Smoking and Radiation-induced Skin Injury: Analysis of a Multiracial, Multiethnic Prospective Clinical Trial

Published:September 16, 2022DOI:


      • Analysis of radiation-induced skin injury (RISI) after breast radiotherapy (RT)
      • Urinary cotinine (UCot) was measured in 980 patients at baseline and end RT
      • The risk of moderate-severe late RISI was weakly associated with UCot
      • No association between UCot and acute RISI was identified



      Smoking during breast radiotherapy (RT) may be associated with radiation-induced skin injury (RISI). We aimed to determine if a urinary biomarker of tobacco smoke exposure is associated with increased rates of RISI during and after breast RT.

      Patients and Methods

      Women with Stage 0-IIIA breast cancer treated with breast-conserving surgery or mastectomy followed by RT to the breast or chest wall with or without regional nodal irradiation were prospectively enrolled on a multicenter study assessing acute/late RISI. 980 patients with urinary cotinine (UCot) measurements (baseline and end-RT) were categorized into three groups. Acute and late RISI was assessed using the ONS Acute Skin Reaction scale and the LENT-SOMA Criteria.


      Late Grade 2+ and Grade 3+ RISI occurred in 18.2% and 1.9% of patients, respectively—primarily fibrosis, pain, edema, and hyperpigmentation. Grade 2+ late RISI was associated with UCot group (p=0.006). Multivariable analysis identified UCot-based light smoker/secondhand smoke exposure (HR 1.79, p=0.10) and smoking (HR 1.60, p=0.06) as non-significantly associated with increased risk of late RISI. Hypofractionated breast RT was associated with decreased risk of late RISI (HR 0.51, p=0.03). UCot was not associated with acute RISI, multivariable analysis identified race, obesity, RT site/fractionation, and bra size to be associated with acute RISI.


      Tobacco exposure during breast RT may be associated with an increased risk of late RISI without an effect on acute toxicity. Smoking cessation should be encouraged prior to radiotherapy to minimize these and other ill effects of smoking.
      In this analysis of a prospective study of radiation-induced skin injury in breast cancer patients treated with radiotherapy (RT), urinary cotinine (UCot) was measured for 980 participants at baseline and end RT. High UCot was associated with a higher rate of late RISI but not acute RISI. Smoking cessation is recommended to reduce the risk of late RISI.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Clinical Breast Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Early Breast Cancer Trialists' Collaborative G
        • 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.
        The Lancet. 2011; 378: 1707-1716
        • Fisher B
        • Anderson S
        • Bryant J
        • 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.
        N Engl J Med. 2002; 347: 1233-1241
        • Overgaard M
        • Hansen PS
        • Overgaard J
        • et al.
        Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial.
        N Engl J Med. 1997; 337: 949-955
        • Overgaard M
        • Jensen MB
        • Overgaard J
        • et al.
        Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial.
        Lancet. 1999; 353: 1641-1648
        • Ragaz J
        • Olivotto IA
        • Spinelli JJ
        • et al.
        Locoregional radiation therapy in patients with high-risk breast cancer receiving adjuvant chemotherapy: 20-year results of the British Columbia randomized trial.
        J Natl Cancer Inst. 2005; 97: 116-126
        • Creamer MR
        • Wang TW
        • Babb S
        • et al.
        Tobacco Product Use and Cessation Indicators Among Adults — United States, 2018.
        MMWR Morb Mortal Wkly Rep. 2019; 68: 1013-1019
        • Tsai J
        • Homa DM
        • Gentzke AS
        • et al.
        Exposure to Secondhand Smoke Among Nonsmokers — United States, 1988–2014.
        MMWR Morb Mortal Wkly Rep. 2018; 67: 1342-1346
        • Wong G
        • Lam E
        • Karam I
        • et al.
        The impact of smoking on adjuvant breast cancer radiation treatment: A systematic review.
        Cancer Treatment and Research Communications. 2020; 24100185
        • Hu JJ
        • Urbanic JJ
        • Case LD
        • et al.
        Association Between Inflammatory Biomarker C-Reactive Protein and Radiotherapy-Induced Early Adverse Skin Reactions in a Multiracial/Ethnic Breast Cancer Population.
        Journal of Clinical Oncology. 2018; 36: 2473-2482
        • Lee E
        • Takita C
        • Wright JL
        • et al.
        Genome-wide enriched pathway analysis of acute post-radiotherapy pain in breast cancer patients: a prospective cohort study.
        Human Genomics. 2019; 13: 28
        • Burnett LR
        • Hughes RT
        • Rejeski AF
        • et al.
        Review of the terminology describing ionizing radiation-induced skin injury: a case for standardization.
        Technology in Cancer Research & Treatment. 2021;
        • Lilla C
        • Ambrosone CB
        • Kropp S
        • et al.
        Predictive factors for late normal tissue complications following radiotherapy for breast cancer.
        Breast Cancer Res Treat. 2007; 106: 143-150
        • Spierer MM
        • Hong LX
        • Wagman RT
        • Katz MS
        • Spierer RL
        • McCormick B.
        Postmastectomy CT-based electron beam radiotherapy: dosimetry, efficacy, and toxicity in 118 patients.
        Int J Radiat Oncol Biol Phys. 2004; 60: 1182-1189
        • Hehr T
        • Budach W
        • Paulsen F
        • Gromoll C
        • Christ G
        • Bamberg M.
        Evaluation of predictive factors for local tumour control after electron-beam-rotation irradiation of the chest wall in locally advanced breast cancer.
        Radiotherapy and Oncology. 1999; 50: 283-290
        • Pignol JP
        • 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
        • Collette S
        • Collette L
        • Budiharto T
        • et al.
        Predictors of the risk of fibrosis at 10 years after breast conserving therapy for early breast cancer: a study based on the EORTC Trial 22881-10882 'boost versus no boost'.
        Eur J Cancer. 2008; 44: 2587-2599
        • Vicini F
        • Cecchini R
        • White J
        • et al.
        Abstract GS4-04: Primary results of NSABP B-39/RTOG 0413 (NRG Oncology): A randomized phase III study of conventional whole breast irradiation (WBI) versus partial breast irradiation (PBI) for women with stage 0, I, or II breast cancer.
        Cancer Research. 2019; 79 (SupplementGS4-04-GS04-04)
        • Shaitelman SF
        • Lei X
        • Thompson A
        • et al.
        Three-Year Outcomes With Hypofractionated Versus Conventionally Fractionated Whole-Breast Irradiation: Results of a Randomized, Noninferiority Clinical Trial.
        Journal of Clinical Oncology. 2018; 36: 3495-3503
        • Hecht SS.
        Carcinogen derived biomarkers: applications in studies of human exposure to secondhand tobacco smoke.
        Tob Control. 2004; 13 (SupplSuppl 1): i48-i56
        • Jarvis MJ
        • Russell MA
        • Benowitz NL
        • Feyerabend C.
        Elimination of cotinine from body fluids: implications for noninvasive measurement of tobacco smoke exposure.
        Am J Public Health. 1988; 78: 696-698
        • Benowitz NL.
        Cotinine as a biomarker of environmental tobacco smoke exposure.
        Epidemiol Rev. 1996; 18: 188-204
        • CDC
        Fourth national report on human exposure to environmental chemicals.
        US Department of Health and Human Services C. US Department of Health and Human Services, CDC, Atlanta, GA2015
        • NHANES 2013–2014 laboratory methods
        US Department of Health and Human Services, CDC.
        National Center for Health Statistics, 2013
        • CDC
        Laboratory Procedure Manual: Cotinine and Hydroxycotinine (Total).
        US Department of Health and Human Services C, 2018 (ed)
        • Fentiman IS
        • Allen DS
        • Hamed H.
        Smoking and prognosis in women with breast cancer.
        International Journal of Clinical Practice. 2005; 59: 1051-1054
        • Holmes MD
        • Murin S
        • Chen WY
        • Kroenke CH
        • Spiegelman D
        • Colditz GA.
        Smoking and survival after breast cancer diagnosis.
        Int J Cancer. 2007; 120: 2672-2677
        • Pierce JP
        • Patterson RE
        • Senger CM
        • et al.
        Lifetime cigarette smoking and breast cancer prognosis in the After Breast Cancer Pooling Project.
        J Natl Cancer Inst. 2014; 106 (djt359-djt359)
        • Steinberger E
        • Kollmeier M
        • McBride S
        • Novak C
        • Pei X
        • Zelefsky MJ.
        Cigarette smoking during external beam radiation therapy for prostate cancer is associated with an increased risk of prostate cancer-specific mortality and treatment-related toxicity.
        BJU International. 2015; 116: 596-603
        • Chen AM
        • Chen LM
        • Vaughan A
        • et al.
        Tobacco Smoking During Radiation Therapy for Head-and-Neck Cancer Is Associated With Unfavorable Outcome.
        International Journal of Radiation Oncology, Biology, Physics. 2011; 79: 414-419
        • Browman GP
        • Wong G
        • Hodson I
        • et al.
        Influence of cigarette smoking on the efficacy of radiation therapy in head and neck cancer.
        N Engl J Med. 1993; 328: 159-163
        • Kunutsor Setor K
        • Spee Julia M
        • Kieneker Lyanne M
        • et al.
        Self-Reported Smoking, Urine Cotinine, and Risk of Cardiovascular Disease: Findings From the PREVEND (Prevention of Renal and Vascular End-Stage Disease) Prospective Cohort Study.
        Journal of the American Heart Association. 2022; 7e008726
        • Wells AJ
        • English PB
        • Posner SF
        • Wagenknecht LE
        • Perez-Stable EJ.
        Misclassification rates for current smokers misclassified as nonsmokers.
        American Journal of Public Health. 1998; 88: 1503-1509
        • Nighbor TD
        • Doogan NJ
        • Roberts ME
        • et al.
        Smoking prevalence and trends among a U.S. national sample of women of reproductive age in rural versus urban settings.
        PLOS ONE. 2018; 13e0207818
        • Pignol J-P
        • Vu TTT
        • Mitera G
        • Bosnic S
        • Verkooijen HM
        • Truong P.
        Prospective Evaluation of Severe Skin Toxicity and Pain During Postmastectomy Radiation Therapy.
        International Journal of Radiation Oncology*Biology*Physics. 2015; 91: 157-164
        • Sharp L
        • Johansson H
        • Hatschek T
        • Bergenmar M.
        Smoking as an independent risk factor for severe skin reactions due to adjuvant radiotherapy for breast cancer.
        The Breast. 2013; 22: 634-638
        • Kelemen G
        • Varga Z
        • Lázár G
        • Thurzó L
        • Kahán Z.
        Cosmetic Outcome 1–5 Years After Breast Conservative Surgery, Irradiation and Systemic Therapy.
        Pathology & Oncology Research. 2012; 18: 421-427
        • Taylor C
        • Correa C
        • Duane FK
        • 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
        • Komenaka IK
        • Hsu C-H
        • Martinez ME
        • et al.
        Preoperative Chemotherapy for Operable Breast Cancer Is Associated with Better Compliance with Adjuvant Therapy in Matched Stage II and IIIA Patients.
        The Oncologist. 2011; 16: 742-751
        • Johansen J
        • Overgaard J
        • Rose C
        • et al.
        Cosmetic outcome and breast morbidity in breast-conserving treatment–results from the Danish DBCG-82TM national randomized trial in breast cancer.
        Acta Oncol. 2002; 41: 369-380
        • Arsenault J
        • Parpia S
        • Goldberg M
        • et al.
        Acute Toxicity and Quality of Life of Hypofractionated Radiation Therapy for Breast Cancer.
        International Journal of Radiation Oncology*Biology*Physics. 2020; 107: 943-948
        • McFarlane MR
        • Hochstedler KA
        • Laucis AM
        • et al.
        Predictors of Pneumonitis After Conventionally Fractionated Radiotherapy for Locally Advanced Lung Cancer.
        International Journal of Radiation Oncology, Biology, Physics. 2021; 111: 1176-1185
        • Johansen J
        • Overgaard J
        • Overgaard M.
        Effect of adjuvant systemic treatment on cosmetic outcome and late normal-tissue reactions after breast conservation.
        Acta Oncol. 2007; 46: 525-533
        • Whelan TJ
        • Pignol JP
        • Levine MN
        • et al.
        Long-term results of hypofractionated radiation therapy for breast cancer.
        N Engl J Med. 2010; 362: 513-520
        • Wong LS
        • Martins-Green M.
        Firsthand cigarette smoke alters fibroblast migration and survival: implications for impaired healing.
        Wound Repair and Regeneration. 2004; 12: 471-484
        • Jensen JA
        • Goodson WH
        • Hopf HW
        • Hunt TK.
        Cigarette smoking decreases tissue oxygen.
        Arch Surg. 1991; 126: 1131-1134
        • Astori E
        • Garavaglia ML
        • Colombo G
        • et al.
        Antioxidants in Smokers.
        Nutr Res Rev. 2021; : 1-77
        • Prantl L
        • Moellhoff N
        • Fritschen UV
        • et al.
        Impact of Smoking Status in Free Deep Inferior Epigastric Artery Perforator Flap Breast Reconstruction: A Multicenter Study.
        J Reconstr Microsurg. 2020; 36: 694-702
        • Sørensen LT
        • Hørby J
        • Friis E
        • Pilsgaard B
        • Jørgensen T.
        Smoking as a risk factor for wound healing and infection in breast cancer surgery.
        Eur J Surg Oncol. 2002; 28: 815-820
        • Blanchet MR
        • Israël-Assayag E
        • Cormier Y.
        Inhibitory effect of nicotine on experimental hypersensitivity pneumonitis in vivo and in vitro.
        Am J Respir Crit Care Med. 2004; 169: 903-909
        • Archambeau JO
        • Pezner R
        • Wasserman T.
        Pathophysiology of irradiated skin and breast.
        International Journal of Radiation Oncology*Biology*Physics. 1995; 31: 1171-1185
        • Brush J
        • Lipnick SL
        • Phillips T
        • Sitko J
        • McDonald JT
        • McBride WH.
        Molecular Mechanisms of Late Normal Tissue Injury.
        Seminars in Radiation Oncology. 2007; 17: 121-130
        • Powell JT.
        Vascular damage from smoking: disease mechanisms at the arterial wall.
        Vasc Med. 1998; 3: 21-28
        • Rodemann HP
        • Bamberg M.
        Cellular basis of radiation-induced fibrosis.
        Radiotherapy and Oncology. 1995; 35: 83-90
        • Morita A
        • Torii K
        • Maeda A
        • Yamaguchi Y.
        Molecular Basis of Tobacco Smoke-Induced Premature Skin Aging.
        Journal of Investigative Dermatology Symposium Proceedings. 2009; 14: 53-55
        • Wright JL
        • Takita C
        • Reis IM
        • et al.
        Prospective evaluation of radiation-induced skin toxicity in a race/ethnically diverse breast cancer population. Cancer medicine. 2016; 5: 454-464
        • Shumway DA
        • Kapadia N
        • Walker EM
        • et al.
        Development of an Illustrated Scale for Acute Radiation Dermatitis in Breast Cancer Patients.
        Practical Radiation Oncology. 2021; 11: 168-176
        • Morgan G
        • Schnoll RA
        • Alfano CM
        • et al.
        National Cancer Institute Conference on Treating Tobacco Dependence at Cancer Centers.
        Journal of Oncology Practice. 2011; 7: 178-182
        • Stead LF
        • Koilpillai P
        • Fanshawe TR
        • Lancaster T.
        Combined pharmacotherapy and behavioural interventions for smoking cessation.
        Cochrane Database Syst Rev. 2016; 3Cd008286
      1. Evans WK, Truscott R, Cameron E, et al. Implementing smoking cessation within cancer treatment centres and potential economic impacts. Translational Lung Cancer Research. 2019:S11-S20.

        • Slatore CG
        • Au DH
        • Hollingworth W.
        Cost-effectiveness of a smoking cessation program implemented at the time of surgery for lung cancer.
        J Thorac Oncol. 2009; 4: 499-504
        • Bellinger C
        • Foley KL
        • Dressler EV
        • et al.
        Organizational Characteristics and Smoking Cessation Support in Community-Based Lung Cancer Screening Programs.
        J Am Coll Radiol. 2022; 19: 529-533
        • Wang GX
        • Narayan AK
        • Park ER
        • Lehman CD
        • Gorenstein JT
        • Flores EJ.
        Screening Mammography Visits as Opportunities to Engage Smokers With Tobacco Cessation Services and Lung Cancer Screening.
        J Am Coll Radiol. 2020; 17: 606-612
        • Gosselin T
        • Ginex PK
        • Backler C
        • et al.
        ONS Guidelines™ for Cancer Treatment-Related Radiodermatitis.
        Oncol Nurs Forum. 2020; 47: 654-670
        • Ginex PK
        • Backler C
        • Croson E
        • et al.
        Radiodermatitis in Patients With Cancer: Systematic Review and Meta-Analysis.
        Oncol Nurs Forum. 2020; 47: E225-e236
        • Wong RK
        • Bensadoun RJ
        • Boers-Doets CB
        • et al.
        Clinical practice guidelines for the prevention and treatment of acute and late radiation reactions from the MASCC Skin Toxicity Study Group.
        Support Care Cancer. 2013; 21: 2933-2948
        • Ho AY
        • Olm-Shipman M
        • Zhang Z
        • et al.
        A Randomized Trial of Mometasone Furoate 0.1% to Reduce High-Grade Acute Radiation Dermatitis in Breast Cancer Patients Receiving Postmastectomy Radiation.
        Int J Radiat Oncol Biol Phys. 2018; 101: 325-333