Breast Cancer Research and Treatment

, Volume 148, Issue 2, pp 345–353 | Cite as

Concurrent administration of trastuzumab with locoregional breast radiotherapy: long-term results of a prospective study

  • J. Jacob
  • L. Belin
  • J.-Y. Pierga
  • A. Gobillion
  • A. Vincent-Salomon
  • R. Dendale
  • P. Beuzeboc
  • F. Campana
  • A. Fourquet
  • Y. M. Kirova
Clinical trial


This single-center prospective study aims to assess the outcomes and the toxicities related to the concurrent administration of trastuzumab (T) with adjuvant locoregional radiotherapy (RT) in localized breast cancer. Data of 308 patients were analyzed. T was delivered every 3 weeks (loading dose of 8 mg/kg, then 6 mg/kg) for 1 year. Left ventricular ejection fraction (LVEF), measured by echocardiography or myocardial scintigraphy, was considered as impaired when below 55 %. Toxicities were assessed according to the Common Terminology Criteria for Adverse Events version 3.0. Univariate and multivariate analyses were carried out using the Cox model. Median follow-up was 50.2 months (13.0–126.0). Median age at diagnosis was 52 years (25–83). Internal mammary node (IMN) RT was performed in 227 patients (73.7 %). After completion of RT, 26 patients (8.4 %) presented an impaired LVEF: 17 (5.5 %) of grade 1, 7 (2.3 %) of grade 2, and 2 (0.6 %) of grade 3. At 48 months, locoregional control rate was 95 % [95 % CI 92; 98], and overall survival rate was 98 % [95 % CI 96; 100]. In univariate analysis, neither the treated breast side (p = 0.655) nor IMN RT (p = 0.213) exposed patients to LVEF alteration. In multivariate analysis, clinical lymph node involvement was associated with an increased risk of locoregional and distant recurrence (p = 0.016 and p = 0.007, respectively). In this prospective study, the toxicities of concurrent T with locoregional breast RT were acceptable and the outcomes favorable. Longer follow-up is warranted to confirm these results.


Breast cancer Radiotherapy Toxicity Trastuzumab Concurrent treatment 



We would like to thank the patients followed throughout this study and the members of the Institut Curie Breast Cancer Study Group. We would also like to thank Dr Marc Bollet, Dr Caroline Daveau-Bergerault, Dr Lucas Caussa, and Mrs. Chantal Gautier for their help in the patient data management.

Conflict of interest

J.-Y. P.: fees, research grants received from Roche® laboratories. P. B.: fees received from Roche® laboratories. All remaining authors have declared no conflicts of interest.


The authors have declared no funding sources for this work.


  1. 1.
    Spector NL, Blackwell KL (2009) Understanding the mechanisms behind trastuzumab therapy for human epidermal growth factor receptor-2 positive breast cancer. J Clin Oncol 27:5838–5847PubMedCrossRefGoogle Scholar
  2. 2.
    Slamon DJ, Clark GM, Wong SG et al (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177–182PubMedCrossRefGoogle Scholar
  3. 3.
    Voduc KD, Cheang MC, Tyldesley S et al (2010) Breast cancer subtypes and the risk of local and regional relapse. J Clin Oncol 28:1684–1691PubMedCrossRefGoogle Scholar
  4. 4.
    Slamon DJ, Leyland-Jones B, Shak S et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792PubMedCrossRefGoogle Scholar
  5. 5.
    Piccart-Gebhart MJ, Procter M, Leyland-Jones B et al (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659–1672PubMedCrossRefGoogle Scholar
  6. 6.
    Romond EH, Perez EA, Bryant J et al (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673–1684PubMedCrossRefGoogle Scholar
  7. 7.
    Clarke M, Collins R, Darby S et al (2005) Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15 year survival: an overview of the randomised trials. Lancet 366:2087–2106PubMedCrossRefGoogle Scholar
  8. 8.
    Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Darby S, Mc Gale P et al (2011) Effect of radiotherapy after breast-conserving surgery on 10 year recurrence and 15 year breast cancer death: meta-analysis on individual patient data for 10,801 women in 17 randomised trials. Lancet 378:1707–1716CrossRefGoogle Scholar
  9. 9.
    Pietras RJ, Poen JC, Gallardo D et al (1999) Monoclonal antibody to HER-2/neu receptor modulates repair of radiation-induced DNA damage and enhances radiosensitivity of human breast cancer cells overexpressing this oncogene. Cancer Res 59:1347–1355PubMedGoogle Scholar
  10. 10.
    Belkacémi Y, Gligorov J, Ozsahin M et al (2008) Concurrent trastuzumab with adjuvant radiotherapy in HER2-positive breast cancer patients: acute toxicity analyses from the French multicentric study. Ann Oncol 19:1110–1116PubMedCrossRefGoogle Scholar
  11. 11.
    Shaffer R, Tyldesley S, Rolles M et al (2009) Acute cardiotoxicity with concurrent trastuzumab and radiotherapy including internal mammary chain nodes: a retrospective single-institution study. Radiother Oncol 90:122–126PubMedCrossRefGoogle Scholar
  12. 12.
    Bellon JR, Gover MT, Burstein HJ et al (2005) Concurrent trastuzumab and radiation therapy (RT) in the adjuvant treatment of breast cancer. Int J Radiat Oncol Biol Phys 63(Suppl 1):S55–S56CrossRefGoogle Scholar
  13. 13.
    Meattini I, Cecchini S, Muntoni C et al (2014) Cutaneous and cardiac toxicity of concurrent trastuzumab and adjuvant breast radiotherapy: a single institution series. Med Oncol 31:891PubMedCrossRefGoogle Scholar
  14. 14.
    Caussa L, Kirova YM, Gault N et al (2011) The acute skin and heart toxicity of a concurrent association of trastuzumab and locoregional breast radiotherapy including internal mammary chain: a single-institution study. Eur J Cancer 47:65–73PubMedCrossRefGoogle Scholar
  15. 15.
    Raben A, Sammons S, Hanlon A et al (2006) Comparison of acute breast and chest wall toxicity in women treated with external beam irradiation with and without concurrent herceptin in a community cancer center. Int J Radiat Oncol Biol Phys 66(Suppl):S541–S542CrossRefGoogle Scholar
  16. 16.
    Horton JK, Halle J, Ferraro M et al (2010) Radiosensitization of chemotherapy-refractory, locally advanced or locally recurrent breast cancer with trastuzumab: a phase II trial. Int J Radiat Oncol Biol Phys 76:998–1004PubMedCrossRefGoogle Scholar
  17. 17.
    American Joint Committee on Cancer (2010) AJCC cancer staging manual, 7th edn. Springer, New YorkCrossRefGoogle Scholar
  18. 18.
    Pierga JY, Bidard FC, Mathiot C et al (2008) Circulating tumor cell detection predicts early metastatic relapse after neoadjuvant chemotherapy in large operable and locally advanced breast cancer in a phase II randomized trial. Clin Cancer Res 14:7004–7010PubMedCrossRefGoogle Scholar
  19. 19.
    Bollet MA, Sigal-Zafrani B, Gambotti L et al (2006) Pathological response to preoperative concurrent chemo-radiotherapy for breast cancer: results of a phase II study. Eur J Cancer 42:2286–2295PubMedCrossRefGoogle Scholar
  20. 20.
    Roché H, Fumoleau P, Spielmann M et al (2006) Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 Trial. J Clin Oncol 24:5664–5671PubMedCrossRefGoogle Scholar
  21. 21.
    Kirova YM, Hijal T, Campana F et al (2014) Whole breast radiotherapy in the lateral decubitus position: a dosimetric and clinical solution to decrease the doses to the organs at risk (OAR). Radiother Oncol 110:477–481PubMedCrossRefGoogle Scholar
  22. 22.
    Fournier-Bidoz N, Kirova YM, Campana F et al (2012) Simplified field-in-field technique for a large-scale implementation in breast radiation treatment. Med Dosim 2012 Summer 37:131–137Google Scholar
  23. 23.
    Kirova YM, Campana F, Fournier-Bidoz N et al (2007) Postmastectomy electron beam chest wall irradiation in women with breast cancer: a clinical step toward conformal electron therapy. Int J Radiat Oncol Biol Phys 69:1139–1144PubMedCrossRefGoogle Scholar
  24. 24.
    Hurkmans CW, Borger JH, Bos LJ et al (2000) Cardiac and lung complication probabilities after breast cancer irradiation. Radiother Oncol 55:145–151PubMedCrossRefGoogle Scholar
  25. 25.
    Kong FM, Klein EE, Bradley JD et al (2002) The impact of central lung distance, maximal heart distance, and radiation technique on the volumetric dose of the lung and heart dose for intact breast radiation. Int J Radiat Oncol Biol Phys 54:963–971PubMedCrossRefGoogle Scholar
  26. 26.
    Halyard MY, Pisansky TM, Dueck AC et al (2009) Radiotherapy and adjuvant trastuzumab in operable breast cancer: tolerability and adverse event data from the NCCTG phase III Trial N9831. J Clin Oncol 27:2638–2644PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Belkacémi Y, Gligorov J (2010) Concurrent trastuzumab-internal mammary irradiation for HER2 positive breast cancer: “It hurts to be on the cutting edge”. Radiother Oncol 94:119–120PubMedCrossRefGoogle Scholar
  28. 28.
    Prosnitz RG, Marks LB (2005) Radiation-induced heart disease: vigilance is still required. J Clin Oncol 23:7391–7394PubMedCrossRefGoogle Scholar
  29. 29.
    Whelan TJ, Olivotto I, Ackerman I et al (2011) NCIC-CTG MA.20: an intergroup trial of regional nodal irradiation in early breast cancer. J Clin Oncol 29 (Suppl):abstract LBA1003Google Scholar
  30. 30.
    Poortmans P, Struikmans H, Kirkove C et al (2013) Irradiation of the internal mammary and medial supraclavicular lymph nodes in stage I to III breast cancer: 10 years results of the EORTC Radiation Oncology and Breast Cancer Groups phase III trial 22922/10925. Eur J Cancer 49(Suppl 3):S1–S2Google Scholar
  31. 31.
    Hennequin C, Bossard N, Servagi-Vernat S et al (2013) Ten-year survival results of a randomized trial of irradiation of internal mammary nodes after mastectomy. Int J Radiat Oncol Biol Phys 86:860–866PubMedCrossRefGoogle Scholar
  32. 32.
    Chang JS, Park W, Kim YB et al (2013) Long-term survival outcomes following internal mammary node irradiation in stage II–III breast cancer: results of a large retrospective study with 12 year follow-up. Int J Radiat Oncol Biol Phys 86:867–872PubMedCrossRefGoogle Scholar
  33. 33.
    Harris EE, Correa C, Hwang WT et al (2006) Late cardiac mortality and morbidity in early stage breast cancer patients after breast-conservation treatment. J Clin Oncol 24:4100–4106PubMedCrossRefGoogle Scholar
  34. 34.
    Tarantini L, Cioffi G, Gori S et al (2012) Trastuzumab adjuvant chemotherapy and cardiotoxicity in real-world women with breast cancer. J Card Fail 18:113–119PubMedCrossRefGoogle Scholar
  35. 35.
    Tarantini L, Gori S, Faggiano P et al (2012) Adjuvant trastuzumab cardiotoxicity in patients over 60 years of age with early breast cancer: a multicenter cohort analysis. Ann Oncol 23:3058–3063PubMedCrossRefGoogle Scholar
  36. 36.
    Taylor CW, McGale P, Povall JM et al (2009) Estimating cardiac exposure from breast cancer radiotherapy in clinical practice. Int J Radiat Oncol Biol Phys 73:1061–1068PubMedCrossRefGoogle Scholar
  37. 37.
    Bornstein BA, Chang CW, Rhodes LM et al (1990) Can simulation measurements be used to predict the irradiated lung volume in the tangential fields in patients treated for breast cancer? Int J Radiat Oncol Biol Phys 18:181–187PubMedCrossRefGoogle Scholar
  38. 38.
    Neal AJ, Yarnold JR (1995) Estimating the volume of lung irradiated during tangential breast irradiation using the central lung distance. Br J Radiol 68:1004–1008PubMedCrossRefGoogle Scholar
  39. 39.
    Das IJ, Cheng EC, Freedman G et al (1998) Lung and heart dose volume analyses with CT simulator in radiation treatment of breast cancer. Int J Radiat Oncol Biol Phys 42:11–19PubMedCrossRefGoogle Scholar
  40. 40.
    Coon AB, Dickler A, Kirk MC et al (2010) Tomotherapy and multifield intensity-modulated radiotherapy planning reduce cardiac doses in left-sided breast cancer patients with unfavorable cardiac anatomy. Int J Radiat Oncol Biol Phys 78:104–110PubMedCrossRefGoogle Scholar
  41. 41.
    Quinn A, Holloway L, Hardcastle N et al (2013) Normal tissue dose and second cancer risk due to megavoltage fan-beam CT, static tomotherapy and helical tomotherapy in breast radiotherapy. Radiother Oncol 108:266–268PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • J. Jacob
    • 1
  • L. Belin
    • 2
  • J.-Y. Pierga
    • 3
  • A. Gobillion
    • 2
  • A. Vincent-Salomon
    • 4
  • R. Dendale
    • 1
  • P. Beuzeboc
    • 3
  • F. Campana
    • 1
  • A. Fourquet
    • 1
  • Y. M. Kirova
    • 1
  1. 1.Department of Radiation OncologyInstitut CurieParis Cedex 05France
  2. 2.Department of BiostatisticsInstitut CurieParisFrance
  3. 3.Department of Medical OncologyInstitut CurieParisFrance
  4. 4.Department of PathologyInstitut CurieParisFrance

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