Radiation-induced Late Side Effects Research Articles

Late Side Effects in Normal Mouse Brain Tissue After Proton Irradiation

Radiation-induced late side effects such as cognitive decline and normal tissue complications can severely affect quality of life and outcome in long-term survivors of brain tumors. Proton therapy offers a favorable depth-dose deposition with the potential to spare tumor-surrounding normal tissue, thus potentially reducing such side effects. In this study, we describe a preclinical model to reveal underlying biological mechanisms caused by precise high-dose proton irradiation of a brain subvolume. We studied the dose- and time-dependent radiation response of mouse brain tissue, using a high-precision image-guided proton irradiation setup for small animals established at the University Proton Therapy Dresden (UPTD). The right hippocampal area of ten C57BL/6 and ten C3H/He mice was irradiated. Both strains contained four groups (nirradiated = 3, ncontrol = 1) treated with increasing doses (0 Gy, 45 Gy, 65 Gy or 85 Gy and 0 Gy, 40 Gy, 60 Gy or 80 Gy, respectively). Follow-up examinations were performed for up to six months, including longitudinal monitoring of general health status and regular contrast-enhanced magnetic resonance imaging (MRI) of mouse brains. These findings were related to comprehensive histological analysis. In all mice of the highest dose group, first symptoms of blood-brain barrier (BBB) damage appeared one week after irradiation, while a dose-dependent delay in onset was observed for lower doses. MRI contrast agent leakage occurred in the irradiated brain areas and was progressive in the higher dose groups. Mouse health status and survival corresponded to the extent of contrast agent leakage. Histological analysis revealed tissue changes such as vessel abnormalities, gliosis, and granule cell dispersion, which also partly affected the non-irradiated contralateral hippocampus in the higher dose groups. All observed effects depended strongly on the prescribed radiation dose and the outcome, i.e. survival, image changes, and tissue alterations, were very consistent within an experimental dose cohort. The derived dose–response model will determine endpoint-specific dose levels for future experiments and may support generating clinical hypotheses on brain toxicity after proton therapy.

Impact of VEGF gene polymorphisms and haplotypes on radiation-induced late toxicity in prostate cancer patients

Vascular endothelial growth factor (VEGF) is an important determinant of microvascular permeability and angiogenesis and has been shown to be up-regulated during the late phase of radiation injury. The present prospective study was performed to evaluate the role of VEGF gene polymorphisms and haplotypes in the development of radiation-induced late side effects in prostate cancer patients. The association of VEGF gene polymorphisms and haplotypes with high-grade late rectal or urinary toxicity (defined as late toxicity EORTC/RTOG ≥ 2) was analyzed using 493 prostate cancer patients from the Austrian PROCAGENE study treated with definitive radiotherapy. Seven candidate polymorphisms in the VEGF gene were selected and determined by 5'-nuclease (TaqMan) assays. Within a median follow-up time of 48 months, 42 patients (8.6%) developed high-grade late rectal and 47 patients (9.6%) urinary toxicity, respectively. In a Kaplan-Meier analysis, carriers of the VEGF -7C > T polymorphism were at increased risk of high-grade late rectal toxicity (p = 0.003) and in a multivariate analysis including clinical and dosimetric parameters as potential confounders the VEGF -7C > T polymorphism remained a significant predictor (HR = 2.8, 95% CI 1.349-5.813; p = 0.006). Furthermore, the ATTGT haplotype formed by five polymorphisms upstream of the coding sequence demonstrated a significant association with late rectal toxicity grade ≥ 2 (p = 0.001). No significant associations were found for the remaining polymorphisms and haplotypes. We conclude that genetic variants in the VEGF gene may influence the risk of high-grade late rectal toxicity after definitive radiotherapy for prostate cancer.

Association between single nucleotide polymorphisms in the gene for XRCC1 and radiation-induced late toxicity in prostate cancer patients

Background and purposePolymorphisms in genes responsible for DNA damage signaling and repair might modulate DNA repair capacity and, therefore, affect cell and tissue response to radiation and influence individual radiosensitivity. The purpose of the present prospective investigation was to evaluate the association of single nucleotide polymorphisms in XRCC1 with radiation-induced late side effects in prostate cancer patients treated with radiotherapy. Material and methodsTo analyze the role of XRCC1 polymorphisms for late toxicity 603 participants from the Austrian PROCAGENE study treated with three-dimensional conformal radiotherapy were included in the present investigation. Three non-synonymous candidate polymorphisms in the X-ray repair cross-complementing group 1 (XRCC1) gene (Arg194Trp; Arg280His; Arg399Gln) were selected and determined by 5´-nuclease (TaqMan) assays. ResultsWithin a median follow-up time of 35months, 91 patients (15.7%) developed high-grade late toxicities (defined as late bladder and/or rectal toxicity RTOG⩾2). In a Kaplan–Meier analysis, carriers of the XRCC1 Arg280His polymorphism were at decreased risk of high-grade late toxicity (p=0.022), in multivariate analysis including clinical and dosimetric parameters as potential confounders the XRCC1 Arg280His polymorphism remained a significant predictor for high-grade late toxicity (HR=0.221, 95% CI 0.051–0.956; p=0.043). No significant associations were found for the remaining polymorphisms. ConclusionsWe conclude that the XRCC1 Arg280His polymorphism may be protective against the development of high-grade late toxicity after radiotherapy in prostate cancer patients.

Facteurs de radiosensibilité tardive des tissus sains

The impact of curative radiotherapy depends mainly on the total dose delivered homogenously in the targeted volume. Nevertheless, the dose delivered to the surrounding healthy tissues may reduce the therapeutic ratio of many radiation treatments. Two different side effects (acute and late) can occur during and after radiotherapy. Of particular interest are the radiation-induced sequelae due to their irreversibility and the potential impact on daily quality of life. In a same population treated in one centre with the same technique, it appears that individual radiosensitivity clearly exists. In the hypothesis that genetic is involved in this area of research, lymphocytes seem to be the tissue of choice due to easy accessibility. Recently, low percentage of CD4 and CD8 lymphocyte apoptosis were shown to be correlated with high grade of sequelae. In addition, recent data suggest that patients with severe radiation-induced late side effects possess four or more single nucleotide polymorphisms (SNP) in candidate genes (ATM, SOD2, TGFB1, XRCC1, and XRCC3) and low radiation-induced CD8 lymphocyte apoptosis in vitro. On-going studies are being analyzing the entire genome using a Genome-wide association study (GWAS) analysis.

Séquelles radio-induites et tests prédictifs

The impact of curative radiotherapy depends mainly on the total dose delivered homogenously in the targeted volume. Nevertheless, the dose delivery is limited by the tolerated dose of the surrounding healthy tissues. Two different side effects (acute and late) can occur during and after radiotherapy. Of particular interest are the radiation-induced sequelae due to their irreversibility and the potential impact on daily quality of life. In a population treated in one center with the same technique, it appears that individual radiosensitivity clearly exists. In the hypothesis that genetic is involved in this area of research, lymphocytes seem to be the tissue of choice due to easy accessibility. Recently, low percentage of CD4 and CD8 lymphocyte apoptosis were shown to be correlated with high grade of sequelae. In addition, recent data suggest that patients with severe radiation-induced late side effects possess four or more SNP in candidate genes ( ATM, SOD2, TGFB1, XRCC1 et XRCC3) and low radiation-induced CD8 lymphocyte apoptosis in vitro.

Improved Quality of Life with Hyperbaric Oxygen Therapy in Patients with Persistent Pelvic Radiation-induced Toxicity

Aims We report the results of hyperbaric oxygen therapy (HBOT) used in the treatment of radiation-induced persistent side-effects after the irradiation of pelvic tumours. Materials and methods Between January 2001 and December 2005, 13 women (median age 60.3 years) with radiation combined proctitis/cystitis ( n = 6), longstanding vaginal ulcers and fistulas ( n = 5) and longstanding skin injuries ( n = 2) underwent HBOT in a multiplace chamber for a median of 27 sessions (range 16–40). The treatment schedule was HBOT 100% oxygen, at 2 absolute atmospheres, for 90 min, once a day. For radiation-induced toxicity grading we used the National Cancer Institute Common Toxicity Criteria (CTC) grading system, before and after HBOT. Results Thirteen patients underwent an adequate number of HBOT sessions. The mean CTC grading score before HBOT was 3.3 ± 0.75, whereas the mean CTC grading score after HBOT was 0.3 ± 0.63. The scores showed a significant improvement after HBOT ( P = 0.001; exact Wilcoxon signed-rank test). Rectal bleeding ceased in five of six patients with proctitis and dysuria resolved in six of seven cystitis patients. Macroscopic haematuria stopped in seven of seven patients. Scar complications resolved in two of two patients. None reported HBOT-associated side-effects. Conclusion HBOT is apparently safe and effective in managing radiation-induced late side-effects, such as soft tissue necrosis (skin and vagina), cystitis, proctitis and fistulas.

The efficacy of hyperbaric oxygen therapy (HBOT) in the treatment of pelvic radiation-induced late side effects

18576 Background: The treatment of pelvic malignancies (uterine, cervix, rectum, etc) often include radiation. Radiation-induced late side effects (longer than 3 months) are developed in 5–10% of those patients. We wanted to investigate the efficacy of hyperbaric oxygen therapy (HBOT) in the management of those patients. Methods: Thirteen women were evaluated. The primary cancer sources were: cervix (7), vagina (2), uterus (2), rectum (1) and bladder (1). All patients were treated with a full pelvic dose of radiotherapy. Eight patients also underwent post-radiation surgery (4 post-hysterectomy, 1 post-colectomy, 1 post-vaginectomy, 1 post-cystectomy and 1 post-exanteration). Eleven patients suffered from pelvic pain, 7 from chronic cystitis (including 2 with vesico-vaginal fistulas), 7 had chronic proctitis (including 2 with recto-vaginal fistulas), 3 had long-standing vaginal ulcers, and one presented with a long-standing open skin wound following surgery. All patients underwent imaging studies and biopsies to rule out active malignant disease, and all received HBOT 100% oxygen, at 2 absolute atmospheres, for 90 minutes (2ATA 90 min). Results: The mean patient age was 61 years (range 32–88). The mean time between completion of radiation therapy and onset of symptoms was 32 months (range 4–60). The patients received an average of 27 HBOTs (range 16–40). Twelve patients reported improvement in pelvic pain, bladder and bowel symptoms and decrease in vaginal discharge. One patient developed lung metastasis and another developed pelvic recurrence. No patient reported side effects associated with HBOT. Conclusion: HBOT appears to be safe and effective in the management of pelvic radiation-induced late side effects, such as soft tissue necrosis (skin and vagina), cystitis, proctitis and fistulas. No significant financial relationships to disclose.

The efficacy of hyperbaric oxygen therapy in the treatment of radiation-induced late side effects

Purpose We investigated the efficacy of hyperbaric oxygen therapy (HBOT) in the management of patients with radiation-induced late side effects, the majority of whom had failed previous interventions. Methods and materials Of 105 eligible subjects, 30 had either died or were not contactable, leaving 75 who qualified for inclusion in this retrospective study. Patients answered a questionnaire documenting symptom severity before and after treatment (using Radiation Therapy Oncology Group criteria), duration of improvement, relapse incidence, and HBOT-related complications. Results The rate of participation was 60% (45/75). Improvement of principal presenting symptoms after HBOT was noted in 75% of head-and-neck, 100% of pelvic, and 57% of “other” subjects (median duration of response of 62, 72, and 68 weeks, respectively). Bone and bladder symptoms were most likely to benefit from HBOT (response rate, 81% and 83%, respectively). Fifty percent of subjects with soft tissue necrosis/mucous membrane side effects improved with HBOT. The low response rate of salivary (11%), neurologic (17%), laryngeal (17%), and upper gastrointestinal symptoms (22%) indicates that these were more resistant to HBOT. Relapse incidence was low (22%), and minor HBOT-related complications occurred in 31% of patients. Conclusion Hyperbaric oxygen therapy is a safe and effective treatment modality offering durable relief in the management of radiation-induced osteoradionecrosis either alone or as an adjunctive treatment. Radiation soft tissue necrosis, cystitis, and proctitis also seemed to benefit from HBOT, but the present study did not have sufficient numbers to reliably predict long-term response.