Association of Staphylococcus aureus Colonization With Severity of Acute Radiation Dermatitis in Patients With Breast or Head and Neck Cancer

Key Points

Question  Is Staphylococcus aureus (SA) colonization associated with acute radiation dermatitis (ARD) severity in patients with breast or head and neck cancer?

Findings  This cohort study of 76 patients with breast or head and neck cancer found that nasal SA colonization prior to radiation therapy was present in 35% of patients who developed grade 2 or higher ARD compared with 13% of patients who developed grade 1 ARD, a significant difference.

Meaning  The findings suggest that SA colonization may be associated with grade 2 or higher ARD development in patients with breast or head and neck cancer.

Importance  Pathogenesis of acute radiation dermatitis (ARD) is not completely understood. Pro-inflammatory cutaneous bacteria may contribute to cutaneous inflammation after radiation therapy.

Objective  To evaluate whether nasal colonization with Staphylococcus aureus (SA) before radiation therapy is associated with ARD severity in patients with breast or head and neck cancer.

Design, Setting, and Participants  This prospective cohort study with observers blinded to colonization status was conducted from July 2017 to May 2018 at an urban academic cancer center. Patients aged 18 years or older with breast or head and neck cancer and plans for fractionated radiation therapy (≥15 fractions) with curative intent were enrolled via convenience sampling. Data were analyzed from September to October 2018.

Exposures  Staphylococcus aureus colonization status before radiation therapy (baseline).

Main Outcomes and Measures  The primary outcome was ARD grade using the Common Terminology Criteria for Adverse Event Reporting, version 4.03.

Results  Among 76 patients analyzed, mean (SD) age was 58.5 (12.6) years and 56 (73.7%) were female. All 76 patients developed ARD: 47 (61.8%) with grade 1, 22 (28.9%) with grade 2, and 7 (9.2%) with grade 3. The prevalence of baseline nasal SA colonization was higher among patients who developed grade 2 or higher ARD compared with those who developed grade 1 ARD (10 of 29 [34.5%] vs 6 of 47 [12.8%]; P = .02, by χ² test).

Conclusions and Relevance  In this cohort study, baseline nasal SA colonization was associated with development of grade 2 or higher ARD in patients with breast or head and neck cancer. The findings suggest that SA colonization may play a role in the pathogenesis of ARD.

Acute radiation dermatitis (ARD) affects up to 95% of patients with cancer treated with radiotherapy (RT).¹ Acute radiation dermatitis presents within 90 days of RT initiation as skin erythema and may evolve into dry or moist desquamation, full-thickness ulceration, or necrosis.¹ Acute radiation dermatitis may negatively effect patient quality of life and disrupt oncologic treatment plans, yet evidence-based treatment options are limited.^1,2 The pathogenesis of ARD remains unknown, hindering development of robust prevention strategies.¹ Staphylococcus aureus (SA) has been hypothesized to play an important role in ARD.^3,4 In other inflammatory dermatoses, such as atopic dermatitis, SA has been shown to contribute to pathogenesis.⁵ In ARD, proinflammatory cutaneous bacteria may contribute to pathogenesis by promoting inflammation and preventing re-epithelialization of keratinocytes exposed to RT.³

We hypothesized that presence of nasal SA colonization prior to RT would be associated with more severe ARD compared with absence of SA colonization. Herein, we report results from a prospective cohort study.

This prospective cohort study assessed the association of SA colonization with ARD severity. Eligible patients were adults with cancer of the breast or head and neck with plans for fractionated RT (≥15 fractions) with curative intent. Patients with prior RT or an existing dermatologic condition affecting the field of radiation were ineligible. Patients were enrolled between July 2017 and May 2018. The study was approved by the Albert Einstein College of Medicine institutional review board. Written informed consent was obtained. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Bacterial culture samples were collected via swab from the nares, skin in the radiated field, and contralateral unirradiated skin at 2 time points: prior to initiation of RT (baseline) and during the final week of treatment.

Radiation dermatitis was graded weekly by the treating radiation oncologist blinded to patient colonization status using Common Terminology Criteria for Adverse Event Reporting, version 4.03. The primary outcome was the development of grade 2 or higher ARD at any point during RT.

Data were analyzed from September to October 2018. The sample size was calculated based on the documented observation that SA colonization has been recorded to be as high as 70% in analogous diseases such as atopic dermatitis.⁶ We conservatively hypothesized that approximately 35% of patients with ARD would also be colonized by pathogenic microorganisms. Assuming an incidence of 33% of grade 2 or higher ARD among noncolonized patients, a sample size of 80 participants can achieve 77% to 85% power to detect an odds ratio (OR) between 3.5 and 4.0, with a 2-sided error rate of 5% or lower.

Patients with baseline nasal SA colonization were compared with those without. Demographic and clinical characteristics were tabulated for the total sample and by group based on presence of baseline nasal SA colonization. Continuous variables were summarized as means and SDs, and associations with nasal SA colonization were tested using a 2-sample t test or Wilcoxon rank sum test. Categorical variables were described with counts and proportions, and associations with nasal SA colonization were tested using Pearson χ² test or Fisher exact test. To examine changes in SA colonization over the RT course, rates of SA colonization for each site were calculated before and after treatment and were compared using the McNemar test. Associations of baseline non-SA bacteria and posttreatment SA colonization with grade 2 or higher ARD were examined. Logistic regression analysis was applied to quantify the association of baseline SA colonization with development of grade 2 or higher ARD. In addition to baseline nasal SA colonization status and sex, factors known to be associated with ARD, including body mass index, diabetes, cancer type, radiation dose, and concurrent chemotherapy, were included in the model. However, to limit the potential of overfitting resulting from a small sample size, we used the best subsets approach, which resulted in a model with the lowest penalized score χ² statistics.^7,8 To eliminate the effect of multicollinearity between cancer type and sex, we created an indicator for each cancer-sex combination. Estimation of ORs and 95% CIs was provided. Analyses were conducted using SAS, version 9.4 (SAS Institute Inc). Two-sided P ≤ .05 was considered statistically significant.

Among 76 patients, mean (SD) age was 58.5 (12.6) years, 56 (73.7%) were female, and 20 (26.3%) were male. A total of 41 patients (53.9%) had breast cancer, and 35 (46.1%) had head and neck cancer. Patients received a mean (SD) total radiation dose of 58.5 (10.1) Gy delivered in a mean (SD) number of 28.0 (5.9) fractions. There were no differences in clinical or demographic characteristics between the 2 groups (Table 1). A total of 16 patients (21.1%) had a positive nasal SA culture result at baseline. All 76 patients developed ARD: 47 (61.8%) with grade 1, 22 (28.9%) with grade 2, and 7 (9.2%) with grade 3. The prevalence of baseline nasal SA colonization was higher among patients who developed grade 2 or higher ARD compared with those who developed grade 1 ARD (10 of 29 [34.5%] vs 6 of 47 [12.8%]; P = .02, by χ² test). At RT completion, the SA colonization rate at every tested site (nares, radiated skin, and contralateral skin) was significantly greater among patients who developed grade 2 or higher ARD compared with patients who developed grade 1 ARD (Table 2). Other bacteria (eTable in Supplement 1) were identified; however, baseline and post-RT rates of non-SA bacteria did not differ between patients with grade 1 ARD and those with grade 2 or higher ARD. Additionally, regression modeling revealed an association between baseline SA nasal colonization and development of grade 2 or higher ARD (OR, 4.24; 95% CI, 1.24-14.51; P = .02) (Table 3).

Colonization with SA has been increasingly implicated in the pathogenesis of inflammatory dermatoses, including atopic dermatitis, in which it has been shown to precede development of disease.^9,10 In this study, SA was more likely to be found on the skin in patients with higher-grade ARD after RT was completed. This finding suggests that in patients who are colonized in the nares at baseline, radiation-induced disruption of the skin barrier may allow SA to proliferate on the skin, amplifying the inflammatory process.

Our results revealed a potentially pathogenic role of SA in the development of ARD that should be further examined. In addition to validating the results in larger cohorts including other cancer types, studies investigating the clinical utility of wound cultures and topical antibiotics for patients with grade 2 or higher ARD are needed. Notably, as prophylactic bacterial decolonization has been shown to reduce infections in other clinical contexts, such as orthopedic surgery,¹¹ SA decolonization prior to RT to reduce ARD severity should be studied.⁶ Decolonization has been shown to be beneficial and cost-effective in patients admitted to the intensive care unit and prior to cardiac procedures.¹² A better understanding of the association between bacterial colonization and ARD pathogenesis is crucial as it can inform how to treat patients who develop ARD.

Our study has limitations. One limitation is sensitivity of the bacterial cultures. Screening of the anterior nares alone may identify only 67% of all patients colonized with SA. It is therefore possible that our data included 8 false-negative baseline nares culture results. However, even if we conservatively assume that half of these patients developed grade 2 or 3 ARD, our results would maintain significance, with 48.3% (14 of 29) of patients with grade 2 or 3 ARD vs 21.3% (10 of 47) of patients with grade 1 ARD being positive for SA in the nares at baseline (P = .01). Lastly, this is a pilot study with a relatively small sample size. Carriage of SA has been shown to vary among geographic locations, and both persistent and transient carriage patterns of colonization are possible, adding complexity to SA detection.¹³ However, this study found significant results and should be validated in larger studies.

In this cohort study, baseline nasal SA colonization was associated with development of grade 2 or higher ARD in patients with breast or head and neck cancer. The results suggest that SA colonization may play an important role in the pathogenesis of ARD.

Accepted for Publication: February 1, 2023.

Published Online: May 4, 2023. doi:10.1001/jamaoncol.2023.0454

Corresponding Author: Beth N. McLellan, MD, Division of Dermatology, Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, 3411 Wayne Ave, 2nd Floor, Bronx, NY 10467 (bmclella@montefiore.org).

Author Contributions: Ms Kost and Dr Rzepecki contributed equally. Dr McLellan had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Rzepecki, Deutsch, Birnbaum, Ohri, Daily, McLellan.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Kost, Rzepecki, Deutsch, Birnbaum, Ohri, Daily, Shinoda, McLellan.

Critical revision of the manuscript for important intellectual content: Rzepecki, Deutsch, Hosgood, Lin, Ohri, Daily, Shinoda, McLellan.

Statistical analysis: Kost, Rzepecki, Hosgood, Lin, Shinoda, McLellan.

Administrative, technical, or material support: Kost, Deutsch, Birnbaum, Ohri, Daily, Shinoda, McLellan.

Supervision: Ohri, Daily, Shinoda, McLellan.

Conflict of Interest Disclosures: Dr Ohri reported receiving grants from AstraZeneca and Merck and personal fees from AstraZeneca, Merck, and Genentech outside the submitted work. Dr McLellan reported receiving personal fees from Laroche-Posay and Paula's Choice, grants from Pfizer, and nonfinancial support from Paxman and working on clinical trials for OnQuality and Kintara outside the submitted work. No other disclosures were reported.

Data Sharing Statement: See Supplement 2.