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Pooled analysis of individual patient data from capecitabine monotherapy clinical trials in locally advanced or metastatic breast cancer

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Abstract

We assessed the efficacy and safety of capecitabine across treatment lines, and the impact of patient and disease characteristics on outcomes using data from phase II/III trials. Individual patient data were pooled from seven Roche/Genentech-led trials conducted from 1996 to 2008 where single-agent capecitabine was the test or control regimen for metastatic breast cancer (MBC). Data were analyzed from 805 patients: 268 in the first-line metastatic setting and 537 in the second-line or later setting. Baseline characteristics were balanced across treatment lines. Patients receiving second-line or later versus first-line capecitabine had lower objective response rates (ORR: 19.0 vs. 25.0 %, respectively, odds ratio 0.70; 95 % CI: 0.5–1.0) and significantly shorter progression-free survival (PFS: median 112.0 days [3.7 months] vs. 150.0 days [4.9 months]; p < 0.0001) and overall survival (OS: median 396.0 days [13.0 months] vs. 666.0 days [21.9 months]; p < 0.0001). In multivariate analysis by backward elimination, significantly improved ORR (p = 0.0036), PFS (p < 0.0001) and OS (p < 0.0001) with capecitabine were demonstrated in patients with estrogen receptor (ER) and/or progesterone receptor (PgR)-positive versus both ER and PgR-negative tumors. Hand-foot syndrome (HFS) was the most common adverse event (AE) in 63 % of patients. Overall, 7 % of patients discontinued and two patients (<1 %) died from treatment-related AEs. Significantly improved survival was observed in patients developing capecitabine-related HFS (p < 0.0001 PFS/OS) or diarrhea (p = 0.004 OS; p = 0.0045 PFS) versus patients without these events. In this pooled analysis of individual patient data, first-line capecitabine was associated with improved ORR, PFS, and OS versus second or later lines. Multivariate analyses identified greater ORR, PFS, and OS with capecitabine in patients with ER and/or PgR-positive versus ER/PgR-negative tumors. Safety was in-line with previous phase III trials in MBC.

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References

  1. Blum JL, Jones SE, Buzdar AU, LoRusso PM, Kuter I, Vogel C, Osterwalder B, Burger HU, Brown CS, Griffin T (1996) Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 17:485–493

    Google Scholar 

  2. Blum JL, Dieras V, Lo Russo PM, Horton J, Rutman O, Buzdar A, Osterwalder B (2001) Multicenter, phase II study of capecitabine in taxane-pretreated metastatic breast carcinoma patients. Cancer 92:1759–1768

    Article  PubMed  CAS  Google Scholar 

  3. Reichardt P, Von Minckwitz G, Thuss-Patience PC, Jonat W, Kölbl H, Jänicke F, Kieback DG, Kuhn W, Schindler AE, Mohrmann S, Kaufmann M, Lück HJ (2003) Multicenter phase II study of oral capecitabine (Xeloda®) in patients with metastatic breast cancer relapsing after treatment with a taxane-containing therapy. Ann Oncol 14:1227–1233

    Article  PubMed  CAS  Google Scholar 

  4. Fumoleau P, Largillier R, Clippe C, Dièras V, Orfeuvre H, Lesimple T, Culine S, Audhuy B, Serin D, Curé H, Vuillemin E, Morère JF, Montestruc F, Mouri Z, Namer M (2004) Multicentre, phase II study evaluating capecitabine monotherapy in patients with anthracycline-and taxane-pretreated metastatic breast cancer. Eur J Cancer 40:536–542

    Article  PubMed  CAS  Google Scholar 

  5. Miller KD, Chap LI, Holmes FA, Cobleigh MA, Marcom PK, Fehrenbacher L, Dickler M, Overmoyer BA, Reimann JD, Sing AP, Langmuir V, Rugo HS (2005) Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 23:792–799

    Article  PubMed  CAS  Google Scholar 

  6. Largillier R, Fumoleau P, Clippe C et al (2006) Capecitabine monotherapy after anthracycline and taxane failure in metastatic breast cancer (MBC): long-term survival data. Ann Oncol 17(Abstract 161P)

  7. Kusama M, Nomizu T, Aogi K, Yoshimoto M, Horikoshi N, Tabei T, Noguchi S, Miura S, Yoshimura N, Kimura M, Toyama K, Shin E (2010) Phase II study of 4-weekly capecitabine monotherapy in advanced/metastatic breast cancer. Breast Cancer 17:233–240

    Article  PubMed  Google Scholar 

  8. Mikhail SE, Sun JF, Marshall JL (2010) Safety of capecitabine: a review. Expert Opin Drug Saf 9:831–841

    Article  PubMed  CAS  Google Scholar 

  9. Zielinski C, Gralow J, Martin M (2010) Optimising the dose of capecitabine in metastatic breast cancer: confused, clarified or confirmed? Ann Oncol 21:2145–2152

    Article  PubMed  CAS  Google Scholar 

  10. Leonard R, Hennessy BT, Blum JL, O’Shaughnessy J (2011) Dose-adjusting capecitabine minimizes adverse effects while maintaining efficacy: a retrospective review of capecitabine for metastatic breast cancer. Clin Breast Cancer 11:349–356

    Article  PubMed  CAS  Google Scholar 

  11. Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berger M, Oliva C, Rubin SD, Stein S, Cameron D (2006) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355:2733–2743

    Article  PubMed  CAS  Google Scholar 

  12. Cameron D, Casey M, Press M, Lindquist D, Pienkowski T, Romieu CG, Chan S, Jagiello-Gruszfeld A, Kaufman B, Crown J, Chan A, Campone M, Viens P, Davidson N, Gorbounova V, Raats JI, Skarlos D, Newstat B, Roychowdhury D, Paoletti P, Oliva C, Rubin S, Stein S, Geyer CE (2008) A phase III randomized comparison of lapatinib plus capecitabine vs capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat 112:533–543

    Article  PubMed  CAS  Google Scholar 

  13. von Minckwitz G, du Bois A, Schmidt M, Maass N, Cufer T, de Jongh FE, Maartense E, Zielinski C, Kaufmann M, Bauer W, Baumann KH, Clemens MR, Duerr R, Uleer C, Andersson M, Stein RC, Nekljudova V, Loibl S (2009) Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a German breast group 26/breast international group 03–05 study. J Clin Oncol 27:1999–2006

    Article  Google Scholar 

  14. Thomas ES, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, Jassem J, Pivot XB, Klimovsky JV, de Mendoza FH, Xu B, Campone M, Lerzo GL, Peck RA, Mukhopadhyay P, Vahdat LT, Roché HH (2007) Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol 25:5210–5217

    Article  PubMed  CAS  Google Scholar 

  15. Hortobagyi GN, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, Jassem J, Lerzo GL, Pivot XB, Hurtado de Mendoza F, Xu B, Vahdat LT, Peck RA, Mukhopadhyay P, Roché HH (2010) Analysis of overall survival from a phase III study of ixabepilone plus capecitabine vs capecitabine in patients with MBC resistant to anthracyclines and taxanes. Breast Cancer Res Treat 122:409–418

    Article  PubMed  CAS  Google Scholar 

  16. Hortobagyi GN, Perez E, Vrdoljak E, Medina C, Xu B, Conte P, Roche H, Peck R, Poulart V, Sparano JA (2008) Analysis of overall survival (OS) among patients (pts) with metastatic breast cancer (MBC) receiving either ixabepilone (I) plus capecitabine (C) or C alone: Results from two randomized phase III trials. ASCO 2008 Breast Cancer Symposium; September 5–7, 2008; Washington, DC. (Abstract 186)

  17. Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O’Neill V, Rugo HS (2011) RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 29:4286–4293

    Article  PubMed  CAS  Google Scholar 

  18. Barrios CH, Liu MC, Lee SC, Vanlemmens L, Ferrero JM, Tabei T, Pivot X, Iwata H, Aogi K, Lugo-Quintana R, Harbeck N, Brickman MJ, Zhang K, Kern KA, Martin M (2010) Phase III randomized trial of sunitinib versus capecitabine in patients with previously treated HER2-negative advanced breast cancer. Breast Cancer Res Treat 121:121–131

    Article  PubMed  CAS  Google Scholar 

  19. Crown J, Dieras V, Staroslawska E, Yardley DA, Davidson N, Bachelot TD, Tassell VR, Huang X, Kern KA, Romieu G (2010) Phase III trial of sunitinib (SU) in combination with capecitabine (C) versus C in previously treated advanced breast cancer (ABC). J Clin Oncol 28(Abstract LBA 1011)

  20. Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O’Shaughnessy J (2011) RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol 29:1252–1260

    Article  PubMed  CAS  Google Scholar 

  21. O’Shaughnessy JA, Blum J, Moiseyenko V, Jones SE, Miles D, Bell D, Rosso R, Mauriac L, Osterwalder B, Burger HU, Laws S (2001) Randomized, open-label, phase II trial of oral capecitabine (Xeloda®) vs a reference arm of intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) as first-line therapy for advanced/metastatic breast cancer. Ann Oncol 12:1247–1254

    Article  Google Scholar 

  22. Talbot DC, Moiseyenko V, Van Belle S, O’Reilly SM, Alba Conejo E, Ackland S, Eisenberg P, Melnychuk D, Pienkowski T, Burger HU, Laws S, Osterwalder B (2002) Randomised, phase II trial comparing oral capecitabine (Xeloda) with paclitaxel in patients with metastatic/advanced breast cancer pretreated with anthracyclines. Br J Cancer 86:1367–1372

    Article  PubMed  CAS  Google Scholar 

  23. Sparano JA, Vrdoljak E, Rixe O, Xu B, Manikhas A, Medina C, Da Costa SC, Ro J, Rubio G, Rondinon M, Perez Manga G, Peck R, Poulart V, Conte P (2010) Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 28:3256–3263

    Article  PubMed  CAS  Google Scholar 

  24. Kaufmann M, Maass N, Costa SD, Schneeweiss A, Loibl S, Sütterlin MW, Schrader I, Gerber B, Bauer W, Wiest W, Tomé O, Distelrath A, Hagen V, Kleine-Tebbe A, Ruckhaeberle E, Mehta K, von Minckwitz G, GBG-39 Trialists (2010) First-line therapy with moderate dose capecitabine in metastatic breast cancer is safe and active: results of the MONICA trial. Eur J Cancer 46:3184–3191

    Article  PubMed  CAS  Google Scholar 

  25. Stockler MR, Harvey VJ, Francis PA, Byrne MJ, Ackland SP, Fitzharris B, Van Hazel G, Wilcken NR, Grimison PS, Nowak AK, Gainford MC, Fong A, Paksec L, Sourjina T, Zannino D, Gebski V, Simes RJ, Forbes JF, Coates AS (2011) Capecitabine versus classical cyclophosphamide, methotrexate, and fluorouracil as first-line chemotherapy for advanced breast cancer. J Clin Oncol 29:4498–4504

    Article  PubMed  CAS  Google Scholar 

  26. Jäger E, Al-Batran S, Saupe S, Schmidt M, Kreienberg R, Müller L, Otremba BJ, Warm M, Waldenmaier D, Harbeck N (2010) A randomized phase III study evaluating pegylated liposomal doxorubicin (PLD) vs capecitabine (CAP) as first-line therapy for metastatic breast cancer (MBC): results of the PELICAN study. J Clin Oncol 28(Abstract 1022)

  27. Vahdat L, Fein LE, Karwal MW, Campone M, Peck R, Mukhopadhyay P, Jassem J (2009) Ixabepilone plus capecitabine vs capecitabine in patients with metastatic breast cancer receiving ixabepilone in the first line setting: a pooled analysis from two phase III studies. Cancer Res 69(Abstract 6117)

  28. Baselga J, Segalla JG, Roché H, Del Giglio A, Pinczowski H, Ciruelos EM, Filho SC, Gómez P, Van Eyll B, Bermejo B, Llombart A, Garicochea B, Durán MÁ, Hoff PM, Espié M, de Moraes AA, Ribeiro RA, Mathias C, Gil Gil M, Ojeda B, Morales J, Kwon Ro S, Li S, Costa F (2012) Sorafenib in combination with capecitabine: an oral regimen for patients with HER2-negative locally advanced or metastatic breast cancer. J Clin Oncol 30:1484–1491

    Article  PubMed  CAS  Google Scholar 

  29. Glück S, Russell C, O’Shaughnessy J, Yuan G, Odom D, Sherrill B, Blum J (2009) Relationship between survival and estrogen receptor (ER) status in pts with metastatic breast cancer (MBC) treated with capecitabine (C) and docetaxel (D): an exploratory data analysis. J Clin Oncol 27(Abstract 1024)

  30. Gilabert M, Bertucci F, Esterni B, Madroszyk A, Tarpin C, Jacquemier J, Extra JM, Viens P, Gonçalves A (2011) Capecitabine after anthracycline and taxane exposure in HER2-negative metastatic breast cancer patients: response, survival and prognostic factors. Anticancer Res 31:1079–1086

    PubMed  CAS  Google Scholar 

  31. Pippen JE, Paul D, Stokoe CT, Blum JL, Krekow L, Holmes FA, Lindquist DL, Sedlacek SM, Rivera RR, Brooks RJ, Vukelja SJ, McIntyre K, Lopez-Diaz C, O’Shaughnessy J (2011) Randomized, phase III study of adjuvant doxorubicin plus cyclophosphamide (AC) followed by docetaxel (T) with or without capecitabine (X) in high-risk early breast cancer: Exploratory Ki-67 analyses. J Clin Oncol;29(Abstract 500)

  32. Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, Jukkola-Vuorinen A, Tanner M, Kokko R, Ahlgren J, Auvinen P, Paija O, Helle L, Villman K, Nyandoto P, Nilsson G, Pajunen M, Asola R, Poikonen P, Leinonen M, Kataja V, Bono P, Lindman H (2012) Adjuvant capecitabine, docetaxel, cyclophosphamide, and epirubicin for early breast cancer: final analysis of the randomized FinXX trial. J Clin Oncol 30:11–18

    Article  PubMed  CAS  Google Scholar 

  33. Blum JL, Kohles J, McKenna E, Scotto N, Hu S, Odom D, Kaye JA, Glück S (2011) Association of age and overall survival in capecitabine-treated patients with metastatic breast cancer in clinical trials. Breast Cancer Res Treat 125:431–439

    Article  PubMed  CAS  Google Scholar 

  34. Twelves C, Scheithauer W, McKendrick J, Nowacki M, Seitz J, Van Hazel G, Wong A, Diaz-Rubio E, Gilberg F, Cassidy J (2008) Capecitabine versus 5-FU/LV in stage III colon cancer: updated 5-year efficacy data from X-ACT trial and preliminary analysis of relationship between hand-foot syndrome (HFS) and efficacy. ASCO 2008 Gastrointestinal Cancers Symposium (Abstract 274)

  35. Diab SG, Elledge RM, Clark GM (2000) Tumor characteristics and clinical outcome of elderly women with breast cancer. J Natl Cancer Inst 92:550–556

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Support for third-party writing assistance for this manuscript was provided by Hoffmann-La Roche Inc.

Conflicts of interest

Dr. Blum has held consultant/advisory roles for Roche. Professor Barrios has held consultant/advisory roles for Roche, GSK, and Novartis. Dr. Feldman has received remuneration as a speaker for Roche, Takeda. Dr. Verma has held consultant/advisory roles for Roche and EISAI. Dr. McKenna is an employee of, and has stock ownership in, Genentech/Roche. Dr. Lee is an employee of, and has stock ownership in, Roche. Dr. Scotto is an employee of Roche. Dr. Gralow has received funding from Genentech, Roche, Amgen and Novartis.

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Authors and Affiliations

  1. Baylor-Charles A. Sammons Cancer Center, Texas Oncology, US Oncology, 3410 Worth Street, Suite 400, Dallas, TX, 75246, USA

    Joanne L. Blum

  2. PUCRS School of Medicine, Porto Alegre, Brazil

    Carlos H. Barrios

  3. Division of Hematology/Oncology, Olive View-UCLA Medical Center, Sylmar, CA, USA

    Nancy Feldman

  4. Division of Medical Oncology, Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, Canada

    Sunil Verma

  5. Genentech Inc., San Francisco, CA, USA

    Edward F. McKenna & Luen F. Lee

  6. F. Hoffmann-La Roche Ltd., Basel, Switzerland

    Nana Scotto

  7. Department of Medicine, University of Washington, Seattle, WA, USA

    Julie Gralow

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  1. Joanne L. Blum
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Correspondence to Joanne L. Blum.

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Blum, J.L., Barrios, C.H., Feldman, N. et al. Pooled analysis of individual patient data from capecitabine monotherapy clinical trials in locally advanced or metastatic breast cancer. Breast Cancer Res Treat 136, 777–788 (2012). https://doi.org/10.1007/s10549-012-2288-x

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  • DOI: https://doi.org/10.1007/s10549-012-2288-x

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