Prostatic irradiation-induced sexual dysfunction: a review and multidisciplinary guide to management in the radical radiotherapy era (Part I defining the organ at risk for sexual toxicities)

Prostate cancer is the most common malignancy and the second leading cause of cancer-related death in men. Radiotherapy is a curative option that is administered via external beam radiation, brachytherapy, or in combination. Erectile, ejaculatory and orgasm dysfunction(s) is/are known potential and common toxicities associated with prostate radiotherapy. Our multidisciplinary team of physicians and/or scientists have written a three (3) part comprehensive review of the pathogenesis and management radiation-induced sexual dysfunction. Part I reviews pertinent anatomy associated with normal sexual function and then considers the pathogenesis of prostate radiation-induced sexual toxicities. Next, our team considers the associated radiobiological (including the effects of time, dose and fractionation) and physical (treatment planning and defining a novel Organ at Risk (OAR)) components that should be minded in the context of safe radiation treatment planning. The authors identify an OAR (i.e., the prostatic plexus) and provide suggestions on how to minimize injury to said OAR during the radiation treatment planning process.     

Functional response difference between diabetic/normal cancerous patients to inflammatory cytokines and oxidative stresses after radiotherapy

Diabetes, which is considered as a chronic metabolic disorder leads to an increase in inflammatory cytokines and oxidative stresses. Studies have shown several functional differences in the oxidative stress and inflammatory cytokines responses in diabetic/normal cancerous patients candidate for radiotherapy. Also, radiotherapy as a cancer treatment modality is known as a carcinogen due to oxidative damage via generation of reactive oxygen metabolites and also causing inflammation of the tissue by increasing the inflammatory cytokines. Therefore, the consequence of diabetes on oxidative stress and increased inflammatory factors and synergistic effects of radiotherapy on these factors cause complications in diabetics undergoing radiotherapy. It is considered as one of the most interesting objectives to control inflammation and oxidative stress in these patients. This review aims to concentrate on the influence of factors such as MPO, MDA, IL-1β, and TNF-α in diabetic patients by emphasizing the effects related to radiation-induced toxicity and inflammation by proposing therapeutic approaches which could be helpful in reduction of the complications.     

A critical literature review on the use of bellyboard devices to control small bowel dose for pelvic radiotherapy

Delivering curative radiotherapy doses for rectal and gynaecological tumours has historically been complicated by the dose tolerance of the small bowel. Acute radiation-induced small bowel toxicity includes side effects such as abdominal pain, nausea and diarrhoea. With the advent of new treatment delivery modalities, such as IMRT (Intensity modulated radiotherapy) and VMAT (Volumetric modulated Arc radiotherapy), there has been an expectation that small bowel doses can be better controlled with the use of these technologies. These capabilities enable the creation of treatment plans that can better avoid critical radiosensitive organs. The purpose of this review is to look beyond advances in linear accelerator technology in seeking improvements to small bowel dose and toxicity. This review examines whether an alternative prone patient positioning approach using a bellyboard device in conjunction with IMRT and VMAT treatment delivery can reduce small bowel doses further than using these technologies with the patient in a traditional supine position.     

Bystander effects and radiotherapy

Radiation-induced bystander effects are defined as biological effects expressed after irradiation by cells whose nuclei have not been directly irradiated. These effects include DNA damage, chromosomal instability, mutation, and apoptosis. There is considerable evidence that ionizing radiation affects cells located near the site of irradiation, which respond individually and collectively as part of a large interconnected web. These bystander signals can alter the dynamic equilibrium between proliferation, apoptosis, quiescence or differentiation. The aim of this review is to examine the most important biological effects of this phenomenon with regard to areas of major interest in radiotherapy. Such aspects include radiation-induced bystander effects during the cell cycle under hypoxic conditions when administering fractionated modalities or combined radio-chemotherapy. Other relevant aspects include individual variation and genetics in toxicity of bystander factors and normal tissue collateral damage. In advanced radiotherapy techniques, such as intensity-modulated radiation therapy (IMRT), the high degree of dose conformity to the target volume reduces the dose and, therefore, the risk of complications, to normal tissues. However, significant doses can accumulate out-of-field due to photon scattering and this may impact cellular response in these regions. Protons may offer a solution to reduce out-of-field doses. The bystander effect has numerous associated phenomena, including adaptive response, genomic instability, and abscopal effects. Also, the bystander effect can influence radiation protection and oxidative stress. It is essential that we understand the mechanisms underlying the bystander effect in order to more accurately assess radiation risk and to evaluate protocols for cancer radiotherapy.     

Tissue TGF-β expression following conventional radiotherapy and pulsed low-dose-rate radiation

The release of inflammatory cytokines has been implicated in the toxicity of conventional radiotherapy (CRT). Transforming growth factor β (TGF-β) has been suggested to be a risk marker for pulmonary toxicity following radiotherapy. Pulsed low-dose rate radiotherapy (PLDR) is a technique that involves spreading out a conventional radiotherapy dose into short pulses of dose with breaks in between to reduce toxicities. We hypothesized that the more tolerable toxicity profile of PLDR compared with CRT may be related to differential expression of inflammatory cytokines such as TGF-β in normal tissues. To address this, we analyzed tissues from mice that had been subjected to lethal doses of CRT and PLDR by histology and immunohistochemistry (IHC). Equivalent physical doses of CRT triggered more cellular atrophy in the bone marrow, intestine, and pancreas when compared with PLDR as indicated by hematoxylin and eosin staining. IHC data indicates that TGF-β expression is increased in the bone marrow, intestine, and lungs of mice subjected to CRT as compared with tissues from mice subjected to PLDR. Our in vivo data suggest that differential expression of inflammatory cytokines such as TGF-β may play a role in the more favorable normal tissue late response following treatment with PLDR.     

Glycolytic inhibitor, 2-deoxy-D-glucose, does not enhance radiation-induced apoptosis in mouse thymocytes and splenocytes in vitro

Earlier studies have shown that 2-deoxy-D-glucose (2-DG), a glucose analogue and inhibitor of glycolytic ATP production selectively enhances radiation-induced damage in cancer cells by inhibiting the energy (ATP) dependent postirradiation DNA and cellular repair processes. A reduction in radiation induced cytogenetic damage has been reported in normal cells viz., peripheral blood lymphocytes and bone marrow cells. Since induction of apoptosis plays a major role in determining the radiosensitivity of some most sensitive normal cells including splenocytes and thymocytes, we investigated the effects of 2-DG on radiation induced apo tosis in these cells in vitro. Thymocytes and splenocytes isolated from normal Swiss albino mouse were irradiated with Co60 gamma-rays and analyzed for apoptosis at various post-irradiation times. 2-DG added at the time of irradiation was present till the termination of cultures. A time dependent, spontaneous apoptosis was evident in both the cell systems, with nearly 40% of the cells undergoing apoptosis at 12 hr of incubation. The dose response of radiation-induced apoptosis was essentially similar in both the cell systems and was dependent on the incubation time. More than 70% of the splenocytes and 60% of the thymocytes were apoptotic by 12 hr following an absorbed dose of 2 Gy. Presence of 2-DG marginally reduced the fraction of splenocytes undergoing apoptosis at all absorbed doses, while no change was observed in thymocytes. Presence of 2-DG did not significantly alter either the level or the rate of induction of spontaneous apoptosis in both these cell systems. These results are consistent with the earlier findings on radiation-induced cytogenetic damage in human PBL in vitro and mouse bone marrow cells and lend further support to the proposition that 2-DG does not enhance radiation damage in normal cells, while radiosensitizing the tumors and hence is an ideal adjuvant in the radiotherapy of tumors.     

Cancer risk estimates from the combined Japanese A-bomb and Hodgkin cohorts for doses relevant to radiotherapy

Most information on the dose–response of radiation-induced cancer is derived from data on the A-bomb survivors who were exposed to γ-rays and neutrons. Since, for radiation protection purposes, the dose span of main interest is between 0 and 1 Gy, the analysis of the A-bomb survivors is usually focused on this range. However, estimates of cancer risk for doses above 1 Gy are becoming more important for radiotherapy patients and for long-term manned missions in space research. Therefore in this work, emphasis is placed on doses relevant for radiotherapy with respect to radiation-induced solid cancer. The analysis of the A-bomb survivor’s data was extended by including two extra high-dose categories (4–6 Sv and 6–13 Sv) and by an attempted combination with cancer data on patients receiving radiotherapy for Hodgkin’s disease. In addition, since there are some recent indications for a high neutron dose contribution, the data were fitted separately for three different values for the relative biological effectiveness (RBE) of the neutrons (10, 35 and 100) and a variable RBE as a function of dose. The data were fitted using a linear, a linear-exponential and a plateau-dose–response relationship. Best agreement was found for the plateau model with a dose-varying RBE. It can be concluded that for doses above 1 Gy there is a tendency for a nonlinear dose–response curve. In addition, there is evidence of a neutron RBE greater than 10 for the A-bomb survivor data. Many problems and uncertainties are involved in combing these two datasets. However, since very little is currently known about the shape of dose–response relationships for radiation-induced cancer in the radiotherapy dose range, this approach could be regarded as a first attempt to acquire more information on this area. The work presented here also provides the first direct evidence that the bending over of the solid cancer excess risk dose response curve for the A-bomb survivors, generally observed above 2 Gy, is due to cell killing effects.     

Intraoperative radiation therapy-induced sarcomas in dogs

In a canine model the tolerance of normal and surgically manipulated tissue to intraoperative radiotherapy (IORT) was investigated to provide guidelines for the clinical use of IORT in human cancer patients. A dose of 20 Gy IORT, with or without external beam radiotherapy, was generally well tolerated without significant increased treatment morbidity. Higher doses of IORT (over 30 Gy) have produced radiation-induced sarcomas in some animals followed over a long period. Therefore IORT should be used only in human cancer patients in well controlled studies, in which complications are well documented, and the possibility of radiation-induced malignancies in long-term survival should be considered.     

Mathematical modelling of radiotherapy strategies for early breast cancer

Targeted intraoperative radiotherapy (Targit) is a new concept of partial breast irradiation where single fraction radiotherapy is delivered directly to the tumour bed. Apart from logistic advantages, this strategy minimizes the risk of missing the tumour bed and avoids delay between surgery and radiotherapy. It is presently being compared with the standard fractionated external beam radiotherapy (EBRT) in randomized trials. In this paper we present a mathematical model for the growth and invasion of a solid tumour into a domain of tissue (in this case breast tissue), and then a model for surgery and radiation treatment of this tumour. We use the established linear-quadratic (LQ) model to compute the survival probabilities for both tumour cells and irradiated breast tissue and then simulate the effects of conventional EBRT and Targit. True local recurrence of the tumour could arise either from stray tumour cells, or the tumour bed that harbours morphologically normal cells having a predisposition to genetic changes, such as a loss of heterozygosity (LOH) in genes that are crucial for tumourigenesis, e.g. tumour suppressor genes (TSGs). Our mathematical model predicts that the single high dose of radiotherapy delivered by Targit would result in eliminating all these sources of recurrence, whereas the fractionated EBRT would eliminate stray tumour cells, but allow (by virtue of its very schedule) the cells with LOH in TSGs or cell-cycle checkpoint genes to pass on low-dose radiation-induced DNA damage and consequently mutations that may favour the development of a new tumour. The mathematical model presented here is an initial attempt to model a biologically complex phenomenon that has until now received little attention in the literature and provides a 'proof of principle' that it is possible to produce clinically testable hypotheses on the effects of different approaches of radiotherapy for breast cancer.     

Pathophysiological Responses in Rat and Mouse Models of Radiation-Induced Brain Injury

The brain is the major dose-limiting organ in patients undergoing radiotherapy for assorted conditions. Radiation-induced brain injury is common and mainly occurs in patients receiving radiotherapy for malignant head and neck tumors, arteriovenous malformations, or lung cancer-derived brain metastases. Nevertheless, the underlying mechanisms of radiation-induced brain injury are largely unknown. Although many treatment strategies are employed for affected individuals, the effects remain suboptimal. Accordingly, animal models are extremely important for elucidating pathogenic radiation-associated mechanisms and for developing more efficacious therapies. So far, models employing various animal species with different radiation dosages and fractions have been introduced to investigate the prevention, mechanisms, early detection, and management of radiation-induced brain injury. However, these models all have limitations, and none are widely accepted. This review summarizes the animal models currently set forth for studies of radiation-induced brain injury, especially rat and mouse, as well as radiation dosages, dose fractionation, and secondary pathophysiological responses.     

Epigenetic modifications in radiation-induced non-targeted effects and their clinical significance

BackgroundIonizing radiation (IR) plays an important role in the diagnosis and treatment of cancer. Besides the targeted effects, the non-targeted effects, which cause damage to non-irradiated cells and genomic instability in normal tissues, also play a role in the side effects of radiotherapy and have been shown to involve both alterations in DNA sequence and regulation of epigenetic modifications.Scope of reviewWe summarize the recent findings regarding epigenetic modifications that are involved in radiation-induced non-targeted effects as well as their clinical significance in radiotherapy and radioprotection.Major conclusionsEpigenetic modifications play an important role in both the realization and modulation of radiobiological effects. However, the molecular mechanisms underlying non-targeted effects still need to be clarified.General significanceA better understanding of the epigenetic mechanisms related to radiation-induced non-targeted effects will guide both individualized clinical radiotherapy and individualized precise radioprotection.     

The Antioxidant,MnTE-2-PyP,Prevents Side-Effects Incurred by Prostate Cancer Irradiation

Prostate cancer is the most commonly diagnosed cancer, with an estimated 240,000 new cases reported annually in the United States. Due to early detection and advances in therapies, more than 90% of patients will survive 10 years post diagnosis and treatment. Radiation is a treatment option often used to treat localized disease; however, while radiation is very effective at killing tumor cells, normal tissues are damaged as well. Potential side-effects due to prostate cancer-related radiation therapy include bowel inflammation, erectile dysfunction, urethral stricture, rectal bleeding and incontinence. Currently, radiation therapy for prostate cancer does not include the administration of therapeutic agents to reduce these side effects and protect normal tissues from radiation-induced damage. In the current study, we show that the small molecular weight antioxidant, MnTE-2-PyP, protects normal tissues from radiation-induced damage in the lower abdomen in rats. Specifically, MnTE-2-PyP protected skin, prostate, and testes from radiation-induced damage. MnTE-2-PyP also protected from erectile dysfunction, a persistent problem regardless of the type of radiation techniques used because the penile neurovascular bundles lay in the peripheral zones of the prostate, where most prostate cancers reside. Based on previous studies showing that MnTE-2-PyP, in combination with radiation, further reduces subcutaneous tumor growth, we believe that MnTE-2-PyP represents an excellent radioprotectant in combination radiotherapy for cancer in general and specifically for prostate cancer.     

Intraoperative electron radiation therapy after salvage surgery in gynecological cancers and retroperitoneal sarcomas: outcomes and adverse effects

BackgroundSalvage surgery is considered an option for isolated recurrences of retroperitoneal and pelvic tumors, in patients who have undergone previous radiotherapy. In order to increase local control intra operative electron radiation therapy (IOERT) can be used in these patients to administer additional radiation dose. We evaluated the outcomes and adverse effects in patients with retroperitoneal sarcoma and gynecologic tumors after salvage surgery and IOERT.Materials and methodsTwenty patients were retrospectively analyzed. Twenty-three IOERT treatments were performed after surgery. Six (30%) were sarcoma and 14 (70%) were gynecological carcinoma. Administered dose depended on previous dose received with external beam radiotherapy (EBRT) and proximity to critical structures. The toxicities were scored using the Common Terminology Criteria for Adverse Events version 4.0.ResultsThe median age of the patients was 51 years (range 34–70). After a median follow-up of 32 months (range 1–68), in the sarcoma group the local control rate was 66.6%; while in the gynecological group the local control rate was 64.3%. In relation to late toxicity, one patient had a Grade 2 vesicovaginal fistula, and one patient presented Grade 4 enterocolitis and enteric intestinal fistula.ConclusionsIOERT could have a role in the treatment of retroperitoneal sarcomas in primary tumors after EBRT, as it may suggest a benefit in local control or recurrences after surgical resection in those at high risk of microscopic residual disease. The addition of IOERT to salvage resection for isolated recurrence of gynecologic cancers suggest favorable local control in cases with concern for residual microscopic disease.     

Radiation risk estimates after radiotherapy: application of the organ equivalent dose concept to plateau dose–response relationships

Estimates of secondary cancer risk after radiotherapy are becoming more important for comparative treatment planning. Modern treatment planning systems provide accurate three-dimensional (3D) dose distributions for each individual patient. The dose distributions can be converted into organ equivalent doses to describe radiation-induced cancer after radiotherapy (OED_rad-ther) in the irradiated organs. The OED_rad-ther concept assumes that any two dose distributions in an organ are equivalent if they cause the same radiation-induced cancer risk. In this work, this concept is applied to dose–response relationships, which are leveling off at high dose. The organ-dependent operational parameter of this dose–response relationship was estimated by analyzing secondary cancer incidence data of patients with Hodgkin’s disease. The dose distributions of a typical radiotherapy treatment plan for treating Hodgkin’s disease was reconstructed. Dose distributions were calculated in individual organs from which cancer incidence data were available. The model parameter was obtained by comparing dose and cancer incidence rates for the individual organs.     

Cardiac toxicity of lung cancer radiotherapy

Radical radiotherapy of lung cancer with dose escalation has been associated with increased tumor control. However, these attempts to continually improve local control through dose escalation, have met mixed results culminating in the findings of the RTOG trial 0617, where the heart dose was associated with a worse overall survival, indicating a significant contribution to radiation-induced cardiac morbidity. It is, therefore, very likely that poorly understood cardiac toxicity may have offset any potential improvement in overall survival derived from dose escalation and may be an obstacle that limits disease control and survival of patients. The manifestations of cardiac toxicity are relatively common after high dose radiotherapy of advanced lung cancers and are independently associated with both heart dose and baseline cardiac risk. Toxicity following the treatment may occur earlier than previously thought and, therefore, heart doses should be minimized. In patients with lung cancer, who not only receive substantial heart dose, but are also older with more comorbidities, all cardiac events have the potential to be clinically significant and life-threatening.Sophisticated radiation treatment planning techniques, charged particle therapy, and modern imaging methods in radiotherapy planning, may lead to reduction of the heart dose, which could potentially improve the clinical outcomes in patients with lung cancer. Efforts should be made to minimize heart radiation exposure whenever possible even at doses lower than those generally recommended. Heart doses should be limited as much as possible.A heart dosimetry as a whole is important for patient outcomes, rather than emphasizing just one parameter.     

愈创紫草油对头颈部恶性肿瘤患者放疗所致放射性皮肤黏膜损伤的改善作用研究

摘要 目的：探讨愈创紫草油改善头颈部恶性肿瘤放疗患者所致放射性皮肤黏膜损伤的临床疗效,以期为头颈部恶性肿瘤放疗患者所致放射性皮肤黏膜损伤提供新的治疗方法。方法：选取安徽中医药大学附属六安医院2021年3月-2023年3月头颈部恶性肿瘤放疗患者100例作为研究对象,随机数字表随机分为观察组和对照组,各50例。两组均采用适形调强放射治疗,对照组给予常规放疗皮肤管理与宣教,观察组在对照组基础上给予涂抹愈创紫草油治疗。比较两组皮肤黏膜损伤程度、临床疗效、放疗完成率、皮损愈合时间,放疗2、4、6周时数字评分法（NRS）评分、Karnofsky功能状态（KPS）评分、皮肤病生活质量量表（DLQI）评分;放疗前、放疗6周时炎性细胞因子[白介素-6（IL-6）、降钙素原（PCT）、超敏C反应蛋白（hs-CRP）]水平及皮肤不良反应。结果：观察组皮肤黏膜损伤程度分级低于对照组（P＜0.05）;观察组总有效率94.00%较对照组80.00%高（P＜0.05）;放疗4、6周时观察组NRS评分、DLQI评分低于对照组,KPS评分高于对照组（P＜0.05）;两组放疗完成率均为100%,观察组皮损愈合时间较对照组短（P＜0.05）;放疗6周时观察组血清IL-6、PCT、hs-CRP水平低于对照组（P＜0.05）;两组患者均未出现过敏所致皮疹、红肿、瘙痒等皮肤不良反应。结论：愈创紫草油可有效减轻头颈部恶性肿瘤放疗所致放射性皮肤黏膜损伤,降低血清炎性细胞因子水平,促进患者皮损愈合,提高生活质量,疗效显著,且安全性高。     

Dose-dependence, sex- and tissue-specificity, and persistence of radiation-induced genomic DNA methylation changes

Radiation is a well-known genotoxic agent and human carcinogen that gives rise to a variety of long-term effects. Its detrimental influence on cellular function is actively studied nowadays. One of the most analyzed, yet least understood long-term effects of ionizing radiation is transgenerational genomic instability. The inheritance of genomic instability suggests the possible involvement of epigenetic mechanisms, such as changes of the methylation of cytosine residues located within CpG dinucleotides. In the current study we evaluated the dose-dependence of the radiation-induced global genome DNA methylation changes. We also analyzed the effects of acute and chronic high dose (5Gy) exposure on DNA methylation in liver, spleen, and lung tissues of male and female mice and evaluated the possible persistence of the radiation-induced DNA methylation changes. Here we report that radiation-induced DNA methylation changes were sex- and tissue-specific, dose-dependent, and persistent. In parallel we have studied the levels of DNA damage in the exposed tissues. Based on the correlation between the levels of DNA methylation and DNA damage we propose that radiation-induced global genome DNA hypomethylation is DNA repair-related.     

The effect of carbon irradiation is associated with greater oxidative stress in mouse intestine and colon relative to γ-rays

Carbon irradiation due to its higher biological effectiveness relative to photon radiation is a concern for toxicity to proliferative normal gastrointestinal (GI) tissue after radiotherapy and long-duration space missions such as mission to Mars. Although radiation-induced oxidative stress is linked to chronic diseases such as cancer, effects of carbon irradiation on normal GI tissue have not been fully understood. This study assessed and compared chronic oxidative stress in mouse intestine and colon after different doses of carbon and γ radiation, which are qualitatively different. Mice (C57BL/6J) were exposed to 0.5 or 1.3?Gy of γ or carbon irradiation, and intestinal and colonic tissues were collected 2 months after irradiation. While part of the tissues was used for isolating epithelial cells, tissue samples were also fixed and paraffin embedded for 4 µm thick sections as well as frozen for biochemical assays. In isolated epithelial cells, reactive oxygen species and mitochondrial status were studied using fluorescent probes and flow cytometry. We assessed antioxidant enzymes and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in tissues and formalin-fixed tissue sections were stained for 4-hydroxynonenal, a lipid peroxidation marker. Data show that mitochondrial deregulation, increased NADPH oxidase activity, and decreased antioxidant activity were major contributors to carbon radiation-induced oxidative stress in mouse intestinal and colonic cells. When considered along with higher lipid peroxidation after carbon irradiation relative to γ-rays, our data have implications for functional changes in intestine and carcinogenesis in colon after carbon radiotherapy as well as space travel.     

Skin radioprotection by 5-thio-D-glucose

The radioprotective effect of 5-thio-D-glucose on mouse skin was studied. Intraperitoneal injection of A/J mice with 1.5 g/kg of 5-thio-D-glucose 2 hr prior to X irradiation of the foot reduced early foot skin damage through Day 40 postirradiation by a dose modification factor of 1.3 +/- 0.1. Similarly, late foot deformity during Days 60-90 postirradiation was reduced by a factor of 1.2 +/- 0.1. The radioprotective effect of 5-thio-D-glucose was also compared with that of WR-2721, an aminothiol radioprotector, in CDF1 mice. An intraperitoneal injection of 1.5 g/kg of 5-thio-D-glucose reduced early radiation-induced skin damage by a dose modification factor of 1.2 +/- 0.1 as compared to that of 1.5 +/- 0.2 by 0.65 g/kg of WR-2721 in this strain of mice. 5-Thio-D-glucose is also known to specifically kill and radiosensitize hypoxic tumor cells. Consequently, this drug may be a useful radiotherapy adjuvant, reducing normal tissue damage and enhancing tumor control by minimizing hypoxic protection.