title: Joint Estimation of Cardiac Toxicity and Recurrence Risks After Comprehensive Nodal Photon Versus Proton Therapy for Breast Cancer.
abstract: The study aims to perform joint estimation of the risk of recurrence caused by inadequate radiation dose coverage of lymph node targets and the risk of cardiac toxicity caused by radiation exposure to the heart. Delivered photon plans are compared with realistic proton plans, thereby providing evidence-based estimates of the heterogeneity of treatment effects in consecutive cases for the 2 radiation treatment modalities.
  
  
  
  Forty-one patients referred for postlumpectomy comprehensive nodal photon irradiation for left-sided breast cancer were included. Comparative proton plans were optimized by a spot scanning technique with single-field optimization from 2 en face beams. Cardiotoxicity risk was estimated with the model of Darby et al, and risk of recurrence following a compromise of lymph node coverage was estimated by a linear dose-response model fitted to the recurrence data from the recently published EORTC (European Organisation for Research and Treatment of Cancer) 22922/10925 and NCIC-CTG (National Cancer Institute of Canada Clinical Trials Group) MA.20 randomized controlled trials.
  
  
  
  Excess absolute risk of cardiac morbidity was small with photon therapy at an attained age of 80 years, with median values of 1.0% (range, 0.2%-2.9%) and 0.5% (range, 0.03%-1.0%) with and without cardiac risk factors, respectively, but even lower with proton therapy (0.13% [range, 0.02%-0.5%] and 0.06% [range, 0.004%-0.3%], respectively). The median estimated excess absolute risk of breast cancer recurrence after 10 years was 0.10% (range, 0.0%-0.9%) with photons and 0.02% (range, 0.0%-0.07%) with protons. The association between age of the patient and benefit from proton therapy was weak, almost non-existing (Spearman rank correlations of -0.15 and -0.30 with and without cardiac risk factors, respectively).
  
  
  
  Modern photon therapy yields limited risk of cardiac toxicity in most patients, but proton therapy can reduce the predicted risk of cardiac toxicity by up to 2.9% and the risk of breast cancer recurrence by 0.9% in individual patients. Predicted benefit correlates weakly with age. Combined assessment of the risk from cardiac exposure and inadequate target coverage is desirable for rational consideration of competing photon and proton therapy plans.
authors.affiliation: Department of Clinical Oncology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Niels Bohr Institute, Faculty of Science, University of Copenhagen, Copenhagen, Denmark. Electronic address: line.bjerregaard.stick@regionh.dk.
authors.forename: Line B
authors.initials: LB
authors.lastname: Stick
authors.affiliation: Maryland Proton Treatment Center, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Jen
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Clinical Oncology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Maja V
authors.initials: MV
authors.lastname: Maraldo
authors.affiliation: Department of Clinical Oncology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Nuffield Department of Population Health, University of Oxford, Oxford, UK.
authors.forename: Marianne C
authors.initials: MC
authors.lastname: Aznar
authors.affiliation: Department of Clinical Oncology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Anders N
authors.initials: AN
authors.lastname: Pedersen
authors.affiliation: Department of Clinical Oncology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Maryland Proton Treatment Center, University of Maryland School of Medicine, Baltimore, Maryland; Greenebaum Comprehensive Cancer Center and Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Søren M
authors.initials: SM
authors.lastname: Bentzen
authors.affiliation: Department of Clinical Oncology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Ivan R
authors.initials: IR
authors.lastname: Vogelius
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000401:mortality* / Q000532:radiotherapy*; D015984:Causality; D015897:Comorbidity; D018572:Disease-Free Survival; D005260:Female; D006331:Heart Diseases / Q000401:mortality*; D006801:Humans; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000401:mortality* / Q000517:prevention & control; D016016:Proportional Hazards Models; D061766:Proton Therapy / Q000401:mortality* / Q000706:statistics & numerical data; D011832:Radiation Injuries / Q000401:mortality*; D011879:Radiotherapy Dosage; D011880:Radiotherapy Planning, Computer-Assisted / Q000379:methods*; D018570:Risk Assessment / Q000379:methods; D012307:Risk Factors; D000071036:Sentinel Lymph Node / Q000528:radiation effects; D015996:Survival Rate