To summarize current knowledge about gastrointestinal radiation toxicity, with emphasis on mechanisms and clinical diagnosis and management.
While there has been only modest change in cancer ...incidence and cancer mortality rates during the past 30 years, the number of cancer survivors has more than doubled. Moreover, the recognition of uncomplicated cancer cure as the ultimate goal in oncology has intensified efforts to prevent, diagnose, and manage side effects of radiation therapy. These efforts have been facilitated by recent insight into the underlying pathophysiology.
The risk of injury to the intestine is dose limiting during abdominal and pelvic radiation therapy. Delayed bowel toxicity is difficult to manage and adversely impacts the quality of life of cancer survivors. More than 200,000 patients per year receive abdominal or pelvic radiation therapy, and the estimated number of cancer survivors with postradiation intestinal dysfunction is 1.5-2 million. Worthwhile progress towards reducing toxicity of radiation therapy has been made by dose-sculpting treatment techniques. Approaches derived from an improved understanding of the pathophysiology of bowel injury, however, will result in further advances. This article discusses the mechanisms of radiation-induced bowel toxicity and reviews current principles in diagnosis and management.
Purpose: To quantify the oral mucosal cell density and proliferation rate during conventional radiotherapy of head-and-neck tumors and to compare these parameters with clinical scoring of oral ...mucositis.
Methods and Materials: Between 1996 and 1999, 22 patients were included in this study. Mucosal biopsies were taken before or during the radiotherapy course (5 × 2 Gy/wk). Biopsies were incubated in vitro with tritiated thymidine immediately after excision to label DNA-synthesizing cells.
Results: Epithelial cell density followed a biphasic radiation response. A steep decrease to about 50% of the preirradiation value (1000 cells/mm epithelium) during Week 1 was followed by a more gradual loss to about 400 cells at the end of treatment. The initial phase was based on the depression of proliferation, with 5–10 labeled cells/mm at the end of Week 1 vs. 60 labeled cells/mm in controls. Subsequently, proliferation was partially restituted at 20 labeled cells/mm. A significant difference in cell numbers was seen between Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer Grade 0 (∼850 cell/mm) and Grade 2 (325/mm) or Grade 3 (370/mm). No significant differences were observed between reaction grades 1, 2, and 3.
Conclusion: Conventionally fractionated radiotherapy induces a rapid suppression in cell production in Week 1, which results in a prompt reduction in cell numbers. Subsequently, a partial restoration of proliferation significantly reduces the rate of cell loss. These processes clearly precede the clinical response. Regeneration, defined as restoration of cellularity, is already under way when the maximal clinical response is observed. Clinical reaction grading corresponds poorly to cellular density measures during conventional fractionation.
The intestine is often dose limiting during abdominal and pelvic radiation therapy. Delayed bowel toxicity is difficult to manage and adversely impacts the quality of life of long-term cancer ...survivors. Of the 8 to 9 million cancer survivors currently living in the United States, more than half have had abdominal or pelvic tumors, and about 60% of these patients have undergone or will undergo radiation therapy. Therefore, interventions that limit postradiation intestinal dysfunction would significantly improve outcomes in a large number of patients. Worthwhile steps toward reducing toxicity of treatments have been taken recently by introducing dose-sculpting treatment techniques. However, prophylactic or therapeutic approaches derived from an improved understanding of the pathophysiology of bowel injury will result in further advances. This article reviews current principles in the diagnosis and management of intestinal radiation injury. It also provides an overview of investigational strategies aimed at reducing radiation-induced bowel toxicity. These strategies include free radical scavengers, antioxidants, cytoprotective agents, cytokines, and enterotrophic interventions, as well as modulators of intraluminal factors, endothelial dysfunction, and neuroimmune interactions. Preclinical testing in clinically relevant animal models will facilitate translation of these strategies into the clinic and contribute to improving cancer cure rates and quality of life in cancer survivors.
We assessed the association of the spatial distribution of dose to the bladder surface, described using dose-surface maps, with the risk of urinary dysfunction.
The bladder dose-surface maps of 754 ...participants from the TROG 03.04-RADAR trial were generated from the volumetric data by virtually cutting the bladder at the sagittal slice, intersecting the bladder center-of-mass through to the bladder posterior and projecting the dose information on a 2-dimensional plane. Pixelwise dose comparisons were performed between patients with and without symptoms (dysuria, hematuria, incontinence, and an International Prostate Symptom Score increase of ≥10 ΔIPSS10). The results with and without permutation-based multiple-comparison adjustments are reported. The pixelwise multivariate analysis findings (peak-event model for dysuria, hematuria, and ΔIPSS10; event-count model for incontinence), with adjustments for clinical factors, are also reported.
The associations of the spatially specific dose measures to urinary dysfunction were dependent on the presence of specific symptoms. The doses received by the anteroinferior and, to lesser extent, posterosuperior surface of the bladder had the strongest relationship with the incidence of dysuria, hematuria, and ΔIPSS10, both with and without adjustment for clinical factors. For the doses to the posteroinferior region corresponding to the area of the trigone, the only symptom with significance was incontinence.
A spatially variable response of the bladder surface to the dose was found for symptoms of urinary dysfunction. Limiting the dose extending anteriorly might help reduce the risk of urinary dysfunction.
To describe the natural history of mucosal changes, in particular the development of telangiectases in the rectum, after radiotherapy (RT) for prostate cancer.
Twenty patients undergoing local-field, ...nonconformal RT for prostate cancer underwent flexible sigmoidoscopy every 6 months for up to 3 years after RT completion. Telangiectasis was scored as absent, single, multiple, or multiple confluent. The site and circumferential extent were also documented. The patients filled in a diary to document the symptoms they were experiencing, including rectal bleeding.
Of the 20 patients, 12 developed multiple telangiectases, and 10 of these had rectal bleeding, which in all cases was mild. Telangiectasis was most commonly seen between 4 (anorectal junction) and 8 cm from the anal verge. In 5 patients, 4 of whom had multiple telangiectases, spontaneous resolution occurred.
Late radiation effects in the rectum do not appear to be permanent in all cases. This first prospective prolonged evaluation may provide an explanation for the observation that rectal bleeding resolves in a large proportion of patients with mild symptoms after RT. The reasons for improvement in the late radiation changes in the rectum compared with the permanent changes seen in organs such as the skin are unknown.
Abstract Background and purpose A multi-centre clinical trial for prostate cancer patients provided an opportunity to introduce conformal radiotherapy with dose escalation. To verify adequate ...treatment accuracy prior to patient recruitment, centres submitted details of a set-up accuracy study (SUAS). We report the results of the SUAS, the variation in clinical practice and the strategies used to help centres improve treatment accuracy. Materials and methods The SUAS required each of the 24 participating centres to collect data on at least 10 pelvic patients imaged on a minimum of 20 occasions. Software was provided for data collection and analysis. Support to centres was provided through educational lectures, the trial quality assurance team and an information booklet. Results Only two centres had recently carried out a SUAS prior to the trial opening. Systematic errors were generally smaller than those previously reported in the literature. The questionnaire identified many differences in patient set-up protocols. As a result of participating in this QA activity more than 65% of centres improved their treatment delivery accuracy. Conclusions Conducting a pre-trial SUAS has led to improvement in treatment delivery accuracy in many centres. Treatment techniques and set-up accuracy varied greatly, demonstrating a need to ensure an on-going awareness for such studies in future trials and with the introduction of dose escalation or new technologies.
Purpose:
Electronic portal imaging devices (EPIDs) are high resolution systems that produce electronic dose maps with minimal time required for equipment setup, and therefore potentially present a ...time-saving alternative for intensity modulated radiation therapy (IMRT) pretreatment verification. A modified commercial EPID was investigated operated with an opaque sheet blocking the optical signal produced in the phosphor layer as a precursor to a switched mode dual dosimetry-imaging EPID system. The purpose of this study was to investigate the feasibility of using this system for direct dose to water dosimetry for pretreatment IMRT verification.
Methods:
A Varian amorphous silicon EPID was modified by placing an opaque sheet between the Gd2S2O:Tb phosphor layer and the photodiode array to block the optical photons. The EPID was thus converted to a direct-detecting system (dEPID), in which the high energy radiation deposits energy directly in the photodiode array. The copper build-up was replaced with dmax solid water. Sixty-one IMRT beams of varying complexity were delivered to the EPID, to EDR2 dosimetric film and to a 2D ion chamber array (MapCheck). EPID data was compared to film and MapCheck data using gamma analysis with 3%, 3mm pass criteria.
Results:
The fraction of points that passed the gamma test was on average 98.1% and 98.6%, for the EPID versus film and EPID versus MapCheck comparisons, respectively. In the case of comparison with film, the majority of observed discrepancies were associated with problems related to film sensitivity or processing.
Conclusions:
The very close agreement between EPID and both film and MapCheck data demonstrates that the modified EPID is suitable for direct dose to water measurement for pretreatment IMRT verification. These results suggest a reconfigured EPID could be an efficient and accurate dosimeter. Alternatively, optical switching methods could be developed to produce a dual-mode EPID with both dosimetry and imaging capabilities.
The findings show that in terms of the trial's primary endpoint, the mean difference in change in score on the IBDQ-B instrument between baseline and 6 months, both gastroenterologist-led care (5·47, ...95% CI 1·14-9·81; p=0·01) and nurse-led care (4·12, 0·04-8·19; p=0·04) were superior to usual care; in other words, both men and women with a range of RBIs can have clinical and statistically significant improvements in their symptoms with tailored management programmes determined by an investigative and therapeutic algorithm.
Abstract Purpose/objective To identify dosimetry, clinical factors and medication intake impacting urinary symptoms after prostate radiotherapy. Material and methods Data describing clinical factors ...and bladder dosimetry (reduced with principal component (PC) analysis) for 754 patients treated with external beam radiotherapy accrued by TROG 03.04 RADAR prostate radiotherapy trial were available for analysis. Urinary symptoms (frequency, incontinence, dysuria and haematuria) were prospectively assessed using LENT-SOMA to a median of 72 months. The endpoints assessed were prevalence (grade ⩾1) at the end of radiotherapy (representing acute symptoms), at 18-, 36- and 54-month follow-ups (representing late symptoms) and peak late incidence including only grade ⩾2. Impact of factors was assessed using multivariate logistic regression models with correction for over-optimism. Results Baseline symptoms, non-insulin dependent diabetes mellitus, age and PC1 (correlated to the mean dose) impact symptoms at >1 timepoints. Associations at a single timepoint were found for cerebrovascular condition, ECOG status and non-steroidal anti-inflammatory drug intake. Peak incidence analysis shows the impact of baseline, bowel and cerebrovascular condition and smoking status. Conclusions The prevalence and incidence analysis provide a complementary view for urinary symptom prediction. Sustained impacts across time points were found for several factors while some associations were not repeated at different time points suggesting poorer or transient impact.
PDF
