Advertisement

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)

Published:December 11, 2020DOI:https://doi.org/10.1016/j.ijrobp.2020.12.005

      Purpose

      In the modern era, improvements in radiation therapy techniques have paved the way for simultaneous integrated boost irradiation in adjuvant breast radiation therapy after breast conservation surgery. Nevertheless, randomized trials supporting the noninferiority of this treatment to historical standards of care approach are lacking.

      Methods

      A prospective, multicenter, randomized phase 3 trial (NCT01322854) was performed to analyze noninferiority of conventional fractionated intensity modulated radiation therapy with simultaneous integrated boost (IMRT-SIB) to 3-D conformal radiation therapy with sequential boost (3-D-CRT-seqB) for breast cancer patients. Primary outcomes were local control (LC) rates at 2 and 5 years (noninferiority margin at hazard ratio [HR] of 3.5) as well as cosmetic results 6 weeks and 2 years after radiation therapy (evaluated via photo documentation calculating the relative breast retraction assessment [pBRA] score [noninferiority margin of 1.25]).

      Results

      A total of 502 patients were randomly assigned from 2011 to 2015. After a median follow-up of 5.1 years, the 2-year LC for the IMRT-SIB arm was noninferior to the 3-D-CRT-seqB arm (99.6% vs 99.6%, respectively; HR, 0.602; 95% CI, 0.123-2.452; P = .487). In addition, noninferiority was also shown for cosmesis after IMRT-SIB and 3-D-CRT-seqB at both 6 weeks (median pBRA, 9.1% vs 9.1%) and 2 years (median pBRA, 10.4% vs 9.8%) after radiation therapy (95% CI, –0.317 to 0.107 %; P = .332). Cosmetic assessment according to the Harvard scale by both the patient and the treating physician as well as late-toxicity evaluation with the late effects normal tissues- subjective, objective, management, analytic criteria, a score for the evaluation of long-term adverse effects in normal tissue, revealed no significant differences between treatment arms. In addition, there was no difference in overall survival rates (99.6% vs 99.6%; HR, 3.281; 95% CI: –0.748 to 22.585; P = .148) for IMRT-SIB and 3-D-CRT-seqB, respectively.

      Conclusions

      To our knowledge, this is the first prospective trial reporting the noninferiority of IMRT-SIB versus 3-D-CRT-seqB with respect to cosmesis and LC at 2 years of follow-up. This treatment regimen considerably shortens adjuvant radiation therapy times without compromising clinical outcomes.
      To read this article in full you will need to make a payment
      ASTRO Member Login
      ASTRO Members, full access to the journal is a member benefit. Use your society credentials to access all journal content and features.
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • European Cancer Information System
        2020 Cancer incidence and mortality in EU-27 countries.
        (Available at:)
        • Darby S.
        • McGale P.
        • et al.
        • Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)
        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: 1707-1716
        • Smith B.D.
        • Bellon J.R.
        • Blitzblau R.
        • et al.
        Radiation therapy for the whole breast: Executive summary of an American Society for Radiation Oncology (ASTRO) evidence-based guideline.
        Pract Radiat Oncol. 2018; 8: 145-152
        • Wenz F.
        • Budach W.
        Personalized radiotherapy for invasive breast cancer in 2017: National S3 guidelines and DEGRO and AGO recommendations.
        Strahlenther Onkol. 2017; 193: 601-603
        • Hurkmans C.W.
        • Meijer G.J.
        • van Vliet-Vroegindeweij C.
        • et al.
        High-dose simultaneously integrated breast boost using intensity-modulated radiotherapy and inverse optimization.
        Int J Radiat Oncol Biol Phys. 2006; 6: 923-930
        • Kestin L.L.
        • Sharpe M.B.
        • Frazier R.C.
        • et al.
        Intensity modulation to improve dose uniformity with tangential breast radiotherapy: Initial clinical experience.
        Int J Radiat Oncol Biol Phys. 2000; 48: 1559-1568
        • Harsolia A.
        • Kestin L.
        • Grills I.
        • et al.
        Intensity-modulated radiotherapy results in significant decrease in clinical toxicities compared with conventional wedge-based breast radiotherapy.
        Int J Radiat Oncol Biol Phys. 2007; 68: 1375-1380
        • Donovan E.
        • Bleakley N.
        • Denholm E.
        • et al.
        Randomised trial of standard 2D radiotherapy (RT) versus intensity modulated radiotherapy (IMRT) in patients prescribed breast radiotherapy.
        Radiother Oncol. 2007; 82: 254-264
        • Mukesh M.B.
        • Barnett G.C.
        • Wilkinson J.S.
        • et al.
        Randomized controlled trial of intensity-modulated radiotherapy for early breast cancer: 5-Year results confirm superior overall cosmesis.
        J Clin Oncol. 2013; 31: 4488-4495
        • Pignol J.P.
        • Olivotto I.
        • Rakovitch E.
        • et al.
        A multicenter randomized trial of breast intensity-modulated radiation therapy to reduce acute radiation dermatitis.
        J Clin Oncol. 2008; 26: 2085-2092
        • Askoxylakis V
        • Jensen AD
        • Hafner MF
        • et al.
        Simultaneous integrated boost for adjuvant treatment of breast cancer--intensity modulated vs. conventional radiotherapy.
        The IMRT-MC2 trial. BMC Cancer. 2011; 11: 249
        • Sautter-Bihl M-L
        • Budach W
        • Dunst J
        • et al.
        DEGRO practical guidelines for radiotherapy of breast cancer I.
        Strahlenther Onkol. 2007; 183: 661-666
        • Sautter-Bihl M-L
        • Souchon R
        • Budach W
        • et al.
        DEGRO practical guidelines for radiotherapy of breast cancer II.
        Strahlenther Onkol. 2008; 184: 347-353
        • Vrieling C.
        • Collette L.
        • Bartelink E.
        • et al.
        Validation of the methods of cosmetic assessment after breast-conserving therapy in the EORTC “boost versus no boost” trial.
        Int J Radiat Oncol Biol Phys. 1999; 45: 667-676
        • Salvadori B.
        • Marubini E.
        • Miceli R.
        • et al.
        Reoperation for locally recurrent breast cancer in patients previously treated with conservative surgery.
        Br J Surg. 1999; 86: 84-87
        • Cardoso M.J.
        • Cardoso J.
        • Amaral N.
        • et al.
        Turning subjective into objective: The BCCT.core software for evaluation of cosmetic results in breast cancer conservative treatment.
        Breast. 2007; 16: 456-461
        • Cardoso M.J.
        • Cardoso J.S.
        • Oliveira H.P.
        • et al.
        The breast cancer conservative treatment. Cosmetic results – BCCT.core – Software for objective assessment of esthetic outcome in breast cancer conservative treatment: A narrative review.
        Comput Methods Programs Biomed. 2016; 126: 154-159
        • Pezner R.D.
        • Patterson M.P.
        • Hill L.R.
        • et al.
        Breast retraction assessment: An objective evaluation of cosmetic results of patients treated conservatively for breast cancer.
        Int J Radiat Oncol Biol Phys. 1985; 11: 575-578
        • Van Limbergen E.
        • Rijnders A.
        • van der Schueren E.
        • et al.
        Cosmetic evaluation of breast conserving treatment for mammary cancer. 2. A quantitative analysis of the influence of radiation dose, fractionation schedules and surgical treatment techniques on cosmetic results.
        Radiother Oncol. 1989; 16: 253-267
        • Van Limbergen E.
        • van der Schueren E.
        • Van Tongelen K.
        Cosmetic evaluation of breast conserving treatment for mammary cancer. 1. Proposal of a quantitative scoring system.
        Radiother Oncol. 1989; 16: 159-167
        • Harris J.R.
        • Levene M.B.
        • Svensson G.
        • et al.
        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: 257-261
        • Pavy J.J.
        • Denekamp J.
        • Letschert J.
        • et al.
        Late effects toxicity scoring: The SOMA scale.
        Int J Radiat Oncol Biol Phys. 1995; 31: 1043-1047
        • Barnett G.C.
        • Wilkinson J.
        • Moody A.M.
        • et al.
        A randomised controlled trial of forward-planned radiotherapy (IMRT) for early breast cancer: Baseline characteristics and dosimetry results.
        Radiother Oncol. 2009; 92: 34-41
        • Pignol J.P.
        • Truong P.
        • Rakovitch E.
        • et al.
        Ten years results of the Canadian breast intensity modulated radiation therapy (IMRT) randomized controlled trial.
        Radiother Oncol. 2016; 121: 414-419
        • Bantema-Joppe E.J.
        • Schilstra C.
        • de Bock G.H.
        • 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-e477
        • Bantema-Joppe E.J.
        • Vredeveld E.J.
        • de Bock G.H.
        • et al.
        Five year outcomes of hypofractionated simultaneous integrated boost irradiation in breast conserving therapy; Patterns of recurrence.
        Radiother Oncol. 2013; 108: 269-272
        • McDonald M.W.
        • Godette K.D.
        • Whitaker D.J.
        • et al.
        Three-year outcomes of breast intensity-modulated radiation therapy with simultaneous integrated boost.
        Int J Radiat Oncol Biol Phys. 2010; 77: 523-530
        • Pasquier D.
        • Le Tinier F.
        • Bennadji R.
        • et al.
        Intensity-modulated radiation therapy with simultaneous integrated boost for locally advanced breast cancer: A prospective study on toxicity and quality of life.
        Sci Rep. 2019; 9: 2759
        • Meng J.
        • Huang W.
        • Mei X.
        • et al.
        Adjuvant breast inversely planned intensity-modulated radiotherapy with simultaneous integrated boost for early stage breast cancer: Results from a phase II trial.
        Strahlenther Onkol. 2020; 196: 764-770
        • 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: 30-36
        • Van Parijs H.
        • Miedema G.
        • Vinh-Hung V.
        • et al.
        Short course radiotherapy with simultaneous integrated boost for stage I-II breast cancer, early toxicities of a randomized clinical trial.
        Radiat Oncol. 2012; 7: 80
        • Cooper B.T.
        • Formenti-Ujlaki G.F.
        • Li X.
        • et al.
        Prospective randomized trial of prone accelerated intensity modulated breast radiation therapy with a daily versus weekly boost to the tumor bed.
        Int J Radiat Oncol Biol Phys. 2016; 95: 571-578
        • Hamilton D.G.
        • Bale R.
        • Jones C.
        • et al.
        Impact of tumour bed boost integration on acute and late toxicity in patients with breast cancer: A systematic review.
        Breast. 2016; 27: 126-135
        • Teh A.Y.M.
        • Walsh L.
        • Purdie T.G.
        • et al.
        Concomitant intensity modulated boost during whole breast hypofractionated radiotherapy—A feasibility and toxicity study.
        Radiother Oncol. 2012; 102: 89-95
        • Hickey B.E.
        • James M.L.
        • Lehman M.
        • et al.
        Fraction size in radiation therapy for breast conservation in early breast cancer.
        Cochrane Database Syst Rev. 2016; 7CD003860
        • Haviland J.S.
        • Owen J.R.
        • Dewar J.A.
        • 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: 1086-1094
        • Whelan T.J.
        • Pignol J.-P.
        • Levine M.N.
        • et al.
        Long-term results of hypofractionated radiation therapy for breast cancer.
        N Engl J Med. 2010; 362: 513-520
        • Galecki J.
        • Hicer-Grzenkowicz J.
        • Grudzien-Kowalska M.
        • et al.
        Radiation-induced brachial plexopathy and hypofractionated regimens in adjuvant irradiation of patients with breast cancer—A review.
        Acta Oncol. 2006; 45: 280-284
        • Krug D.
        • Baumann R.
        • Budach W.
        • et al.
        Individualization of post-mastectomy radiotherapy and regional nodal irradiation based on treatment response after neoadjuvant chemotherapy for breast cancer: A systematic review.
        Strahlenther Onkol. 2018; 194: 607-618
        • Recht A.
        • McArthur H.
        • Solin L.J.
        • et al.
        Contemporary guidelines in whole-breast irradiation: An alternative perspective.
        Int J Radiat Oncol Biol Phys. 2019; 104: 567-573
      1. 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: https://www.nrgoncology.org/Clinical-Trials/Protocol/rtog-1005?filter=rtog-1005. Accessed December 14, 2020

      2. Hypofractionation With Simultaneous Integrated Boost vs. Standard Fractionation in Early Breast Cancer (HYPOSIB). Available at: https://clinicaltrials.gov/ct2/show/NCT02474641. Accessed December 14, 2020.

        • Brunt A.M.
        • Haviland J.S.
        • Sydenham M.
        • et al.
        Ten-year results of FAST: A randomized controlled trial of 5-fraction whole-breast radiotherapy for early breast cancer.
        J Clin Oncol. 2020; 38: 3261-3272
        • Murray Brunt A.
        • Haviland J.S.
        • Wheatley D.A.
        • 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: 1613-1626
        • Lee B.
        • Lee S.
        • Sung J.
        • et al.
        Radiotherapy-induced secondary cancer risk for breast cancer: 3D conformal therapy versus IMRT versus VMAT.
        J Radiol Prot. 2014; 34: 325-331
        • Abo-Madyan Y.
        • Aziz M.H.
        • Aly M.M.
        • et al.
        Second cancer risk after 3D-CRT, IMRT and VMAT for breast cancer.
        Radiother Oncol. 2014; 110: 471-476
        • Kaufman E.L.
        • Jacobson J.S.
        • Hershman D.L.
        • et al.
        Effect of breast cancer radiotherapy and cigarette smoking on risk of second primary lung cancer.
        J Clin Oncol. 2008; 26: 392-398
        • Ford M.B.
        • Sigurdson A.J.
        • Petrulis E.S.
        • et al.
        Effects of smoking and radiotherapy on lung carcinoma in breast carcinoma survivors.
        Cancer. 2003; 98: 1457-1464
        • Taylor C.
        • Correa C.
        • Duane F.K.
        • et al.
        Estimating the risks of breast cancer radiotherapy: Evidence from modern radiation doses to the lungs and heart and from previous randomized trials.
        J Clin Oncol. 2017; 35: 1641-1649
        • Jagsi R.
        • Griffith K.A.
        • Moran J.M.
        • et al.
        A randomized comparison of radiation therapy techniques in the management of node-positive breast cancer: Primary outcomes analysis.
        Int J Radiat Oncol Biol Phys. 2018; 101: 1149-1158

      Comments

      Commenting Guidelines

      To submit a comment for a journal article, please use the space above and note the following:

      • We will review submitted comments as soon as possible, striving for within two business days.
      • This forum is intended for constructive dialogue. Comments that are commercial or promotional in nature, pertain to specific medical cases, are not relevant to the article for which they have been submitted, or are otherwise inappropriate will not be posted.
      • We require that commenters identify themselves with names and affiliations.
      • Comments must be in compliance with our Terms & Conditions.
      • Comments are not peer-reviewed.