Multicenter Phase II Study of Intraoperative Radiotherapy of Early Breast Cancer: Ipsilateral Tumor Recurrence

  • Masataka SawakiEmail author
  • Takeshi Miyamoto
  • Tomomi Fujisawa
  • Yoshiyuki Itoh
  • Takeshi Ebara
  • Hiroyuki Tachibana
  • Takeshi Kodaira
  • Toyone Kikumori
  • Yasuhiro Yanagita
  • Hiroji Iwata
Breast Oncology



We performed a multicenter phase II study on the efficacy and safety of intraoperative radiotherapy (IORT) as partial breast irradiation using multiple devices.


The primary endpoint was ipsilateral breast tumor recurrence (IBTR). Key inclusion criteria were T < 2.5 cm, age > 50 years, surgical margin > 1 cm, intraoperative pathologically free margins, and sentinel node negative. After resection of the tumor, radiation at 21 Gy was delivered directly to the mammary gland employing an electron linear accelerator in the operating room, otherwise the patient was transported from the surgical suite to the radiation room.


Overall, 142 patients were enrolled in this study and 129 underwent IORT. Stage 0: n = 4 (3.1%); stage I: n = 98 (76.0%); and stage IIA: n = 27 (20.9%). Luminal type: n = 116 (89.9%); triple-negative: n = 9 (7.0%); and human epidermal growth factor receptor 2: n = 4 (3.1%). Median follow-up time was 59.5 months (range 27.5–99.0), and the rate of IBTR was 3.1% (95% confidence interval 0.9–7.8). The toxicities included fibrosis in deep-connective tissue: grade 1, 78.1%; wound infection: grade 3, 1.6% and grade 2, 1.6%; and soft tissue necrosis: grade 3, 0.8% and grade 2, 0.8%. Recurrence in the breast occurred in four cases; the site of recurrence was just under the skin near the primary tumor site, with similar histology and subtype.


In this multicenter phase II study, the rate of IBTR was low and IORT at 21 Gy was feasible in properly selected patients. It is important to use a careful surgical technique to reduce local recurrence because the skin is not included in the radiation field of IORT.



Masataka Sawaki, Takeshi Miyamoto, Tomomi Fujisawa, Yoshiyuki Itoh, Takeshi Ebara, Hiroyuki Tachibana, Takeshi Kodaira, Toyone Kikumori, Yasuhiro Yanagita, and Hiroji Iwata have no conflicts of interest to declare.


  1. 1.
    Clarke M, Collins R, Darby S, et al. 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. 2005;366:2087–106.CrossRefGoogle Scholar
  2. 2.
    Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med. 2002;347:1227–32.CrossRefGoogle Scholar
  3. 3.
    Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med. 2002;347:1233–41.CrossRefGoogle Scholar
  4. 4.
    Veronesi U, Marubini E, Mariani L, et al. Radiotherapy after breast-conserving surgery in small breast carcinoma: long-term results of a randomized trial. Ann Oncol. 2001;12:997–1003.CrossRefGoogle Scholar
  5. 5.
    Njeh CF, Saunders MW, Langton CM. Accelerated partial breast irradiation (APBI): a review of available techniques. Radiat Oncol. 2010;5:90.CrossRefGoogle Scholar
  6. 6.
    Correa C, Harris EE, Leonardi MC, et al. Accelerated partial breast irradiation: executive summary for the update of an ASTRO evidence-based consensus statement. Pract Radiat Oncol. 2017;7:73–9.CrossRefGoogle Scholar
  7. 7.
    Jacobs DHM, Speijer G, Petoukhova AL, et al. Acute toxicity of intraoperative radiotherapy and external beam-accelerated partial breast irradiation in elderly breast cancer patients. Breast Cancer Res Treat. 2018;169:549–59.CrossRefGoogle Scholar
  8. 8.
    Veronesi U, Orecchia R, Luini A, et al. A preliminary report of intraoperative radiotherapy (IORT) in limited-stage breast cancers that are conservatively treated. Eur J Cancer. 2001;37:2178–83.CrossRefGoogle Scholar
  9. 9.
    Veronesi U, Orecchia R, Luini A, et al. Intraoperative radiotherapy during breast conserving surgery: a study on 1,822 cases treated with electrons. Breast Cancer Res Treat. 2010;124:141–51.CrossRefGoogle Scholar
  10. 10.
    Sawaki M, Sato S, Kikumori T, et al. A phase I study of intraoperative radiotherapy for early breast cancer in Japan. World J Surg. 2009;33:2587–92.CrossRefGoogle Scholar
  11. 11.
    Sawaki M, Sato S, Noda S, et al. Phase I/II study of intraoperative radiotherapy for early breast cancer in Japan. Breast Cancer. 2012;19:353–9.CrossRefGoogle Scholar
  12. 12.
    Sawaki M, Kondo N, Horio A, et al. Feasibility of intraoperative radiation therapy for early breast cancer in Japan: a single-center pilot study and literature review. Breast Cancer. 2014;21:415–22.CrossRefGoogle Scholar
  13. 13.
    Harris JR, Levene MB, Svensson G, Hellman S. Analysis of cosmetic results following primary radiation therapy for stages I and II carcinoma of the breast. Int J Radiat Oncol Biol Phys. 1979;5:257–61.CrossRefGoogle Scholar
  14. 14.
    Oshima T, Aoyama Y, Shimozato T, et al. An experimental attenuation plate to improve the dose distribution in intraoperative electron beam radiotherapy for breast cancer. Phys Med Biol. 2009;54:3491–500.CrossRefGoogle Scholar
  15. 15.
    Smith BD, Arthur DW, Buchholz TA, et al. Accelerated partial breast irradiation consensus statement from the American society for radiation oncology (ASTRO). Int J Radiat Oncol Biol Phys. 2009;74:987–1001.CrossRefGoogle Scholar
  16. 16.
    Vicini F, Arthur D, Wazer D, et al. Limitations of the American society of therapeutic radiology and oncology consensus panel guidelines on the use of accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys. 2011;79:977–84.CrossRefGoogle Scholar
  17. 17.
    Polgár C, Limbergen EV, Pötter R, et al. Patient selection for accelerated partial-breast irradiation (APBI) after breast-conserving surgery: recommendations of the Groupe Européen de Curiethérapie-European Society for therapeutic radiology and oncology (GEC-ESTRO) breast cancer working group based on clinical evidence (2009). Radiother Oncol. 2010;94:264–73.CrossRefGoogle Scholar
  18. 18.
    Lorenzen AW, Kiriazov B, De Andrade JP, et al. Intraoperative Radiotherapy for breast cancer treatment in a rural community. Ann Surg Oncol. 2018;25:3004–10.CrossRefGoogle Scholar
  19. 19.
    Coles CE, Griffin CL, Kirby AM, et al. Partial-breast radiotherapy after breast conservation surgery for patients with early breast cancer (UK IMPORT LOW trial): 5-year results from a multicentre, randomised, controlled, phase 3, non-inferiority trial. Lancet. 2017;390:1048–60.CrossRefGoogle Scholar
  20. 20.
    Strnad V, Ott OJ, Hildebrandt G, et al. 5-year results of accelerated partial breast irradiation using sole interstitial multicatheter brachytherapy versus whole-breast irradiation with boost after breast-conserving surgery for low-risk invasive and in situ carcinoma of the female breast: a randomised, phase 3, non-inferiority trial. Lancet. 2016;387:229–38.CrossRefGoogle Scholar
  21. 21.
    Vaidya JS, Wenz F, Bulsara M, et al. Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial. Lancet. 2014;383:603–13.CrossRefGoogle Scholar
  22. 22.
    Veronesi U, Orecchia R, Maisonneuve P, et al. Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a randomised controlled equivalence trial. Lancet Oncol. 2013;14:1269–77.CrossRefGoogle Scholar
  23. 23.
    Luini A, Orecchia R, Gatti G, et al. The pilot trial on intraoperative radiotherapy with electrons (ELIOT): update on the results. Breast Cancer Res Treat. 2005;93:55–9.CrossRefGoogle Scholar
  24. 24.
    Polgár C, Ott OJ, Hildebrandt G, et al. Late side-effects and cosmetic results of accelerated partial breast irradiation with interstitial brachytherapy versus whole-breast irradiation after breast-conserving surgery for low-risk invasive and in situ carcinoma of the female breast: 5-year results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2017;18:259–68.CrossRefGoogle Scholar
  25. 25.
    Shah C, Badiyan S, Ben Wilkinson J, et al. Treatment efficacy with accelerated partial breast irradiation (APBI): final analysis of the American Society of Breast Surgeons MammoSite® breast brachytherapy registry trial. Ann Surg Oncol. 2013;20:3279–85.CrossRefGoogle Scholar
  26. 26.
    Park CC, Mitsumori M, Nixon A, et al. Outcome at 8 years after breast-conserving surgery and radiation therapy for invasive breast cancer: influence of margin status and systemic therapy on local recurrence. J Clin Oncol. 2000;18:1668–75.CrossRefGoogle Scholar
  27. 27.
    Fisher ER. Lumpectomy margins and much more. Canc. 1997;79:1453–8; discussion 9–60.Google Scholar
  28. 28.
    Cao D, Tsangaris TN, Kouprina N, et al. The superficial margin of the skin-sparing mastectomy for breast carcinoma: factors predicting involvement and efficacy of additional margin sampling. Ann Surg Oncol. 2008;15:1330–40.CrossRefGoogle Scholar
  29. 29.
    Beal K, McCormick B, Zelefsky M, et al. Single-fraction intraoperative radiotherapy for breast cancer: early cosmetic results. Int J Radiat Oncol Biol Phys. 2007;69:19–24.CrossRefGoogle Scholar
  30. 30.
    Chism D, Freedman G, Li T, Anderson P. Re-excision of margins before breast radiation—diagnostic or therapeutic? Int J Radiat Oncol Biol Phys. 2006;65:1416–21.CrossRefGoogle Scholar
  31. 31.
    Mariani L, Salvadori B, Marubini E, et al. Ten year results of a randomised trial comparing two conservative treatment strategies for small size breast cancer. Eur J Cancer. 1998;34:1156–62.CrossRefGoogle Scholar
  32. 32.
    Fukamachi K, Ishida T, Usami S, et al. Total-circumference intraoperative frozen section analysis reduces margin-positive rate in breast-conservation surgery. Jpn J Clin Oncol. 2010;40:513–20.CrossRefGoogle Scholar
  33. 33.
    Kyndi M, Sorensen FB, Knudsen H, Overgaard M, Nielsen HM, Overgaard J. Estrogen receptor, progesterone receptor, HER-2, and response to postmastectomy radiotherapy in high-risk breast cancer: the danish breast cancer cooperative group. J Clin Oncol. 2008;26:1419–26.CrossRefGoogle Scholar
  34. 34.
    Nguyen PL, Taghian AG, Katz MS, et al. Breast cancer subtype approximated by estrogen receptor, progesterone receptor, and HER-2 is associated with local and distant recurrence after breast-conserving therapy. J Clin Oncol. 2008;26:2373–8.CrossRefGoogle Scholar
  35. 35.
    Solin LJ. Tailored local-regional treatment for early-stage breast cancer. Clin Breast Cancer. 2010;10:343–4.CrossRefGoogle Scholar

Copyright information

© Society of Surgical Oncology 2019

Authors and Affiliations

  • Masataka Sawaki
    • 1
    Email author
  • Takeshi Miyamoto
    • 2
  • Tomomi Fujisawa
    • 2
  • Yoshiyuki Itoh
    • 3
  • Takeshi Ebara
    • 4
  • Hiroyuki Tachibana
    • 5
  • Takeshi Kodaira
    • 5
  • Toyone Kikumori
    • 6
  • Yasuhiro Yanagita
    • 2
  • Hiroji Iwata
    • 1
  1. 1.Department of Breast OncologyAichi Cancer Center HospitalNagoyaJapan
  2. 2.Department of Breast OncologyGunma Prefectural Cancer CenterOtaJapan
  3. 3.Department of RadiologyNagoya University Graduate School of MedicineNagoyaJapan
  4. 4.Department of Radiation OncologyGunma Prefectural Cancer CenterOtaJapan
  5. 5.Department of Radiation OncologyAichi Cancer Center HopsitalNagoyaJapan
  6. 6.Department of Breast and Endocrine SurgeryNagoya University School of MedicineNagoyaJapan

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