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Quality of life after simultaneously integrated boost with intensity-modulated versus conventional radiotherapy with sequential boost for adjuvant treatment of breast cancer: 2-year results of the multicenter randomized IMRT-MC2 trial

  • Tobias Forster
    Affiliations
    Department of Radiation Oncology, Heidelberg University Hospital, Germany

    Heidelberg Institute of Radiation Oncology (HIRO), Germany

    National Center for Tumor Diseases (NCT), Heidelberg, Germany
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  • Adriane Hommertgen
    Affiliations
    Department of Radiation Oncology, Heidelberg University Hospital, Germany

    Heidelberg Institute of Radiation Oncology (HIRO), Germany

    National Center for Tumor Diseases (NCT), Heidelberg, Germany
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  • Matthias Felix Häfner
    Affiliations
    Department of Radiation Oncology, Heidelberg University Hospital, Germany

    Heidelberg Institute of Radiation Oncology (HIRO), Germany

    National Center for Tumor Diseases (NCT), Heidelberg, Germany
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  • Nathalie Arians
    Affiliations
    Department of Radiation Oncology, Heidelberg University Hospital, Germany

    Heidelberg Institute of Radiation Oncology (HIRO), Germany

    National Center for Tumor Diseases (NCT), Heidelberg, Germany
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  • Laila König
    Affiliations
    Department of Radiation Oncology, Heidelberg University Hospital, Germany

    Heidelberg Institute of Radiation Oncology (HIRO), Germany

    National Center for Tumor Diseases (NCT), Heidelberg, Germany
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  • Semi Ben Harrabi
    Affiliations
    Department of Radiation Oncology, Heidelberg University Hospital, Germany

    Heidelberg Institute of Radiation Oncology (HIRO), Germany

    National Center for Tumor Diseases (NCT), Heidelberg, Germany
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  • Ingmar Schlampp
    Affiliations
    Department of Radiation Oncology, Heidelberg University Hospital, Germany

    Heidelberg Institute of Radiation Oncology (HIRO), Germany

    National Center for Tumor Diseases (NCT), Heidelberg, Germany
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  • Clara Köhler
    Affiliations
    Department of Radiation Oncology, Heidelberg University Hospital, Germany
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  • Eva Meixner
    Affiliations
    Department of Radiation Oncology, Heidelberg University Hospital, Germany

    Heidelberg Institute of Radiation Oncology (HIRO), Germany

    National Center for Tumor Diseases (NCT), Heidelberg, Germany
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  • Vanessa Heinrich
    Affiliations
    Department of Radiation Oncology, Eberhard-Karls-University Tuebingen, Germany
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  • Nicola Weidner
    Affiliations
    Department of Radiation Oncology, Eberhard-Karls-University Tuebingen, Germany
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  • Johannes Hüsing
    Affiliations
    Division of Biostatistics, Coordination Centre for Clinical Trials, University of Heidelberg, Germany
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  • Christof Sohn
    Affiliations
    Department of Gynecology and Obstetrics, University of Heidelberg, Germany
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  • Jörg Heil
    Affiliations
    Department of Gynecology and Obstetrics, University of Heidelberg, Germany
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  • Michael Golatta
    Affiliations
    Department of Gynecology and Obstetrics, University of Heidelberg, Germany
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  • Holger Hof
    Affiliations
    Strahlentherapie Rhein-Pfalz, Neustadt, Germany
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  • David Krug
    Affiliations
    Department of Radiation Oncology, Heidelberg University Hospital, Germany

    Heidelberg Institute of Radiation Oncology (HIRO), Germany

    National Center for Tumor Diseases (NCT), Heidelberg, Germany

    Department of Radiation Oncology, University Hospital Schleswig Holstein, Kiel, Germany
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  • Jürgen Debus
    Affiliations
    Department of Radiation Oncology, Heidelberg University Hospital, Germany

    Heidelberg Institute of Radiation Oncology (HIRO), Germany

    National Center for Tumor Diseases (NCT), Heidelberg, Germany

    Department of Radiation Oncology, University Hospital Schleswig Holstein, Kiel, Germany

    Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Heidelberg Ion-Beam Therapy Center (HIT), Department of Radiation Oncology, Heidelberg University Hospital, Germany
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  • Juliane Hörner-Rieber
    Correspondence
    Corresponding author at: Department of Radiation Oncology, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.
    Affiliations
    Department of Radiation Oncology, Heidelberg University Hospital, Germany

    Heidelberg Institute of Radiation Oncology (HIRO), Germany

    National Center for Tumor Diseases (NCT), Heidelberg, Germany

    Department of Radiation Oncology, University Hospital Schleswig Holstein, Kiel, Germany

    German Cancer Consortium (DKTK), partner site, Heidelberg, Germany
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      Highlights

      • Randomized phase III trial with 502 breast cancer patients, evaluating quality of life.
      • Intensity-modulated radiotherapy with simultaneously integrated boost compared to 3D-conformal radiotherapy with sequential boost.
      • After 6 weeks, pain and arm symptoms superior for simultaneously integrated boost.
      • Non-inferior quality of life compared to 3D-conformal radiotherapy with sequential boost.
      • Results support simultaneously integrated boost application to shorten treatment times.

      Abstract

      Background

      We recently published 2-year results of the prospective, randomized IMRT-MC2 trial, showing non-inferior local control and cosmesis in breast cancer patients after conventionally fractionated intensity-modulated radiotherapy with simultaneously integrated boost (IMRT-SIB), compared to 3D-conformal radiotherapy with sequential boost (3D-CRT-seqB). Here, we report on 2-year quality of life results.

      Patients and Methods

      502 patients were enrolled and randomized to IMRT-SIB (50.4 Gy in 1.8 Gy fractions with a 64.4 Gy SIB to the tumor bed) or to 3D-CRT-seqB (50.4 Gy in 1.8 Gy fractions, followed by a sequential boost of 16 Gy in 2 Gy fractions). For quality of life (QoL) assessment, patients completed the QLQ-C30 and QLQ-BR23 questionnaires at baseline, 6 weeks and 2 years after radiotherapy.

      Results

      Significant differences between treatment arms were seen 6 weeks after radiotherapy for pain (22.3 points for IMRT vs. 27.0 points for 3D-CRT-seqB; p = 0.033) and arm symptoms (18.1 points for IMRT vs. 23.6 points for 3D-CRT-seqB; p = 0.013), both favoring IMRT-SIB.
      Compared to baseline values, both arms showed significant improvement in global score (IMRT: p = 0.009; 3D-CRT: p = 0.001) after 2 years, with slight deterioration on the role (IMRT: p = 0.008; 3-D-CRT: p = 0.001) and social functioning (IMRT: p = 0.013, 3D-CRT: p = 0.001) as well as the future perspectives scale (IMRT: p = 0.003; 3D-CRT: p = 0.0034).

      Conclusion

      This is the first randomized phase III trial demonstrating that IMRT-SIB was associated with slightly superior QoL compared to 3-D-CRT-seqB. These findings further support the clinical implementation of SIB in adjuvant breast cancer treatment.

      Abbreviations:

      3D-CRT (3-D-conformal radiotherapy), 3D-CRT-seqB (3D-conformal radiotherapy with sequential boost), ASTRO (the American Society of Radiation Oncology), BCS (Breast-conserving surgery), CT (computed tomography), DEGRO (German Society for Radiation Oncology), EBCP (early-stage breast cancer patients), EBCTCG (Early Breast Cancer Trialists’ Collaborative Group), IMRT (intensity-modulated radiotherapy), IMRT-SIB (conventional fractionated intensity-modulated radiotherapy with simultaneously integrated boost), LC (local control), OS (overall survival), PFS (progression free survival), QLQ-BR23 (Breast Cancer Module Questionnaire), QLQ-C30 (Quality of Life Questionnaire C30), QoL (quality-of-life), SD (standard deviation), seqB (sequential boost), SIB (simultaneously integrated boost), WBI (whole breast irradiation)

      Keywords

      Breast-conserving surgery (BCS) and adjuvant whole breast irradiation (WBI) has become the standard-therapy for early-stage breast cancer with equivalent overall survival and local control rates compared to mastectomy [

      Early Breast Cancer Trialists' Collaborative, G., S. Darby, P. McGale, C. Correa, C. Taylor, R. Arriagada, M. Clarke, D. Cutter, C. Davies, M. Ewertz, et al., Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 2011. 378(9804): p. 1707–16.

      ,
      • Fisher B.
      • Anderson S.
      • Bryant J.
      • Margolese R.G.
      • Deutsch M.
      • Fisher E.R.
      • 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.
      ,
      • van Maaren M.C.
      • de Munck L.
      • de Bock G.H.
      • Jobsen J.J.
      • van Dalen T.
      • Linn S.C.
      • et al.
      10 year survival after breast-conserving surgery plus radiotherapy compared with mastectomy in early breast cancer in the Netherlands: a population-based study.
      ]. For further improvement of local control in younger patients or patients with high-risk tumors, an additional boost irradiation to the former tumor bed is recommended, which is usually delivered sequentially [
      • Bartelink H.
      • Horiot J.-C.
      • Poortmans P.M.
      • Struikmans H.
      • Van den Bogaert W.
      • Fourquet A.
      • et al.
      Impact of a higher radiation dose on local control and survival in breast-conserving therapy of early breast cancer: 10-year results of the randomized boost versus no boost EORTC 22881–10882 trial.
      ]. However, with techniques like intensity-modulated radiotherapy (IMRT) a simultaneously integrated boost (SIB) may be applied. Furthermore, IMRT offers a more homogenous dose distribution throughout the breast, as well as minimization of overdosage outside the boost volume and a shorter treatment period [
      • Aly M.M.
      • Glatting G.
      • Jahnke L.
      • Wenz F.
      • Abo-Madyan Y.
      Comparison of breast simultaneous integrated boost (SIB) radiotherapy techniques.
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      • Hurkmans C.W.
      • Meijer G.J.
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      • van der Sangen M.J.
      • Cassee J.
      High-dose simultaneously integrated breast boost using intensity-modulated radiotherapy and inverse optimization.
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      • Van Parijs H.
      • Reynders T.
      • Heuninckx K.
      • Verellen D.
      • Storme G.
      • De Ridder M.
      Breast conserving treatment for breast cancer: dosimetric comparison of sequential versus simultaneous integrated photon boost.
      ,
      • Kestin L.L.
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      • Frazier R.C.
      • Vicini F.A.
      • Yan D.
      • Matter R.C.
      • et al.
      Intensity modulation to improve dose uniformity with tangential breast radiotherapy: initial clinical experience.
      ,
      • Wu S.
      • Lai Y.
      • He Z.
      • Zhou Y.
      • Chen S.
      • Dai M.
      • et al.
      Dosimetric comparison of the simultaneous integrated boost in whole-breast irradiation after breast-conserving surgery: IMRT, IMRT plus an electron boost and VMAT.
      ]. Initial promising toxicity results of the IMPORT HIGH trial, investigating SIB in breast cancer therapy, delivered either with forward- or inverse-planned IMRT, have been presented at the 2018 San Antonio Breast Cancer Symposium (SABCS) and final results are awaited [

      C. E. Coles, C.L.G., A. M. Kirby, J. S. Haviland, J. C. Titley, K. Benstead, A. M. Brunt, C. Chan, L. Ciurlionis, O. S Din et al, Dose escalated simultaneous integrated boost radiotherapy for women treated by breast conservation surgery for early breast cancer: 3-year adverse effects in the IMPORT HIGH trial (CRUK/06/003), in 2018 San Antonio Breast Cancer Symposium. 2018. Available from: https://www.sabcs.org/SABCS/2018/AllAbstracts_2018-12-03_Updated.pdf.

      ]. Nevertheless, in its guidelines for breast cancer, the American Society of Radiation Oncology (ASTRO) still recommends a sequential boost concept for adjuvant radiotherapy outside of clinical studies since randomized controlled trials evaluating adjuvant radiotherapy with SIB are scarce [
      • Smith B.D.
      • Bellon J.R.
      • Blitzblau R.
      • Freedman G.
      • Haffty B.
      • Hahn C.
      • et al.
      Radiation therapy for the whole breast: Executive summary of an American Society for Radiation Oncology (ASTRO) evidence-based guideline.
      ]. In clinical reality the community increasingly uses SIB techniques. To address this lack of evidence in the area of breast cancer, the IMRT-MC2 trial (ClinicalTrial.gov Protocol ID: NCT01322854), a prospective, two-armed, multicenter, randomized phase III trial was initiated at Heidelberg University in March 2011. A total of 502 breast cancer patients were randomly assigned to receive either intensity-modulated radiotherapy with simultaneously integrated boost irradiation (IMRT-SIB) or 3-D conformal radiotherapy followed by sequential boost irradiation (3D-CRT-seqB) for adjuvant treatment after BCS. At a median follow-up of 5.11 years, 2-year results have recently been published, demonstrating non-inferior local control (LC) (IMRT-SIB: 99.6%, 3D-CRT-seqB: 99.6%, HR 0.602, 95%-CI: [0.123–2.452], p = 0.487) and cosmesis (median pBRA at 6 weeks: IMRT-SIB: 9.1%, 3D-CRT-seqB: 9.1%; median pBRA at 2 years: IMRT-SIB: 10.4%, 3D-CRT-seqB: 9.8%; 95%-CI [ 0.317; 0.107] %/year, p = 0.332) for IMRT-SIB compared to 3-D-CRT-seqB [
      • Hörner-Rieber J.
      • Forster T.
      • Hommertgen A.
      • Haefner M.F.
      • Arians N.
      • König L.
      • et al.
      Intensity Modulated Radiation Therapy (IMRT) With Simultaneously Integrated Boost Shortens Treatment Time and Is Noninferior to Conventional Radiation Therapy Followed by Sequential Boost in Adjuvant Breast Cancer Treatment: Results of a Large Randomized Phase III Trial (IMRT-MC2 Trial).
      ]. Patient-reported outcomes are increasingly recognized as important in the evaluation of different treatment concepts in breast cancer therapy independently from survival and recurrence outcomes [
      • Haviland J.S.
      • Hopwood P.
      • Mills J.
      • Sydenham M.
      • Bliss J.M.
      • Yarnold J.R.
      Do patient-reported outcome measures agree with clinical and photographic assessments of normal tissue effects after breast radiotherapy? The Experience of the Standardisation of Breast Radiotherapy (START) trials in early breast cancer.
      ]. QoL is not only relevant from an economic, social and personal perspective, but also has a significant impact on the employment status of breast cancer survivors [
      • Schmidt M.E.
      • Scherer S.
      • Wiskemann J.
      • Steindorf K.
      Return to work after breast cancer: The role of treatment-related side effects and potential impact on quality of life.
      ]. In this current publication, we report QoL data of the prospective, two-armed, multicenter, randomized phase III IMRT-MC2 trial.

      Patients and methods

      Study design and participants

      The IMRT-MC2 trial was designed to demonstrate non-inferiority of IMRT-SIB with respect to local control and cosmesis. QoL assessment was not the primary endpoint of the whole trial, but a secondary endpoint. The trial started in March 2011 and recruited until August 2015 at the University Hospital Heidelberg and at the University Hospital Tübingen. The protocol was approved by the University of Heidelberg ethics committee (S-041/2009) and the Federal Office of Radiation Protection (BfS) (Z5-22461/2-2009-18) (ClinicalTrial.gov Protocol ID is NCT01322854). The trial was sponsored by the German Aerospace Center (DLR)/Federal Ministry of Education and Research (BMBF) of German (01ZP0504). After BCS, breast cancer patients were eligible for the trial if they had an indication for adjuvant whole-breast irradiation (WBI) with boost irradiation to the tumor bed, were aged ≥18 years and <70 years or aged ≥70 years with one of the following risk factors: tumor stage ≥T2, multifocal disease, lymphangiosis, extensive intraductal component and resection margins ≤3 mm. Exclusion criteria were Karnofsky Performance Score ≤70%, metastatic disease (M1), other malignancies in the previous 5 years, previous radiotherapy of the same breast or thorax or pregnancy. Detailed information on the eligibility criteria have been published previously [
      • Askoxylakis V.
      • Jensen A.D.
      • Hafner M.F.
      • Fetzner L.
      • Sterzing F.
      • Heil J.
      • et al.
      Simultaneous integrated boost for adjuvant treatment of breast cancer–intensity modulated vs. conventional radiotherapy: the IMRT-MC2 trial.
      ]. We obtained written informed consent from all patients.

      Randomization

      Eligible patients were enrolled at the participating study sites and randomized centrally into the two trial arms at Heidelberg University. The randomization was stratified by baseline (postoperative, pre-radiation) physician-assessed cosmesis, receipt of chemotherapy or trastuzumab therapy, tumor size as well as treatment center. Patients were randomly assigned (1:1) to either IMRT-SIB or 3D-CRT-seqB.

      Procedures

      Patients in the IMRT arm received IMRT with an inverse treatment planning technique (multifield step-and-shoot technique or helical tomotherapy) to a total dose of 50.4 Gy in 1.8 Gy single fractions with SIB to the tumor bed to a total dose of 64.4 Gy in 28 fractions of 2.3 Gy (IMRT-SIB). Patients in the control arm were treated with 3-D-conformal radiotherapy (3-D-CRT) to the whole breast, using tangential beam arrangements to a total dose of 50.4 Gy and 1.8 Gy per fraction in 28 fractions, followed by a sequential boost (seqB) to a total dose of 66.4 Gy at 2 Gy dose per fraction in 8 fractions (3-D-CRT-seqB) [
      • Hörner-Rieber J.
      • Forster T.
      • Hommertgen A.
      • Haefner M.F.
      • Arians N.
      • König L.
      • et al.
      Intensity Modulated Radiation Therapy (IMRT) With Simultaneously Integrated Boost Shortens Treatment Time and Is Noninferior to Conventional Radiation Therapy Followed by Sequential Boost in Adjuvant Breast Cancer Treatment: Results of a Large Randomized Phase III Trial (IMRT-MC2 Trial).
      ,
      • Askoxylakis V.
      • Jensen A.D.
      • Hafner M.F.
      • Fetzner L.
      • Sterzing F.
      • Heil J.
      • et al.
      Simultaneous integrated boost for adjuvant treatment of breast cancer–intensity modulated vs. conventional radiotherapy: the IMRT-MC2 trial.
      ]. The target volume delineation was performed according to the guidelines for radiotherapy of breast cancer of the German Society for Radiation Oncology (DEGRO) [
      • Sautter-Bihl M.L.
      • Budach W.
      • Dunst J.
      • Feyer P.
      • Haase W.
      • Harms W.
      • et al.
      DEGRO practical guidelines for radiotherapy of breast cancer I: breast-conserving therapyDEGRO-Leitlinien für die Radiotherapie des Mammakarzinoms I: Brusterhaltende Therapie.
      ]. For patients in the experimental arm, the clinical target volume (CTV) comprised the residual breast up to 5 mm under the skin surface. A margin of 10 mm in all directions was added to the CTV to generate the planning target volume (PTV). However, the PTV was not extended over the skin surface. For regular image-guidance during treatment, MV-CT or cone-beam CT were used for positioning control.
      For the control arm, the residual breast to the skin surface was delineated based on anatomical landmarks on CT in order to generate the CTV. A margin of 10 mm in medio-lateral and cranio-caudal direction as well as 20 mm in ventral direction was added to create the PTV. For the control arm, weekly conventional verification films were used for positioning control. The definition of the boost was equal in both treatment arms. In the experimental arm, the boost dose was delivered simultaneously integrated, while in the control arm it was applied sequentially after completion of whole breast radiotherapy. The protocol specified the V45.0 Gy ≥100% for the PTV and V50.4 Gy ≥95% for the CTV in both treatment arms. Detailed treatment procedures including dose prescriptions, dose constraints and CT-based treatment planning have been reported previously [
      • Hörner-Rieber J.
      • Forster T.
      • Hommertgen A.
      • Haefner M.F.
      • Arians N.
      • König L.
      • et al.
      Intensity Modulated Radiation Therapy (IMRT) With Simultaneously Integrated Boost Shortens Treatment Time and Is Noninferior to Conventional Radiation Therapy Followed by Sequential Boost in Adjuvant Breast Cancer Treatment: Results of a Large Randomized Phase III Trial (IMRT-MC2 Trial).
      ,
      • Askoxylakis V.
      • Jensen A.D.
      • Hafner M.F.
      • Fetzner L.
      • Sterzing F.
      • Heil J.
      • et al.
      Simultaneous integrated boost for adjuvant treatment of breast cancer–intensity modulated vs. conventional radiotherapy: the IMRT-MC2 trial.
      ]. Regional nodal irradiation was permitted if indicated by the practical guidelines for irradiation of the regional lymphatics in locally advanced breast cancer of the German Society for Radiation Oncology (DEGRO) [
      • Hörner-Rieber J.
      • Forster T.
      • Hommertgen A.
      • Haefner M.F.
      • Arians N.
      • König L.
      • et al.
      Intensity Modulated Radiation Therapy (IMRT) With Simultaneously Integrated Boost Shortens Treatment Time and Is Noninferior to Conventional Radiation Therapy Followed by Sequential Boost in Adjuvant Breast Cancer Treatment: Results of a Large Randomized Phase III Trial (IMRT-MC2 Trial).
      ,
      • Sautter-Bihl M.L.
      • Souchon R.
      • Budach W.
      • Sedlmayer F.
      • Feyer P.
      • Harms W.
      • et al.
      DEGRO practical guidelines for radiotherapy of breast cancer II. Postmastectomy radiotherapy, irradiation of regional lymphatics, and treatment of locally advanced disease.
      ].

      Study endpoints

      Two-years cosmetic results and two- and 5-years local control rates were the primary endpoints of the IMRT-MC2 trial. Detailed analyses of the primary endpoints at 6 weeks and 2 years after radiotherapy [
      • Hörner-Rieber J.
      • Forster T.
      • Hommertgen A.
      • Haefner M.F.
      • Arians N.
      • König L.
      • et al.
      Intensity Modulated Radiation Therapy (IMRT) With Simultaneously Integrated Boost Shortens Treatment Time and Is Noninferior to Conventional Radiation Therapy Followed by Sequential Boost in Adjuvant Breast Cancer Treatment: Results of a Large Randomized Phase III Trial (IMRT-MC2 Trial).
      ] as well as post-hoc analysis on acute toxicity [
      • Krug D.
      • Köder C.
      • Häfner M.F.
      • Arians N.
      • Harrabi S.B.
      • Koerber S.A.
      • et al.
      Acute toxicity of normofractionated intensity modulated radiotherapy with simultaneous integrated boost compared to three-dimensional conformal radiotherapy with sequential boost in the adjuvant treatment of breast cancer.
      ] have been published recently. The current analysis focuses on quality-of-life before, 6 weeks and 2 years after radiotherapy.

      QoL measures

      Patient reported QoL was assessed using the Quality of Life Questionnaire C30 (QLQ-C30) and the Breast Cancer Module (QLQ-BR23). Both QoL questionnaires show good reliability, validity and responsiveness in patients with cancer [

      Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al., The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993;85:365–76.

      ,
      • Osoba D.
      • Zee B.
      • Pater J.
      • Warr D.
      • Kaizer L.
      • Latreille J.
      Psychometric properties and responsiveness of the EORTC quality of Life Questionnaire (QLQ-C30) in patients with breast, ovarian and lung cancer.
      ,
      • Hjermstad M.J.
      • Fossa S.D.
      • Bjordal K.
      • Kaasa S.
      Test/retest study of the European Organization for Research and Treatment of Cancer Core Quality-of-Life Questionnaire.
      ,
      • Sprangers M.A.
      • Groenvold M.
      • Arraras J.I.
      • Franklin J.
      • te Velde A.
      • Muller M.
      • et al.
      The European Organization for Research and Treatment of Cancer breast cancer-specific quality-of-life questionnaire module: first results from a three-country field study.
      ]. The QLQ-C30 questionnaire consists of a global quality of life scale, five functional scales and nine symptom scales. The QLQ-BR23 questionnaire consists of four functional scales and four symptom scales. Both questionnaires were evaluated based in the recommendations of the EORTC [

      Fayers P, A.N., Bjordal K, Curran D, Groenvold M on behalf of the EORTC Quality of Life Study Group, EORTC QLQ-C30 Scoring Manual. 2001, Brussels: EORTC Quality of Life Group.

      ]: For both questionnaires, scores were derived using the sum of the responses from all of the associated questions and standardized to the range 0–100, with higher scores of functional scales indicating a greater functioning and a better QoL, while higher scores of symptom scales indicate worse symptoms and a worse QoL. Patients were asked to complete the paper-based QLQ-C30 and QLQ-BR23 questionnaire at baseline (5 weeks after surgery, before start of radiotherapy), at 6 weeks and 2 years after radiotherapy during the regular follow-up visits in the treatment center.

      Statistical methods

      The sample size was calculated for the primary endpoints of the IMRT-MC2 trial (local control, cosmesis and toxicity) to demonstrate non-inferiority of the IMRT arm. QoL assessment was not a primary endpoint of the whole study. QoL data were primarily evaluated in the intention-to-treat population. Comparisons between treatment groups were made at 6 weeks and 2 years after radiotherapy, using Mann-Whitney U-test. The Friedmann test was used to compare QoL at different time points during follow-up (baseline, 6 weeks and 2 years after radiotherapy) and to detect significant changes of QoL over all time points. All subscales of the QLQ-C30 and the QLQ-BR23 were analyzed for the present study, focusing on the differences in mean scale as frequently done in the literature. For the multi-item scales with answers for at least half of the items, missing responses were imputed based on the average of those items answered. If more than half of the responses were missing, the score was classified as missing. Missing single-items were not substituted. Only complete data sets for all time points were included in the analysis for the Friedmann test. Baseline patient, tumor and treatment characteristics between patients who returned versus did not return questionnaires were compared using the Mann–Whitney U tests or χ2 tests for continuous or categorical data, respectively. Data analyses were performed with the IBM Statistical Package for Social Sciences software, version 19 (SPSS Inc., Chicago, IL) to calculate p-values and the effect size. The level of statistical significance was set at p ≤ 0.05.

      Results

      After BCS, from March 2011 to August 2015, 502 breast cancer patients were enrolled in the study and randomized to receive either IMRT-SIB (N = 253) or 3D-CRT-seqB (N = 249).
      After one withdrawal of written consent in the IMRT group prior to the baseline visit, 252 patients who received IMRT-SIB and 249 patients who underwent 3D-CRT-seqB were eligible for QoL analysis at baseline (intention-to-treat). After six weeks and two years, 237 and 212 QoL questionnaires (94% and 84%) were available in the IMRT group, 231 and 210 (93% and 84%) in the control group, respectively (Fig. 1). No significant differences between baseline characteristics were detected for patients who returned questionnaires and patients who did not. Not all questionnaires were completed in all single items, leading to different numbers of available data sets in the respective subscales of the questionnaires. The numbers of valid assessments are shown in the tables.
      Figure thumbnail gr1
      Fig. 1Consort diagram. IMRT-SIB: intensity-modulated radiotherapy with simultaneously integrated boost. 3-D-CRT-seqB: 3-dimensional conventional radiotherapy followed by sequential boost irradiation.
      Baseline characteristics of patients, tumors and treatments were well balanced between the two treatment groups of the trial (Table 1). The mean values (+−SD) of the different QLQ-C30 and QLQ-BR23 scores of all analyzed patients at baseline as well as 6 weeks and 2 years after radiotherapy are presented in Table 2. The only significant difference of QoL scores between the IMRT and the control group was seen 6 weeks after radiotherapy for pain (QLQ-C30; 22.3 points for IMRT vs. 27.0 points for 3D-CRT-seqB; p = 0.033; r = 0.102) and for arm symptoms (QLQ-BR23; 18.1 points for IMRT vs. 23.6 points for 3D-CRT-seqB; p = 0.013; r = 0.118), both favoring IMRT. The means (+−SD) of selected patient reported QoL scores with significant changes between groups and/or different time points are depicted in Figs. 2 and 3.
      Table 1Baseline characteristics of patients with completed QLQ-C30 and QLQ-BR23 questionnaires eligible for QoL analysis.
      IMRT-SIB

      (252)
      3D-CRT-seqB

      (249)
      Total

      (501)
      CharacteristicNo.%No.%No.%
      Patient characteristics
       Age at diagnosis, years
        Median (years)56.055.056.0
        Range (years)30–8127–7627–81
       Physician-assessed cosmesis
        Excellent or good21284.121285.142484.6
        Fair or poor3714.73413.77114.2
        Missing data31.231.261.2
       Arm circumference
        Ipsilateral (median/mean), cm29.5/30.129/29.629.0/30.1
        Ipsilateral (range), cm22.5 – 45.021.0 – 43.521.0 – 45.0
        Contralateral (median/mean), cm29.8/30.329.0/29.729.5/30.2
        Contralateral (range), cm23.0 – 43.521.0 – 43.521.0 – 43.5
        Ratio ipsi-/contralateral (median/mean)1/11/11/1
        Ratio ipsi-/contralateral (range), cm0.8–1.20.8–1.20.8–1.2
      Tumor characteristics
       Side
        Right breast10340.911847.422144.1
        Left breast14959.113152.628055.9
       Quadrant
        Lower inner3011.9228.85210.4
        Lower outer3815.13915.77715.4
        Upper inner6325.05522.111823.6
        Upper outer15360.715562.230861.5
        Multiple quadrants239.1187.2418.2
       Tumor grade
        15220.64618.59819.6
        213955.213554.227454.7
        36124.26827.312925.7
       Resection margin
        Resection margin <3 mm6325.05923.712224.4
        Median (mm)6.05.05.0
        Mean (mm)6.36.06.2
        Range (mm)0–220–170–22
       Estrogen receptor status
        Positive20380.620381.540681.0
        Negative4919.44518.19418.8
        Not tested0010.410.2
       Progesterone receptor status
        Positive17971.018975.936873.5
        Negative7329.05923.713226.3
        Not tested0010.410.2
       HER2-neu status
        Positive5019.84016.19018.0
        Negative20280.220682.740881.4
        Not tested0031.230.6
       Pathologic stage among patients without neoadjuvant therapy (N = 417)
        pT1mic - pT1a72.8104.0173.4
        pT1b4116.33614.57715.4
        pT1c9638.110241.019839.5
        pT26124.25522.111623.2
        pT331.220.851.0
        pT420.820.840.8
        pN015963.116265.132164.1
        pN14216.73413.77615.2
        pN283.283.2163.2
        pN30041.640.8
       Clinical stage among patients with neoadjuvant therapy (N = 84)
        cT152.0124.8173.4
        cT23714.72710.86412.8
        cT30020.820.4
        cT410.40010.2
        cN03313.13012.06312.6
        cN193.683.2173.4
        cN20010.410.2
        cN310.420.830.6
       Pathologic stage among patients with neoadjuvant therapy (N = 84)
        ypT02610.3208.0469.2
        ypT1mic - ypT1a72.810.481.6
        ypT1b41.662.4102.0
        ypT1c52.093.6142.8
        ypT210.452.061.2
        ypN04015.93714.97715.4
        ypN131.220.851.0
        ypN20010.410.2
        ypN30010.410.2
      Treatment characteristics
       Axillary dissection
        Yes5220.65622.510821.6
        No20079.419377.539378.4
       Nodal irradiation
        Yes2811.14417.77214.4
        No22488.920582.342985.6
       Chemotherapy
        None14055.514257.028256.3
        Neoadjuvant only4317.13815.38116.2
        Adjuvant only6927.46626.513526.9
        Neoadjuvant and adjuvant0031.230.6
       Anthracycline-based chemotherapy
        Yes7529.86827.314328.5
        No17770.218172.735871.5
       Taxane-based chemotherapy
        Yes8232.58835.317033.9
        No17067.516164.733166.1
       Herceptin-based therapy
        Yes135.2124.8255.0
        No23994.823795.247695.0
       Endocrine therapy
        Yes17870.617269.135069.9
        No7429.47730.915130.1
       Treatment location
        Heidelberg University23593.322791.246292.2
        Tübingen University176.7228.8397.8
      Baseline characteristics between patients who returned versus did not return questionnaires were compared using the Mann–Whitney U tests or χ2 tests for continuous or categorical data, respectively. No significant differences between baseline characteristics were detected. Estrogen receptor positive: ≥1% of cells stained for estrogen receptor; Progesterone receptor positive: ≥1% of cells stained for progesterone receptor; HER2-neu positive: ≥3% by immunohistochemistry or gene amplification by fluorescence in situ hybridization. Abbreviations: No.: number; IMRT-SIB: intensity-modulated radiotherapy with simultaneous integrated boost irradiation; 3-D-CRT-seqB: 3-dimensional conventional radiotherapy followed by sequential boost irradiation.
      Table 2Quality of Life Scores (EORTC QLQ-C30 and -BR23) of patients allocated to IMRT-SIB versus 3D-CRT-seqB.
      Arm A (IMRT-SIB)Arm B (3D-CRT-seqB)Arm A vs. Arm B
      ScaleNMean (+−SD)MedianNMean (+−SD)Medianp-valuer
      Baseline
      EORTC QLQ-C30
      Functional scales (higher scores indicate a better QoL)
       Global quality of life23764.2 (+−20.2)66.723062.0 (+−20.0)66.7
       Physical functioning24017.0 (+−17.1)13.323518.4 (+−17.8)13.3
       Role functioning23932.9 (+−29.8)33.323435.5 (+−27.3)33.3
       Cognitive functioning23817.4 (+−21.9)16.723118.5 (+−22.3)16.7
       Emotional functioning23831.8 (+−25.5)25.023133.5 (+−25.6)33.3
       Social functioning23825.7 (+−26.9)16.723130.1 (+−28.4)33.3
      Symptom scales (lower values indicate a better QoL)
       Pain24020.5 (+−25.3)16.723525.5 (+−26.2)16.7
       Fatigue24033.4 (+−26.4)33.323536.8 (+−25.3)33.3
       Nausea and vomiting2404.6 (+−13.2)02356.0 (+−14.3)0
       Dyspnoe23719.7 (+−26.7)023425.1 (+−30.5)0
       Insomnia24035.1 (+−33.6)33.323336.8 (+−32.9)33.3
       Appetite loss23911.7 (+−22.9)023311.7 (+−23.5)0
       Constipation2378.2 (+−19.4)023110.4 (+−21.5)0
       Diarrhea2389.0 (+−21.3)023011.3 (+−23.1)0
       Financial difficulties23716.7 (+−27.2)022916.6 (+−26.2)0
      EORTC QLQ-BR23
      Functional scales (higher scores indicate a better QoL)
       Body image23221.0 (+−24.8)16.723320.6 (+−24.3)8.3
       Sexual functioning21729.2 (+−26.3)33.322227.9 (+−26.6)33.3
       Sexual enjoyment10062.7 (+−31.2)66.78869.3 (+−30.0)66.7
       Future perspective23253.9 (+−30.5)66.723352.2 (+−31.5)66.7
      Symptom scales (lower values indicate a better QoL)
       Systemic therapy side effects23426.3 (+−21.2)19.023326.8 (+−21.9)22.2
       Breast symptoms23919.6 (+−19.5)16.723021.3 (+−19.3)16.7
       Arm symptoms23918.5 (+−22.0)11.123020.1 (+−21.0)11.1
       Upset by hair loss9748.5 (+−40.0)33.38648.1 (+−36.4)33.3
      6 Weeks after Radiotherapy
      EORTC QLQ-C30
      Functional scales (higher scores indicate a better QoL)
       Global quality of life22867.8 (+−19.7)66.720967.4 (+−21.2)66.70.966
       Physical functioning22917.1 (+−16.9)13.321318.4 (+−18.2)13.30.676
       Role functioning22826.3 (+−26.4)16.721327.9 (+−26.5)33.30.486
       Cognitive functioning22820.9 (+−24.7)16.721124.2 (+−25.4)16.70.108
       Emotional functioning22829.6 (+−23.9)25.021130.3 (+−23.8)25.00.721
       Social functioning22823.1 (+−24.4)16.721124.2 (+−25.2)16.70.712
      Symptom scales (lower values indicate a better QoL)
       Pain22922.3 (+−26.8)16.721427.0 (+−26.9)25.00.0330.102
       Fatigue22934.3 (+−25.6)33.321438.3 (+−25.2)33.30.068
       Nausea and vomiting2294.9 (+−11.7)02136.1 (+−15.5)00.835
       Dyspnoe22925.3 (+−30.1)021225.5 (+−29.9)33.30.914
       Insomnia22938.7 (+−34.6)33.321343.7 (+−34.7)33.30.118
       Appetite loss22910.6 (+−22.9)021311.1 (+−23.5)00.904
       Constipation2288.8 (+−22.4)02109.7 (+−21.0)00.259
       Diarrhea2276.6 (+−16.6)02118.7 (+−20.4)00.411
       Financial difficulties22818.1 (+−29.1)021120.9 (+−28.9)00.172
      EORTC QLQ-BR23
      Functional scales (higher scores indicate a better QoL)
       Body image22419.3 (+−23.6)8.320620.1 (+−24.6)8.30.942
       Sexual functioning20133.5 (+−26.3)33.319335.7 (+−27.5)33.30.457
       Sexual enjoyment11066.1 (+−27.1)66.710565.7 (+−28.3)66.70.995
       Future perspective22246.2 (+−30.8)33.320546.2 (+−31.7)33.30.959
      Symptom scales (lower values indicate a better QoL)
       Systemic therapy side effects22423.3 (+−17.2)19.020825.1 (+−17.08)23.80.150
       Breast symptoms22630.2 (+−21.3)25.021329.2 (+−22.0)25.00.464
       Arm symptoms22618.1 (+−21.2)11.121323.6 (+−24.6)16.70.0130.118
       Upset by hair loss6341.8 (+−36.4)33.36039.4 (+−37.1)33.30.691
      2 Years after Radiotherapy
      EORTC QLQ-C30
      Functional scales (higher scores indicate a better QoL)
       Global quality of life19970.0 (+−20.4)75.019371.4 (+−21.8)75.00.370
       Physical functioning20216.2 (+−18.9)13.319515.9 (+−17.2)13.30.986
       Role functioning20222.1 (+−26.1)16.719319.9 (+−25.9)00.293
       Cognitive functioning19920.0 (+−23.1)16.719320.6 (+−23.0)16.70.818
       Emotional functioning19928.7 (+−24.0)25.019329.3 (+−25.6)25.00.923
       Social functioning19917.8 (+−22.8)019218.7 (+−24.0)16.70.814
      Symptom scales (lower values indicate a better QoL)
       Pain20223.5 (+−29.9)16.719522.9 (+−27.6)16.70.878
       Fatigue20231.4 (+−26.9)33.319532.2 (+−25.7)33.30.643
       Nausea and vomiting2023.7 (+−12.6)01954.9 (+−13.2)00.197
       Dyspnoe20224.1 (+−30.2)019423.9 (+−28.3)00.838
       Insomnia20039.3 (+−35.0)33.319340.2 (+−34.7)33.30.766
       Appetite loss2016.0 (+−17.9)01954.6 (+−15.4)00.400
       Constipation19810.3 (+−22.3)019210.1 (+−20.2)00.752
       Diarrhea1997.7 (+−20.0)01917.3 (+−17.9)00.890
       Financial difficulties19913.2 (+−25.7)019214.2 (+−26.1)00.605
      EORTC QLQ-BR23
      Functional scales (higher scores indicate a better QoL)
       Body image19518.5 (+−24.1)8.319217.3 (+−21.4)8.30.983
       Sexual functioning18235.4 (+−29.4)33.318434.6 (+−27.3)33.30.919
       Sexual enjoyment10164.7 (+−29.7)66.79268.8 (+−28.3)66.70.346
       Future perspective19440.2 (+−32.0)33.319142.2 (+−29.8)33.30.357
      Symptom scales (lower values indicate a better QoL)
       Systemic therapy side effects19823.8 (+−17.3)19.019325.4 (+−18.5)19.00.512
       Breast symptoms20118.5 (+−20.5)16.719317.3 (+−19.5)8.30.550
       Arm symptoms20120.2 (+−24.5)11.119321.3 (+−23.1)11.10.404
       Upset by hair loss7345.7 (+−41.0)33.38939.3 (+−38.5)33.30.340
      Mann-Whitney U-test was used to compare treatment groups. P-values indicate differences between treatment groups. The values of significantly different scores between treatment groups are presented in bold and the effect size is given.
      Abbreviations: N, number of valid assessments; i, Effect size; QoL, Quality of Life; +−SD, +− standard deviation; vs., versus; IMRT-SIB, conventional fractionated intensity-modulated radiotherapy with simultaneously integrated boost; 3D-CRT-seqB, 3D-conformal radiotherapy with sequential boost.
      Figure thumbnail gr2
      Fig. 2Significant changes in Quality of Life Scores (EORTC QLQ-C30) Selected functional scales (A; higher scores indicate a better QoL) and symptom scales (B; lower values indicate a better QoL) of the EORTC QLQ-C30 with statistically significant changes over time or between groups are depicted. IMRT-SIB, conventional fractionated intensity-modulated radiotherapy with simultaneously integrated boost. 3D-CRT-seqB, 3D-conformal radiotherapy with sequential boost. * significant (p ≤ 0.05) according to Friedmann test. ** significant change over all time points (p ≤ 0.05) according to Friedmann test. *** significant (p ≤ 0.05) according to Mann-Whitney U-test.
      Figure thumbnail gr3
      Fig. 3Significant changes in Quality of Life Scores (EORTC QLQ-BR23) Selected functional scales (A; higher scores indicate a better QoL) and symptom scales (B; lower values indicate a better QoL) of the EORTC QLQ-Br23 with statistically significant changes over time or between groups are depicted. IMRT-SIB, conventional fractionated intensity-modulated radiotherapy with simultaneously integrated boost. 3D-CRT-seqB, 3D-conformal radiotherapy with sequential boost. * significant (p ≤ 0.05) according to Friedmann test. ** significant change over all time points (p ≤ 0.05) according to Friedmann test. *** significant (p ≤ 0.05) according to Mann-Whitney U-test.
      There was no significant difference between treatment groups in patient reported QoL in the other subscales of the QLQ-C30 and QLQ-BR23.
      Changes of QoL over time after radiotherapy are presented in Table 3 for the respective treatment arm. The mean values (+−SD) of the different QLQ-C30 and QLQ-BR23 scores are shown for the different time points. There was a significant increase in global quality of life (QLQ-C30) 6 weeks (p = 0.019) and 2 years (p = 0.009) after radiotherapy for patients in the IMRT group. In the control group, a significant improvement in global quality of life (QLQ-C30) was only found for 2 years after radiotherapy (p = 0.001; r = 0.028) (Table 3 and Fig. 2). In both the experimental and the control group, a significant decrease in QoL was detected for role functioning, social functioning (both QLQ-C30, Fig. 2) and future perspective (QLQ-BR23, Fig. 3). With a longer temporal distance to therapy, there was a significant increase of QoL for appetite loss (QLQ-C30) over the whole follow-up period for both treatment groups (Fig. 2). Regarding tissue toxicity, worst breast symptoms were seen shortly after radiotherapy, but these increased symptom scores significantly fell below baseline values at 2 years after radiotherapy in both treatment groups (Table 3 and Fig. 3). In the 3D-CRT-seqB group, there were also increased point values for pain and fatigue at 6 weeks after radiotherapy, while these QoL scores were stable over time in the IMRT-SIB group (Table 3 and Fig. 2).
      Table 3Changes of Quality of Life Scores (EORTC QLQ-C30 and -BR23) over Time after Radiotherapy.
      Baseline6 Weeks2 YearsBaseline vs. 6 Weeks6 Weeks vs. 2 YearsBaseline vs. 2 Years
      ScaleNMean (+− SD)Mean (+− SD)Mean (+− SD)p-value*prprpr
      Arm A (IMRT-SIB)
      EORTC QLQ-C30
      Functional scales (higher scores indicate a better QoL)
       Global quality of life19563.3 (+−19.5)67.4 (+−19.7)70.0 (+−20.5)0.0020.0190.0201.0000.0090.021
       Physical functioning20217.4 (+−17.2)17.4 (+−16.9)16.2 (+−18.2)0.535
       Role functioning20033.3 (+−30.1)27.3 (+−26.8)22.2 (+−26.2)0.0040.5310.2970.0080.021
       Cognitive functioning19618.1 (+−21.9)22.0 (+−25.3)19.8 (+−23.2)0.578
       Emotional functioning19632.5 (+−25.7)30.7 (+−24.2)28.7 (+−24.2)0.265
       Social functioning19625.8 (+−27.5)23.2 (+−24.4)17.6 (+−22.7)0.0031.0000.0790.0130.021
      Symptom scales (lower values indicate a better QoL)
       Pain20220.4 (+−25.2)22.2 (+−26.9)23.5 (+−29.9)0.941
       Fatigue20233.6 (+−25.7)34.4 (+−25.4)31.4 (+−26.9)0.766
       Nausea and vomiting2024.6 (+−13.8)5.3 (+−12.1)3.7 (+−12.6)0.093
       Dyspnoe19920.6 (+−26.7)27.0 (+−30.6)24.1 (+−30.1)0.116
       Insomnia20035.7 (+−33.5)39.8 (+−35.2)39.3 (+−35.0)0.516
       Appetite loss20011.2 (+−22.2)10.3 (+−22.8)6.0 (+−17.9)0.0061.0000.4850.204
       Constipation1948.8 (+−20.0)9.5 (+−22.9)10.5 (+−22.5)0.615
       Diarrhea1959.6 (+−21.7)7.0 (+−17.3)7.7 (+−20.1)0.488
       Financial difficulties19517.8 (+−28.6)18.8 (+−29.5)13.2 (+−25.6)0.152
      EORTC QLQ-BR230.941
      Functional scales (higher scores indicate a better QoL)
       Body image18421.2 (+−25.3)18.5 (+−23.3)18.8 (+−24.1)0.453
       Sexual functioning14629.2 (+−25.8)33.8 (+−26.2)35.4 (+−26.6)0.209
       Sexual enjoyment2462.5 (+−30.0)65.3 (+−26.9)59.7 (+−29.5)0.840
       Future perspective18154.9 (+−30.6)44.6 (+−30.9)40.7 (+−32.5)0.00010.0350.01961.0000.0030.026
      Symptom scales (lower values indicate a better QoL)
       Systemic therapy side effects18926.8 (+−21.0)23.7 (+−17.6)23.5 (+−17.3)0.746
       Breast symptoms19819.9 (+−19.8)30.8 (+−20.8)18.5 (+−20.6)0.00010.00010.0330.00010.0381.000
       Arm symptoms19818.1 (+−21.8)18.9 (+−21.6)20.2 (+−24.6)0.841
       Upset by hair loss933.3 (+−37.3)55.6 (+−40.8)37.0 (+−42.3)0.273
      Arm B (3D-CRT-seqB)
      EORTC QLQ-C30
      Functional scales (higher scores indicate a better QoL)
       Global quality of life18161.4 (+−20.3)67.0 (+−21.8)71.0 (+−21.9)0.0010.1370.3270.0010.028
       Physical functioning19219.2 (+−18.0)18.8 (+−18.1)15.8 (+−17.2)0.250
       Role functioning18935.7 (+−27.1)28.3 (+−25.7)19.9 (+−25.9)0.00010.2410.0030.0250.00010.038
       Cognitive functioning18418.3 (+−21.8)24.0 (+−25.1)21.0 (+−23.0)0.077
       Emotional functioning18433.1 (+−25.5)30.4 (+−23.4)29.7 (+−25.8)0.170
       Social functioning18330.9 (+−27.7)24.6 (+−24.9)18.8 (+−24.2)0.00010.1690.0640.00010.033
      Symptom scales (lower values indicate a better QoL)
       Pain19326.3 (+−26.3)28.1 (+−26.8)22.8 (+−27.5)0.0460.6370.0861.000
       Fatigue19337.3 (+−25.3)37.9 (+−24.8)32.3 (+−25.7)0.0321.0000.0750.104
       Nausea and vomiting1954.8 (+−11.4)5.6 (+−14.8)4.9 (+−13.3)0.733
       Dyspnoe19027.5 (+−31.7)25.3 (+−30.0)23.5 (+−28.0)0.697
       Insomnia18937.0 (+−33.4)43.9 (+−35.3)40.2 (+−34.5)0.245
       Appetite loss19011.8 (+−23.4)10.4 (+−22.3)4.7 (+−15.6)0.0021.0000.3180.163
       Constipation1828.1 (+−19.1)9.7 (+−21.5)10.3 (+−20.5)0.605
       Diarrhea18112.2 (+−24.1)9.0 (+−21.0)7.4 (+−17.8)0.069
       Financial difficulties18217.0 (+−27.1)20.9 (+−29.0)14.5 (+−26.5)0.064
      EORTC QLQ-BR23
      Functional scales (higher scores indicate a better QoL)
       Body image18220.9 (+−24.9)20.9 (+−25.0)17.3 (+−21.7)0.386
       Sexual functioning15628.7 (+−26.6)36.3 (+−28.2)34.3 (+−27.3)0.0420.0821.0000.268
       Sexual enjoyment1476.2 (+−20.4)69.0 (+−15.8)73.8 (+−29.8)0.723
       Future perspective18053.1 (+−32.0)46.9 (+−31.7)42.2 (+−30.4)0.0140.2461.0000.0340.020
      Symptom scales (lower values indicate a better QoL)
       Systemic therapy side effects18526.6 (+−21.1)25.2 (+−17.4)25.5 (+−18.4)0.657
       Breast symptoms18621.4 (+−19.1)29.9 (+−22.0)17.2 (+−19.6)0.00010.0020.0260.00010.0420.138
       Arm symptoms18621.2 (+−21.7)24.3 (+−25.3)21.4 (+−23.2)0.553
       Upset by hair loss738.1 (+−48.8)52.4 (+−26.2)23.8 (+−25.2)0.337
      Friedmann test was used to compare repeated measures over time. P-values indicate differences between different time points. * p-value over all time points. For subscales with significant changes over all time points a further analysis was done (Friedmann test) to detect whether there are significant changes between specific points of time. The values of significantly different scores between time points are presented in bold and the effect size is given.
      Abbreviations: N, number of patients with valid assessments at all time points; p, p-value; r, Effect size; QoL, Quality of Life; +−SD, +− standard deviation; vs., versus; IMRT-SIB, conventional fractionated intensity-modulated radiotherapy with simultaneously integrated boost; 3D-CRT-seqB, 3D-conformal radiotherapy with sequential boost.
      The patient reported QoL scores of the per-protocol analysis did not differ from the results of the intention-to-treat population.

      Discussion

      The data reported here are the first to examine patient reported QoL after IMRT-SIB compared to 3-D-CRT-seqB in a randomized, controlled trial for adjuvant breast radiotherapy. The proportion of available QLQ-C30 and QLQ-BR23 questionnaires after 2 years was high with 84% (N = 212) in the IMRT-SIB group and 84% (N = 210) in the control group (3-D-CRT-seqB).
      Significant differences in QoL scores between treatment groups were found 6 weeks after radiotherapy for pain (QLQ-C30) and for arm symptoms (QLQ-BR23), both favoring IMRT-SIB. However, the effect size was rather small and the group difference was diminishing over time. For pain, a significant deterioration was found in the 3-D-CRT-seqB arm over time, while there was none for patients in the IMRT-SIB group. In breast cancer survivors, it is well documented that radiotherapy may increase pain symptoms and that pain symptoms are significantly associated with poorer QoL [
      • Hamood R.
      • Hamood H.
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      • Keinan-Boker L.
      Chronic pain and other symptoms among breast cancer survivors: prevalence, predictors, and effects on quality of life.
      ]. Patient-reported pain after radiotherapy and the recovery of pain scores over time during follow-up, as seen in the 3-D-CRT-seqB group, was also confirmed by others [
      • Zhang J.J.
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      Relationship between time elapsed since completion of radiotherapy and quality of life of patients with breast cancer.
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      • de la Cruz S.
      • Ibañez B.
      • et al.
      Quality of life evolution in elderly survivors with localized breast cancer treated with radiotherapy over a three-year follow-up.
      ,
      • Lam E.
      • Wong G.
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      • Karam I.
      • Yee C.
      • et al.
      Self-reported pain in breast cancer patients receiving adjuvant radiotherapy.
      ]. Moist desquamation may be one reason for pain after radiotherapy of the breast, and seems to appear more often and to last longer in patients treated with standard radiotherapy compared to IMRT: In a multicenter, randomized clinical trial of Pignol et al. testing the potential impact of IMRT on reducing acute skin reaction in comparison to standard wedge radiotherapy, the use of IMRT resulted in a significantly decreased risk of moist desquamation, which was associated with less pain. This effect was explained by a more homogeneous dose distribution achieved with IMRT, including a smaller clinically significant dose maximum and a smaller relative volume receiving 105%, 107%, 110% and 115% of the prescribed dose as well as a more precise sagittal dose gradient. However, there were some patient related factors like body mass index and breast size, that influenced the occurrence of moist desquamation as well [
      • Pignol J.-P.
      • Olivotto I.
      • Rakovitch E.
      • Gardner S.
      • Sixel K.
      • Beckham W.
      • et al.
      A multicenter randomized trial of breast intensity-modulated radiation therapy to reduce acute radiation dermatitis.
      ]. For arm symptoms after radiotherapy in breast cancer patients, no significant changes over time were reported by others [
      • Zhang J.J.
      • Shu H.
      • Hu S.S.
      • Yu Y.
      • Sun Y.
      • Lv Y.
      Relationship between time elapsed since completion of radiotherapy and quality of life of patients with breast cancer.
      ,
      • Arraras J.I.
      • Manterola A.
      • Illarramendi J.J.
      • Asin G.
      • de la Cruz S.
      • Ibañez B.
      • et al.
      Quality of life evolution in elderly survivors with localized breast cancer treated with radiotherapy over a three-year follow-up.
      ,
      • Versmessen H.
      • Vinh-Hung V.
      • Van Parijs H.
      • Miedema G.
      • Voordeckers M.
      • Adriaenssens N.
      • et al.
      Health-related quality of life in survivors of stage I-II breast cancer: randomized trial of post-operative conventional radiotherapy and hypofractionated tomotherapy.
      ]. This is in line with the present study, demonstrating differences for arm symptoms between the two study arms, but no significant changes over time.
      In general, our findings show a significant trend for improved QoL after IMRT-SIB compared to 3-D-CRT-seqB and demonstrate for the first time in a prospective randomized phase III trial that simultaneously integrated boost administration is at least equally tolerated in breast cancer patients. These results are in line with first single arm studies demonstrating well preserved QoL after IMRT-SIB [
      • Pasquier D.
      • Le Tinier F.
      • Bennadji R.
      • Jouin A.
      • Horn S.
      • Escande A.
      • et al.
      Intensity-modulated radiation therapy with simultaneous integrated boost for locally advanced breast cancer: a prospective study on toxicity and quality of life.
      ,
      • Franco P.
      • Zeverino M.
      • Migliaccio F.
      • Cante D.
      • Sciacero P.
      • Casanova Borca V.
      • et al.
      Intensity-modulated and hypofractionated simultaneous integrated boost adjuvant breast radiation employing statics ports of tomotherapy (TomoDirect): a prospective phase II trial.
      ] and with long-term results of two randomized controlled trials of Donovan et al. and Pignol et al. presenting no significant differences in QoL between forward-planned IMRT with field-in-field tangents and 2D radiotherapy (standard wedges) for adjuvant treatment of breast cancer patients [
      • Donovan E.
      • Bleakley N.
      • Denholm E.
      • Evans P.
      • Gothard L.
      • Hanson J.
      • et al.
      Randomised trial of standard 2D radiotherapy (RT) versus intensity modulated radiotherapy (IMRT) in patients prescribed breast radiotherapy.
      ,
      • Pignol J.P.
      • Truong P.
      • Rakovitch E.
      • Sattler M.G.
      • Whelan T.J.
      • Olivotto I.A.
      Ten years results of the Canadian breast intensity modulated radiation therapy (IMRT) randomized controlled trial.
      ].
      Concerning QoL changes over time, symptom scales, affected by acute toxicity like breast symptoms as well as fatigue and pain were increased 6 weeks after radiotherapy in both treatment groups with successive recovery over time. These results suggest that symptoms directly related to radiotherapy occur temporarily after treatment. This long-term recovery of acute toxicity was also observed by others [
      • Arraras J.I.
      • Manterola A.
      • Illarramendi J.J.
      • Asin G.
      • de la Cruz S.
      • Ibañez B.
      • et al.
      Quality of life evolution in elderly survivors with localized breast cancer treated with radiotherapy over a three-year follow-up.
      ]. Interestingly, changes observed in fatigue and pain were only significant in the 3-D-CRT-seqB group, while for IMRT-SIB there was no significant increase in these symptom scores. Perhaps this group difference is due to a more homogeneous dose distribution and a shorter treatment time for the IMRT technique. This corresponds to results of Versmessen et al. reporting of a better long-term recovery from fatigue after tomotherapy compared to conventional radiotherapy [
      • Versmessen H.
      • Vinh-Hung V.
      • Van Parijs H.
      • Miedema G.
      • Voordeckers M.
      • Adriaenssens N.
      • et al.
      Health-related quality of life in survivors of stage I-II breast cancer: randomized trial of post-operative conventional radiotherapy and hypofractionated tomotherapy.
      ] and correlates to our already published post-hoc analysis on acute toxicity, demonstrating significantly more common breast/chest wall pain in patients treated with 3-D-CRT-seqB [
      • Krug D.
      • Köder C.
      • Häfner M.F.
      • Arians N.
      • Harrabi S.B.
      • Koerber S.A.
      • et al.
      Acute toxicity of normofractionated intensity modulated radiotherapy with simultaneous integrated boost compared to three-dimensional conformal radiotherapy with sequential boost in the adjuvant treatment of breast cancer.
      ].
      Of course, radiotherapy in general is associated with some unavoidable side effects for breast cancer patients. Our results suggest, that significant strains of breast cancer treatment result in impairments of functional scales, including role functioning, social functioning and future perspective. The decrease in functioning scores after radiotherapy, seen in both treatment arms was confirmed by the results of Versmessen et al. [
      • Versmessen H.
      • Vinh-Hung V.
      • Van Parijs H.
      • Miedema G.
      • Voordeckers M.
      • Adriaenssens N.
      • et al.
      Health-related quality of life in survivors of stage I-II breast cancer: randomized trial of post-operative conventional radiotherapy and hypofractionated tomotherapy.
      ]. However, after a more extended follow-up these impairments of functioning scores are also expected to recover, as demonstrated by Zhang et al. in a cross-sectional analysis of 212 breast cancer patients [
      • Zhang J.J.
      • Shu H.
      • Hu S.S.
      • Yu Y.
      • Sun Y.
      • Lv Y.
      Relationship between time elapsed since completion of radiotherapy and quality of life of patients with breast cancer.
      ]. Furthermore, scores for role functioning and social functioning may also be influenced by impaired cosmesis after surgery or by endocrine therapy. The negative impact of chemotherapy and endocrine therapy on global QoL, role functioning and social functioning in breast cancer survivors has been well documented by others [
      • Ferreira A.R.
      • Di Meglio A.
      • Pistilli B.
      • Gbenou A.S.
      • El-Mouhebb M.
      • Dauchy S.
      • et al.
      Differential impact of endocrine therapy and chemotherapy on quality of life of breast cancer survivors: a prospective patient-reported outcomes analysis.
      ].
      Furthermore, in the present trial a significant increase in global QoL and an improvement of appetite loss were detected in both treatment groups after radiotherapy. These improvements may be caused by successive recovery from the surgical procedure and neoadjuvant chemotherapy [
      • Zhang J.J.
      • Shu H.
      • Hu S.S.
      • Yu Y.
      • Sun Y.
      • Lv Y.
      Relationship between time elapsed since completion of radiotherapy and quality of life of patients with breast cancer.
      ,
      • Ferreira A.R.
      • Di Meglio A.
      • Pistilli B.
      • Gbenou A.S.
      • El-Mouhebb M.
      • Dauchy S.
      • et al.
      Differential impact of endocrine therapy and chemotherapy on quality of life of breast cancer survivors: a prospective patient-reported outcomes analysis.
      ], but they also demonstrate that radiotherapy was tolerated very well in the present trial. Contrary to our results, an analysis of Versmessen et al. showed an impairment of global QoL reported at the last day of radiotherapy in breast cancer patients [
      • Versmessen H.
      • Vinh-Hung V.
      • Van Parijs H.
      • Miedema G.
      • Voordeckers M.
      • Adriaenssens N.
      • et al.
      Health-related quality of life in survivors of stage I-II breast cancer: randomized trial of post-operative conventional radiotherapy and hypofractionated tomotherapy.
      ], which was not assessed in the IMRT-MC2-trial. However, in their trial some patients received mastectomy, what may have had a more pronounced impact on global QoL. After radiotherapy, successive recovery of impaired QoL in breast cancer patients, was also demonstrated by others [
      • Zhang J.J.
      • Shu H.
      • Hu S.S.
      • Yu Y.
      • Sun Y.
      • Lv Y.
      Relationship between time elapsed since completion of radiotherapy and quality of life of patients with breast cancer.
      ,
      • Arraras J.I.
      • Manterola A.
      • Illarramendi J.J.
      • Asin G.
      • de la Cruz S.
      • Ibañez B.
      • et al.
      Quality of life evolution in elderly survivors with localized breast cancer treated with radiotherapy over a three-year follow-up.
      ,
      • Lam E.
      • Wong G.
      • Zhang L.
      • Drost L.
      • Karam I.
      • Yee C.
      • et al.
      Self-reported pain in breast cancer patients receiving adjuvant radiotherapy.
      ]. Again, our results suggest IMRT-SIB to lead to at least comparable Qol compared to 3-D-CRT-seqB.
      The application of the validated, most widely used QLQ-C30 and QLQ-BR23 questionnaires, which ensure good comparability and interpretability of our findings is a strength of the present trial. The presented baseline values of over 500 women might help as groundwork for further QoL studies. Furthermore, the presented study is the first randomized phase III trial demonstrating IMRT-SIB to result in slightly superior QoL compared to 3-D-CRT-seqB, further supporting the widely clinical implementation of SIB in adjuvant breast cancer treatment.
      However, there are also some limitations: It has to be mentioned, that the QLQ-C30 and QLQ-BR23 questionnaires were not designed to specifically capture effects of breast radiotherapy, but to measure effects of breast cancer treatment in general. Several patients did not fill out every single item of the questionnaires, resulting in an unequal proportion of available answers for the different subscales (Tables 2 and 3). This might have impaired the statistical power, and for some subscales the sample size might have been too small to detect potential existing differences. Furthermore, QoL was not a primary endpoint of the IMRT-MC2 trial, what may potentially have weakened the validity of the presented QoL results. Breast sizes and boost sizes may vary between different patients, what might have influenced the QoL results. However, the size of the study group should be sufficient to overcome these differences. A detailed analysis of dosimetric data was not part of the present trial. Therefore, it cannot be excluded that the slightly increased pain scores in the 3-D-CRT-seqB arm were caused by increased dose inhomogeneities, as described by Pignol et al. [
      • Pignol J.-P.
      • Olivotto I.
      • Rakovitch E.
      • Gardner S.
      • Sixel K.
      • Beckham W.
      • et al.
      A multicenter randomized trial of breast intensity-modulated radiation therapy to reduce acute radiation dermatitis.
      ]. It also needs to be mentioned that treatment recommendations changed during follow-up of the trial: When the trial was initiated in 2011, the criteria for the indication of a boost irradiation were different than current practice and the inclusion criteria were based on the recommendations which were valid, when the trial was designed. For example, the cut off for resection margins for invasive breast cancer are no longer ≤3 mm, but no ink on tumor. Furthermore, in 2011 conventional fractionation was still the standard for adjuvant WBI. But later on, hypofractionated WBI was recommended as the preferred fractionation scheme and guidelines adopted hypofractionation as standard for adjuvant WBI in most node negative breast cancer cases [
      • Smith B.D.
      • Bellon J.R.
      • Blitzblau R.
      • Freedman G.
      • Haffty B.
      • Hahn C.
      • et al.
      Radiation therapy for the whole breast: Executive summary of an American Society for Radiation Oncology (ASTRO) evidence-based guideline.
      ,
      • Wenz F.
      • Budach W.
      Personalized radiotherapy for invasive breast cancer in 2017: National S3 guidelines and DEGRO and AGO recommendations.
      ,

      Balic, M., C. Thomssen, R. Wurstlein, M. Gnant, N. Harbeck, St. Gallen/Vienna 2019: A Brief Summary of the Consensus Discussion on the Optimal Primary Breast Cancer Treatment. Breast Care (Basel), 2019;14:103-110.

      ] due to at least equivalent oncologic results and improved functional and cosmetic outcomes [

      Hickey, B.E., M.L. James, M. Lehman, P.N. Hider, M. Jeffery, D.P. Francis, and A.M. See, Fraction size in radiation therapy for breast conservation in early breast cancer. Cochrane Database Syst Rev, 2016. 7: p. CD003860.

      ,
      • Haviland J.S.
      • Owen J.R.
      • Dewar J.A.
      • Agrawal R.K.
      • Barrett J.
      • Barrett-Lee P.J.
      • 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.
      ,
      • Whelan T.J.
      • Pignol J.-P.
      • Levine M.N.
      • Julian J.A.
      • MacKenzie R.
      • Parpia S.
      • et al.
      Long-term results of hypofractionated radiation therapy for breast cancer.
      ,
      • Offersen B.V.
      • Alsner J.
      • Nielsen H.M.
      • Jakobsen E.H.
      • Nielsen M.H.
      • Krause M.
      • et al.
      Hypofractionated Versus Standard Fractionated Radiotherapy in Patients With Early Breast Cancer or Ductal Carcinoma In Situ in a Randomized Phase III Trial: The DBCG HYPO Trial.
      ]: Results of ongoing clinical trials comparing simultaneous versus sequential boost administration for hypofractionated WBI in breast cancer patients are still awaited [

      1005, R. 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. [cited 2020 24.07.2020]; Available from: https://clinicaltrials.gov/ct2/show/NCT01349322.

      ,

      Hypofractionation with simultaneous intergrated boost versus standard fractionation in early breast cancer (HYPOSIB). [cited 2020 24.07.2020]; Available from: https://clinicaltrials.gov/ct2/show/NCT02474641.

      ]. The multicenter randomized HYPOSIB trial recruited 2324 women with breast cancer to receive in the control arm either conventionally fractionated radiotherapy of the whole breast (50.4 Gy/28 fractions) followed by a sequential tumor bed boost (10.0–16.0 Gy/5–8 fractions), or conventionally fractionated radiotherapy of the breast (50.4 Gy/28 fractions) with simultaneous integrated boost to the tumor bed (63.0 Gy/58.8 Gy/28 fractions), or hypofractionated radiotherapy of the breast (42.5 Gy/16 fractions) followed by a sequential tumor bed boost (10.0–16.0 Gy/5–8 fractions). In the experimental arm, patients received hypofractionated radiotherapy of the breast with simultaneous integrated boost to the tumor bed (48 Gy/40 Gy/16 fractions) [

      Hypofractionation with simultaneous intergrated boost versus standard fractionation in early breast cancer (HYPOSIB). [cited 2020 24.07.2020]; Available from: https://clinicaltrials.gov/ct2/show/NCT02474641.

      ]. The prospective randomized DBCG Skagen trial is recruiting 2000 breast cancer patients to investigate hypofractionated WBI with simultaneously integrated boost in 4 dose levels (63 Gy/51.52 Gy/28 fractions, 57 Gy/50 Gy/25 fractions, 52.2 Gy/42.3 Gy/18 fractions, and 45.75 Gy/40 Gy/15 fractions) in comparison to standard fractionated WBI (50 Gy/25 fractions) [

      Offersen, B.V., Moderately hypofractionated loco-regional adjuvant radiation therapy of early breast cancer combined with a simultaneous integrated boost in patients with an indication for boost: DBCG HYPO II, a randomised clinically controlled trial. 2015, ClinicalTrials.gov Available from: https://www.dbcg.dk/PDF%20Filer/SKAGEN%20Trial%201_%20protokol.pdf.

      ]. Another prospective trial, the RTOG 1005 randomized 2312 stage 0-II breast cancer patients to receive either standard WBI (50 Gy/25 fractions) followed by a sequential boost to the lumpectomy site (12–14 Gy/6–7 fractions) or to receive accelerated hypofractionated WBI with a concurrent boost to the lumpectomy site (40.05 Gy/48 Gy/15 fractions) [

      1005, R. 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. [cited 2020 24.07.2020]; Available from: https://clinicaltrials.gov/ct2/show/NCT01349322.

      ]. Results from these recent trials will clarify, if single fraction doses of 3 Gy or higher, delivered in a SIB, will be accompanied with higher acute and late toxicity. Even though the St. Gallen recommendations recently endorsed hypofractionation for adjuvant radiation for breast cancer, most national and international guidelines including the two German guidelines and the NCCN guideline still prefer conventionally fractionated radiotherapy for patients who also receive regional nodal irradiation, due to concerns about an increased risk of radiation-induced brachial plexopathy with hypofractionation [

      NCCN Guideline Version 5.2021 Breast Cancer. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf, (access online 29/07/2021).

      ,

      AGO guideline for adjuvant radiotherapy. https://www.ago-online.de/leitlinien-empfehlungen/leitlinien-empfehlungen/kommission-mamma, (access online 29/07/2021).

      ,

      Juni 2021 https://www.awmf.org/uploads/tx_szleitlinien/032-045OLk_S3_Mammakarzinom_2021-07_1.pdf, (access online 29/07/2021).

      ,

      Thomssen, C., M. Balic, N. Harbeck, and M. Gnant, St. Gallen/Vienna 2021: A Brief Summary of the Consensus Discussion on Customizing Therapies for Women with Early Breast Cancer. Breast Care (Basel), 2021. 16(2): p. 135-143.

      ,
      • Galecki J.
      • Hicer-Grzenkowicz J.
      • Grudzien-Kowalska M.
      • Michalska T.
      • Zalucki W.
      Radiation-induced brachial plexopathy and hypofractionated regimens in adjuvant irradiation of patients with breast cancer–a review.
      ].

      Conclusions

      The presented data of the IMRT-MC2 study demonstrate that simultaneously integrated boost irradiation is well tolerated. At least for some symptom scores, this technique results in superior QoL compared with sequential boost administration in adjuvant conventionally fractionated breast radiotherapy. These results on patient-reported outcomes further underline that simultaneously integrated boost irradiation can be recommended as an alternative to standard sequential boost administration.

      Conflicts of interest

      Juliane Hörner-Rieber received speaker fees and travel reimbursement from ViewRay Inc, as well as travel reimbursement form IntraOP Medical and Elekta Instrument AB outside the submitted work. David Krug received honoraria from Merck Sharp & Dome outside the submitted work. Jürgen Debus received grants from CRI – The Clinical Research Institute GmbH, View Ray Inc., Accuray International, Accuray Incorporated, RaySearch Laboratories AB, Vision RT limited, Astellas Pharma GmbH, Merck Serono GmbH, Astra Zeneca GmbH, Solution Akademie GmbH, Ergomed PLC Surrey Research Park, Siemens Healthcare GmbH, Quintiles GmbH, Pharmaceutecal Research Associates GmbH, Boehringer Ingelheim Pharma GmbH Co, PTW-Freiburg Dr. Pychlau GmbH, Nanobiotix A.A. as well as IntraOP Medical outside the submitted work. All other authors declare that they have no conflict of interest.

      Funding

      The IMRT-MC2-trial was funded by the German Aerospace Center (DLR)/Federal Ministry of Education and Research (BMBF) (01ZP0504). The funding source had no role in the study design, collection, analysis and interpretation of data. We acknowledge financial support by the Medical Faculty of Heidelberg University within the physician scientist program.

      Trial Registration

      The ClinicalTrial.gov Protocol ID is NCT01322854.

      Acknowledgement

      Not applicable.

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