorelbine combination therapies were efficacious in phase II and phase III studies as first-line breast cancer treatment. Thus, Arm A and Arm B combinations were investigated in patients pretreated with anthracycline and taxanes. Women with advanced breast cancer, with ≥1 measurable lesion per RECIST, were stratified by line of treatment (1st, 2nd), visceral disease (yes/no), ECOG PS (0-1 vs. 2) and randomized 1:1 to Arm A (pemetrexed 600 mg/m2, D1 i.v. q21; carboplatin, AUC 5, D1 i.v. q21) or Arm B (gemcitabine 1,200 mg/m2 D1, D8 i.v. q21; vinorelbine 30 mg/m2 D1, D8 i.v. q21). Treatment continued until progression. The primary endpoint was objective response rate (RR). Secondary endpoints were duration of response (DoR), time-to-response (TTR), time-to-progressive disease (TTPD), time-to-treatment failure (TTTF) and safety. A two-stage design was employed independently for each arm. Of 135 randomized patients, 125 (Arm A, n=64; Arm B, n=61) qualified for tumor-response analysis. The mean (standard deviation) number of cycles administered was 6.3 (4.13) in Arm A and 6.2 (4.39) in Arm B. Efficacy in Arm A and Arm B were: RR (95% CI), 26.6 (16.3-39.1) and 29.5 (18.5-42.6); time-to-events (months), DoR 7.7 and 7.5; TTPD, 5.1 and 5.6; TTR, 1.8 and 1.8; TTTF, 4.8 and 5.1; respectively. Most common grade 3/4 adverse events possibly related to study-drug were neutropenia, thrombocytopenia, anemia and leucopenia in Arm A and neutropenia, leucopenia and fatigue in Arm B. In this study, both combinations showed moderate activity as predefined RR was not reached and were well tolerated.

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1.	Ferlay J, Shin HR, Bray F, et al: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 127:2893–2917. 2010. View Article : Google Scholar : PubMed/NCBI
2.	Jemal A, Bray F, Center MM, et al: Global Cancer Statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar
3.	Henderson IC, Berry DA, Demetri GD, et al: Improved outcomes from adding sequential Paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol. 21:976–983. 2003. View Article : Google Scholar
4.	Hortobagyi GN: Treatment of breast cancer. N Engl J Med. 339:974–984. 1998. View Article : Google Scholar
5.	Dean-Colomb W and Esteva FJ: Emerging agents in the treatment of anthracycline- and taxane-refractory metastatic breast cancer. Semin Oncol. 35:S31–S38. 2008. View Article : Google Scholar : PubMed/NCBI
6.	Overmoyer B: Options for the treatment of patients with taxane-refractory metastatic breast cancer. Clin Breast Cancer. 8:S61–S70. 2008. View Article : Google Scholar : PubMed/NCBI
7.	Llombart-Cussac A, Theodoulou M, Rowland K, et al: Pemetrexed in patients with locally advanced or metastatic breast cancer who had received previous anthracycline and taxane treatment: phase II study. Clin Breast Cancer. 7:380–385. 2006. View Article : Google Scholar
8.	Martin M, Spielmann M, Namer M, et al: Phase II study of pemetrexed in breast cancer patients pretreated with anthracyclines. Ann Oncol. 14:1246–1252. 2003. View Article : Google Scholar : PubMed/NCBI
9.	Miles DW, Smith IE, Coleman RE, et al: A phase II study of pemetrexed disodium (LY231514) in patients with locally recurrent or metastatic breast cancer. Eur J Cancer. 37:1366–1371. 2001. View Article : Google Scholar : PubMed/NCBI
10.	Crown J and Pegram M: Platinum-taxane combinations in metastatic breast cancer: an evolving role in the era of molecularly targeted therapy. Breast Cancer Res Treat. 79:S11–S18. 2003. View Article : Google Scholar : PubMed/NCBI
11.	Martín M: Platinum compounds in the treatment of advanced breast cancer. Clin Breast Cancer. 2:190–208. 2001.PubMed/NCBI
12.	Perez EA, Hillman DW, Stella PJ, et al: A phase II study of paclitaxel plus carboplatin as first-line chemotherapy for women with metastatic breast carcinoma. Cancer. 88:124–131. 2000. View Article : Google Scholar : PubMed/NCBI
13.	Garin A, Manikhas A, Biakhov M, et al: A phase II study of pemetrexed and carboplatin in patients with locally advanced or metastatic breast cancer. Breast Cancer Res Treat. 110:309–315. 2008. View Article : Google Scholar : PubMed/NCBI
14.	Heinemann V, Stemmler HJ, Wohlrab A, et al: High efficacy of gemcitabine and cisplatin in patients with predominantly anthracycline- and taxane-pretreated metastatic breast cancer. Cancer Chemother Pharmacol. 57:640–646. 2006. View Article : Google Scholar : PubMed/NCBI
15.	Perez EA: Carboplatin in combination therapy for metastatic breast cancer. Oncologist. 9:518–527. 2004. View Article : Google Scholar : PubMed/NCBI
16.	Brodowicz T, Kostler WJ, Möslinger R, et al: Single-agent gemcitabine as second- and third-line treatment in metastatic breast cancer. Breast. 9:338–342. 2000. View Article : Google Scholar : PubMed/NCBI
17.	Spielmann M, Llombart-Cussac A, Kalla S, et al: Single-agent gemcitabine is active in previously treated metastatic breast cancer. Oncology. 60:303–307. 2001. View Article : Google Scholar : PubMed/NCBI
18.	Blackstein M, Vogel CL, Ambinder R, et al: Gemcitabine as first-line therapy in patients with metastatic breast cancer: a phase II trial. Oncology. 62:2–8. 2002. View Article : Google Scholar : PubMed/NCBI
19.	Heinemann V: Role of gemcitabine in the treatment of advanced and metastatic breast cancer. Oncology. 64:191–206. 2003. View Article : Google Scholar : PubMed/NCBI
20.	Heinemann V: Gemcitabine in metastatic breast cancer. Expert Rev Anticancer Ther. 5:429–443. 2005. View Article : Google Scholar : PubMed/NCBI
21.	Modi S, Currie VE, Seidman AD, et al: A phase II trial of gemcitabine in patients with metastatic breast cancer previously treated with an anthracycline and taxane. Clin Breast Cancer. 6:55–60. 2005. View Article : Google Scholar : PubMed/NCBI
22.	Albain KS, Nag SM, Calderillo-Ruiz G, et al: Gemcitabine plus Paclitaxel versus Paclitaxel monotherapy in patients with meta-static breast cancer and prior anthracycline treatment. J Clin Oncol. 26:3950–3957. 2008. View Article : Google Scholar : PubMed/NCBI
23.	Seo JH, Oh SC, Choi CW, et al: Phase II study of a gemcitabine and cisplatin combination regimen in taxane resistant meta-static breast cancer. Cancer Chemother Pharmacol. 59:269–274. 2007.PubMed/NCBI
24.	Silvestris N, D’Aprile M, Andreola G, et al: Rationale for the use of gemcitabine in breast cancer (Review). Int J Oncol. 24:389–398. 2004.PubMed/NCBI
25.	Jones S, Winer E, Vogel C, et al: Randomized comparison of vinorelbine and melphalan in anthracycline-refractory advanced breast cancer. J Clin Oncol. 13:2567–2574. 1995.PubMed/NCBI
26.	Martín M, Ruiz A, Muñoz M, et al: Gemcitabine plus vinorelbine monotherapy in patients with metastatic breast cancer previously treated with anthracyclines and taxanes: final results of the phase III Spanish Breast Cancer Research Group (GEICAM) trial. Lancet Oncol. 8:219–225. 2007.
27.	Pallis AG, Boukovinas I, Ardavanis A, et al: A multicenter randomized phase III trial of vinorelbine/gemcitabine doublet versus capecitabine monotherapy in anthracycline- and taxanepretreated women with metastatic breast cancer. Ann Oncol. 23:1164–1169. 2012. View Article : Google Scholar
28.	Degardin M, Bonneterre J, Hecquet B, et al: Vinorelbine (navelbine) as a salvage treatment for advanced breast cancer. Ann Oncol. 5:423–426. 1994.PubMed/NCBI
29.	Gregory RK and Smith IE: Vinorelbine - a clinical review. Br J Cancer. 82:1907–1913. 2000.PubMed/NCBI
30.	Haider K, Kornek GV, Kwasny W, et al: Treatment of advanced breast cancer with gemcitabine and vinorelbine plus human granulocyte colony-stimulating factor. Breast Cancer Res Treat. 55:203–211. 1999. View Article : Google Scholar : PubMed/NCBI
31.	Valenza R, Leonardi V, Gebbia V, et al: Gemcitabine and vinorelbine in pretreated advanced breast cancer: a pilot study. Ann Oncol. 11:495–496. 2000. View Article : Google Scholar : PubMed/NCBI
32.	Stathopoulos GP, Rigatos SK, Pergantas N, et al: Phase II trial of biweekly administration of vinorelbine and gemcitabine in pretreated advanced breast cancer. J Clin Oncol. 20:37–41. 2002. View Article : Google Scholar : PubMed/NCBI
33.	Stemmler HJ, diGioia D, Freier W, Tessen, et al: Randomised phase II trial of gemcitabine plus vinorelbine vs gemcitabine plus cisplatin vs gemcitabine plus capecitabine in patients with pretreated metastatic breast cancer. Br J Cancer. 104:1071–1078. 2011. View Article : Google Scholar : PubMed/NCBI
34.	Therasse P, Arbuck SG, Eisenhauer EA, et al: 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. 92:205–216. 2000. View Article : Google Scholar
35.	Hughes A, Calvert P, Azzabi A, et al: Phase I clinical and pharmacokinetic Study of pemetrexed and carboplatin in patients with malignant pleural mesothelioma. J Clin Oncol. 20:3533–3544. 2002. View Article : Google Scholar : PubMed/NCBI
36.	Cancer Therapy Evaluation Program: Common Terminology Criteria for Adverse Events, Version 3.0, 2003. National Cancer Institute. Available, Published online August 9, 2006; available at: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcev3.pdf. Accessed November 14, 2011.
37.	Nagel GC, Schmidt S, Strauss BM, et al: Quality of life in breast cancer patients: a cluster analytic approach. Empirically derived subgroups of the EORTC-QLQ BR 23 - a clinically oriented assessment. Breast Cancer Res Treat. 68:75–87. 2001. View Article : Google Scholar
38.	Simon R: Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 10:1–10. 1989. View Article : Google Scholar : PubMed/NCBI
39.	Clopper CJ and Pearson ES: The use of confidence or fiducial limits illustrated in the case of the binomial. Biometrika. 26:404–413. 1934. View Article : Google Scholar
40.	Kaplan EL and Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc. 53:457–481. 1958. View Article : Google Scholar
41.	Brookmeyer R and Crowley J: A confidence interval for the median survival time. Biometrics. 38:29–41. 1982. View Article : Google Scholar
42.	Nicolaides C, Dimopoulos MA, Samantas E, et al: Gemcitabine and vinorelbine as second-line treatment in patients with meta-static breast cancer progressing after first-line taxane-based chemotherapy: a phase II study conducted by the Hellenic Cooperative Oncology Group. Ann Oncol. 11:873–875. 2000. View Article : Google Scholar
43.	Park IH, Ro J, Lee KS, et al: Phase II study of gemcitabine in combination with vinorelbine versus gemcitabine followed by vinorelbine for metastatic breast cancer. Invest New Drugs. 28:659–669. 2010. View Article : Google Scholar : PubMed/NCBI
44.	Shehata S, Saad E, Goda Y, et al: A phase II study of gemcitabine combined with vinorelbine as first-line chemotherapy for metastatic breast cancer. Hematol Oncol Stem Cell Ther. 3:1–6. 2010. View Article : Google Scholar : PubMed/NCBI
45.	Morabito A, Filippelli G, Palmeri S, et al: The combination of gemcitabine and vinorelbine is an active regimen as second-line therapy in patients with metastatic breast cancer pretreated with taxanes and/or anthracyclines: a phase I–II study. Breast Cancer Res Treat. 78:29–36. 2003.