Radiotherapy For Pelvic Cancer Research Articles

Exploring the protective effect and mechanism of icariside II on the bladder in a rat model of radiation cystitis based on transcriptome sequencing

Purpose Radiation cystitis (RC) is a complex and common complication after radiotherapy for pelvic cancer. Icariside II (ICAII) is a flavonoid compound extracted from Epimedium, a traditional Chinese medicine, with various pharmacological activities. The aim of the present study was to investigate the cysto-protective effects of ICAII in RC rats and its possible mechanisms. Materials and Methods A rat model of induced radiation cystitis using pelvic X-ray irradiation was used, and bladder function was assessed by bladder volume and bladder leakage point pressure (LPP) after ICAII treatment. HE and Masson stains were used to assess the histopathological changes in the bladder. IL-6, TNF-α, IL-10, IL-4 and IL-1β were measured by ELISA to assess the level of inflammation. The gene-level changes in ICAII-treated RC were observed by transcriptome sequencing, and then the potential targets of action and biological mechanisms were explored by PPI, GO and KEGG enrichment analysis of the differentially expressed genes. Finally, the predicted targets of action were experimentally validated using immunohistochemistry, RT–qPCR, molecular docking and CETSA. Results ICAII significantly increased bladder volume and the LPP, ameliorated pathological damage to bladder tissues, decreased the levels of IL-6, TNF-α, and IL-1β, and increased the levels of IL-10 and IL-4 in radiation-injured rats. A total of 90 differentially expressed genes were obtained by transcriptome sequencing, and PPI analysis identified H3F3C, ISG15, SPP1, and LCN2 as possible potential targets of action. GO and KEGG analyses revealed that these differentially expressed genes were mainly enriched in the pathways metabolism of xenobiotics by cytochrome P450, arachidonic acid metabolism, Staphylococcus aureus infection and chemical carcinogenesis - reactive oxygen species. Experimental validation showed that ICAII could significantly increase the expression of H3F3C and ISG15 and inhibit the expression of SPP1 and LCN2. ICAII binds well to H3F3C, ISG15, SPP1 and LCN2, with the best binding ability to H3F3C. Furthermore, ICAII inhibited the protein degradation of H3F3C in bladder epithelial cells. Conclusions ICAII may alleviate the bladder inflammatory response and inhibit the fibrosis process of bladder tissues through the regulation of H3F3C, ISG15, SPP1, and LCN2 targets and has a protective effect on the bladder of radioinjured rats. In particular, H3F3C may be one of the most promising therapeutic targets.

Altered Gut Microbiota Associated With Hemorrhage in Chronic Radiation Proctitis.

Pelvic cancer radiotherapy may cause chronic radiation proctitis (CRP) that adversely affects patient’s quality of life, especially in patients with prolonged hematochezia. However, previous studies of radiation enteropathy mainly focused on acute irradiation hazards, and the detailed pathogenesis process and mechanism of prolonged hematochezia associated with radiation-induced toxicity remain unclear. In this study, we characterized the gut microbiota of 32 female CRP patients with or without hematochezia. Differential patterns of dysbiosis were observed. The abundance of Peptostreptococcaceae, Eubacterium, and Allisonella was significantly higher in CRP patients with hematochezia, while the compositions of the Lachnospiraceae, Megasphera, Megamonas, and Ruminococcaceae were lower in the microbiota of non-hematochezia patients. Functional prediction suggested significant difference in the expression of mineral absorption and the arachidonic acid metabolism proteins between hematochezia and non-hematochezia patients, possibly interdependent on radiation-induced inflammation. This study provides new insight into the altered composition and function of gut microbiota in patients with hematochezia, implying the potential use of probiotics and prebiotics for assessment and treatment of CRP.

MP08-12 GUANYLATE CYCLASE-C AGONIST IW-3300 ATTENUATES CHRONIC COLONIC AND BLADDER HYPERSENSITIVITY IN A RAT MODEL OF PELVIC RADIATION INJURY

INTRODUCTION AND OBJECTIVE:Radiotherapy for pelvic cancers can lead to radiation-induced visceral organ injuries that develop into persistent chronic radiation proctitis, colitis, and cystitis. One...

Pre-clinical Research on Bladder Toxicity After Radiotherapy for Pelvic Cancers: State-of-the Art and Challenges.

Despite the dramatic advancements in pelvic radiotherapy, urinary toxicity remains a significant side-effect. The assessment of clinico-dosimetric predictors of radiation cystitis (RC) based on clinical data has improved substantially over the last decade; however, a thorough understanding of the physiopathogenetic mechanisms underlying the onset of RC, with its variegated acute and late urinary symptoms, is still largely lacking, and data from pre-clinical research is still limited. The aim of this review is to provide an overview of the main open issues and, ideally, to help investigators in orienting future research. First, anatomy and physiology of bladder, as well as the current knowledge of dose and dose-volume effects in humans, are briefly summarized. Subsequently, pre-clinical radiobiology aspects of RC are discussed. The findings suggest that pre-clinical research on RC in animal models is a lively field of research with growing interest in the development of new radioprotective agents. The availability of new high precision micro-irradiators and the rapid advances in small animal imaging might lead to big improvement into this field. In particular, studies focusing on the definition of dose and fractionation are warranted, especially considering the growing interest in hypo-fractionation and ablative therapies for prostate cancer treatment. Moreover, improvement in radiotherapy plans optimization by selectively reducing radiation dose to more radiosensitive substructures close to the bladder would be of paramount importance. Finally, thanks to new pre-clinical imaging platforms, reliable and reproducible methods to assess the severity of RC in animal models are expected to be developed.

Gastrointestinal symptoms of pelvic radiation disease (part 2): impact on patients and carers

Background: Radiotherapy for pelvic cancers can affect any organ within the pelvis, including the gastrointestinal tract. These late effects, or consequences of treatment, can have a significant impact. These symptoms are collectively known as pelvic radiation disease (PRD). Aims: To identify and consider the experiences of people affected by PRD, including both the patient and their family and friends. Methods: Exploratory interviews were conducted with patients and their carers. The transcripts underwent framework analysis to identify key themes. Findings: Three main areas of concern were feelings of stigma, experiences of contact with healthcare services and the need, and occasional lack, of support from family and friends. Conclusion: PRD has a significant physical, psychological and social impact on quality of life for those affected, as well as their carers.

Gastroenterologist and nurse management of symptoms after pelvic radiotherapy for cancer: an economic evaluation of a clinical randomized controlled trial (the ORBIT study).

BackgroundOver 20 distressing gastrointestinal symptoms affect many patients after pelvic radiotherapy, but in the United Kingdom few are referred for assessment. Algorithmic-based treatment delivered by either a consultant gastroenterologist or a clinical nurse specialist has been shown in a randomized trial to be statistically and clinically more effective than provision of a self-help booklet. In this study, we assessed cost-effectiveness.MethodsOutcomes were measured at baseline (pre-randomization) and 6 months. Change in quality-adjusted life years (QALYs) was the primary outcome for the economic evaluation; a secondary analysis used change in the bowel subset score of the modified Inflammatory Bowel Disease Questionnaire (IBDQ-B). Intervention costs, British pounds 2013, covered visits with the gastroenterologist or nurse, investigations, medications and treatments. Incremental outcomes and incremental costs were estimated simultaneously using multivariate linear regression. Uncertainty was handled non-parametrically using bootstrap with replacement.ResultsThe mean (SD) cost of treatment was £895 (499) for the nurse and £1101 (567) for the consultant. The nurse was dominated by usual care, which was cheaper and achieved better outcomes. The mean cost per QALY gained from the consultant, compared to usual care, was £250,455; comparing the consultant to the nurse, it was £25,875. Algorithmic care produced better outcomes compared to the booklet only, as reflected in the IBDQ-B results, at a cost of ~£1,000.ConclusionAlgorithmic treatment of radiation bowel injury by a consultant or a nurse results in significant symptom relief for patients but was not found to be cost-effective according to the National Institute for Health and Care Excellence (NICE) criteria.

GI Consequences of Cancer Treatment: A Clinical Perspective.

In an era when extensive research is being funded to mitigate the radiation risks of a human traveling to Mars or the potential effects of a nuclear detonation in an urban environment, it is difficult to understand why the medical and research community remains largely uninterested in pelvic radiation disease (PRD), a condition that afflicts half a million patients every year after radiotherapy for pelvic cancer. There has been significant progress in understanding the nature of normal tissue injury, especially as it affects the GI tract. Clear clinical data exist on how best to assess and improve symptoms and there are a number of options for how to modulate the underlying progressive pathophysiology of PRD. Annually, there are more patients who develop PRD than inflammatory bowel disease (IBD). Despite the similarity in PRD and IBD symptoms, the same expertise that promotes assessment, treatment and disease-modifying approaches as standard of care in IBD is almost nonexistent for those suffering from PRD, and as a result the unmet need is enormous. Curing or controlling cancer without addressing quality of life is no longer acceptable when half of all patients diagnosed with cancer live for 10 years after treatment. For those patients afflicted with PRD it can cause significant misery, and this situation is unacceptable; investment in training and research cannot be delayed any longer.

Vaginal dilator therapy for women receiving pelvic radiotherapy.

Vaginal dilation therapy is advocated after pelvic radiotherapy to prevent stenosis (abnormal narrowing of the vagina), but can be uncomfortable and psychologically distressing. To assess the benefits and harms of different types of vaginal dilation methods offered to women treated by pelvic radiotherapy for cancer. Searches included the Cochrane Central Register of Controlled Trials (CENTRAL 2013, Issue 5), MEDLINE (1950 to June week 2, 2013), EMBASE (1980 to 2013 week 24) and CINAHL (1982 to 2013). Comparative data of any type, which evaluated dilation or penetration of the vagina after pelvic radiotherapy treatment for cancer. Two review authors independently assessed whether potentially relevant studies met the inclusion criteria. We found no trials and therefore analysed no data. We identified no studies for inclusion in the original review or for this update. However, we felt that some studies that were excluded warranted discussion. These included one randomised trial (RCT), which showed no improvement in sexual scores associated with encouraging women to practise dilation therapy; a recent small RCT that did not show any advantage to dilation over vibration therapy during radiotherapy; two non-randomised comparative studies; and five correlation studies. One of these showed that objective measurements of vaginal elasticity and length were not linked to dilation during radiotherapy, but the study lacked power. One study showed that women who dilated tolerated a larger dilator, but the risk of objectivity and bias with historical controls was high. Another study showed that the vaginal measurements increased in length by a mean of 3 cm after dilation was introduced 6 to 10 weeks after radiotherapy, but there was no control group; another case series showed the opposite. Three recent studies showed less stenosis associated with prophylactic dilation after radiotherapy. One small case series suggested that dilation years after radiotherapy might restore the vagina to a functional length. There is no reliable evidence to show that routine, regular vaginal dilation during radiotherapy treatment prevents stenosis or improves quality of life. Several observational studies have examined the effect of dilation therapy after radiotherapy. They suggest that frequent dilation practice is associated with lower rates of self reported stenosis. This could be because dilation is effective or because women with a healthy vagina are more likely to comply with dilation therapy instructions compared to women with strictures. We would normally suggest that a RCT is needed to distinguish between a casual and causative link, but pilot studies highlight many reasons why RCT methodology is challenging in this area.

Intravesical instillations with polydeoxyribonucleotides reduce symptoms of radiation-induced cystitis in patients treated with radiotherapy for pelvic cancer: a pilot study

Chronic radiation cystitis (CRC) is a serious complication that can arise in patients with pelvic malignancies treated with radiotherapy. Polydeoxyribonucleotides (PDRNs) are known to reduce inflammation and improve tissue perfusion and angiogenesis. In this manuscript, we describe our observational experience regarding intravesical instillation of PDRNs in improving symptoms of CRC in subjects unresponsiveness to conventional medical therapy. Eight patients with persistent and/or worsening CRC symptoms, despite conventional therapy, received biweekly intravesical instillation of PDRNs for two consecutive months. Symptoms were scored according to the Late Effects of Normal Tissues-Subjective, Objective, Management, Analytic (LENT-SOMA) scale, before, at the end, and after 4 months following the PDRNs treatment. Four months after instillations, a significant improvement in the subjective perception of CRC symptoms was experienced by participants. The mean LENT-SOMA score was reduced from 1.16+0.26 before to 0.34+0.035 after 4 months from instillations (p<0.001). No adverse effect related to instillations was reported. Subjective perception of persistent and/or worsening CRC symptoms, despite conventional therapy, is improved after intravesical instillation with PDRNs without adverse events. Even though we deduced suggestive insights, the results need to be collected and verified from a large-scale study.

Management of Radiation-Induced Rectal Bleeding

Pelvic radiation disease is one of the major complication after radiotherapy for pelvic cancers. The most commonly reported symptom is rectal bleeding which affects patients' quality of life. Therapeutic strategies for rectal bleeding are generally ignored and include medical, endoscopic, and hyperbaric oxygen treatments. Most cases of radiation-induced bleeding are mild and self-limiting, and treatment is normally not indicated. In cases of clinically significant bleeding (i.e. anaemia), medical therapies, including stool softeners, sucralfate enemas, and metronidazole, should be considered as first-line treatment options. In cases of failure, endoscopic therapy, mainly represented by argon plasma coagulation and hyperbaric oxygen treatments, are valid and complementary second-line treatment strategies. Although current treatment options are not always supported by high-quality studies, patients should be reassured that treatment options exist and success is achieved in most cases if the patient is referred to a dedicated centre.

Pelvic Radiotherapy and Sexual Function in Men and Women

Despite the decrease in overall cancer incidence and mortality rates in developed countries since the early 1990 s, cancer remains a major public health problem. Sexual dysfunction is one of the more common consequences of cancer treatment. To shortly review the literature and level of evidence on sexual dysfunction in men and women following pelvic radiotherapy. Male and female sexual dysfunction. Literature review. Sexual dysfunction in cancer patients is multidimensional and may result from biological, psychological, and social factors. Anatomic changes caused by surgery and/or radiotherapy, physiological changes following hormonal manipulation, and the secondary effect of medical intervention may impede or preclude sexual functioning, even when sexual desire is intact. Pelvic irradiation constitutes the primary or adjuvant treatment for a large number of both female and male cancers. No randomized controlled trials could be identified regarding the effect of radiotherapy on sexual dysfunction. However, prospective and clinical controlled trials all demonstrated a severe negative effect on sexual functioning in men and women following radiotherapy for a pelvic cancer. Following pelvic radiotherapy for prostate cancer, a positive effect of phosphodiesterase type 5 inhibitors on erectile dysfunction has been demonstrated, whereas no significant effect on female sexuality was found. Few studies evaluated treatment of female sexual dysfunction following radiotherapy; hormone replacement therapy and the use of vaginal dilator in combination with psycho-educational support is recommended. Pelvic radiotherapy plays a significant negative role in the complex scenario of male and female sexual dysfunction. The literature has focused on sexual dysfunction and intervention in prostate and cervical cancer patients. Sexual dysfunction following pelvic radiotherapy for cancer in other pelvic organs, e.g., bladder, rectum, and anus, requires more attention in future studies. Health care providers should pay attention to and provide psychological and medical support regarding sexual dysfunction to all patients who have received pelvic radiotherapy.

Two cases of radiation-induced cutaneous angiosarcoma

We report two cases of radiation-induced cutaneous angiosarcoma that occurred years after radiotherapy for pelvic cancer. The tumors in both cases were inoperable because of the poor performance status of the patient or the extent of the lesion. We treated the tumors with concurrent chemotherapy and radiotherapy. The chemotherapy consisted of the weekly administration of 70 mg/m2 paclitaxel. Both patients received radiotherapy at the prescribed dose of 50 Gy in 2.0-Gy fractions. Two months after the treatment, the lesions of both cases diminished or disappeared. However, a few months after the treatment, both patients suffered from in-field local recurrence and distant metastases, and they subsequently died of their distant metastases. The initial responses of two cases to concurrent chemoradiotherapy were good, and their quality of life was improved without severe complication. Although the long-term control of radiation-induced cutaneous angiosarcoma was difficult, chemoradiotherapy was one of the safe and effective palliative treatments.

A mechanism for abnormal angiogenesis in human radiation proctitis: analysis of expression profile for angiogenic factors

Radiation proctitis is an increasingly prevalent problem, with many patients being treated with radiotherapy for pelvic cancers. However, the mechanisms by which radiation proctitis develops in humans are not well understood. In this study, the expression profiles of angiogenic factors were analyzed to clarify their role in the etiology of radiation proctitis. Rectal biopsies were taken from 8 patients with radiation proctitis and 8 normal subjects. Protein lysates of the tissues were applied to an antibody array for angiogenesis-related factors. The mRNA level of each factor was evaluated by Taqman real-time PCR. Immunohistochemistry was performed using the labeled streptavidin biotin method. Antibody array analysis revealed 2.12- to 7.31-fold higher expression levels of angiogenin, fibroblast growth factor 1 (FGF1), endoglin, matrix metalloproteinase (MMP)-8, urokinase-type plasminogen activator (uPA) and maspin in radiation proctitis tissues compared with normal rectal mucosa. The mRNA level of each factor in radiation proctitis tissue was significantly higher than in normal rectal mucosa, suggesting their transcriptional activation. Immunohistochemical staining showed strong expression of angiogenin and maspin in rectal epithelia, MMP-8 and uPA in infiltrating lymphocytes, FGF1 in fibroblasts and endoglin in endothelial cells. The expression of VEGF was not evident. Our results suggest that in radiation proctitis, MMP-8 and uPA cooperatively degrade the extracellular matrix and basement membrane to provide space for angiogenesis. Simultaneously, angiogenin and FGF1 promote endothelial cell proliferation, and endoglin induces vessel formation, culminating in angiogenesis. Inhibitors of angiogenic factors such as angiogenin and FGF1 may be effective for treating radiation proctitis.

What the journals say

Approximately 12 000 people each year undergo radiotherapy for pelvic cancers in the UK, and the rapidly dividing cells of the gut are at high risk of damage. Side effects include abdominal pain, diarrhoea, faecal urgency and incontinence, and bloating.

Glucagon-Like Peptide-2 Improves Both Acute and Late Experimental Radiation Enteritis in the Rat

Acute and/or chronic radiation enteritis can develop after radiotherapy for pelvic cancers. Experimental and clinical observations have provided evidence of a role played by acute mucosal disruption in the appearance of late effects. The therapeutic potential of acute administration of glucagon-like peptide-2 (GLP-2) against acute and chronic intestinal injury was investigated in this study. Intestinal segments were surgically exteriorized and exposed to 16.7 or 19 Gy X-rays. The rats were treated once daily with vehicle or a protease-resistant GLP-2 derivative for 14 days before irradiation, with or without 7 days of GLP-2 after treatment. Macroscopic and microscopic observations were made 2 and 15 weeks after radiation exposure. In the control animals, GLP-2 induced an increase in intestinal mucosal mass, along with an increase in villus height and crypt depth. GLP-2 administration before and after irradiation completely prevented the acute radiation-induced mucosal ulcerations observed after exposure to 16.7 Gy. GLP-2 treatment strikingly reduced the late radiation damage observed after 19 Gy irradiation. Microscopic observations revealed an improved organization of the intestinal wall and an efficient wound healing process, especially in the smooth muscle layers. GLP-2 has a clear therapeutic potential against both acute and chronic radiation enteritis. This therapeutic effect is mediated through an increased mucosal mass before tissue injury and the stimulation of still unknown mechanisms of tissue response to radiation damage. Although these preliminary results still need to be confirmed, GLP-2 might be a way to limit patient discomfort during radiotherapy and reduce the risk of consequential late effects.

The clinical needs of patients with chronic gastrointestinal symptoms after pelvic radiotherapy

After radiotherapy for pelvic cancer, gastrointestinal symptoms affecting quality of life are common. How they affect daily living is unknown. To investigate the day-to-day impact of gastrointestinal symptoms in patients after pelvic radiotherapy. New patients referred for gastroenterological evaluation of radiotherapy-induced symptoms were sent a questionnaire. Over 15 months, 75 of 100 questionnaires were completed before the gastroenterology appointment by 45 men (median age 70) and 30 women (median age 57) treated for urological (n = 44), gynaecological (n = 27) and gastrointestinal (n = 4) cancers. Time since radiotherapy was 3 years (median) for women and 1.5 years (men). Women experienced 6 (median) symptoms whilst men experienced 4. Having someone listen to problems was often as important as treatment. Urgency, diarrhoea, pain, rectal bleeding, flatulence and bloating were particularly troublesome. 57% women and 33% men were 'very affected'. Symptoms rarely improved with time and in 33% had been present for more than 2 years. Gastrointestinal symptoms affected quality of life through change of routine (F 37%, M 22%), social limitation (F 17%, M 33%), physical limitations (F 33%, M 16%), emotional difficulties (F 47%, M 18%) and sexual problems (F 30%, M 51%). Patients experience a high number of physical symptoms for long periods before referral. Clinicians must focus systematically on physical, emotional and psychosexual issues.

A modified Inflammatory Bowel Disease questionnaire and the Vaizey Incontinence questionnaire are simple ways to identify patients with significant gastrointestinal symptoms after pelvic radiotherapy

After radiotherapy for pelvic cancer, chronic gastrointestinal problems may affect quality of life (QOL) in 6–78% of patients. This variation may be due to true differences in outcome in different diseases, and may also represent the inadequacy of the scales used to measure radiotherapy-induced gastrointestinal side effects. The aim of this study was to assess whether outcome measures used for nonmalignant gastrointestinal disease are useful to detect gastrointestinal morbidity after radiotherapy. Results obtained from a Vaizey Incontinence questionnaire and a modified Inflammatory Bowel Disease questionnaire (IBDQ) – both patient completed – were compared to those from a staff administered Late Effects on Normal Tissue (LENT) – Subjective, Objective, Management and Analytic (SOMA) questionnaire in patients who had completed radiotherapy for a pelvic tumour at least 3 months previously. In all, 142 consecutive patients were recruited, 72 male and 70 female, median age 66 years (range 26–90 years), a median of 27 (range 3–258) months after radiotherapy. In total, 62 had been treated for a gynaecological, 58, a urological and 22, a gastrointestinal tract tumour. Of these, 21 had undergone previous gastrointestinal surgery and seven suffered chronic gastrointestinal disorders preceding their diagnosis of cancer. The Vaizey questionnaire suggested that 27% patients were incontinent for solid stools, 35% for liquid stools and 37% could not defer defaecation for 15 min. The IBDQ suggested that 89% had developed a chronic change in bowel habit and this change significantly affected 49% patients: 44% had more frequent or looser bowel movements, 30% were troubled by abdominal pain, 30% were troubled by bloating, 28% complained of tenesmus, 27% were troubled by their accidental soiling and 20% had rectal bleeding. At least 34% suffered emotional distress and 22% impairment of social function because of their bowels. The small intestine/colon SOMA median score was 0.1538 (range 0–1) and the rectal SOMA median score was 0.1428 (range 0–1). Pearson's correlations for the IBDQ score and small intestine/colon SOMA score was −0.630 (P<0.001), IBDQ and rectum SOMA −0.616 (P<0.001), IBDQ and Vaizey scores −0.599 (P<0.001), Vaizey and small intestine/colon SOMA 0.452 (P<0.001) and Vaizey and rectum SOMA 0.760 (P<0.001). After radiotherapy for a tumour in the pelvis, half of all patients develop gastrointestinal morbidity, which affects their QOL. A modified IBDQ and Vaizey questionnaire are reliable in assessing new gastrointestinal symptoms as well as overall QOL and are much easier to use than LENT SOMA.

The role of radiological imaging in the patient with gastrointestinal symptoms after pelvic radiotherapy

In recent years there have been sustained improvements in the outcomes from pelvic malignancy, with the introduction of new radiotherapy or combined chemotherapy–radiation treatment schedules [1, 2]. Approximately four out of 10 people with cancer will have radiotherapy as part of their treatment. In the UK this includes about 12000 patients annually who are treated with radiotherapy for pelvic cancer, mainly with curative intent.