Dose-response relationships of the sigmoid for urgency syndrome after gynecological radiotherapy.

PURPOSE: To find out what organs and doses are most relevant for 'radiation-induced urgency syndrome' in order to derive the corresponding dose-response relationships as an aid for avoiding the syndrome in the future. MATERIAL AND METHODS: From a larger group of gynecological cancer survivors followed-up 2-14 years, we identified 98 whom had undergone external beam radiation therapy but not brachytherapy and not having a stoma. Of those survivors, 24 developed urgency syndrome. Based on the loading factor from a factor analysis, and symptom frequency, 15 symptoms were weighted together to a score interpreted as the intensity of radiation-induced urgency symptom. On reactivated dose plans, we contoured the small intestine, sigmoid colon and the rectum (separate from the anal-sphincter region) and we exported the dose-volume histograms for each survivor. Dose-response relationships from respective risk organ and urgency syndrome were estimated by fitting the data to the Probit, RS, LKB and gEUD models. RESULTS: The rectum and sigmoid colon have steep dose-response relationships for urgency syndrome for Probit, RS and LKB. The dose-response parameters for the rectum were D50: 51.3, 51.4, and 51.3 Gy, γ50 = 1.19 for all models, s was 7.0e-09 for RS and n was 9.9 × 107 for LKB. For Sigmoid colon, D50 were 51.6, 51.6, and 51.5 Gy, γ50 were 1.20, 1.25, and 1.27, s was 2.8 for RS and n was 0.079 for LKB. CONCLUSIONS: Primarily the dose to sigmoid colon as well as the rectum is related to urgency syndrome among gynecological cancer survivors. Separate delineation of the rectum and sigmoid colon in order to incorporate the dose-response results may aid in reduction of the incidence of the urgency syndrome.

A novel mouse model of radiation-induced cancer survivorship diseases of the gut.

A deeper understanding of the radiation-induced pathophysiological processes that develop in the gut is imperative to prevent, alleviate, or eliminate cancer survivorship diseases after radiotherapy to the pelvic area. Most rodent models of high-dose gastrointestinal radiation injury are limited by high mortality. We therefore established a model that allows for the delivering of radiation in fractions at high doses while maintaining long-term survival. Adult male C57/BL6 mice were exposed to small-field irradiation, restricted to 1.5 cm of the colorectum using a linear accelerator. Each mouse received 6 or 8 Gy, two times daily in 12-h intervals in two, three, or four fractions. Acute cell death was examined at 4.5 h postirradiation and histological changes at 6 wk postirradiation. Another group was given four fractions of 8 Gy and followed over time for development of visible symptoms. Irradiation caused immediate cell death, mainly limited to the colorectum. At 6 wk postirradiation, several crypts displayed signs of radiation-induced degeneration. The degenerating crypts were seen alongside crypts that appeared perfectly healthy. Crypt survival was reduced after the fourth fraction regardless of dose, whereas the number of macrophages increased. Angiogenesis was induced, likely as a compensatory mechanism for hypoxia. Four months postirradiation, mice began to show radiation-induced symptoms, and histological examination revealed an extensive crypt loss and fibrosis. Our model is uniquely suitable for studying the long-term trajectory and underlying mechanisms of radiation-induced gastrointestinal injury.NEW & NOTEWORTHY A novel mouse model for studying the long-term trajectory of radiation-induced gut injury. The method allows for the use of high doses and multiple fractions, with minor impact on animal health for at least 3 mo. Crypt loss and a slow progression of fibrosis is observed. Crypt degeneration is a process restricted to isolated crypts. Crypt degeneration is presented as a convenient proxy endpoint for long-term radiation-induced gut injury.

Late radiation-induced bowel syndromes, tobacco smoking, age at treatment and time since treatment - gynecological cancer survivors.

BACKGROUND: It is unknown whether smoking; age at time of radiotherapy or time since radiotherapy influence the intensity of late radiation-induced bowel syndromes. MATERIAL AND METHODS: We have previously identified 28 symptoms decreasing bowel health among 623 gynecological-cancer survivors (three to twelve years after radiotherapy) and 344 matched population-based controls. The 28 symptoms were grouped into five separate late bowel syndromes through factor analysis. Here, we related possible predictors of bowel health to syndrome intensity, by combining factor analysis weights and symptom frequency on a person-incidence scale. RESULTS: A strong (p < .001) association between smoking and radiation-induced urgency syndrome was found with a syndrome intensity (normalized factor score) of 0.4 (never smoker), 1.2 (former smoker) and 2.5 (current smoker). Excessive gas discharge was also related to smoking (p = .001). Younger age at treatment resulted in a higher intensity, except for the leakage syndrome. For the urgency syndrome, intensity decreased with time since treatment. CONCLUSIONS: Smoking aggravates the radiation-induced urgency syndrome and excessive gas discharge syndrome. Smoking cessation may promote bowel health among gynecological-cancer survivors. Furthermore, by understanding the mechanism for the decline in urgency-syndrome intensity over time, we may identify new strategies for prevention and alleviation.

Defecation into clothing without forewarning and mean radiation dose to bowel and anal-sphincter among gynecological cancer survivors.

BACKGROUND: To analyze the relationship between mean radiation dose to the bowels and the anal-sphincter and occurrence of 'defecation into clothing without forewarning', a specific and serious fecal incontinence symptom after gynecological radiotherapy. Additional potential risk factors associated with the symptom are explored. MATERIAL AND METHODS: Data were collected for 519 eligible gynecological cancer survivors, treated with pelvic radiotherapy, with a median follow-up of 5.8 years, using a study-specific questionnaire and medical records. Correlations between defecation into clothing without forewarning and mean dose to organs at risk; the anal-sphincter region, the rectum, the sigmoid and the small intestines were investigated, also taking other risk factors into account. RESULTS: Twelve percent reported having had the symptom at least once in the preceding six months. Mean doses >50 Gy to the anal-sphincter region, the rectum, the sigmoid and the small intestines were related to the occurrence of the symptom. Significantly associated risk factors were deliveries with high birth weight, heart failure and lactose and/or gluten intolerance. After adjusting for these factors, mean doses >50 Gy to the anal-sphincter region, the sigmoid and the small intestines remained related to the occurrence of the symptom. CONCLUSION: Mean doses to the bowels and anal-sphincter region are related to the risk of defecation into clothing without forewarning in long-term gynecological cancer survivors treated with pelvic radiotherapy. Further radiobiological modeling may distinguish which organ(s) contribute most to development of the symptom.

Intra-abdominal Surgery and Intestinal Syndromes After Pelvic Radiation Therapy.

Purpose: To determine the effects of intra-abdominal surgery on the intensities of 5 radiation-induced intestinal syndromes in survivors of pelvic cancer. Methods and Materials: The analysis included 623 women born in 1927 or later who had survived cancer. They all had received external radiation therapy toward the pelvic area to treat gynecologic cancers. Information from 344 women who did not undergo irradiation, matched for age and residency, was also included. Main outcome measures after the surgical procedures were the intensity scores for 5 radiation-induced intestinal syndromes: urgency-tenesmus syndrome, fecal-leakage syndrome, excessive mucus discharge, excessive gas discharge, and blood discharge. The scores were based on symptom frequencies obtained from patient-reported outcomes and on factor loadings obtained from a previously reported factor analysis. Follow-up was 2 to 15 years after radiation therapy. Results: Among survivors of cancer, intra-abdominal surgery increased the intensity of the urgency-tenesmus syndrome, the fecal-leakage syndrome, excessive gas discharge, and blood discharge but had a negligible effect on mucus discharge. Intra-abdominal surgery had an especially negative effect on the urgency-tenesmus syndrome. Although the combination of appendectomy with 1 or more other intra-abdominal surgeries resulted in the highest score for all syndromes, appendectomy alone had weak to no effect. In women who did not undergo irradiation, a similar pattern was seen, albeit with much lower scores. Conclusions: We found intra-abdominal surgery to be a risk factor among survivors of gynecologic cancer, increasing the intensity score of 4 out of 5 radiation-induced intestinal syndromes. During radiation therapy, it may be worthwhile to pay extra attention to the dose of unwanted ionizing radiation to the intestines if the patient previously has undergone intra-abdominal surgery.

Dose-response relationships for an atomized symptom of fecal incontinence after gynecological radiotherapy.

PURPOSE: The aim of this study was to investigate what bowel organ and delivered dose levels are most relevant for the development of 'emptying of all stools into clothing without forewarning' so that the related dose-responses could be derived as an aid in avoiding this distressing symptom in the future. MATERIAL AND METHODS: Of the 77 gynecological cancer survivors treated with radiotherapy (RT) for gynecological cancer, 13 developed the symptom. The survivors were treated between 1991 and 2003. The anal-sphincter region, the rectum, the sigmoid and the small intestines were all delineated and the dose-volume histograms were exported for each patient. The dose-volume parameters were estimated fitting the data to the Relative Seriality (RS), the Lyman and the generalized Equivalent Uniform Dose (gEUD) model. RESULTS: The dose-response parameters for all three models and four organs at risk (OARs) were estimated. The data from the sigmoid fits the studied models best: D50 was 58.8 and 59.5 Gy (RS, Lyman), γ50 was 1.60 and 1.57 (RS, Lyman), s was 0.32, n was 0.13 and a was 7.7 (RS, Lyman, gEUD). The estimated volume parameters indicate that the investigated OARs behave serially for this endpoint. Our results for the three models studied indicate that they have the same predictive power (similar LL values) for the symptom as a function of the dose for all investigated OARs. CONCLUSIONS: In our study, the anal-sphincter region and sigmoid fit our data best, but all OARs were found to have steep dose-responses for 'emptying of all stools into clothing without forewarning' and thus, the outcome can be predicted with an NTCP model. In addition, the dose to the four studied OARs may be considered when minimizing the risk of the symptom.

Dose-response relationships of intestinal organs and excessive mucus discharge after gynaecological radiotherapy.

BACKGROUND: The study aims to determine possible dose-volume response relationships between the rectum, sigmoid colon and small intestine and the 'excessive mucus discharge' syndrome after pelvic radiotherapy for gynaecological cancer. METHODS AND MATERIALS: From a larger cohort, 98 gynaecological cancer survivors were included in this study. These survivors, who were followed for 2 to 14 years, received external beam radiation therapy but not brachytherapy and not did not have stoma. Thirteen of the 98 developed excessive mucus discharge syndrome. Three self-assessed symptoms were weighted together to produce a score interpreted as 'excessive mucus discharge' syndrome based on the factor loadings from factor analysis. The dose-volume histograms (DVHs) for rectum, sigmoid colon, small intestine for each survivor were exported from the treatment planning systems. The dose-volume response relationships for excessive mucus discharge and each organ at risk were estimated by fitting the data to the Probit, RS, LKB and gEUD models. RESULTS: The small intestine was found to have steep dose-response curves, having estimated dose-response parameters: γ50: 1.28, 1.23, 1.32, D50: 61.6, 63.1, 60.2 for Probit, RS and LKB respectively. The sigmoid colon (AUC: 0.68) and the small intestine (AUC: 0.65) had the highest AUC values. For the small intestine, the DVHs for survivors with and without excessive mucus discharge were well separated for low to intermediate doses; this was not true for the sigmoid colon. Based on all results, we interpret the results for the small intestine to reflect a relevant link. CONCLUSION: An association was found between the mean dose to the small intestine and the occurrence of 'excessive mucus discharge'. When trying to reduce and even eliminate the incidence of 'excessive mucus discharge', it would be useful and important to separately delineate the small intestine and implement the dose-response estimations reported in the study.

Identifying radiation-induced survivorship syndromes affecting bowel health in a cohort of gynecological cancer survivors.

BACKGROUND: During radiotherapy unwanted radiation to normal tissue surrounding the tumor triggers survivorship diseases; we lack a nosology for radiation-induced survivorship diseases that decrease bowel health and we do not know which symptoms are related to which diseases. METHODS: Gynecological-cancer survivors were followed-up two to 15 years after having undergone radiotherapy; they reported in a postal questionnaire the frequency of 28 different symptoms related to bowel health. Population-based controls gave the same information. With a modified factor analysis, we determined the optimal number of factors, factor loadings for each symptom, factor-specific factor-loading cutoffs and factor scores. RESULTS: Altogether data from 623 survivors and 344 population-based controls were analyzed. Six factors best explain the correlation structure of the symptoms; for five of these a statistically significant difference (P< 0.001, Mann-Whitney U test) was found between survivors and controls concerning factor score quantiles. Taken together these five factors explain 42 percent of the variance of the symptoms. We interpreted these five factors as radiation-induced syndromes that may reflect distinct survivorship diseases. We obtained the following frequencies, defined as survivors having a factor loading above the 95 percent percentile of the controls, urgency syndrome (190 of 623, 30 percent), leakage syndrome (164 of 623, 26 percent), excessive gas discharge (93 of 623, 15 percent), excessive mucus discharge (102 of 623, 16 percent) and blood discharge (63 of 623, 10 percent). CONCLUSION: Late effects of radiotherapy include five syndromes affecting bowel health; studying them and identifying the underlying survivorship diseases, instead of the approximately 30 long-term symptoms they produce, will simplify the search for prevention, alleviation and elimination.

Toward Restored Bowel Health in Rectal Cancer Survivors.

As technology gets better and better, and as clinical research provides more and more knowledge, we can extend our ambition to cure patients from cancer with restored physical health among the survivors. This increased ambition requires attention to grade 1 toxicity that decreases quality of life. It forces us to document the details of grade 1 toxicity and improve our understanding of the mechanisms. Long-term toxicity scores, or adverse events as documented during clinical trials, may be regarded as symptoms or signs of underlying survivorship diseases. However, we lack a survivorship nosology for rectal cancer survivors. Primarily focusing on radiation-induced side effects, we highlight some important observations concerning late toxicity among rectal cancer survivors. With that and other data, we searched for a preliminary survivorship-disease nosology for rectal cancer survivors. We disentangled the following survivorship diseases among rectal cancer survivors: low anterior resection syndrome, radiation-induced anal sphincter dysfunction, gut wall inflammation and fibrosis, blood discharge, excessive gas discharge, excessive mucus discharge, constipation, bacterial overgrowth, and aberrant anatomical structures. The suggested survivorship nosology may form the basis for new instruments capturing long-term symptoms (patient-reported outcomes) and professional-reported signs. For some of the diseases, we can search for animal models. As an end result, the suggested survivorship nosology may accelerate our understanding on how to prevent, ameliorate, or eliminate manifestations of treatment-induced diseases among rectal cancer survivors.

Time-dependent dose-response relation for absence of vaginal elasticity after gynecological radiation therapy.

BACKGROUND AND PURPOSE: To investigate the dose-response relation between the dose to the vagina and the patient-reported symptom 'absence of vaginal elasticity' and how time to follow-up influences this relation. MATERIAL AND METHODS: The study included 78 long-term gynecological cancer survivors treated between 1991 and 2003 with external beam radiation therapy. Of those, 24 experienced absence of vaginal elasticity. A normal tissue complication model is introduced that takes into account the influence of time to follow-up on the dose-response relation and the patient's age. The best estimates of the dose-response parameters were calculated using Probit, Probit-Relative Seriality (RS) and Probit-time models. Log likelihood (LL) values and the Akaike Information Criterion (AIC) were used to evaluate the model fit. RESULTS: The dose-response parameters for 'absence of vaginal elasticity' according to the Probit and Probit-time models with the 68% Confidence Intervals (CI) were: LL=-39.8, D50=49.7 (47.2-52.4) Gy, γ50=1.40 (1.12-1.70) and LL=-37.4, D50=46.9 (43.5-50.9) Gy, γ50=1.81 (1.17-2.51) respectively. CONCLUSIONS: The proposed model, which describes the influence of time to follow-up on the dose-response relation, fits our data best. Our data indicate that the steepness of the dose-response curve of the dose to the vagina and the symptom 'absence of vaginal elasticity' increases with time to follow-up, while D50 decreases.

Relative importance of hip and sacral pain among long-term gynecological cancer survivors treated with pelvic radiotherapy and their relationships to mean absorbed doses.

PURPOSE: To investigate the relative importance of patient-reported hip and sacral pain after pelvic radiotherapy (RT) for gynecological cancer and its relationship to the absorbed doses in these organs. METHODS AND MATERIALS: We used data from a population-based study that included 650 long-term gynecological cancer survivors treated with pelvic RT in the Gothenburg and Stockholm areas in Sweden with a median follow-up of 6 years (range, 2-15) and 344 population controls. Symptoms were assessed through a study-specific postal questionnaire. We also analyzed the hip and sacral dose-volume histogram data for 358 of the survivors. RESULTS: Of the survivors, one in three reported having or having had hip pain after completing RT. Daily pain when walking was four times as common among the survivors compared to controls. Symptoms increased in frequency with a mean absorbed dose >37.5 Gy. Also, two in five survivors reported pain in the sacrum. Sacral pain also affected their walking ability and tended to increase with a mean absorbed dose >42.5 Gy. CONCLUSIONS: Long-term survivors of gynecological cancer treated with pelvic RT experience hip and sacral pain when walking. The mean absorbed dose was significantly related to hip pain and was borderline significantly related to sacral pain. Keeping the total mean absorbed hip dose below 37.5 Gy during treatment might lower the occurrence of long-lasting pain. In relation to the controls, the survivors had a lower occurrence of pain and pain-related symptoms from the hips and sacrum compared with what has previously been reported for the pubic bone.

Dose-response relations for stricture in the proximal oesophagus from head and neck radiotherapy.

BACKGROUND AND PURPOSE: Determination of the dose-response relations for oesophageal stricture after radiotherapy of the head and neck. MATERIAL AND METHODS: In this study 33 patients who developed oesophageal stricture and 39 patients as controls are included. The patients received radiation therapy for head and neck cancer at Karolinska University Hospital, Stockholm, Sweden. For each patient the 3D dose distribution delivered to the upper 5 cm of the oesophagus was analysed. The analysis was conducted for two periods, 1992-2000 and 2001-2005, due to the different irradiation techniques used. The fitting has been done using the relative seriality model. RESULTS: For the treatment period 1992-2005, the mean doses were 49.8 and 33.4 Gy, respectively, for the cases and the controls. For the period 1992-2000, the mean doses for the cases and the controls were 49.9 and 45.9 Gy and for the period 2001-2005 were 49.8 and 21.4 Gy. For the period 2001-2005 the best estimates of the dose-response parameters are D(50)=61.5 Gy (52.9-84.9 Gy), γ=1.4 (0.8-2.6) and s=0.1 (0.01-0.3). CONCLUSIONS: Radiation-induced strictures were found to have a dose response relation and volume dependence (low relative seriality) for the treatment period 2001-2005. However, no dose response relation was found for the complete material.

Esophageal stricture after radiotherapy in patients with head and neck cancer: experience of a single institution over 2 treatment periods.

BACKGROUND: Risk factors for development of a stricture of the upper esophagus after radiotherapy for head and neck cancer are poorly defined. METHODS: This was a retrospective case-control study of patients diagnosed and treated for esophageal stricture after radiotherapy for head and neck cancer. RESULTS: The incidence of esophageal stricture after external beam radiation therapy (EBRT) was 3.3%. Seventy patients with stricture and 66 patients without stricture were identified. A multivariate analysis showed that there was increased risk of stricture in receiving enteral feeding during EBRT or in receiving a mean dose of >45 Gy to the upper esophagus. CONCLUSIONS: Enteral feeding during EBRT is strongly associated with the development of stricture of the esophagus, as is a mean dose of >45 Gy to the upper esophagus. Treatment of the stricture with Savary-Gilliard bougienage or through scope balloon dilatation is safe and successful but often has to be repeated.