Introduction
Radiotherapy is a principal treatment for head and neck cancer (HNC). Definitive radiotherapy in patients with advanced HNC can preserve laryngopharyngeal functions such as speaking, swallowing, and breathing. Radiotherapy for HNCs must minimise exposure to a large number of organs-at-risk (OARs). Intensity-modulated radiotherapy (IMRT) reduces complications and escalates dose delivery [
1]. The radiation dose necessary to achieve local tumour control is limited by doses to normal tissues within the irradiation field [
2,
3]. Radiation dermatitis is one of the most common adverse events associated with head and neck (HN) radiotherapy, and is radiation dose-dependent [
4]. During two- or three-dimensional conformal radiotherapy (2D/3D-CRT), dose distribution to the skin is homogeneous and can be easily estimated, but the radiation dose delivered by IMRT is inhomogeneous and difficult to calculate. The significance of dose-volume factors when performing radiotherapy is well recognised, and it is preferable to minimise the skin dose, but no clear indication of the severity of acute skin reactions is available. Radiation dermatitis has a profound impact not only on quality of life (QOL) but also on treatment outcomes; radiation schedules may be interrupted [
5‐
7]. Thus, prediction of radiation dermatitis risk is essential for appropriate management. A previous report suggested several predictors of acute toxicities [
8]; our current study includes both dose-volume parameters and other clinical factors.
Here, we evaluated the relationship between skin dose distributions and the incidence of severe, acute radiation dermatitis in HNC patients treated with IMRT and volumetrically modulated arc therapy (VMAT). We developed a scoring system combining dose parameters with clinical factors that usefully predicted acute skin reactions, facilitating the appropriate management of radiation dermatitis.
Discussion
We evaluated the relationship between skin dose-volume distributions and the incidence of severe, acute radiation dermatitis in HNC patients treated with IMRT and VMAT. We constructed a risk analysis model combining dose parameters with concurrent chemotherapy, age, and BMI. The model usefully predicted acute skin reactions, facilitating the appropriate management of radiation dermatitis.
Acute dermatitis is the most common side effect of HNC radiotherapy, and usually develops within 90 days of exposure [
15]. The skin of the anterior neck is the most sensitive region of the body [
16]. During radiotherapy, ionisation of cellular water and generation of short-lived free radicals trigger irreversible double-stranded breaks in nuclear and mitochondrial DNA, as well as inflammation [
17‐
19]. Repeated exposure to low-dose ionizing radiation prevents DNA and tissue repair. Accumulation of radiation-induced changes in the dermal vasculature, appendageal structures, and epidermal stem cells results in dermatitis progression through characteristic stages that increase in severity. Radiation dermatitis is a dose-dependent toxic effect. The total dose, dose per fraction, and dose volume to surfaces exposed to radiation affect radiation dermatitis risk. In the era of low-energy techniques, skin changes depend on the radiation dose (erythema after doses ≥2 Gy; dry desquamation after doses of 12–20 Gy, moist desquamation at doses > 20 Gy, and necrosis at doses ≥35 Gy). In terms of necrosis/ulceration endpoints, the skin TD5/5 (the 5% probability of a complication within 5 years of treatment) was 55 Gy for a 100 cm
2 field. The TD3/5 was 57 Gy for a 30 cm
2 field and 69 Gy for a 10 cm
2 field [
20]. These data revealed dose dependency of late skin reaction, but they cannot be extrapolated to acute dermatitis. It was needed to build the new indication of acute dermatitis with dose volume analysis. In our study V
60Gy over 38cm
3 related to 43.4% of Grade 3 dermatitis, and it could be a new indication to predict the severity of radiation dermatitis induced by head and neck IMRT/VMAT.
IMRT delivers radiation to the planned treatment volume while minimizing the dose to normal tissues outside the target, thus reducing skin reactions. Using breast IMRT, a multicenter randomised trial showed that fewer patients in the IMRT than the conventional radiotherapy group experienced moist desquamation (31% vs. 48%) [
21]. In HNC patients receiving IMRT, skin dose accumulation markedly increased (reflecting the intrinsic dose distribution profile) if no correction was applied in terms of inverse planning optimisation after initial clinical implementation [
12]. When a thermoplastic mask was used for immobilisation, the skin doses were higher than those delivered without a mask because of a bolus effect. By contouring the skin as an OAR during optimisation, the volumes of neck skin receiving > 45 Gy and > 55 Gy fell to 58 and 17% of the initial values, respectively. Penoncello et al. [
22] reported that VMAT is associated with fewer skin reactions than IMRT and is better at reducing skin doses. In addition, integrated boost regimens trigger higher skin doses, particularly to the shoulders, compared to traditional boost regimens. Price et al. found that a 4 mm PTV-to-skin distance minimised the odds ratio for developing superficial “hot spots” to < 1.1 when high-conformal rotational techniques such as VMAT were applied [
23]. It has been suggested that the PTVs should be cropped 3 mm below the contoured body surface to prevent optimisation issues in build-up regions, except when the skin is part of the CTV (ICRU Report 83; [
24]). Treatment protocol 1015 of the Japan Clinical Oncology Group, derived from a clinical trial of concurrent chemoradiotherapy to treat nasopharyngeal cancer, suggests cropping 2–3 mm below the body surface [
25]. During real-life IMRT, we do not constrain the skin contour or draw DVHs, but potential skin issues should be discussed with high-risk patients. Many anti-cancer agents enhance the sensitivity to radiotherapy and may increase cellular damage and hinder tissue repair. Conventional chemotherapeutic agents and anticancer therapies featuring EGFR inhibitors increase the risk of severe radiation dermatitis. Giro et al. reported that a high rate of severe dermatitis was observed during radiotherapy combined with concurrent chemotherapy, and recommended treatment interruption if confluent moist desquamation develops at a total dose < 40 Gy [
26]. Radiation dermatitis profoundly impacts the QOL, causing pain, infections, and bleeding, and also compromises treatment outcomes because of interruption to radiation schedules [
4‐
6]. Appropriate management by risk classification is essential.
Generally, patients with Grade 1 radiation dermatitis are treated nonspecifically via general prevention measures. Dry desquamation can be treated with hydrophilic moisturisers, and pruritus and irritation respond to low- to mid-potency steroids. For patients with Grade 2–3 dermatitis featuring moist desquamation, treatment should be directed towards prevention of secondary infection and dressing the desquamation [
27‐
30]. Treatment of each dermatitis grade requires a multidisciplinary approach, involving a radiation oncologist, nurse, wound specialist, and dermatologist.
In our study, BMI, age, and concurrent chemotherapy were significant predictor as other factors of acute toxicities. Treatment technique, sex, co-existing morbidities, diabetes, hypertension, smoking were not significant. Low Nutritional status and older age may delay wound repair, and concurrent chemotherapy enhances radiosensitizing effect, which increase not only therapeutic effects but also adverse events. A previous study reported the predictors of acute radiotherapeutic toxicities include sex, performance status, and nutritional status, and TNM stage [
8]. Sex and TNM stage reflect RT doses in this previous study, so dose parameter and nutritional status are compatible with our study.
To the best of our knowledge, this is the first DVH-based analysis of how skin structure combined with other factors predicts the risk for acute dermatitis in HNC patients undergoing IMRT. During 2D/3D-CRT, the skin dose is homogeneous and can be estimated, but the dose is not homogeneous during IMRT, and conversion of isodoses to structure-level doses is required. No clear dose indications in terms of risk for severe, acute skin reactions are available. Our model calculates the probability of severe acute dermatitis for individual patients. Of all patients, 58.6% of high-risk, 20.5% of intermediate-risk, and 0% of low-risk patients developed severe acute dermatitis. Using dose parameters, and clinical factors including BMI, age, and concurrent chemotherapy status, we predicted the development of acute skin reactions more accurately than that predicted using dose parameters alone, facilitating the appropriate management of radiation dermatitis.
This scoring system should be evaluated prospectively or validated on retrospective multicentre cohort prior to implementation into clinical practice. In addition, our model should be expanded to include other physical parameters or genotypic data to improve sensitivity and specificity. Finally, an objective dermatitis evaluation method is needed, as CTCAE is subjective. One potential option is real-time laser Doppler flowmetry, which quantitatively detects changes in cutaneous microcirculation reflecting radiation-induced skin injury; use of this method should be investigated in the future [30].