Late Skin Reactions Research Articles

Abstract PO1-22-03: Radiation Toxicity and Treatment Outcomes in Breast Cancer Patients with ATM Pathogenic and VUS Mutations: Implications for Personalized Therapy

Abstract Introduction: Previous studies have shown that ATM (ataxia-telangiectasia mutated) mutations may be associated with increased radiation sensitivity and altered treatment response. However, there is a limited understanding of the clinical implications and optimal management strategies for breast cancer patients with ATM mutations receiving radiotherapy (RT). The aim of our study is to assess the impact of ATM mutations on radiation response and treatment outcomes in breast cancer patients undergoing RT. Material and Methods: A total of 79 female patients diagnosed with breast cancer were included in the study, with 31 (39.3%) having pathogenic (P) and likely pathogenic (LP) variants (all of the variants were heterozygous) and 48 (60.8%) having VUS variants detected through whole ATM gene sequencing screening for patients in accordance with NCCN clinical practice guideline. Statistical analysis, including descriptive, graphical, and inferential methods, such as the Kolmogorov-Smirnov test, Mann-Whitney U Test, and Chi-square tests, was conducted using SPSS version 25.0 to evaluate the normal distribution of continuous variable scores and perform quantitative and qualitative comparisons between groups at a 95% confidence level (p < 0.05). Results: The median age of the patients was 44 years (range: 24-74), with 75% of them being 50 years old or younger .The rate of breast cancer in patients with VUS variants was significantly higher in those aged 50 and below compared to those with P/LP variants (83% vs. 61%, p=0.028). There was no statistically significant difference in clinical stage, tumour histological type, and molecular subtype classification based on ATM gene variant type (P/LP vs. VUS) among the patients (p>0.05), but the rate of high tumour grade was significantly higher in the VUS variant group (65% vs. 40%, p=0.034). The rate of patients who received RT was 87%, with 26 patients receiving radiation to the breast or chest wall and 43 patients receiving additional regional lymph node irradiation. There were no statistically significant differences in surgical and systemic treatment types and RT dose based on ATM gene variant type (P/LP vs. VUS) (p>0.05). Among the patients who received RT, 33 (48%) experienced early-stage skin reactions, and 15 (22%) experienced late-stage skin reactions according to Common Terminology Criteria for Adverse Events (CTCAE) v5. No Grade 3, 4 and 5 early and late toxicity were observed . The rate of early (83% vs. 23%; p< 0.001) and late (35% vs. 13%; p=0.029) skin reactions was significantly higher in the P/LP variant group compared to the VUS variant group. Grade I lymphedema was observed in 2 (2.5%) patients, 1 (3.2%) in the P/LP group and 1 (2.1%) in the VUS group (p>0.05). Among the 23 patients who underwent breast reconstruction, 1 (4%) had implant revision and 1 (4%) experienced implant loss, both of which were observed in the pathogenic variant group (p>0.05). Conclusion: Limited clinical data exists on RT toxicity in breast cancer patients with ATM gene mutations, and clear guidelines for decision-making are lacking. Our study revealed higher rates of acute and chronic skin reactions in the P/LP variant group, highlighting the need for further investigation into the impact of these variants on treatment outcomes and patient management. However, it is crucial to manage these reactions effectively and not allow them to hinder treatment. Additional research and interventions are warranted to better understand and address these reactions, aiming to enhance the overall treatment experience and outcomes for patients with ATM gene mutations. Citation Format: Evrim Tezcanli, Seda Eroz, Ugur Ozbek, Ahmet Yesilyurt, CIHAN URAS, Nuran Bese. Radiation Toxicity and Treatment Outcomes in Breast Cancer Patients with ATM Pathogenic and VUS Mutations: Implications for Personalized Therapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-22-03.

Immune response profiles from humans experimentally exposed to Phlebotomus duboscqi bites.

Cutaneous leishmaniasis is a neglected vector-borne parasitic disease prevalent in 92 countries with approximately one million new infections annually. Interactions between vector saliva and the human host alter the response to infection and outcome of disease. To characterize the human immunological responses developed against saliva of Phlebotomus duboscqi, a Leishmania major (L. major) vector, we repeatedly exposed the arms of 14 healthy U.S volunteers to uninfected P. duboscqi bites. Blood was collected a week after each exposure and used to assess total IgG antibodies against the proteins of P. duboscqi salivary gland homogenate (SGH) and the levels of IFN-gamma and IL-10 from peripheral blood mononuclear cells (PBMCs) stimulated with SGH or recombinant sand fly proteins. We analyzed skin punch biopsies of the human volunteer arms from the insect bite site and control skin site after multiple P. duboscqi exposures (four volunteers) using immunohistochemical staining. A variety of immediate insect bite skin reactions were observed. Late skin reactions to insect bites were characterized by macular hyperpigmentation and/or erythematous papules. Hematoxylin and eosin staining showed moderate mononuclear skin infiltrate with eosinophils in those challenged recently (within 2 months), eosinophils were not seen in biopsies with recall challenge (6 month post bites). An increase in plasma antigen-specific IgG responses to SGH was observed over time. Western Blot results showed strong plasma reactivity to five P. duboscqi salivary proteins. Importantly, volunteers developed a cellular immunity characterized by the secretion of IFN-gamma upon PBMC stimulation with P. duboscqi SGH and recombinant antigens. Our results demonstrate that humans mounted a local and systemic immune response against P. duboscqi salivary proteins. Specifically, PduM02/SP15-like and PduM73/adenosine deaminase recombinant salivary proteins triggered a Th1 type immune response that might be considered in future development of a potential Leishmania vaccine.

Dosimetry Predictors of Late Skin Reactions after Whole Breast Radiotherapy on a Large Mono-Institutional Cohort of Patients

To develop an NTCP model predicting late skin toxicity using dosimetric parameters from the breast dermis to identify possible RT constraints on such a structure. The skin structure was defined as the 5 mm inner isotropic expansion from the outer CT body contour. It was retrospectively segmented on a large mono-Institutional cohort of early-stage breast cancer patients enrolled between 2009 and 2017 (n = 1066). Patients were treated with tangential-field RT, delivering 40 Gy in 15 fractions without a RT boost. Toxicity was reported during FU using SOMA/LENT scoring. The study endpoint was moderate-severe late toxicity consisting of Fibrosis-Atrophy-Telangiectasia-Pain (FATP G2+) developed within 42 months after RT completion. Automatic delineation of skin and DVH extraction were accomplished by scripting using the MIM_assistant software. Also, the impact of changes in the dose calculation algorithms during enrolment time was quantified. A logistic model was created by combining multifactorial variables, considering both clinical factors and the absolute skin DVH (cc). Variance Inflation Factor (VIF) was performed to reduce the multicollinearity. Repeated 5-fold cross-validation with SMOTE approach to overcome the class unbalance was applied for model feature selection. The predictive model was then developed on the entire population due to the limited G2+ events. The FATP G2+ rate was 3.8% with 40/1066 experiencing late toxicity. Among them, a 40% had already developed acute symptoms after RT completion showing a consequential effect. The multicollinearity analysis selected 27 clinical-treatment-dosimetric factors. After repeated (20 times) 5-fold cross-validation, the best-performing model included Post-Surgery Cosmetic alterations, Aromatase Inhibitors (as a protective factor), V20 Gy (50% of the prescribed dose - DVH plateau region) and V42 Gy (105% of the prescribed dose - DVH high-dose tail). Accuracy and f1-score were 0.76 and 0.58 in both training and test sets, providing good reliability for selected variables. AUC for the final model on the entire population was 0.76+/-0.04. We quantified the association between fibrosis and skin DVH when delivering 40 Gy in 15fr. The model suggested an independent role of V20 and V42 Gy and a heavy risk modulation by surgical effects and aromatase inhibitors. This last factor could interfere with adipose tissue and water-content distribution within the breast. For this purpose, a CT-based densitometry characterization of toxicity patients is ongoing.

Safety and efficacy of CT-guided radioactive iodine-125 seed implantation as a salvage treatment for recurrent head and neck cancer after two or more courses of radiotherapy

BackgroundIn the past, patients with recurrent head and neck cancer (rHNC) who had previously received a high dose of radiation and were unable to undergo surgery were mainly treated with palliative chemotherapy due to the high incidence of side effects from re-irradiation. With the development of radiotherapy technology, re-irradiation of recurrent lesions by radioactive iodine-125 seed implantation (RISI) has been proposed as a feasible therapeutic approach. This study aimed to investigate the safety and efficacy of computed tomography (CT)-guided RISI in the treatment of rHNC after two or more courses of radiotherapy, and to analyze the prognostic factors.MethodsData of 33 patients with rHNC who received CT-guided RISI after two or more courses of radiotherapy were collected and statistically analyzed. The median cumulative dose of the previous radiotherapy was 110 Gy. Short-term efficacy was assessed by Response Evaluation Criteria in Solid Tumors (version 1.1) criteria, while adverse events were evaluated by Common Terminology Criteria for Adverse Events (version 5.0) criteria.ResultsThe median gross tumor volume (GTV) was 29.5 cc, and the postoperative median dose to 90% of target volume (D90) was 136.8 Gy. For adverse reactions, enhanced pain was found in 3 (9.1%) patients, followed by grade 1 to 2 acute skin reactions in 3 (9.1%) patients, grade 2 to 3 late skin reactions in 2 (6.1%) patients, grade 1 to 2 early mucosal reactions in 4 (12.1%) patients, and mandibular osteonecrosis in 1 (3.0%) patient. Regarding the treatment efficacy, the 1- and 2-year local control (LC) rates were 47.8% and 36.4% (median LC time, 10 months), and the 1- and 2-year overall survival (OS) rates were 41.3% and 32.2% (median OS time, 8 months). The absence of adverse events was associated with better LC.ConclusionsCT-guided RISI, as a salvage therapy, demonstrated acceptable safety and efficacy in the treatment of rHNC after two or more courses of radiotherapy.Trial registrationThis study was registered at Chinese Clinical Trial Register database (Registration No. ChiCTR2200063261) in September 2, 2022.

CANTO-RT: Skin toxicities evaluation of a multicentre large prospective cohort of irradiated patients for early-stage breast cancer.

Skin damage is the most common and most important toxicity during and after radiation therapy (RT). Its assessment and understanding of the factors influencing its occurrence, is a major issue in the management of patients irradiated for an early breast cancer. CANTO is a prospective clinical cohort study of 10 150 patients with stage I-III BC treated from 2012 to 2017 in 26 cancer centres. In our study, we used CANTO-RT, a subcohort of CANTO, including 3480 patients who received RT. We are focus on specific skin toxicities: erythema, fibrosis, telangiectasia and cutaneous pigmentation. The prevalence of toxicities of interest varied over time, so at baseline for early toxicity Month (M) 0-3-6, 41.1% of patients had erythema while 24.8% of patients had fibrosis. At M12 and M36, the prevalence of erythema decreased, respectively, while fibrosis remains stable. The prevalence of telangiectasia increases from 1% to 7.1% from M0-3-6 to M36. After adjustments, we showed an association between the occurrence of skin erythema and obesity; the type of surgery; the presence of axillary dissection; the use of taxane-based CT and the 3D vs IMRT irradiation technique. Regarding fibrosis, an association is found, at M0-3-6, with age at diagnosis, obesity, tobacco and the use of boost. Only obesity and the type of surgery received by the patient remained statistically significant at M12 and M36. In our study we identified several risk factors for acute and late skin reactions. The use of a boost was mainly related to the occurrence of fibrosis while the use of IMRT-type technique decreased the occurrence of skin erythema.

Late Skin Reactions Associated with the Modern Vaccine

The infection by the SARS-CoV-2 virus and the disease generated by COVID-19 that began in 2019 in Wuhan China has had a great impact on global morbidity and mortality, which in turn led to the creation in record time of the first vaccines used in humans against coronavirus. Vaccines such as Sinovac, Janssen, AstraZeneca, Pfizer and Moderna, of which have been authorized and administered in multiple countries with really favorable results. However, late post-vaccination adverse effects have been reported in patients vaccinated especially by Moderna and Pfizer, observing a compromise at the level of the skin causing the appearance in most cases of urticaria, edema, erythema, reactivation of herpes zoster, morbilliform eruptions, among others that are undoubtedly related to the mechanisms of action of the aforementioned vaccines.

Targeted Next-Generation Sequencing for the Identification of Genetic Predictors of Radiation-Induced Late Skin Toxicity in Breast Cancer Patients: A Preliminary Study.

Normal tissue radiosensitivity is thought to be influenced by an individual’s genetic background. However, the specific genetic variants underlying the risk of late skin reactions following radiotherapy for breast cancer remain elusive. To unravel the genetic basis for radiation-induced late skin toxicity, we carried out targeted next-generation sequencing of germline DNA samples from 48 breast cancer patients with extreme late skin toxicity phenotypes, consisting of 24 cases with grade 2–3 subcutaneous fibrosis and/or grade 2–3 telangiectasia (LENT-SOMA scales) and 24 controls with grade 0 fibrosis and grade 0 telangiectasia. In this exploratory study, a total of five single-nucleotide variants (SNVs) located in three genes (TP53, ERCC2, and LIG1) reached nominal levels of statistical significance (p < 0.05). In the replication study, which consisted of an additional 45 cases and 192 controls, none of the SNVs identified by targeted NGS achieved nominal replication. Nevertheless, TP53 rs1042522 (G > C, Pro72Arg) in the replication cohort had an effect (OR per C allele: 1.52, 95%CI: 0.82–2.83, p = 0.186) in the same direction as in the exploratory cohort (OR per C allele: 4.70, 95%CI: 1.51–14.6, p = 0.007) and was found be nominally associated to the risk of radiation-induced late skin toxicity in the overall combined cohort (OR per C allele: 1.79, 95%CI: 1.06–3.02, p = 0.028). These results raise the possibility of an association between TP53 rs1042522 and risk of radiation-induced late skin toxicity in breast cancer patients; however, large replication studies are warranted for conclusive evidence.

Clinical Observation of Hypofractionated Simultaneous Integrated Boost Radiotherapy in Breast-Conserving Surgery

Comparing the skin toxicity, cosmetic effect, myelosuppression and other adverse reactions between hypofractionated simultaneous integrated boost (HF-SIB) and conventional fractionated (CF) radiotherapy for breast cancer patients after breast-conserving surgery, to evaluate the short-term efficacy and safety of HF-SIB. A total of 236 early breast cancer patients received radiotherapy after breast-conserving surgery were prospectively enrolled in this study. All patients divided into two groups according to the dose of radiotherapy. HF-SIB included 126 patients and the dose of whole-breast radiation reach to 42.56Gy in 16 fractions and simultaneously tumor bed boost to 48Gy in 16 fractions, which course of radiotherapy was 22 days. The 110 patients of CF group received whole breast radiation to 50Gy in 25 fractions and followed by tumor bed boost to 10Gy in 5 fractions, which course of radiotherapy was 40 days. The indexes such as acute skin reaction, late skin toxicity, myelosuppression, cosmetic effect and radiation pneumonia were recorded and analyzed by Rank sum test and chi-square test. After a median follow-up of 14.6 months (7-18 months), HF-SIB group have no cases of recurrence (0/126) and the survival rate was 100% (126/126). After a median follow-up of 33.4 month (25-45 months) in CF group, the recurrence rate was 3.6% (4/110) and the 2-year survival rate was 100% (110/ 110). The incidence of acute skin reaction of grade 1, grade 2 and grade 3 in HF-SIB group was 52.7%, 15.8% and 2.6%, respectively and that in CF group is 50%, 25% and 5%. The incidence of late skin reaction in grade 1 and grade 2 was 25% and 5.2% in HF-SIB group and 20% and 3.3% in CF group respectively. The excellent and good rate of cosmetic effect of HF-SIB group and CF group at an interval of six months after radiotherapy was 97.4% vs 90%, and that of one year after radiotherapy was 93.1% vs 86.7%. The incidence of grade 1 and 2 radiation pneumonia in the HF-SIB group was 6.6% and 3.9%, while that in the CF group was 5.0% and 1.7%, respectively. There was no statistical difference in skin toxicity, cosmetic effect and radiation pneumonia between the two groups. In terms of myelosuppression, the HF-SIB group was better than the CF group. There was no significant difference in age, chemotherapy, fractionated dose and posture on skin reaction and cosmetic effect, but there was a correlation between the volume of breast and the incidence of skin reaction. The evaluation of clinic effect in HF-SIB group was not inferior to that in CF group, and there was no significant difference between HF-SIB group and CF group in terms of skin reaction and cosmetic effect. The degree of myelosuppression in HF-SIB group was lower than that in CF group. HF-SIB group can shorten the treatment time and reduce medical expenses. Moreover, the short-term effect was similar to that of CF group, so it can be used as one of the radiotherapy modes for early breast cancer patients after breast-conserving surgery.

Active implications for dermatologists in 'SARS-CoV-2 ERA': Personal experience and review of literature.

Linked articles: COVID‐19 SPECIAL FORUM. J Eur Acad Dermatol Venereol 2020; 34: e346–e380.

Impact of ATM rs1801516 on late skin reactions of radiotherapy for breast cancer: Evidences from a cohort study and a trial sequential meta-analysis.

The relationship between the ataxia-telangiectasia mutated (ATM) rs1801516 gene polymorphism and risk of radiation-induced late skin side effects remains a highly debated issue. In the present study, we assessed the role of ATM rs1801516 as risk factor for radiation-induced fibrosis and telangiectasia, using the LENT-SOMA scoring scale in 285 breast cancer patients who received radiotherapy after breast conserving surgery. A systematic review with meta-analysis and trial sequential analysis (TSA) was then conducted to assess reliability of the accumulated evidence in breast cancer patients. In our cohort study, no association was found between ATM rs1801516 and grade ≥ 2 telangiectasia (GA+AA vs GG, HRadjusted: 0.699; 95%CI: 0.273–1.792, P = 0.459) or grade ≥ 2 fibrosis (GA+AA vs GG, HRadjusted: 1.175; 95%CI: 0.641–2.154, P = 0.604). Twelve independent cohorts of breast cancer patients were identified through the systematic review, of which 11 and 9 cohorts focused respectively on the association with radiation-induced fibrosis and radiation-induced telangiectasia. Pooled analyses of 10 (n = 2928 patients) and 12 (n = 2783) cohorts revealed, respectively, no association of ATM rs1801516 with radiation-induced telangiectasia (OR: 1.14; 95%CI: 0.88–1.48, P = 0.316) and a significant correlation with radiation-induced fibrosis (OR: 1.23; 95%CI: 1.00–1.51, P = 0.049), which however did not remain significant after TSA adjustment (TSA-adjusted 95%CI: 0.85–1.78). These results do not support an impact of ATM rs1801516 on late skin reactions of radiotherapy for breast cancer, nevertheless further large studies are still required for conclusive evidences.

The efficacy and safety of hypofractionated radiotherapy with concurrent anti-HER-2 therapy following breast-conserving therapy for breast cancer.

The purpose of this study wasto report rates and severities of radiation-related toxicities and analyze disease-control outcomes in patients who have received hypofractionated whole breast radiation (HF) with concurrent trastuzumab with or without pertuzumab. We conducted a retrospective cohort study including women with stage I-III HER2-positive breast cancer who received HF at the University of Pennsylvania between 1/2005 and 5/2018 with concurrent trastuzumab with or without pertuzumab. Fractionation was 266cGy daily to a total dose of 4256cGy with or without a sequential tumor bed boost. Eighty patients were included in the cohort with a median follow-up time of 21.44months. There was one grade 3 acute toxicity (fatigue) and no grade 3 late toxicities. 91% and 25% of patients experienced grade 1-2 acute and late skin reactions, respectively. An excellent-good cosmetic outcome was reported by 74% and 95% of patients and physicians, respectively. No patients experienced tumor recurrences, and the only death was due to a secondary cause.These results suggest that hypofractionated whole breast radiation administered concurrently with anti-HER-2 therapies is efficacious and has acceptable toxicity in early-stage breast cancer patients treated with lumpectomy. Continued follow-up is warranted to evaluate long-term outcomes.

P04 - The Efficacy and Safety of Hypofractionated Radiotherapy with Concurrent anti-HER-2 Therapy Following Breast-conserving Therapy for Breast Cancer

The purpose of this study was to report rates and severities of radiation-related toxicities and analyze disease-control outcomes in patients who have received hypofractionated whole breast radiation (HF) with concurrent trastuzumab with or without pertuzumab. We conducted a retrospective cohort study including women with stage I-III HER2-positive breast cancer who received HF at the University of Pennsylvania between 1/2005 and 5/2018 with concurrent trastuzumab with or without pertuzumab. Fractionation was 266 cGy daily to a total dose of 4256 cGy with or without a sequential tumor bed boost. Eighty patients were included in the cohort with a median follow-up time of 21.44 months. There was one grade 3 acute toxicity (fatigue) and no grade 3 late toxicities. 91% and 25% of patients experienced grade 1-2 acute and late skin reactions, respectively. An excellent-good cosmetic outcome was reported by 74% and 95% of patients and physicians, respectively. No patients experienced tumor recurrences, and the only death was due to a secondary cause. These results suggest that hypofractionated whole breast radiation administered concurrently with anti-HER-2 therapies is efficacious and has acceptable toxicity in early-stage breast cancer patients treated with lumpectomy. Continued follow-up is warranted to evaluate long-term outcomes.

Volumetric Modulated Arc Therapy followed by bilateral mastectomy for treating synchronous cancer and sarcoma — a rare case report

Purpose. Bilateral postmastectomy irradiation (BPMI) poses a challenge to radiotherapists. The difficulty lies whenever targets are large, irregular and lying at different depths. When breathing movements occur it is very hard to obtain homogenous dosing on such targets and also to not exceed those doses acceptable for at-risk organs, particularly the lungs and heart. The presented study is an example of using a single isocenter Volumetric Modulated Arc Therapy (VMAT) technique for a BPMI case. Materials and methods. We report the case of a 66-year-old woman with simultaneous malignant sarcoma of the right breast and an invasive ductal carcinoma of the left breast. After modified radical mastectomy of the left breast and simple mastectomy of the right breast, the patient underwent adjuvant irradiation of the bilateral chest wall and left axillary and supraclavicular nodes region. Planning Target Volumes (PTV) and organs at risk (OAR) were deline­ated on CT scans. A single isocenter VMAT plan was created. The radiotherapy consisted of 50 Gy delivered in 2 Gy per fraction to the left side and 56.5 Gy delivered in 2.25 Gy per fraction to the right side in 25 fractions, five times a week over 5 weeks. Results. The left and right CTV (Clinical Target Volume) received 90% of the prescribed dose in 100% of the CTV volume. The mean heart dose was 14.4 Gy and V25 for the heart was 8.9%. The mean lung dose was 16.6 Gy and the V20 for both lungs was 28.3%. The dose to the anterior wall area of the heart was exceeded according to established constraints, but was accepted. One session of irradiation lasted about four minutes during which the patient received 595 monitor units. The treatment was carried out without interruption and complications. The early and late skin reaction was assessed as being second grade. After one year of follow-up, the patient did not present any serious side effects or recurrence. Conclusions. Synchronous irradiation of both sides of the chest wall after bilateral mastectomy with a single isocenter VMAT technique is possible and well tolerated.

Accelerated Partial Breast Irradiation Using Multicatheter High-Dose-Rate Brachytherapy for Selected Early-Stage Breast Cancer

Accelerated Partial Breast Irradiation Using Multicatheter High-Dose-Rate Brachytherapy for Selected Early-Stage Breast Cancer

Whole-breast hypofractionated IMRT and brachytherapy boost after conservative surgery for breast cancer: Early results of a prospective non-randomised trial.

46 Background: To report early results obtained in a prospective group of patients (pts) treated with whole breast IMRT radiotherapy plus a brachytherapy boost to the tumor bed after conservative surgery, given either with hypofractionated or normofractionated radiotherapy. Methods: Between 12/2008 and 06/2014, 829 pts with &lt;4cm, N0-2 breast cancers treated with conservative surgery were assigned to enter the study. Pts were offered to be treated either with IMRT hypofrationated whole breast and lymphnode areas (if needed) radiotherapy 42.6 Gy (266cGyx16 fractions) plus a 7 Gy boost to the tumor bed, (hypofractionated group) or IMRT normofractionated 50 Gy (200cGyx25) to the whole breast and lymphatic areas (when needed) plus 16 Gy brachytherapy boost (200cGyx8 fractions) (normofractionated group). Treatment assignation was done according to the patients preference or, if none, were randomly assigned to have both groups uniformly balanced. During treatment and follow-up special attention was taken to early and late side-effects, breast fibrosis, arm lymphedema, skin reaction, patient satisfaction and local, regional and distant disease control. Results: A total of 309 pts were included in the hypofractionated group and 520 in the normofractionated group. All patients completed treatment. Pts were evaluated weekly during treatment and every 3 months for the first 2 years of follow-up and in a yearly basis after. Photographs were taken at each visit. SOMA-LENT scales were used in every visit. For quality of life EORTC QLQ-C30 plus the BR-15 module were used. No pts had adverse side-effect that required treatment ending in any group. In the hypofractionated group, there were 1 LR, 1 M1 and 1 death due to the disease. In the normofractionated group there were 12 LR, 7 M1 and 4 patients died due to the disease. Conclusions: Hypofractionated IMRT to the whole breast followed by a 1 fraction HDR breast implant was a safe and effective method of treatment for early breast cancer treated with conservative surgery, even in those patients N+ in which the supraclavicular fossa was included in the treatment fields. Pts satisfaction was greater in the hypofractionated group.

Accelerated Partial Breast Irradiation Using Multi-Catheter Brachytherapy for Selected Early-Stage Breast Cancer: Analysis of 377 Cases With 50 Months Median Follow-Up

To report the feasibility, toxicity, cosmesis, and efficacy of accelerated partial breast irradiation (APBI) using interstitial multi-catheter high-dose-rate brachytherapy for early-stage breast cancer. Between March 2004 and June 2013, 377 selected patients with stage I-II breast cancer received APBI using multi-catheter brachytherapy following breast-conserving surgery. Eligibility criteria for the patient selection were based on the indications of the American Brachytherapy Society. The prescription dose was 34 Gy in 10 fractions, 3.4 Gy per fraction, twice a day, in intervals of more than 6 hours and was delivered to the tumor bed plus a 1-2 cm margin. The median follow-up time was 50.4 months. The median age of the patients was 59 years. The median tumor size was 1.3 cm. The local control rate was 97% (eleven local recurrence was detected). No local infection was observed. Acute and late skin reactions were rare and long-term cosmetic outcome was very good to excellent. APBI with interstitial multi-catheter high-dose-rate brachytherapy is feasible in selected patients with early-stage breast cancer. Local control and cosmesis were excellent with acceptable rates of acute and late toxicities.

SKI2162, an inhibitor of the TGF-β type I receptor (ALK5), inhibits radiation-induced fibrosis in mice.

Here we demonstrated that SKI2162, a small-molecule inhibitor of the TGF-β type I receptor (ALK5), prevented radiation-induced fibrosis (RIF) in mice. SKI2162 inhibited phosphorylation of Smad and induction of RIF-related genes in vitro. In RIF a mouse model, SKI2162 reduced late skin reactions and leg-contracture without jeopardizing the acute skin reaction. Irradiation of mouse tissue increased COL1A2 mRNA levels, and topical administration of SKI2162 significantly inhibited this effect. Thus, these findings support that SKI2162 has potential value as novel RIF-protective agent, and could be candidate for clinical trials.

Improved efficacy of temoporfin photodynamic therapy in locally advanced biliary tract carcinoma: a multicenter prospective phase II study

Introduction: Photodynamic therapy using porfimer (P-PDT) is established local tumor ablative therapy in non-resectable hilar bile duct cancer (hBDC) improving palliation and survival time. Tumoricidal penetration depth is only 4 mm with P-PDT, but at least 8 mm with temoporfin PDT (T-PDT). Aim: Therefore, we investigated in a single-arm phase II study (NCT01016002; from 2005 to 2011) non-inferiority of T-PDT vs. previous P-PDT in OS, local tumor control (TTP), and adverse events (ADE). Material and Patients: Patients (n = 29) with unresectable hBDC received median 1.0 (range 1 – 4) T-PDT plus stenting and were followed up at three-month intervals. Results: OS after treatment was median 17.3 (12.6 – 22.0, 95% CI) mon for 19 patients of category M0, and 15.4 mon for all patients (M0 + M1, 11.7 – 19.1, 95% CI). Median time to local tumor progression was 6.5 months (3.6 – 9.4, 95% CI). Cholestasis improved significantly in patients with initially elevated bilirubin levels and 74% of patients with occluded segments at baseline showed local response with reopening of median 3.0 segments. A significant improvement of palliation could be achieved (median +10%, range -20% – +40%). PDT was technically successful in all cases and was generally well tolerated; there was no grade 4 toxicity and no treatment-associated mortality. Adverse events were phototoxic skin reactions (n = 9), three late phototoxic skin reactions (at T-injected vein), cholangitis (n = 4), and liver abscess (n = 1). Conclusions: T-PDT can be delivered safely to patients with biliary tract cancer and shows improved time to treatment patency and prolonged survival compared to P-PDT. It is statistically not inferior to P-PDT concerning improvement of cholestasis and palliation. It is highly tumoricidal and associated with similar rates of infectious complications, but with an elevated rate of skin phototoxicity, which could have been possibly avoided, taking specific precautions.

Partial Breast Radiation Therapy With Proton Beam: 5-Year Results With Cosmetic Outcomes

We updated our previous report of a phase 2 trial using proton beam radiation therapy to deliver partial breast irradiation (PBI) in patients with early stage breast cancer. Eligible subjects had invasive nonlobular carcinoma with a maximal dimension of 3 cm. Patients underwent partial mastectomy with negative margins; axillary lymph nodes were negative on sampling. Subjects received postoperative proton beam radiation therapy to the surgical bed. The dose delivered was 40 Gy in 10 fractions, once daily over 2 weeks. Multiple fields were treated daily, and skin-sparing techniques were used. Following treatment, patients were evaluated with clinical assessments and annual mammograms to monitor toxicity, tumor recurrence, and cosmesis. One hundred subjects were enrolled and treated. All patients completed the assigned treatment and were available for post-treatment analysis. The median follow-up was 60 months. Patients had a mean age of 63 years; 90% had ductal histology; the average tumor size was 1.3 cm. Actuarial data at 5 years included ipsilateral breast tumor recurrence-free survival of 97% (95% confidence interval: 100%-93%); disease-free survival of 94%; and overall survival of 95%. There were no cases of grade 3 or higher acute skin reactions, and late skin reactions included 7 cases of grade 1 telangiectasia. Patient- and physician-reported cosmesis was good to excellent in 90% of responses, was not changed from baseline measurements, and was well maintained throughout the entire 5-year follow-up period. Proton beam radiation therapy for PBI produced excellent ipsilateral breast recurrence-free survival with minimal toxicity. The treatment proved to be adaptable to all breast sizes and lumpectomy cavity configurations. Cosmetic results appear to be excellent and unchanged from baseline out to 5 years following treatment. Cosmetic results may be improved over those reported with photon-based techniques due to reduced breast tissue exposure with proton beam, skin-sparing techniques, and the dose fractionation schedule used in this trial.

Dramatic Increase in Oxidative Stress in Carbon-Irradiated Normal Human Skin Fibroblasts

Skin complications were recently reported after carbon-ion (C-ion) radiation therapy. Oxidative stress is considered an important pathway in the appearance of late skin reactions. We evaluated oxidative stress in normal human skin fibroblasts after carbon-ion vs. X-ray irradiation. Survival curves and radiobiological parameters were calculated. DNA damage was quantified, as were lipid peroxidation (LPO), protein carbonylation and antioxidant enzyme activities. Reduced and oxidized glutathione ratios (GSH/GSSG) were determined. Proinflammatory cytokine secretion in culture supernatants was evaluated. The relative biological effectiveness (RBE) of C-ions vs. X-rays was 4.8 at D0 (irradiation dose corresponding to a surviving fraction of 37%). Surviving fraction at 2 Gy (SF2) was 71.8% and 7.6% for X-rays and C-ions, respectively. Compared with X-rays, immediate DNA damage was increased less after C-ions, but a late increase was observed at D10% (irradiation dose corresponding to a surviving fraction of 10%). LPO products and protein carbonyls were only increased 24 hours after C-ions. After X-rays, superoxide dismutase (SOD) activity was strongly increased immediately and on day 14 at D0% (irradiation dose corresponding to a surviving fraction of around 0%), catalase activity was unchanged and glutathione peroxidase (GPx) activity was increased only on day 14. These activities were decreased after C-ions compared with X-rays. GSH/GSSG was unchanged after X-rays but was decreased immediately after C-ion irradiation before an increase from day 7. Secretion of IL-6 was increased at late times after X-ray irradiation. After C-ion irradiation, IL-6 concentration was increased on day 7 but was lower compared with X-rays at later times. C-ion effects on normal human skin fibroblasts seemed to be harmful in comparison with X-rays as they produce late DNA damage, LPO products and protein carbonyls, and as they decrease antioxidant defences. Mechanisms leading to this discrepancy between the two types of radiation should be investigated.