Acute Radiation-induced Skin Toxicity Research Articles

Non-invasive physical plasma for preventing radiation dermatitis in breast cancer: Results from an intrapatient-randomised double-blind placebo-controlled trial

Background and PurposeTo investigate the effect of topical non-invasive physical plasma (NIPP), a volatile mix generated out of ambient air, on prevention of acute radiation dermatitis (RD) during and after whole-breast irradiation (WBI). Materials and MethodsLateral and medial breast halves were randomised within each patient to receive either 120 s of NIPP or sham treatment daily during WBI. Standard skin care with urea lotion was applied to the whole breast. Blinded acute skin toxicity was assessed weekly for each breast half separately and included clinician- (CTCAE) and patient-reported (modified RISRAS), and objective (spectrophotometry) assessments. As an additional external control, a comparable standard of care (SoC) patient collective from a previous prospective trial was used. ResultsSixty-four patients were included. There were no significant differences between breast halves. Post-hoc comparison with a similar SoC control collective revealed OR = 0.28 (95% CI 0.11–0.76; p = 0.014) for grade ≥ 2 RD upon WBI completion, along with less hyperpigmentation (p < 0.001), oedema (p = 0.020), dry (p < 0.001) and moist desquamation (p = 0.017), pain, itching, and burning (p < 0.001 for each). Tolerability of NIPP was excellent and side effects were not observed. ConclusionEven though there were no differences between intrapatient-randomised breast halves, the overall incidence and severity of acute radiation-induced skin toxicity were considerably lower when compared to a prospectively collected SoC cohort. Our data suggest the potential benefit of NIPP in RD prevention. A randomised trial with a physical control group is warranted to confirm these promising results (DRKS00026225).

Surface Dose and Skin Toxicity Analysis in Breast Cancer Radiotherapy after Conserving Surgery with Five Treatment Modalities

The present study aimed to evaluate surface dose and skin toxicity in breast cancer after breast-conserving surgery with five treatment modalities: flattening filter mode of intensity modulated radiation therapy (IMRT-FF,6MV), flattening filter-free mode of intensity modulated radiation therapy (IMRT-FFF,6MV), direct mode of TOMO (TOMO-direct, FFF, 6MV), helical mode of TOMO (TOMO-helical, FFF, 6MV), intensity modulated proton therapy (IMPT, spot scanning). Ten patients with breast cancer treated at our institution after breast-conserving surgery were randomly selected for this study. Five plans were designed for each patient with the same target coverage and the prescription of 50Gy/25f, IMRT-6FF, IMRT-6FFF, TOMO-direct, TOMO-helical, and IMPT. Based on CT datasets, IMRT-6FFF, TOMO-direct, TOMO-helical, and IMPT were compared to IMRT-6FF with skin dose and skin toxicity. Among the five plannings, the angles of the IMRT-6FF vs. IMRT-6FFF and TOMO-direct were the same. We extracted the relative complement in the Body of its 3Derosion defined by a spherical structuring element of radius r = 3 mm and r = 5mm (skin3 and skin5). To calculate the relative Dose-surface histograms (DSH), we used the surface of patients receiving at least 5Gy to delimit the breast region's skin area and normalize the absolute DSH. Skin dose were assessed with V5Gy, V10Gy, V15Gy, V20Gy, V25Gy, V30Gy, V40Gy, V45Gy, V50Gy of the structure of skin3 and skin5. The published NTCP LKB (normal tissue complication probability, Lyman-Kutcher-Burman) model (TD50 = 39 Gy,m = 0.14,n = 0.38) was employed to evaluate severe acute radiation-induced skin toxicity. There was no statistically significant difference between the structure of skin3 and skin5 between IMRT-6FF and IMRT-6FFF. For the same PTV coverage, the TOMO-helical plans had significantly higher surface dose in terms of V5Gy, V10Gy, and V15Gy than the IMRT plans (p <0.005). For structure of skin3, mean V30Gy, V35Gy, V40Gy, V45Gy, V50Gy were (64.0%,65.8%,79.0%,70.0%,64.6%), (51.3%,55.4%,74.3%,61.7%,59.5%), (32.4%,36.6%,65.2%,53.0%,53.0%), (13.7%,14.1%,45.8%,35.7%,37.6%), (1.6%/0.8%/12.2%,6.6%,1.0%). For the structure of skin5, mean V30Gy, V35Gy, V40Gy, V45Gy, V50Gy were (66.1%,67.1%,76.4%,68.6%,62.6%), (57.9%,60.4%,72.3%,61.2%,57.7%), (45.5%,48.4%,65.2%,53.9%,51.8%), (28.4%,30.8%,51.2%,42.0%,40.0%), (6.8%,6.3%,22.6%,17.9%,8.0%).Compared to IMRT-6FF, TOMO-direct and TOMO-helical had higher surface dose(p<0.05). For IMRT-6FF/IMRT-6FFF/TOMO-direct/TOMO-helical/IMPT, the mean ratio of severe acute radiational skin toxicity were14.7%,17.1%,46.3%,29.4%, and 24.1%. For TOMO-direct and TOMO-helical planning, the skin dose and toxicity ratio were higher than IMRT-6FF. Compared to IMRT-6FF, V45Gy of skin3 and V40Gy of skin5 of IMPT were higher than IMRT-6FF, while the skin toxicity ratio was no significant difference.

Radiobiological modelling of radiation-induced acute skin toxicity (dermatitis): A single institutional study of breast carcinoma.

The purpose of the study was to estimate the fitting parameters of the sigmoidal dose response (SDR) curve of radiation-induced acute dermatitis in breast cancer patients treated with intensity-modulated radiation therapy for calculation of normal tissue complication probability (NTCP). Twenty-five breast cancer patients were enrolled to model the SDR curve for acute dermatitis. The acute radiation-induced (ARI) dermatitis toxicity was assessed weekly for all the patients, and their scores were determined using the common terminology criterion adverse events version 5.0. The radiobiological parameters n, m, TD50, and γ50 were derived using the fitted SDR curve obtained from breast cancer Patient's clinical data. ARI dermatitis toxicity in carcinoma of breast patients was calculated for the end point of acute dermatitis. The n, m, TD50, and γ50 parameters from the SDR curve of Grade-1 dermatitis are found to be 0.03, 0.04, 28.65 ± 1.43 (confidence interval [CI] 95%) and 1.02 and for Grade-2 dermatitis are found to be 0.026, 0.028, 38.65 ± 1.93 (CI. 95%) and 1.01 respectively. This research presents the fitting parameters for NTCP calculation of Grade-1 and Grade-2 acute radiation-induced skin toxicity in breast cancer for the dermatitis end point. The presented nomograms of volume versus complication probability and dose versus complication probability assist radiation oncologists in establishing the limiting dose to reduce acute toxicities for different grades of acute dermatitis in breast cancer patients.

Acute radiation-induced skin toxicity in hypofractionated vs. conventional whole-breast irradiation: An objective, randomized multicenter assessment using spectrophotometry

PurposeRadiation dermatitis represents one of the most frequent side effects in breast cancer patients undergoing adjuvant whole-breast irradiation (WBI). Whether hypofractionated WBI induces comparable or less acute radiation-induced skin reactions than conventional WBI is still not fully clarified, as randomized evidence and objective assessments are limited. The aim of this study was to objectively determine frequency and severity of acute radiation-induced skin reactions during hypofractionated vs. conventionally fractionated adjuvant WBI. MethodsIn this randomized multicenter study, a total of 140 breast cancer patients underwent either hypofractionated or conventional WBI following breast-preserving surgery. Maximum radiation dermatitis severity was assessed at completion and during follow-up by physician-assessed CTCAE v4.03 and the patient-reported RISRAS scale. Additionally, photospectrometric skin readings were performed to objectify skin color differences between both treatment arms. ResultsRadiation dermatitis severity was significantly lower in patients receiving hypofractionation compared with conventional fractionation (mean 1.05 vs. 1.43, p = .024). Grade 0 radiation dermatitis occurred in 21.43% vs. 4.28%, grade ≥2 in 27.14% vs. 42.91% and grade ≥3 in 0% vs. 4.34% of patients following hypofractionated and conventional WBI, respectively. Objective photospectrometric measurements (n = 4200) showed both decreased erythema severity (p = .008) and hyperpigmentation (p = .002) in the hypofractionation arm. Patients allocated to hypofractionated WBI also reported less pain (p = .006), less hyperpigmentation (p = <0.001) and less limitations of day-to-day activities (p = <0.001). ConclusionPhysician and patient-assessed toxicity scorings as well as objective photospectrometric skin measurements revealed that hypofractionated WBI yielded lower rates and severity of acute radiation-induced skin toxicity.

Topical atorvastatin 1% for prevention of skin toxicity in patients receiving radiation therapy for breast cancer: a randomized, double-blind, placebo-controlled trial.

The purpose of this randomized, placebo-controlled, double-blind study was to investigate the preventive effect of topical administration of atorvastatin (ATV) on the acute radiation-induced skin toxicity in patients with breast cancer. Seventy breast cancer patients were randomly assigned to use topical ATV 1% or placebo gels during radiotherapy twice daily. Radiation-induced dermatitis was classified according to the radiation therapy oncology group (RTOG) criteria, as well as pain and itching were scored according to VAS (visual analogue scale) for 6weeks of treatment. Topical administration of ATV gel during radiotherapy reduced significantly radiation-induced breast swelling, itching, and pain in breast cancer patients by factors of 1.8, 1.7, and 1.5, respectively. ATV reduced the redness caused by radiotherapy in patients as compared with placebo; however, this difference was statistically not significant. ATV was able to reduce significantly itching, breast edema, and pain in patients during radiotherapy.

Model-based approach for quantitative estimates of skin, heart, and lung toxicity risk for left-side photon and proton irradiation after breast-conserving surgery

Background: Proton beam therapy represents a promising modality for left-side breast cancer (BC) treatment, but concerns have been raised about skin toxicity and poor cosmesis. The aim of this study is to apply skin normal tissue complication probability (NTCP) model for intensity modulated proton therapy (IMPT) optimization in left-side BC.Material and methods: Ten left-side BC patients undergoing photon irradiation after breast-conserving surgery were randomly selected from our clinical database. Intensity modulated photon (IMRT) and IMPT plans were calculated with iso-tumor-coverage criteria and according to RTOG 1005 guidelines. Proton plans were computed with and without skin optimization. Published NTCP models were employed to estimate the risk of different toxicity endpoints for skin, lung, heart and its substructures.Results: Acute skin NTCP evaluation suggests a lower toxicity level with IMPT compared to IMRT when the skin is included in proton optimization strategy (0.1% versus 1.7%, p < 0.001). Dosimetric results show that, with the same level of tumor coverage, IMPT attains significant heart and lung dose sparing compared with IMRT. By NTCP model-based analysis, an overall reduction in the cardiopulmonary toxicity risk prediction can be observed for all IMPT compared to IMRT plans: the relative risk reduction from protons varies between 0.1 and 0.7 depending on the considered toxicity endpoint.Conclusions: Our analysis suggests that IMPT might be safely applied without increasing the risk of severe acute radiation induced skin toxicity. The quantitative risk estimates also support the potential clinical benefits of IMPT for left-side BC irradiation due to lower risk of cardiac and pulmonary morbidity. The applied approach might be relevant on the long term for the setup of cost-effectiveness evaluation strategies based on NTCP predictions.

Dose-surface analysis for prediction of severe acute radio-induced skin toxicity in breast cancer patients

Background: Severe acute radiation-induced skin toxicity (RIST) after breast irradiation is a side effect impacting the quality of life in breast cancer (BC) patients. The aim of the present study was to develop normal tissue complication probability (NTCP) models of severe acute RIST in BC patients.Patients and methods: We evaluated 140 consecutive BC patients undergoing conventional three-dimensional conformal radiotherapy (3D-CRT) after breast conserving surgery in a prospective study assessing acute RIST. The acute RIST was classified according to the RTOG scoring system. Dose-surface histograms (DSHs) of the body structure in the breast region were extracted as representative of skin irradiation. Patient, disease, and treatment-related characteristics were analyzed along with DSHs. NTCP modeling by Lyman-Kutcher-Burman (LKB) and by multivariate logistic regression using bootstrap resampling techniques was performed. Models were evaluated by Spearman’s Rs coefficient and ROC area.Results: By the end of radiotherapy, 139 (99%) patients developed any degree of acute RIST. G3 RIST was found in 11 of 140 (8%) patients. Mild-moderate (G1-G2) RIST was still present at 40 days after treatment in six (4%) patients. Using DSHs for LKB modeling of acute RIST severity (RTOG G3 vs. G0-2), parameter estimates were TD50=39 Gy, n=0.38 and m=0.14 [Rs = 0.25, area under the curve (AUC) = 0.77, p = 0.003]. On multivariate analysis, the most predictive model of acute RIST severity was a two-variable model including the skin receiving ≥30 Gy (S30) and psoriasis [Rs = 0.32, AUC = 0.84, p < 0.001].Conclusions: Using body DSH as representative of skin dose, the LKB n parameter was consistent with a surface effect for the skin. A good prediction performance was obtained using a data-driven multivariate model including S30 and a pre-existing skin disease (psoriasis) as a clinical factor.

The Impact of Serum IL-8 Level on Acute Radiation-Induced Skin Toxicity in a Prospective Trial Comparing Concomitant or Sequential Anastrozole With Postoperative Radiation Therapy in Postmenopausal Women With Receptor-Positive Breast Cancer

To compare acute skin toxicity in a prospective trial comparing concurrent or sequential anastrozole with radiation therapy in postmenopausal hormone receptor-positive breast cancer patients, and to analyze the impact of serum TGF-β 1 and IL-8 level on radiation-induced skin toxicity. From January 2, 2011 to June 20, 2012, 80 patients were enrolled in this prospective trial. Patients were randomized as concurrent group (n = 40) in which hormonal therapy with anastrozole 1mg per day combined concurrently with radiation therapy, and sequential group (n = 40) in which hormonal therapy with anastrozole were followed after completion of radiation therapy. Both groups were balanced in age, surgical types, and TN staging. Treatment outcomes, acute toxicity and serum TGF-β 1 and IL-8 levels (before and 4 weeks after the start of radiation therapy) were followed up and analyzed. The median age of the 80 patients was 58 yrs (49∼72 yrs). The percentage of stage I, II and III was 12.5%, 22.5% and 65% in the concurrent group and 12.5%, 37.5% and 50% in the sequential group, respectively. The median follow-up time was 24 months (12∼34 months). Five patients in the concurrent group and seven patients in the sequential group developed grade 2 or worse acute skin-related toxicity, the difference between two groups was not statistical significant (P > 0.05). The incidence of hematologic toxicity of two groups was no statistically significant difference (P > 0.05). There was no symptomatic radiation pneumonitis in two groups. The overall survival was 100% in both groups, the difference of metastasis-free survival between two groups was not statistically significant (P = 0.653). Both serum TGF-β 1 and IL-8 levels between two groups were not significantly different (P > 0.05). However, in the entire group, patients developing grade 2 or worse acute skin toxicity had higher serum levels of IL-8 at the 4th week after the start of radiation therapy compared to those with grade 1 skin toxicity only (P = 0.008). The sequence of adjuvant anastrozole with post-operative radiation therapy did not seem to impact the acute radiation-induced toxicity, nor did it appear to influence the therapeutic outcomes with early follow-up. Neither serum TGF-β 1 nor IL-8 level in the course of radiation therapy was influenced by the sequence of anastrozole with radiation therapy. Higher lever of serum IL-8 in the course of radiation therapy might be associated with more severe acute radiation-induced skin toxicity. Further follow-up is needed to identify the impact of serum IL-8 on late radiation toxicity.

Phase 1 Dose Escalation Trial Using Stereotactic Body Radiation Therapy (SBRT) for Partial Breast Irradiation (PBI)

analyze the impact of serum TGF-b 1 and IL-8 level on radiation-induced skin toxicity. Materials/Methods: From January 2, 2011 to June 20, 2012, 80 patients were enrolled in this prospective trial. Patients were randomized as concurrent group (n Z 40) in which hormonal therapy with anastrozole 1mg per day combined concurrently with radiation therapy, and sequential group (n Z 40) in which hormonal therapy with anastrozole were followed after completion of radiation therapy. Both groups were balanced in age, surgical types, and TN staging. Treatment outcomes, acute toxicity and serum TGF-b 1 and IL-8 levels (before and 4 weeks after the start of radiation therapy) were followed up and analyzed. Results: The median age of the 80 patients was 58 yrs (49w72 yrs). The percentage of stage I, II and III was 12.5%, 22.5% and 65% in the concurrent group and 12.5%, 37.5% and 50% in the sequential group, respectively. The median follow-up time was 24 months (12w34 months). Five patients in the concurrent group and seven patients in the sequential group developed grade 2 or worse acute skin-related toxicity, the difference between two groups was not statistical significant (P > 0.05). The incidence of hematologic toxicity of two groups was no statistically significant difference (P > 0.05). There was no symptomatic radiation pneumonitis in two groups. The overall survival was 100% in both groups, the difference of metastasis-free survival between two groups was not statistically significant (P Z 0.653). Both serum TGF-b 1 and IL-8 levels between two groups were not significantly different (P > 0.05). However, in the entire group, patients developing grade 2 or worse acute skin toxicity had higher serum levels of IL-8 at the 4 week after the start of radiation therapy compared to those with grade 1 skin toxicity only (P Z 0.008). Conclusions: The sequence of adjuvant anastrozole with post-operative radiation therapy did not seem to impact the acute radiation-induced toxicity, nor did it appear to influence the therapeutic outcomes with early follow-up. Neither serum TGF-b 1 nor IL-8 level in the course of radiation therapy was influenced by the sequence of anastrozole with radiation therapy. Higher lever of serum IL-8 in the course of radiation therapy might be associated with more severe acute radiation-induced skin toxicity. Further follow-up is needed to identify the impact of serum IL-8 on late radiation toxicity. Author Disclosure: Q. Zhang: None. X. Yu: None. X. Mei: None. L. Cao: None. X. Guo: None. J. Chen: None.

Prophylaxis and management of acute radiation-induced skin toxicity: a survey of practice across Europe and the USA.

Radiation-induced toxicity is a common adverse side effect of radiation therapy. Previous studies have demonstrated a lack of evidence to support common skincare advice for radiotherapy patients. The aim of the current study was to investigate the management of radiation-induced skin toxicity across Europe and the USA. Where previous surveys have focused on national practice or treatment of specific sites, the current study aimed to gain a broader representation of skincare practice. An anonymous online survey investigating various aspects of radiotherapy skincare management was distributed to departments across Europe and the USA (n = 181/737 responded i.e. 25%). The UK was excluded as a similar survey was carried out in 2011. The results highlight the lack of consistency in both the prevention and management of radiation-induced skin toxicity. Recommended products are often not based on evidence-based practice. Examples include the continued use of aqueous cream and gentian violet, as well as the recommendations on washing restrictions during treatment. To our knowledge, this is the most extensive survey to date on the current management of radiation-induced skin toxicity. This study highlights significant disparities between clinical practice and research-based evidence published in recent systematic reviews and guidelines. Ongoing large prospective randomised trials are urgently needed.

Adjuvant chemotherapy and acute toxicity in hypofractionated radiotherapy for early breast cancer.

To evaluate the effect of chemotherapy to the acute toxicity of a hypofractionated radiotherapy (HFRT) schedule for breast cancer. We retrospectively analyzed 116 breast cancer patients with T1, 2N0Mx. The patients received 3-D conformal radiotherapy with a total physical dose of 50.54 Gy or 53.2 Gy in 19 or 20 fractions according to stage, over 23-24 d. The last three to four fractions were delivered as a sequential tumor boost. All patients were monitored for acute skin toxicity according to the European Organization for Research and Treatment of Cancer/Radiation Therapy Oncology Group criteria. The maximum monitored value was taken as the final grading score. Multivariate analysis was performed for the contribution of age, chemotherapy and 19 vs 20 fractions to the radiation acute skin toxicity. The acute radiation induced skin toxicity was as following: grade I 27.6%, grade II 7.8% and grade III 2.6%. No significant correlation was noted between toxicity grading and chemotherapy (P = 0.154, χ(2) test). The mean values of acute toxicity score in terms of chemotherapy or not, were 0.64 and 0.46 respectively (P = 0.109, Mann Whitney test). No significant correlation was also noted between acute skin toxicity and radiotherapy fractions (P = 0.47, χ(2) test). According to univariate analysis, only chemotherapy contributed significantly to the development of acute skin toxicity but with a critical value of P = 0.05. However, in multivariate analysis, chemotherapy lost its statistical significance. None of the patients during the 2-years of follow-up presented any locoregional relapse. There is no clear evidence that chemotherapy has an impact to acute skin toxicity after an HFRT schedule. A randomized trial is needed for definite conclusions.

Acute Radiation-Induced Skin Toxicity in Breast Intensity Modulated Radiation Therapy (IMRT): A Dosimetric Analysis

Acute Radiation-Induced Skin Toxicity in Breast Intensity Modulated Radiation Therapy (IMRT): A Dosimetric Analysis

Perceived stress to predict for acute radiation-induced skin toxicity: The mind-body connection.

62 Background: Previous studies have reported that breast cancer patients with high stress levels at diagnosis develop more frequent and severe side effects of chemotherapy treatment. However, the relationship between stress and radiotherapy (RT) related treatment toxicity has not been evaluated. We investigated whether baseline stress is associated with worse acute skin toxicity in women undergoing breast RT. Methods: Between March 2010 and April 2013, 80 post-lumpectomy breast cancer patients were enrolled on a prospective study prior to undergoing definitive whole breast RT (50 Gy plus a 10 Gy boost). Prior to RT (baseline), at week 6 of RT (T2), and 6 weeks post RT (T3), subjects completed the Perceived Stress Scale (PSS) and underwent objective ultrasound measurements of epidermal thickness over the lumpectomy cavity and in all four quadrants of the treated breast. A skin thickness ratio (STRA) was generated by normalizing for measurements taken of the untreated breast. RT-induced skin toxicity was assessed by measuring the change in STRA from baseline to T2 and T3. Results: Mean STRA increased by 23% (SD 27%) and 33% (SD 25%) from baseline to T2 and T3, respectively. Univariate analysis revealed PSS score at baseline (p=.04), body mass index (p=.03), maximum RT dose (Dmax) (p=.02) and whole breast volume (p&lt;.001) were significantly associated with increased changes in STRA during RT. Depression, fatigue, race, chemotherapy, patient age, and tumor stage were not associated with changes in STRA. On multivariate analysis, PSS (p=.05), breast volume (p=.004), and Caucasian race (p=.04) were associated with greater acute changes in STRA from baseline to T2. Breast volume (p=.01), but not PSS, predicted for greater changes in STRA 6 weeks after RT was completed. Conclusions: In women with breast cancer, a high level of perceived stress prior to RT is associated with more severe acute skin toxicity during RT but not after RT is completed. Strategies to reduce stress prior to RT may improve tolerance of treatment.

The effects of tea extracts on proinflammatory signaling

BackgroundSkin toxicity is a common side effect of radiotherapy for solid tumors. Its management can cause treatment gaps and thus can impair cancer treatment. At present, in many countries no standard recommendation for treatment of skin during radiotherapy exists. In this study, we explored the effect of topically-applied tea extracts on the duration of radiation-induced skin toxicity. We investigated the underlying molecular mechanisms and compared effects of tea extracts with the effects of epigallocatechin-gallate, the proposed most-active moiety of green tea.MethodsData from 60 patients with cancer of the head and neck or pelvic region topically treated with green or black tea extracts were analyzed retrospectively. Tea extracts were compared for their ability to modulate IL-1β, IL-6, IL-8, TNFα and PGE2 release from human monocytes. Effects of tea extracts on 26S proteasome function were assessed. NF-κB activity was monitored by EMSAs. Viability and radiation response of macrophages after exposure to tea extracts was measured by MTT assays.ResultsTea extracts supported the restitution of skin integrity. Tea extracts inhibited proteasome function and suppressed cytokine release. NF-κB activity was altered by tea extracts in a complex, caspase-dependent manner, which differed from the effects of epigallocatechin-gallate. Additionally, both tea extracts, as well as epigallocatechin-gallate, slightly protected macrophages from ionizing radiationConclusionTea extracts are an efficient, broadly available treatment option for patients suffering from acute radiation-induced skin toxicity. The molecular mechanisms underlying the beneficial effects are complex, and most likely not exclusively dependent on effects of tea polyphenols such as epigallocatechin-gallate.