Cancer risk after breast proton therapy considering physiological and radiobiological uncertainties


      • Theoretical calculation of the risk for second primary cancer after breast radiotherapy.
      • Comparison between proton and photon therapy and two risk models.
      • CTs in three different states.
      • Proton therapy gives lower risks in all scenarios.



      The reduced normal tissue dose burden from protons can reduce the risk of second cancer for breast cancer patients. Breathing motion and the impact of variable relative biological effectiveness (RBE) are however concerns for proton dose distributions. This study aimed to quantify the impact of these factors on risk predictions from proton and photon therapy.

      Materials and methods

      Twelve patients were planned in free breathing with protons and photons to deliver 50 Gy (RBE) in 25 fractions (assuming RBE = 1.1 for protons) to the left breast. Second cancer risk was evaluated with several models for the lungs, contralateral breast, heart and esophagus as organs at risk (OARs). Plans were recalculated on CT-datasets acquired in extreme phases to account for breathing motion. Proton plans were also recalculated assuming variable RBE for a range of radiobiological parameters.


      The OARs received substantially lower doses from protons compared to photons. The highest risks were for the lungs (average second cancer risks of 0.31% and 0.12% from photon and proton plans, respectively). The reduced risk with protons was maintained, even when breathing and/or RBE variation were taken into account. Furthermore, while the total risks from the photon plans were seen to increase with the integral dose, no such correlation was observed for the proton plans.


      Protons have an advantage over the photons with respect to the induction of cancer. Uncertainties in physiological movements and radiobiological parameters affected the absolute risk estimates, but not the general trend of lower risk associated with proton therapy.


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      1. Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer Incidence and Mortality Worldwide: IARC CancerBase. IARC CancerBase. 2013;11.

      2. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) EBCTCG, Darby S, McGale P, 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 (London, England). 2011;378:1707–16.

        • Toma-Dasu I.
        • Wojcik A.
        • Kjellsson Lindblom E.
        Risk of second cancer following radiotherapy.
        Phys Medica. 2017; 42: 211-212
        • Grantzau T.
        • Mellemkjær L.
        • Overgaard J.
        Second primary cancers after adjuvant radiotherapy in early breast cancer patients: a national population based study under the Danish Breast Cancer Cooperative Group (DBCG).
        Radiother Oncol. 2013; 106: 42-49
      3. Dasu A, Toma-Dasu I. Long-term effects and secondary tumors. Compr Biomed Phys. Amsterdam: Elsevier; 2014. p. 223–233.

        • Dörr W.
        • Herrmann T.
        Second primary tumors after radiotherapy for malignancies.
        Strahlentherapie und Onkol. 2002; 178: 357-362
        • Cumberlin R.L.
        • Dritschilo A.
        • Mossman K.L.
        Carcinogenic effects of scattered dose associated with radiation therapy.
        Int J Radiat Oncol Biol Phys. 1989; 17: 623-629
        • Flejmer A.M.
        • Edvardsson A.
        • Dohlmar F.
        • et al.
        Respiratory gating for proton beam scanning versus photon 3D-CRT for breast cancer radiotherapy.
        Acta Oncol. 2016; 55: 577-583
        • Tommasino F.
        • Durante M.
        • D’Avino V.
        • et al.
        Model-based approach for quantitative estimates of skin, heart, and lung toxicity risk for left-side photon and proton irradiation after breast-conserving surgery.
        Acta Oncol. 2017; 56: 730-736
        • Lin L.L.
        • Vennarini S.
        • Dimofte A.
        • et al.
        Proton beam versus photon beam dose to the heart and left anterior descending artery for left-sided breast cancer.
        Acta Oncol. 2015; 54: 1032-1039
        • Flejmer A.M.
        • Chehrazi B.
        • Josefsson D.
        • et al.
        Impact of physiological breathing motion for breast cancer radiotherapy with proton beam scanning – an in silico study.
        Phys Medica. 2017; 39: 88-94
        • Ödén J.
        • Toma-Dasu I.
        • Eriksson K.
        • et al.
        The influence of breathing motion and a variable relative biological effectiveness in proton therapy of left-sided breast cancer.
        Acta Oncol. 2017; 56: 1428-1436
        • Wedenberg M.
        • Lind B.K.
        • Hårdemark B.
        A model for the relative biological effectiveness of protons: the tissue specific parameter α/β of photons is a predictor for the sensitivity to LET changes.
        Acta Oncol. 2013; 52: 580-588
        • Ödén J.
        • Eriksson K.
        • Toma-Dasu I.
        Inclusion of a variable RBE into proton and photon plan comparison for various fractionation schedules in prostate radiation therapy.
        Med Phys. 2017; 44: 810-822
        • Wedenberg M.
        • Toma-Dasu I.
        Disregarding RBE variation in treatment plan comparison may lead to bias in favor of proton plans.
        Med Phys. 2014; 41
      4. Dasu A, Toma-Dasu I. Models for the risk of secondary cancers from radiation therapy. Phys Medica 2017;42.

        • Dasu A.
        • Toma-Dasu I.
        • Olofsson J.
        • et al.
        The use of risk estimation models for the induction of secondary cancers following radiotherapy.
        Acta Oncol. 2005; 44: 339-347
        • Ardenfors O.
        Radiation-induced secondary cancers from IMRT and CRT for head-and-neck tumours : differences in risk estimation and influence of risk models.
        ([MSc thesis]) Stockholm University, 2011
      5. ICRP. ICRP Publication 103. The 2007 Recommendations of the International Commission on Radiological Protection. Annals of the ICRP 37 [2-4], 1-332, 2007.

        • Dasu A.
        • Toma-Dasu I.
        Dose – effect models for risk – relationship to cell survival parameters.
        Acta Oncol. 2005; : 829-835
      6. Davis RH. Production and killing of second cancer precursor cells in radiation therapy: in regard to Hall and Wuu (Int J Radiat Oncol Biol Phys 2003;56:83-88). Int J Radiat Oncol Biol Phys.

        • Schneider U.
        • Kaser-Hotz B.
        Radiation risk estimates after radiotherapy: application of the organ equivalent dose concept to plateau dose-response relationships.
        Radiat Environ Biophys. 2005; 44: 235-239
        • Schneider U.
        • Hälg R.
        The impact of neutrons in clinical proton therapy.
        Front Oncol. 2015; : 5
        • Marcu L.G.
        • Santos A.
        • Bezak E.
        Risk of second primary cancer after breast cancer treatment.
        Eur J Cancer Care. 2014; 23: 51-64
        • Abo-Madyan Y.
        • Aziz M.H.
        • Aly M.M.O.M.
        • et al.
        Second cancer risk after 3D-CRT, IMRT and VMAT for breast cancer.
        Radiother Oncol. 2014; 110: 471-476
        • Hoekstra N.
        • Fleury E.
        • Merino Lara T.R.
        • et al.
        Long-term risks of secondary cancer for various whole and partial breast irradiation techniques.
        Radiother Oncol. 2018; 128: 428-433
        • De Rose F.
        • Cozzi L.
        • Meattini I.
        • et al.
        The potential role of intensity-modulated proton therapy in the regional nodal irradiation of breast cancer: a treatment planning study.
        Clin Oncol. 2020; 32: 26-34
        • Ares C.
        • Khan S.
        • MacArtain A.M.
        • et al.
        Postoperative proton radiotherapy for localized and locoregional breast cancer: potential for clinically relevant improvements?.
        Int J Radiat Oncol Biol Phys. 2010; 76: 685-697
        • McNamara A.L.
        • Schuemann J.
        • Paganetti H.
        A phenomenological relative biological effectiveness (RBE) model for proton therapy based on all published in vitro cell survival data.
        Phys Med Biol. 2015; 60: 8399-8416
        • Carabe-Fernandez A.
        • Dale R.G.
        • Jones B.
        The incorporation of the concept of minimum RBE (RBEmin) into the linear-quadratic model and the potential for improved radiobiological analysis of high-LET treatments.
        Int J Radiat Biol. 2007; 83: 27-39
        • Giovannini G.
        • Böhlen T.
        • Cabal G.
        • et al.
        Variable RBE in proton therapy: comparison of different model predictions and their influence on clinical-like scenarios.
        Radiat Oncol. 2016; 11
        • Belli M.
        • Cera F.
        • Cherubini R.
        • et al.
        RBE-LET relationships for cell inactivation and mutation induced by low energy protons in V79 cells: further results at the LNL facility.
        Int J Radiat Biol. 1998; 74: 501-509
        • Hälg R.A.
        • Besserer J.
        • Boschung M.
        • et al.
        Measurements of the neutron dose equivalent for various radiation qualities, treatment machines and delivery techniques in radiation therapy.
        Phys Med Biol. 2014; 59: 2457-2468