Tobacco Exposure During Radiotherapy May Be Tied to Late Radiation-Induced Skin Injury

Tobacco exposure was linked to long-term radiotherapy skin and soft tissue injury.

A high urinary cotinine level is associated with an increased rate of late radiation-induced skin injury (RISI) but not acute RISI in patients with breast cancer treated with radiotherapy (RT), according to findings from a study published in Clinical Breast Cancer.

Researchers assessed the influence of tobacco exposure as measured by urinary cotinine on acute and late RISI during and after breast cancer radiotherapy.

A total of 1000 patients with newly diagnosed stage 0 through IIIA breast cancer scheduled for postoperative radiotherapy were enrolled from 2011 to 2013. The patients were evaluated for skin toxicity before, during, and at the end of radiation therapy (end-RT). Assessments for acute effects were conducted at baseline, week 3 of RT, end-RT, and at 1 and 2 months post-RT, respectively. Late effects were evaluated at 6 months and 12 months post-RT. The Oncology Nursing Society (ONS) Acute Skin Reaction Scale for Acute Dermatitis and the LENT-SOMA Criteria for late RT-induced skin toxicity were clinician-related outcome assessments employed by investigators.

Urine samples were obtained before radiotherapy (pre-RT) and after the last fraction of radiotherapy (end-RT). The distribution of the cotinine marker values in the urinary samples was “highly skewed,” researchers noted, so the variable was categorized using cutoffs of 10 and 100 into 3 categories — nonsmoker (<10 ng/mL), possible former/light smokers or secondhand smoke (SHS) exposure (10-100 ng/mL), and smoker (>100 ng/mL).

These novel findings associate a urinary biomarker of tobacco exposure with long-term [radiotherapy] skin and soft tissue injury and provide additional evidence on the negative effects of smoking during breast [radiotherapy].

Of the cohort, 980 patients with evaluable urinary cotinine measures and RISI assessments were included in the analysis. The participants had a median age of 58.1 years, 62.3% were White, 64.7% had stage 0 or 1 cancer, 64.9% were never smokers, 26.4% were former smokers, and 8.8% were current smokers, respectively.

After RT, analysis of variance of acute RISI according to the ONS Acute Skin Reaction Scale demonstrated no relationship between ONS and the cotinine-based smoking category. Further analysis showed that elevated cotinine level was present at grade 5 or above for ONS.

The late RISI measure had a mean (SD) of 0.91 (0.65) and 0.78 (0.67) at 6 months and 12 months post-RT, respectively, with a range of 0 to 4. Subsequent ANOVA analysis found a significant difference in LENT-SOMA grade across the smoking groups at 12 months (P =.006) and marginal significance at 6 months (P =.06).

Regarding the dichotomized moderate to severe acute ONS (grade 3+) outcome, cotinine-based smoker status was not significant. Factors that did have a significant association with acute risk included all race groups compared with White (Black, hazard ratio [HR] 1.29; Asian/Pacific Islander, HR 1.64; others, 1.41); obesity (HR 1.45) vs normal BMI; hypofractionated breast RT (HR 0.40) and conventionally fractionated chest wall RT (HR 1.38) vs conventionally fractionated breast RT; and large/extra-large bra size (HR 1.46) vs small/medium size.

A low correlation was observed between consecutive observations and ranged from -0.041 to 0.002. For the dichotomized moderate to severe LENT-SOMA (grade 2+) outcome, cotinine-based light smoker/secondhand smoke exposure (HR 1.79, P = .10) and cotinine-based smoker status (HR 1.60, P =.06) were associated with a marginally higher risk for late RISI, although it did not reach statistical significance.

Among several limitations, the study was a secondary analysis of a prospective observational study with breast RT skin reaction as a primary outcome measure, and it was not powered to assess urinary biomarkers of tobacco exposure and their association with acute and late RT toxicity. Also, a limited number of severe toxicity events limited the statistical power.

“These novel findings associate a urinary biomarker of tobacco exposure with long-term RT skin and soft tissue injury and provide additional evidence on the negative effects of smoking during breast RT,” the study authors commented. “Patients should be counseled regarding these effects, and smoking cessation prior to the start of breast RT should be encouraged.”


Hughes RT, Ip EH, Urbanic JJ, et al. Smoking and radiation-induced skin injury: analysis of a multiracial, multiethnic prospective clinical trial. Clin Breast Cancer. Published online September 16, 2022. doi: