Patient reported respiratory symptoms and lung radiation doses 11 years after loco-regional breast cancer radiation therapy in the DBCG RT Nation Study

Authors

  • Maja Bendtsen Sharma Department of Oncology, Aarhus University Hospital, Aarhus, Denmark https://orcid.org/0000-0003-3189-6754
  • Lasse Hindhede Refsgaard Danish Centre for Particle Therapy, Aarhus University Hospital, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark https://orcid.org/0000-0001-7329-8416
  • Elisabeth Bendstrup Centre for Rare Lung Diseases, Department of Respiratory diseases and Allergy, Aarhus University Hospital, Denmark https://orcid.org/0000-0002-4238-6963
  • Emma Skarsø Buhl Danish Centre for Particle Therapy, Aarhus University Hospital, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark https://orcid.org/0000-0001-5408-3014
  • Robert Zachariae Department of Oncology, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; epartment of Psychology and Behavioural Sciences, Aarhus University, Denmark https://orcid.org/0000-0001-9076-3068
  • Rasmus Blechingberg Friis Department of Oncology, Aarhus University Hospital, Aarhus, Denmark https://orcid.org/0000-0002-0564-146X
  • Ingeborg Farver-Vestergaard Department of Medicine, Lillebaelt Hospital, Vejle, Denmark; Department of Regional Health Research, University of Southern Denmark, Odense, Denmark https://orcid.org/0000-0002-5738-4055
  • Stine Sofia Korreman Danish Centre for Particle Therapy, Aarhus University Hospital, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark https://orcid.org/0000-0002-3523-382X
  • Birgitte Vrou Offersen Department of Oncology, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark https://orcid.org/0000-0001-7356-2096

DOI:

https://doi.org/10.2340/1651-226X.2025.43973

Keywords:

Adjuvant loco-regional radiation therapy, breast cancer, late effects, pulmonary late effects

Abstract

Background and purpose: The Danish Patient Association of Late Effects has received numerous inquiries from breast cancer (BC) survivors suspecting that adjuvant radiotherapy (RT) was the reason for respiratory symptoms. This study investigated patient-reported respiratory symptoms after locoregional RT and their association with ipsilateral lung radiation dose.

Patient/material and methods: Patient-reported outcomes (PROs) and RT plans from BC patients treated at a single institution over 2008–2016 were collected. PROs included dyspnoea (EORTC QLQ-C30), cough (PRO-CTCAE), smoking and comorbidities. RT dose-volume metrics were registered including ipsilateral mean lung dose (MLD), and volumes receiving 5 Gy (V5) and 20 Gy (V20). Patients were stratified into MLD tertiles (‘low’, ‘intermediate’, ‘high’) and compared. Additionally, responders were dichotomised by dyspnoea and cough scores (‘low’ vs ‘high’), and dose metrics were compared between symptom groups.

Results: Of 1,011 questionnaire distributed, 490 (49%) were completed and analysed. Median age was 65.8 years (interquartile range [IQR] 58.8;73.4), median time from RT to questionnaire was 11.1 years (IQR 8.9;13.2). Overall MLD was 12.9Gy (standard deviation [SD] 2.8). Any degree of dyspnoea was reported by 203 (41%) and any degree cough was reported by 175 (37%). No differences in dyspnoea/cough scores between MLD groups were found. MLD was 13.0Gy (SD 2.7) in the low dyspnoea group and 12.0Gy (SD 3.0) in the high dyspnoea group, (p = 0.04). MLD was 13.0 Gy (SD 2.7) in the low cough group and 12.5Gy (SD 3.1) in the high cough group (p = 0.23). The same pattern was found for V5lung and V20lung.

Interpretation: No associations between lung dose and patient-reported respiratory symptoms were found for node-positive BC patients 11 years after RT.

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References

Danish Breast Cancer Group. DBCG kvalitetsdatabase for Brystkraeft. 2024. [cited May 27th 2025] Available from: https://www.dbcg.dk/kvalitetsdatabasen/rapporter

Offersen BV, Alsner J, Nielsen H, Krause M, Stenbygaard L, Mjaaland I, 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. J Clin Oncol. 2020;38:3615–25.

https://doi.org/10.1200/JCO.20.01363

Offersen BV, Alsner J, Nielsen HM, Jakobsen EH, Nielsen MH, Stenbygaard L, et al. Partial breast irradiation versus whole breast irradiation for early breast cancer patients in a randomized phase III trial: the Danish Breast Cancer Group partial breast irradiation trial. J Clin Oncol. 2022;40:4189–97.

https://doi.org/10.1200/JCO.22.00451

Thorsen LBJ, Thomsen MS, Berg M, Jensen I, Josipovic M, Overgaard M, et al. CT-planned internal mammary node radiotherapy in the DBCG-IMN study: benefit versus potentially harmful effects. Acta Oncol. 2014;53(8):1027–34.

https://doi.org/10.3109/0284186X.2014.925579

Nielsen AWM, Thorsen LBJ, Özkan D, Matthiessen LW, Maae E, Milo MLH, et al. Internal mammary node irradiation in 4541 node-positive breast cancer patients treated with newer systemic therapies and 3D-based radiotherapy (DBCG IMN2): a prospective, nationwide, population-based cohort study. Lancet Reg. Health – Europe. 2025;49:101160.

https://doi.org/10.1016/j.lanepe.2024.101160

Leeuwen MV, Kieffer JM, Young TE, Annunziata MA, Arndt V, Arraras JI, et al. Phase III study of the European Organisation for Research and Treatment of Cancer Quality of Life cancer survivorship core questionnaire. J Cancer Surviv. 2023;17(4):1111–30.

https://doi.org/10.1007/s11764-021-01160-1

Karlsen J, Tandestad T, Steinshamn S, Salvesen Ø, Parlikar ND, Lundgren S, et al. Pulmonary function and lung fibrosis up to 12 years after breast cancer radiotherapy. Int J Radiat Oncol Biol Phys. 2024;118(4):1066–77.

https://doi.org/10.1016/j.ijrobp.2023.10.026

Gueiderikh A, Sarrade T, Kirova Y, De La Lande B, Vathaire FD, Auzac G, et al. Radiation-induced lung injury after breast cancer treatment: incidence in the CANTO-RT cohort and associated clinical and dosimetric risk factors. Front Oncol. 2023;13:2–12.

De Rose F, De Santis MC, Lucidi S, Colciago RR, Marino L, Cucciarelli F, et al. Dose constraints in breast cancer radiotherapy. A critical review. Radiother Oncol. 2025;202:110591.

https://doi.org/10.1016/j.radonc.2024.110591

Ejlertsen B, Offersen BVO, Overgaard J, Christiansen P, Jensen MB, Kroman N, et al. Forty years of landmark trials undertaken by the Danish Breast Cancer Cooperative Group (DBCG) nationwide or in international collaboration. Acta Oncol. 2018;57(1):3–12.

https://doi.org/10.1080/0284186X.2017.1408962

Refsgaard L, Buhl ES, Yates E, Maae E, Berg M, Al-Rawi S, et al. Evaluating Danish Breast Cancer Group locoregional radiotherapy guideline adherence in clinical treatment data 2008–2016: the DBCG RT Nation study. Radiother Oncol. 2024;199:110289.

https://doi.org/10.1016/j.radonc.2024.110289

The Danish Association of Late Effects. [cited May 27th 2025] Available from: www.senfoelger.dk

Arroyo-Hernández M, Maldonado F, Lozano-Ruiz F, Muñoz-Montaño W, Nuñez-Baez M, Arrieta O. Radiation-induced lung injury: current evidence. BMC Pulm Med. 2021;21(1):9.

https://doi.org/10.1186/s12890-020-01376-4

Meattini I, Guenzi M, Fozza A, Vidali C, Rovea P, Meacci F, et al. Overview on cardiac, pulmonary and cutaneous toxicity in patients treated with adjuvant radiotherapy for breast cancer. Breast Cancer. 2017;24(1):52–62.

https://doi.org/10.1007/s12282-016-0694-3

Käsmann L, Dietrich A, Staab-Weijnitz CA, Manapov F, Behr J, Rimner A, et al. Radiation-induced lung toxicity – cellular and molecular mechanisms of pathogenesis, management, and literature review. Radiat Oncol. 2020;15(1):214.

https://doi.org/10.1186/s13014-020-01654-9

Grantzau T, Overgaard J. Risk of second non-breast cancer after radiotherapy for breast cancer: a systematic review and meta-analysis of 762,468 patients. Radiother Oncol. 2015;114(1):56–65.

https://doi.org/10.1016/j.radonc.2014.10.004

Darby SC, Ewertz M, McGale P, Bennet AM, Blom-Goldman U, Brønnum D, et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med. 2013;368(11):987–8.

https://doi.org/10.1056/NEJMoa1209825

Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)-A metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42(2):377–81.

https://doi.org/10.1016/j.jbi.2008.08.010

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(5):165–376.

https://doi.org/10.1093/jnci/85.5.365

Juul T, Petersen MA, Holzner B, Laurberg S, Christensen P, Grønvold M. Danish population-based reference data for the EORTC QLQ-C30: associations with gender, age and morbidity. Qual Life Res. 2014;23(8):2183–93.

https://doi.org/10.1007/s11136-014-0675-y

Dueck AC, Mendoza TR, Mitchell SA, Reeve BB, Castro KM, Rogak LJ, et al. Validity and reliability of the us national cancer institute’s patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE). JAMA Oncol. 2015;1(8):1051–9.

https://doi.org/10.1001/jamaoncol.2015.2639

Bæksted C, Nissen A, Pappot H, Bidstrup PE, Mitchell SA, Basch E, et al. Danish Translation and Linguistic Validation of the U.S. National Cancer Institute’s Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). J Pain Symptom Manage. 2016;52(2):292–7.

https://doi.org/10.1016/j.jpainsymman.2016.02.008

Andersen K, Mouridsen H. Danish Breast Cancer Cooperative Group (DBCG). A description of the register of the nation-wide programme for primary breast cancer. Acta Oncol. 1988;27(6A):627–47.

https://doi.org/10.3109/02841868809091763

Fayers P, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A. EORTC QLQ-C30 Scoring Manual. 3rd ed. 2001, Brussels: European Organisation for Research and Treatment of Cancer

Basch E, Reeve BB, Mitchell SA, Clauser SB, Minasian LM, Dueck AC, et al. Development of the national cancer institute’s patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE). J Natl Cancer Inst. 2014;106(9):dju244.

https://doi.org/10.1093/jnci/dju244

Refsgaard L, Buhl ES, Nielsen AWM, Thomsen MS, Andersen K, Jensen I, et al. Quality assurance of internal mammary node irradiation in the DBCG IMN2 study. Radiother Oncol. 2025;202:110600.

Refsgaard L, Milo MLH, Buhl ES, Jensen JM, Maae E, Berg M, et al. The effect of coronary artery calcifications and radiotherapy on the risk of coronary artery disease in high-risk breast cancer patients in the DBCG RT-Nation cohort. Radiother Oncol. 2025;204:110705.

https://doi.org/10.1016/j.radonc.2024.110705

Refsgaard L, Skarsø ER, Ravkilde T, Nissen HD, Olsen M, Boye K, et al. End-to-end framework for automated collection of large multicentre radiotherapy datasets demonstrated in a Danish Breast Cancer Group cohort. Phys Imaging Radiat Oncol. 2023;27:100485.

Skarsø ER, Refsgaard L, Saini A, Møller DS, Lorenzen EL, Maae E, et al. Development of a national deep learning-based auto-segmentation model for the heart on clinical delineations from the DBCG RT nation cohort. Acta Oncol. 2023;62(10):1201–7.

https://doi.org/10.1080/0284186X.2023.2252582

Nielsen MH, Berg M, Pedersen AN, Andersen K, Glavicic V, Jakobsen EH, et al. Delineation of target volumes and organs at risk in adjuvant radiotherapy of early breast cancer: national guidelines and contouring atlas by the Danish Breast Cancer Cooperative Group. Acta Oncol. 2013;52(4):703–10.

https://doi.org/10.3109/0284186X.2013.765064

Offersen BV, Boersma LJ, Kirkove C, Hol S, Aznar MC, Biete Sola A, et al. ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer. Radiother Oncol. 2015;114(1):3–10.

https://doi.org/10.1016/j.radonc.2014.11.030

Francolini G, Thomsen MS, Yates ES, Kirkove C, Jensen I, Blix ES, et al. Quality assessment of delineation and dose planning of early breast cancer patients included in the randomized Skagen Trial 1. Radiother Oncol. 2017;123(2):282–7.

https://doi.org/10.1016/j.radonc.2017.03.011

Thorsen LBJ, Offersen BV, Danø H, Berg M, Jensen I, Pedersen AN, et al. DBCG-IMN: a population-based cohort study on the effect of internal mammary node irradiation in early node-positive breast cancer. J Clin Oncol. 2016;34(4):314–20.

https://doi.org/10.1200/JCO.2015.63.6456

Poortmans PM, Collette S, Kirkove C, Van Limbergen E, Budach V, Struikmans H, et al. Internal mammary and medial supraclavicular irradiation in breast cancer. N Engl J Med. 2015;373(4):317–27.

https://doi.org/10.1056/NEJMoa1415369

Whelan TJ, Olivotto IA, Parulekar WR, Ackerman I, Chua BH, Nabid A, et al. Regional nodal irradiation in early-stage breast cancer. N Engl J Med. 2015;373(4):307–16.

https://doi.org/10.1056/NEJMoa1415340

de Boniface J, Filtenborg TT, Rydén L, Szulkin R, Reimer T, Kühn T, et al. Omitting axillary dissection in breast cancer with sentinel-node metastases. N Engl J Med. 2024; 390(13):1163–75.

https://doi.org/10.1056/NEJMoa2313487

Pollard TJ, Johnson AEW, Raffa JD, Mark RG. TableOne: an open source Python package for producing summary statistics for research papers. JAMIA Open. 2018;1(1):26–31.

https://doi.org/10.1093/jamiaopen/ooy012

Løkke A, Fabricius PG, Vestbo J, Marott JL, Lange P. Prevalence of chronic obstructive pulmonary disease in Copenhagen. Results from The Copenhagen City Heart Study. Dan Med J. 2007;169(46):3956–60.

Published

2025-10-01

How to Cite

Sharma, M. B., Refsgaard, L. H., Bendstrup, E., Buhl, E. S., Zachariae, R., Friis, R. B., … Offersen, B. V. (2025). Patient reported respiratory symptoms and lung radiation doses 11 years after loco-regional breast cancer radiation therapy in the DBCG RT Nation Study. Acta Oncologica, 64, 1342–1350. https://doi.org/10.2340/1651-226X.2025.43973

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