The impact of the new ESTRO-ACROP target volume delineation guidelines for postmastectomy radiotherapy after implant-based breast reconstruction on breast complications.

The European Society for Radiotherapy and Oncology-Advisory Committee in Radiation Oncology Practice (ESTRO-ACROP) updated a new target volume delineation guideline for postmastectomy radiotherapy (PMRT) after implant-based reconstruction. This study aimed to evaluate the impact on breast complications with the new guideline compared to the conventional guidelines. In total, 308 patients who underwent PMRT after tissue expander or permanent implant insertion from 2016 to 2021 were included; 184 received PMRT by the new ESTRO-ACROP target delineation (ESTRO-T), and 124 by conventional target delineation (CONV-T). The endpoints were major breast complications (infection, necrosis, dehiscence, capsular contracture, animation deformity, and rupture) requiring re-operation or re-hospitalization and any grade ≥2 breast complications. With a median follow-up of 36.4 months, the cumulative incidence rates of major breast complications at 1, 2, and 3 years were 6.6%, 10.3%, and 12.6% in the ESTRO-T group, and 9.7%, 15.4%, and 16.3% in the CONV-T group; it did not show a significant difference between the groups (p = 0.56). In multivariable analyses, target delineation is not associated with the major complications (sHR = 0.87; p = 0.77). There was no significant difference in any breast complications (3-year incidence, 18.9% vs. 23.3%, respectively; p = 0.56). Symptomatic RT-induced pneumonitis was developed in six (3.2%) and three (2.4%) patients, respectively. One local recurrence occurred in the ESTRO-T group, which was within the ESTRO-target volume. The new ESTRO-ACROP target volume guideline did not demonstrate significant differences in major or any breast complications, although it showed a tendency of reduced complication risks. As the dosimetric benefits of normal organs and comparable oncologic outcomes have been reported, further analyses with long-term follow-up are necessary to evaluate whether it could be connected to better clinical outcomes.

Cell Senescence-Related Pathways Are Enriched in Breast Cancer Patients With Late Toxicity After Radiotherapy and Low Radiation-Induced Lymphocyte Apoptosis.

Background: Radiation-induced late effects are a common cause of morbidity among cancer survivors. The biomarker with the best evidence as a predictive test of late reactions is the radiation-induced lymphocyte apoptosis (RILA) assay. We aimed to investigate the molecular basis underlying the distinctive RILA levels by using gene expression analysis in patients with and without late effects and in whom we had also first identified differences in RILA levels. Patients and Methods: Peripheral blood mononuclear cells of 10 patients with late severe skin complications and 10 patients without symptoms, selected from those receiving radiotherapy from 1993 to 2007, were mock-irradiated or irradiated with 8 Gy. The 48-h response was analyzed in parallel by RILA assay and gene expression profiling with Affymetrix microarrays. Irradiated and non-irradiated gene expression profiles were compared between both groups. Gene set enrichment analysis was performed to identify differentially expressed biological processes. Results: Although differentially expressed mRNAs did not reach a significant adjusted p-value between patients suffering and not suffering clinical toxicity, the enriched pathways indicated significant differences between the two groups, either in irradiated or non-irradiated cells. In basal conditions, the main differentially expressed pathways between the toxicity and non-toxicity groups were the transport of small molecules, interferon signaling, and transcription. After 8 Gy, the differences lay in pathways highly related to cell senescence like cell cycle/NF-κB, G-protein-coupled receptors, and interferon signaling. Conclusion: Patients at risk of developing late toxicity have a distinctive pathway signature driven by deregulation of immune and cell cycle pathways related to senescence, which in turn may underlie their low RILA phenotype.

Melatonin Modulation of Radiation-Induced Molecular Changes in MCF-7 Human Breast Cancer Cells.

Radiation therapy is an important component of cancer treatment scheduled for cancer patients, although it can cause numerous deleterious effects. The use of adjuvant molecules aims to limit the damage in normal surrounding tissues and enhance the effects of radiation therapy, either killing tumor cells or slowing down their growth. Melatonin, an indoleamine released by the pineal gland, behaves as a radiosensitizer in breast cancer, since it enhances the therapeutic effects of ionizing radiation and mitigates side effects on normal cells. However, the molecular mechanisms through which melatonin modulates the molecular changes triggered by radiotherapy remain mostly unknown. Here, we report that melatonin potentiated the anti-proliferative effect of radiation in MCF-7 cells. Treatment with ionizing radiation induced changes in the expression of many genes. Out of a total of 25 genes altered by radiation, melatonin potentiated changes in 13 of them, whereas the effect was reverted in another 10 cases. Among them, melatonin elevated the levels of PTEN and NME1, and decreased the levels of SNAI2, ERBB2, AKT, SERPINE1, SFN, PLAU, ATM and N3RC1. We also analyzed the expression of several microRNAs and found that melatonin enhanced the effect of radiation on the levels of miR-20a, miR-19a, miR-93, miR-20b and miR-29a. Rather surprisingly, radiation induced miR-17, miR-141 and miR-15a but melatonin treatment prior to radiation counteracted this stimulatory effect. Radiation alone enhanced the expression of the cancer suppressor miR-34a, and melatonin strongly stimulated this effect. Melatonin further enhanced the radiation-mediated inhibition of Akt. Finally, in an in vivo assay, melatonin restrained new vascularization in combination with ionizing radiation. Our results confirm that melatonin blocks many of the undesirable effects of ionizing radiation in MCF-7 cells and enhances changes that lead to optimized treatment results. This article highlights the effectiveness of melatonin as both a radiosensitizer and a radioprotector in breast cancer. Melatonin is an effective adjuvant molecule to radiotherapy, promoting anti-cancer therapeutic effects in cancer treatment. Melatonin modulates molecular pathways altered by radiation, and its use in clinic might lead to improved therapeutic outcomes by enhancing the sensitivity of cancerous cells to radiation and, in general, reversing their resistance toward currently applied therapeutic modalities.

Disability pension among gynaecological cancer survivors with or without radiation-induced survivorship syndromes.

PURPOSE: Gynaecological cancer patients treated with external radiation therapy to the pelvis may face long-lasting and long-term gastrointestinal syndromes. The aim of this study was to assess the association between such radiation-induced survivorship syndromes and disability pension among gynaecological cancer survivors treated with pelvic radiation therapy. METHODS: This prospective register study included gynaecological cancer survivors (n=247) treated during 1991-2003, alive at the time of the study, and <65 years of age. In 2006, they completed a postal questionnaire measuring patient-reported outcomes. The self-reported data were linked to the national register on disability pensions. Relative risks and risk differences with 95% confidence intervals (CIs) of being granted a disability pension were estimated using log-binomial regression. RESULTS: Gynaecological cancer survivors with gastrointestinal syndromes had a higher risk of disability pension than survivors without such syndromes. Survivors with blood discharge syndrome had a 2.0 (95% CI 1.3-3.2) times higher risk of disability pension than survivors without blood discharge syndrome. The relative risk among survivors with urgency syndrome was 1.9 (1.3-2.9) and for leakage syndrome, 2.1 (1.4-3.1). Adjusting for age did not affect our interpretation of the results. CONCLUSIONS: Gynaecological cancer survivors with a specific radiation-induced survivorship syndrome have a higher risk of disability pension than survivors without that specific syndrome. IMPLICATIONS FOR CANCER SURVIVORS: The findings highlight the need for more awareness and knowledge regarding the potential role of radiation-induced survivorship syndromes for continuing work among gynaecological cancer survivors. Work-life-related parameters should be considered during radiotherapy and rehabilitation after treatment.

Cardiologic Long-Term Follow-Up of Patients Treated With Chest Radiotherapy: When and How?

Introduction: Radiotherapy may cause valvular (VHD), pericardial, coronary artery disease (CAD), left ventricular dysfunction (LVD), arrhythmias. The risk of radiation induced heart disease (RIHD) increases over time. The current guidelines suggest a screening for RIHD every 5 years in the long-term survivors who had been treated by chest RT. Methods: We reviewed the clinical and instrumental data of 106 patients diagnosed with RIHD. In one group (Group A: 69 patients) RIHD was diagnosed in an asymptomatic phase through a screening with ECG, echocardiogram and stress test. A second group (37 patients) was seen when RIHD was symptomatic. We compared the characteristics of the two groups at the time of RT, of RIHD detection and at last follow-up. Results: Overall, 64 patients (60%) had CAD (associated to other RIHD in 18); 39 (36.7%) had LVD (isolated in 20); 24 (22.6%) had VHD (isolated in 10 cases). The interval between the last negative test and the diagnosis of moderate or severe RIHD was <5 years in 26 patients, and <4 years in 18. In group A, 63% of the patients with CAD had silent ischemia. The two groups did not differ with regard to type of tumor, cardiovascular risk factors, use of anthracycline-based chemotherapy, age at RT treatment, radiation dose and interval between RT and toxicity detection. The mean time from RT and RIHD was 16 years in group A and 15 in group B. Interventional therapy at RIHD diagnosis was more frequent in group B (54 vs. 30%, p < 0.05). At last follow-up, 27 patients had died (12 of cancer, 9 of cardiac causes, 6 of other causes); mean ejection fraction was 60% in group A and 50% in group B (p < 0.01). Patients with ejection fraction ≤ 50% were 14.5% in group A and 40% in group B (p < 0.01). Conclusions: Clinically relevant RIHD become evident at a mean interval of 16 years after RT. The most frequent clinical manifestations are CAD and LVD. RIHD diagnosis in asymptomatic patients may preserve their cardiac function with timely interventions. We suggest -after 10 years from radiotherapy- a screening every 2-3 years.

Radiotherapy and Cytokine Storm: Risk and Mechanism.

Radiotherapy (RT) shows advantages as one of the most important precise therapy strategies for cancer treatment, especially high-dose hypofractionated RT which is widely used in clinical applications due to the protection of local anatomical structure and relatively mild impairment. With the increase of single dose, ranging from 2~20 Gy, and the decrease of fractionation, the question that if there is any uniform standard of dose limits for different therapeutic regimens attracts more and more attention, and the potential adverse effects of higher dose radiation have not been elucidated. In this study, the immunological adverse responses induced by radiation, especially the cytokine storm and the underlying mechanisms such as DAMPs release, pro-inflammatory cytokine secretion and cGAS-STING pathway activation, will be elucidated, which contributes to achieving optimal hypofractionated RT regimen, improving the killing of cancer cells and avoiding the severe side effects.

Alterations of the Gut Microbiome Composition and Lipid Metabolic Profile in Radiation Enteritis.

Radiation enteritis (RE) is a common complication in cancer patients receiving radiotherapy. Although studies have shown the changes of this disease at clinical, pathological and other levels, the dynamic characteristics of local microbiome and metabolomics are hitherto unknown. We aimed to examine the multi-omics features of the gut microecosystem, determining the functional correlation between microbiome and lipid metabolites during RE activity. By delivering single high-dose irradiation, a RE mouse model was established. High-throughput 16S rDNA sequencing and global lipidomics analysis were performed to examine microbial and lipidomic profile changes in the gut microecosystem. Spearman correlation analysis was used to determine the functional correlation between bacteria and metabolites. Clinical samples were collected to validate the above observations. During RE activity, the intestinal inflammation of the mice was confirmed by typical signs, symptoms, imaging findings and pathological evidences. 16S datasets revealed that localized irradiation dramatically altered the gut microbial composition, resulting in a decrease ratio of Bacteroidetes to Firmicutes. Lipidomics analysis indicated the remarkable lipidomic profile changes in enteric epithelial barrier, determining that glycerophospholipids metabolism was correlated to RE progression with the highest relevance. Spearman correlation analysis identified that five bacteria-metabolite pairs showed the most significant functional correlation in RE, including Alistipes-PC(36:0e), Bacteroides-DG(18:0/20:4), Dubosiella-PC(35:2), Eggerthellaceae-PC(35:6), and Escherichia-Shigella-TG(18:2/18:2/20:4). These observations were partly confirmed in human specimens. Our study provided a comprehensive description of microbiota dysbiosis and lipid metabolic disorders in RE, suggesting strategies to change local microecosystem to relieve radiation injury and maintain homeostasis.

Current Management and Progress in Radiotherapy for Small Cell Lung Cancer.

Radiotherapy (RT) and chemotherapy continue to be widely utilized in small cell lung cancer (SCLC) management. In most limited stage (LS)-SCLC cases, the standard initial therapy remains concurrent chemoradiotherapy (CRT), typically with an etoposide and platinum-based regimen. Hyperfractionated twice daily (BID) RT remains the standard of care, though conventional daily (QD) RT is now a viable alternative supported by randomized evidence. In LS-SCLC patients who experienced good response to CRT, prophylactic cranial irradiation (PCI) remains the standard of care. Brain imaging, ideally with MRI, should be performed prior to PCI to screen for clinically apparent brain metastases that may require a higher dose of cranial irradiation. Platinum doublet chemotherapy alone is the historic standard initial therapy in extensive stage (ES)-SCLC. Addition of immunotherapy such as atezolizumab and durvalumab to chemotherapy is now recommended after their benefits were demonstrated in recent trials. In patients with response to chemotherapy, consolidation thoracic RT and PCI could be considered, though with caveats. Emergence of hippocampal avoidance cranial irradiation and SRS in SCLC patients may supplant whole cranial irradiation as future standards of care. Incorporation of novel systemic therapies such as immunotherapies has changed the treatment paradigm and overall outlook of patients with SCLC. This narrative review summarizes the current state, ongoing trials, and future directions of radiotherapy in management of SCLC.

Proton Beam Therapy for Children With Neuroblastoma: Experiences From the Prospective KiProReg Registry.

OBJECTIVE: Radiotherapy (RT) is an integral part of the interdisciplinary treatment of patients with high-risk neuroblastoma (NB). With the continuous improvements of outcome, the interest in local treatment strategies that reduce treatment-related side effects while achieving optimal oncological results is growing. Proton beam therapy (PBT) represents a promising alternative to conventional photon irradiation with regard to the reduction of treatment burden. METHOD: Retrospective analysis of children with high or intermediate risk NB receiving PBT of the primary tumor site during first-line therapy between 2015 and 2020 was performed. Data from the prospective in-house registry Standard Protonentherapie WPE - Kinder- (KiProReg) with respect to tumor control and treatment toxicity were analyzed. Adverse events were classified according to CTCAE Version 4 (V4.0) before, during, and after PBT. RESULTS: In total, 44 patients (24 male, 20 female) with high (n = 39) or intermediate risk NB (n = 5) were included in the analysis. Median age was 3.4 years (range, 1.4-9.9 years). PBT doses ranged from 21.0 to 39.6 Gray (Gy) (median 36.0 Gy). Five patients received PBT to the MIBG-avid residual at the primary tumor site at time of PBT according to the NB-2004 protocol. In 39 patients radiation was given to the pre-operative tumor bed with or without an additional boost in case of residual tumor. After a median follow-up (FU) of 27.6 months, eight patients developed progression, either local recurrence (n = 1) or distant metastases (n = 7). Four patients died due to tumor progression. At three years, the estimated local control, distant metastatic free survival, progression free survival, and overall survival was 97.7, 84.1, 81.8, and 90.9%, respectively. During radiation, seven patients experienced higher-grade (CTCAE ≥ °3) hematologic toxicity. No other higher grade acute toxicity occurred. After PBT, one patient developed transient myelitis while receiving immunotherapy. No higher grade long-term toxicity was observed up to date. CONCLUSION: PBT was a well tolerated and effective local treatment in children with high and intermediate risk NB. The role of RT in an intensive multidisciplinary treatment regimen remains to be studied in the future in order to better define timing, doses, target volumes, and general need for RT in a particularly sensitive cohort of patients.

Evaluation of the Hippocampal Normal Tissue Complication Model in a Prospective Cohort of Low Grade Glioma Patients-An Analysis Within the EORTC 22033 Clinical Trial.

Purpose: To evaluate the performance of the hippocampal normal tissue complication model that relates dose to the bilateral hippocampus to memory impairment at 18 months post-treatment in a population of low-grade glioma (LGG) patients. Methods: LGG patients treated within the radiotherapy-only arm of the EORTC 22033-26033 trial were analyzed. Hippocampal dose parameters were calculated from the original radiotherapy plans. Difference in Rey Verbal Auditory Learning test delayed recall (AVLT-DR) performance pre-and 18 (±4) months post-treatment was compared to reference data from the Maastricht Aging study. The NTCP model published by Gondi et al. was applied to the dosimetric data and model predictions were compared to actual neurocognitive outcome. Results: A total of 29 patients met inclusion criteria. Mean dose in EQD2 Gy to the bilateral hippocampus was 39.8 Gy (95% CI 34.3-44.4 Gy), the median dose to 40% of the bilateral hippocampus was 47.2 EQD2 Gy. The model predicted a risk of memory impairment exceeding 99% in 22 patients. However, only seven patients were found to have a significant decline in AVLT-dr score. Conclusions: In this dataset of only LGG patients treated with radiotherapy the hippocampus NTCP model did not perform as expected to predict cognitive decline based on dose to 40% of the bilateral hippocampus. Caution should be taken when extrapolating this model outside of the range of dose-volume parameters in which it was developed.

Clinical Outcome Assessments Toolbox for Radiopharmaceuticals.

For nearly 40 years, the U.S. National Cancer Institute (NCI) has funded health-related quality-of-life (HRQOL) and symptom management in oncology clinical trials as a method for including a cancer patient's experience during and after treatment. The NCI's planned scope for HRQOL, symptom and patient-reported outcomes management research is explained as it pertains to radiopharmaceutical clinical development. An effort already underway to support protocol authoring via an NCI Cancer Therapy Evaluation Program (CTEP) Centralized Protocol Writing Service (CPWS) is described as this service aids incorporation of HRQOL, symptom and patient-reported outcomes management research into sponsored protocols.

Pelvic Complications After Prostate Cancer Radiation Therapy and Their Management: An International Collaborative Narrative Review.

CONTEXT: Radiotherapy used for treating localized prostate cancer is effective at prolonging cancer-specific and overall survival. Still, acute and late pelvic toxicities are a concern, with gastrointestinal (GI) and genitourinary (GU) sequelae being most common as well as other pelvic complications. OBJECTIVE: To present a critical review of the literature regarding the incidence and risk factors of pelvic toxicity following primary radiotherapy for prostate cancer and to provide a narrative review regarding its management. EVIDENCE ACQUISITION: A collaborative narrative review of the literature from 2010 to present was conducted. EVIDENCE SYNTHESIS: Regardless of the modality used, the incidence of acute high-grade pelvic toxicity is low following conventionally fractionated external beam radiotherapy (EBRT). After moderate hypofractionation, the crude cumulative incidences for late grade 3 or higher (G3+) GI and GU complications are as high as 6% and 7%, respectively. After extreme hypofractionation, the 5-yr incidences of G2+ GU and GI toxicities are 3-9% and 0-4%, respectively. Following brachytherapy monotherapy, crude rates of late G3+ GU toxicity range from 6% to 8%, while late GI toxicity is rare. With combination therapy (EBRT and brachytherapy), the cumulative incidence of late GU toxicity is high, between 18% and 31%; however, the prevalence is lower at 4-14%. Whole pelvic radiotherapy remains a controversial treatment option as there is increased G3+ GI toxicity compared with prostate-only treatment, with no overall survival benefit. Proton beam therapy appears to have similar toxicity to photon therapies currently in use. With respect to specific complications, urinary obstruction and urethral stricture are the most common severe urinary toxicities. Rectal and urinary bleeding can be recurrent long-term toxicities. The risk of hip fracture is also increased following prostate radiotherapy. The literature is mixed on the risk of in-field secondary pelvic malignancies following prostate radiotherapy. Urinary and GI fistulas are rare complications. Management of these toxicities may require invasive treatment and reconstructive surgery for refractory and severe symptoms. CONCLUSIONS: There has been progress in the delivery of radiotherapy, enabling the administration of higher doses with minimal tradeoff in terms of slightly increased or equal toxicity. There is a need to focus future improvements in radiotherapy on sparing critical structures to reduce GU and GI morbidities. While complications such as fistulae, bone toxicity, and secondary malignancy are rare, there is a need for higher-quality studies assessing these outcomes and their management. PATIENT SUMMARY: In this report, we review the literature regarding pelvic complications following modern primary prostate cancer radiotherapy and their management. Modern radiotherapy technologies have enabled the administration of higher doses with minimal increases in toxicity. Overall, high-grade long-term toxicity following prostate radiotherapy is uncommon. Management of late high-grade pelvic toxicities can be challenging, with patients often requiring invasive therapies for refractory cases.

Treatment for radiation retinopathy of uveal melanoma undergone radiotherapy: the current situation / 中华眼底病杂志

Radiotherapy is the prior treatment for uveal melanoma,but a major problem confronted most of the patients is radiation retinopathy,which accompanied with severe visual loss and secondary enucleation potential.There is no optium choice and normative strategy so far,the intraocular melanoma society has focused on application of anti-vascular endothelial growth factor drugs injection and glucocorticoids.This article reviews a series of potential managements for radiation retinopathy and its further stage.

Advanced Interventional Therapy for Radiation-Induced Cardiovascular Disease.

This report describes the case of a 61-year-old woman who presented with dyspnea, aortic stenosis, and coronary artery disease-typical side effects of radiation therapy for Hodgkin lymphoma. A poor candidate for surgery, she underwent successful high-risk percutaneous coronary intervention and subsequent transcatheter aortic valve replacement. This report highlights some of the cardiovascular-specific sequelae of radiation therapy for cancer treatment; in addition, possible directions for future investigations are discussed.

Angiosarcoma Causing Cardiac Constriction Late after Radiation Therapy for Breast Carcinoma.

Therapeutic radiotherapy rarely causes sarcoma, and this occurs years after completion of the intended treatment. In treating breast carcinoma, careful planning in the application of modern radiotherapeutic techniques usually can shield the heart and pericardium. We report a rare case of angiosarcoma of the pericardium, which presented in a 41-year-old woman as constrictive pericarditis 8 years after irradiation for cancer of the left breast. To our knowledge, this is only the 2nd report of angiosarcoma of the pericardium after radiotherapy.

Lymphedema following cancer therapy in Slovenia: a frequently overlooked condition?

INTRODUCTION: Secondary lymphedema following cancer therapy is a frequent, often painful, quality of life disturbing condition, reducing the patients' mobility and predisposing them to complications, e.g. infections and malignancies. The critical aspect of lymphedema therapy is to start as soon as possible to prevent the irreversible tissue damage. PATIENTS AND METHODS: We performed a retrospective study of patients with lymphedema, treated at the Department of Dermatovenereology, University Medical Center Ljubljana, from January 2002 to June 2010. The patients' demographic and medical data were collected, including type of cancer, type and stage of lymphedema, and time to first therapy of lymphedema. The number of referred patients with lymphedema following the therapy of melanoma, breast cancer, and uterine/cervical cancer, was compared to the number of patients expected to experience lymphedema following cancer therapy, calculated from the incidence reported in the literature. RESULTS: In the period of 8.5 years, 543 patients (432 females, 112 males) with lymphedema were treated. The results show that probably many Slovenian patients with secondary lymphedema following cancer therapy remain unrecognized and untreated or undertreated. In the majority of our patients, the management of lymphedema was delayed; on average, the patients first received therapy for lymphedema 3.6 years after the first signs of lymphedema. CONCLUSIONS: To avoid a delay in diagnosis and therapy, and the complications of lymphedema following cancer therapy, the physician should actively look for signs or symptoms of lymphedema during the follow-up period, and promptly manage or refer the patients developing problems.