To report toxicity of a hypofractionated scheme of whole-breast (WB) intensity-modulated radiotherapy (IMRT) with simultaneous integrated boost (SIB) to the tumor bed (TB) using Tomotherapy® with Direct modality.
Patients with early breast cancer, undergoing radiotherapy (RT) in 15 daily fractions to WB (prescription dose 40.05 Gy) and SIB to the TB (48 Gy), between 2013 and 2017, was analyzed. Primary endpoint was acute and intermediate toxicity assessed at the end and within 6 months from RT, according to Radiation Therapy Oncology Group (RTOG) scale. Secondary endpoints included early chronic toxicity at 12-months follow-up, using the Late Effects Normal Tissue Task Subjective, Objective, Management, and Analytic (LENT-SOMA) scale, and cosmesis using Harvard criteria.
The study population was of 287 patients. Acute and intermediate toxicity was collected among 183 patients with data available at the end of RT and within 6 months, 85 (46%) experienced G2 toxicity and 84 (46%) G1 toxicity, while 14 (8%) did not report toxicity at any time. A significant reduction of any grade toxicity was observed between the two time points, with the majority of patients reporting no clinically relevant toxicity at 6 months. At univariate analysis, age < 40 years, breast volume > 1000 cm3 and Dmax ≤ 115% of prescription dose were predictive factors of clinically relevant acute toxicity (G ≥ 2) at any time. At multivariable analysis, only age and breast volume were confirmed as predictive factors, with Relative Risks (95% Confidence Intervals): 2.02 (1.13–3.63) and 1.84 (1.26–2.67), respectively.
At 12-month follow-up, 113 patients had complete information on any toxicity with 53% of toxicity G < 2, while cosmetic evaluation, available for 102 patients, reported a good–excellent result for 86% of patients.
Hypofractionated WB IMRT with a SIB to the TB, delivered with TomoDirect modality, is safe and well-tolerated. Most patients reported no toxicity after 6 months and good–excellent cosmesis. Predictive factors of clinically relevant toxicity might be considered during treatment planning in order to further reduce side effects.
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American Society for Radiation Oncology
Associazione Italiana di Radioterapia e Oncologia Clinica
Clinical target volume
European Organization for Research and Treatment of Cancer
Hypofractionated whole-breast radiotherapy
Late effects normal tissue task subjective, objective, management, and analytic scale
Organs at risk
Numeric rate scale
Planning target volume
Radiation Therapy Oncology Group
Simultaneous integrated boost
Smith BD, Bellon JR, Blitzblau R, et al. Radiation therapy for the whole breast: executive summary of an American Society for Radiation Oncology (ASTRO) evidence-based guideline. Pract Rad Oncol. 2018;8:145–52.
Bellefqih S, Elmajjaoui S, Aarab J, et al. Hypofractionated regional nodal irradiation for women with node-positive breast cancer. Int J Radiation Oncol Biol Phys. 2018;97(3):563–70.
Bartelink H, Maingon P, Poortmans P, et al. European Organisation for Research and Treatment of Cancer Radiation Oncology and Breast Cancer Groups. Whole-breast irradiation with or without a boost for patients treated with breast-conserving surgery for early breast cancer: 20-year follow-up of a randomized phase 3 trial. Lancet Oncol. 2015;16(1):47–56.
Bartelink H, Horiot JC, Poortmans P, et al. European Organisation for Research and Treatment of Cancer Radiation Oncology and Breast Cancer Groups. Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. EORTC 22881. N Engl J Med. 2001;345(19):1378–87.
Whelan TJ, Pignol JP, Levine MN, et al. Long-term results of hypofractionated radiation therapy for breast cancer. N Engl J Med. 2010;362:513–20.
Owen JR, Ashton A, Bliss JM, et al. Effect of radiotherapy fraction size on tumour control in patients with early-stage breast cancer after local tumour excision: long-term results of a randomized trial. Lancet Oncol. 2006;7:467–71.
Haviland JS, Owen JR, Dewar JA, et al. The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials. Lancet Oncol. 2013;14:1086–94.
Bantema-Joppe EJ, Schilstra C, de Bock GH, et al. Simultaneous integrated boost irradiation after breast-conserving surgery: physician-rated toxicity and cosmetic outcome at 30 months’ follow-up. Int J Radiat Oncol Biol Phys. 2012;83:e471–7.
Ditsch N, Untch M, Thill M, et al. AGO recommendations for the diagnosis and treatment of patients with early breast cancer: update 2019. Breast Care. 2019;14:224–45.
Wöckel A, Festl J, Stüber T, et al. Interdisciplinary screening, diagnosis, therapy and follow-up of breast cancer. Guideline of the DGGG and the DKG (S3-level, AWMF registry number 032/045OL, December 2017)—Part 2 with recommendations for the therapy of primary, recurrent and advanced breast cancer. Geburtshilfe Frauenheilkd. 2018;78:1056–88.
Lilla C, Ambrosone CB, Kropp S, et al. Predictive factors of late normal tissue complications following radiotherapy for breast cancer Breast Ca Res Treat, 2007;106:143-50.
Pignol JP, Olivotto I, Rakovitch E, et al. A Phase III multicentre clinical trial of Breast Intensity Modulated Radiation Therapy (IMRT) to reduce skin radiation side effects. J Clin Oncol. 2008;26:2085–92.
Pignol J, Truong P, Rakovitch E, et al. Ten years results of the Canadian breast intensity modulated radiation therapy (IMRT) randomized controlled trial. Radiother Oncol 2016;414–9.
AIRO: Appendice contornamento in: Radiotherapy breast cancer: Indications and guidelines. 2013. http://www.radioterapiaitalia.it/allegato__1222_796.phtml. Accessed 2 Jan 2018.
RTOG 1005. A phase iii trial of accelerated whole breast irradiation with hypofractionation plus concurrent boost versus standard whole breast irradiation plus sequential boost for early-stage breast cancer Available at (15/06/2020): www.rtog.org › ProtocolTable › StudyDetails
Downie WW, Leatham PA, Rhind VM, Wright V, Branco JA, Anderson JA. Studies with pain rating scales. Ann Rheum Dis. 1978;37:378–81.
Bartelink H, Horiot JC, Poortmans PM, et al. Impact of a higher radiation dose on local control and survival in breast-conserving therapy of early breast cancer: 10-years results of the randomized boost versus no boost EORTC 22881–10882 trial. J Clin Oncol. 2007;25:3259–65.
Freedman GM, Anderson PR, Hanlon AL, et al. Pattern of recurrence after conservative surgery and whole-breast irradiation. Int J Radiat Oncol Biol Phys. 2005;61:1328–36.
De Santis MC, Bonfantini F, Di Salvo F, et al. Hypofractionated whole-breast irradiation with or without boost in elderly patients: clinical evaluation of an Italian experience. Clin Breast Cancer. 2018. https://doi.org/10.1016/j.clbc.2018.04.003.
Graham P, Fourquer A. Placing the boost in the breast conservation radiotherapy: a review of the role, indications and techniques for breast boost radiotherapy. Clin Oncol (R Coll Radiol). 2006;18:210–9.
Antonini N, Jones H, Horiot JC, et al. Effect of age and radiation dose on local control after breast conserving treatment: EORTC trial 22881-10882. Radiother Oncol. 2007;82(3):265–71.
START Trialists’ Group, Bentzen SM, Agrawal RK, et al. The UK standardisation of breast radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet Oncol. 2008;9:331–41.
START Trialists’ Group, Bentzen SM, Agrawal RK, et al. The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet Oncol. 2008;371:1098–107.
Murray Brunt A, Haviland JS, Wheatley DA, et al. Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results from a multicentre, non-inferiority, randomised, phase 3 trial. Lancet. 2020;395(10237):1613–26. https://doi.org/10.1016/S0140-6736(20)30932-6.
Franco P, Zeverino M, Migliaccio F, et al. Intensity-modulated and hypofractionated simultaneous integrated boost adjuvant breast radiation employing statics ports of tomotherapy (Tomo Direct): a prospective phase II trial. J Cancer Res Clin Oncol. 2014;140:167–77.
Fiorentino A, Mazzola R, Ricchetti F, et al. Intensity modulated radiation therapy with simultaneous integrated boost in early breast cancer irradiation. Report of feasibility and preliminary toxicity. Cancer Radiother. 2015;19(5):289–94.
De Langhe S, Mulliez T, Veldeman L. Factors modifying the risk for developing acute skin toxicity after whole-breast intensity modulated radiotherapy. BMC Cancer. 2014;14:711.
McDonald MW, Godette KD, Whitaker DJ, et al. Three-year outcomes of breast intensity-modulated radiation therapy with simultaneous integrated boost. Int J Radiat Oncol Biol Phys. 2010;77(2):523–30.
Dewan A, Chufal KS, Dewan AK, et al. Simultaneous integrated boost by Intensity Modulated Radiotherapy (SIB-IMRT) in patients undergoing breast conserving surgery—a clinical and dosimetric perspective. J Egypt Natl Canc Inst. 2018;30(4):165–71. https://doi.org/10.1016/j.jnci.2018.10.001.
Alford SL, Prassas GN, Vogelesang CR, et al. Adjuvant breast radiotherapy using a simultaneous integrated boost: clinical and Dosimetric perspectives. J Med Imaging Radiat Oncol. 2013;57(2):222–9. https://doi.org/10.1111/j.1754-9485.2012.02473.
Bantema EJ, van der Laan HP, de Bock JH, et al. Three-dimensional conformal hypofractionated simultaneous integrated boost in breast conserving therapy: results on local control and survival. Radiother Oncol. 2011;100:215–20.
De Rose F, Fogliata A, Franceschini D, et al. Hypofractionation with simultaneous boost in breast cancer patients receiving adjuvant chemotherapy: a prospective evaluation of a case series and review of the literature. Breast. 2018;42:31–7. https://doi.org/10.1016/j.breast.2018.08.098.
Dellas K, Vonthein R, Zimmer J, et al. Hypofractionation with simultaneous integrated boost for early breast cancer: results of the German multicenter phase II Trial (ARO-2010-01). Strahlenther Onkol. 2014;190(7):646–53. https://doi.org/10.1007/s00066-014-0658-5.
Fiorentino A, Mazzola R, Levra NG, et al. Comorbidities and intensity-modulated radiotherapy with simultaneous integrated boost in elderly breast cancer patients. Aging Clin Exp Res. 2018;30:533–8. https://doi.org/10.1007/s40520-017-0802-z.
Freedman GM, Anderson PR, Bleicher RJ, et al. Five-year local control in a phase II study of hypofractionated intensity modulated radiation therapy with an incorporated boost for early stage breast cancer. Int J Radiat Oncol Biol Phys. 2012;84(4):888–93.
Hammer C, Maduro JH, Bantema-Joppe EJ, et al. Radiation-induced fibrosis in the boost area after three-dimensional conformal radiotherapy with a simultaneous integrated boost technique for early-stage breast cancer: a multivariable prediction model. Radiother Oncol. 2017;122:45–9.
Lee HH, Hou MF, Chuang HY, et al. Intensity modulated radiotherapy with simultaneous integrated boost vs. conventional radiotherapy with sequential boost for breast cancer e A preliminary result. Breast. 2015;24:656–60.
Mondal D, Julka PK, Sharma DN, et al. Accelerated hypofractionated adjuvant whole breast radiation with simultaneous integrated boost using volumetric modulated arc therapy for early breast cancer: a phase I/II dosimetric and clinical feasibility study from a tertiary cancer care centre of India. J Egyptian Natl Cancer Inst. 2017;29:39–45.
Yang Z, Zhang L, Chen X, et al. Multibeam inverse intensity-modulated radiotherapy (IMRT) for whole breast irradiation: a single center experience in China. Oncotarget. 2015;6(33):35063–72. https://doi.org/10.18632/oncotarget.5278.
Scorsetti M, Alongi F, Fogliata A, et al. Phase I-II study of hypofractionated simultaneous integrated boost using volumetric modulated arc therapy for adjuvant radiation therapy in breast cancer patients: a report of feasibility and early toxicity results in the first 50 treatments. Radiation Oncol. 2012;7:145.
Paelinck L, Gulyban A, Lakosi F, et al. Does an integrated boost increase acute toxicity in prone hypofractionated breast irradiation? A randomized controlled trial. Radiother Oncol. 2017;122:30–6.
Franco P, Migliaccio F, Torielli P, et al. Bilateral breast radiation delivered with static angle tomotherapy (TomoDirect): clinical feasibility and dosimetric results of a single patients. Tumori. 2015;101(1):e4-8.
Borca VC, Franco P, Catuzzo P, et al. Does TomoDirect 3DCRT represent a suitable option for post-operative whole breast irradiation? A hypothesis-generating pilot study. Radiat Oncol. 2012;7:211.
Ricotti R, Miglietta E, Leonardi MC, et al. Workload of breast image-guided intensity-modulated radiotherapy delivered with TomoTherapy. Tumori. 2019. https://doi.org/10.1177/0300891619868014.
Orecchia R, Rojas DP, Cattani F, et al. Hypofractionated postmastectomy radiotherapy with helical tomotherapy in patients with immediate breast reconstruction: dosimetric results and acute/intermediate toxicity evaluation. Med Oncol. 2018;35(3):39. https://doi.org/10.1007/s12032-018-1095-6.
Lazzari G, Terlizzi A, Della Vittoria Scarpati G, et al. Predictive parameters in hypofractionated whole-breast 3D conformal radiotherapy according to the Ontario Canadian trial. Onco Targets Ther. 2017;10:1835–42. https://doi.org/10.2147/OTT.S127833.
Fastner G, Reitsamer R, Urbański B, et al. Toxicity and cosmetic outcome after hypofractionated whole breast irradiation and boost-IOERT in early stage breast cancer (HIOB): first results of a prospective multicenter trial (NCT01343459). 2020. Radiother Oncol. https://doi.org/10.1016/j.radonc.2020.02.001.
Polo A, Polgàr C, Hannoun-Levi J-M, et al. Risk factors and state-of-the-art indications for boost irradiation in invasive breast carcinoma. Brachytherapy. 2017;16(3):552–64. https://doi.org/10.1016/j.brachy.2017.03.003.
This work was partially supported by a research grant from Accuray Inc. entitled “Data collection and analysis of Tomotherapy and CyberKnife breast clinical studies, breast physics studies and prostate study” and by the Italian Ministry of Health with Ricerca Corrente and 5x1000 funds. The sponsors did not play any role in the study design, collection, analysis, and interpretation of data, nor in the writing of the manuscript, nor in the decision to submit the manuscript for publication.
The author Maria Alessia Zerella, M.D., was supported in part by research Grants from the Fondazione IEO-CCM (project title: “Preclinical study for single fraction ablative preoperative radiation treatment in early-stage breast cancer: a benchmark for clinical investigation”). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. In this research, no animals were involved.
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Dicuonzo, S., Leonardi, M.C., Raimondi, S. et al. Acute and intermediate toxicity of 3-week radiotherapy with simultaneous integrated boost using TomoDirect: prospective series of 287 early breast cancer patients. Clin Transl Oncol (2021). https://doi.org/10.1007/s12094-020-02538-w
- Hypofractionated radiotherapy
- Simultaneous integrated boost
- Early breast cancer