Towards better quality of life after radiation therapy by improved response modeling

Background: To improve the quality of life of radiotherapy cancer survivors we need to improve our knowledge of the dose, volume and time-response relations of radiotherapy induced late effects. Aims: The aim of the thesis was to investigate predictors for normal-tissue complications of head and neck, and gynecological radiotherapy using response modeling. We aimed to study this effect by using existing and new normal-tissue complication models. Methods: In this thesis, we included 72 patients, who had received external beam radiation therapy (EBRT) for head and neck cancer in Stockholm. Of those, 33 developed esophageal stricture to the proximal esophagus. Gynecological-cancer survivors were treated with pelvic-radiation therapy only or in combination with other treatments in the Stockholm and Gothenburg regions during 1991 to 2003 were also investigated. Dose-volume histograms (DVHs) of 519 gynecological cancer survivors and 73 head and neck cancer survivors were extracted from the treatment planning systems. The dose-effect relations between the symptom ‘emptying of all stools into clothing without forewarning’ and bowel organs and the anal-sphincter were investigated, considering additional possible risk factors. The dose-volume response relations for these organs at risk (OAR) were also investigated for 77 gynecological cancer survivors, who were treated with EBRT only. Moreover, the dose, volume and time-effect of the dose to the vagina and ‘absence of vaginal elasticity’ were investigated for 78 survivors treated with EBRT only. A novel model is proposed, describing the influence of follow-up time on the dose-response relations. To explore the dose-volume effect of the late complications the Relative Seriality, the Lyman and the gEUD models were fitted to the dose volume data. To investigate the dose-effects and the dose-time effects the Probit and the proposed Probit-time models were also used. Results: The best estimates of the dose–response parameters indicated a steep dose-response relation for the radiation induced esophageal strictures for the period of 2001–2005. Mean doses higher than 50 Gy to the anal-sphincter and bowel organs were related with the occurrence of ‘emptying all stools into clothing without fore-warning’. Dose to the anal-sphincter region and sigmoid seemed to be most relevant, but all OARs were found to have steep dose-responses for this symptom. According to the estimated volume parameters the investigated OARs do not show any volume effect for this endpoint. All the studied models had the same predictive power for the symptom as a function of the dose for all investigated OARs. The Probit-time model fit our data better than the pure Probit for ‘absence of vaginal elasticity’. According to the volume parameter from the relative seriality, the vagina has shown a pronounced volume effect for this endpoint. Findings: Dose-response relations and volume dependence were found for the radiation induced esophageal strictures. The EBRT dose to the bowel organs and the anal-sphincter were related to the occurrence of ‘empty-ing of all stools into clothing without forewarning’. The mean dose to the vagina was related to the occurrence of ‘absence of vaginal elasticity’. The steepness of the dose-response relation for the mean dose to the vagina and the symptom increased with time. Implications: The risk of ‘emptying of all stools into clothing without forewarning’ might be lowered by delineating the anal-sphincter region and the sigmoid as well as the rectum and the small intestines during the treatment planning process. This thesis suggests radiobiological parameters for the proximal esophagus, the analsphincter region, the bowel organs and the vagina. Those parameters could be used in terms of avoiding the studied normal-tissue complications in the future. Finally, our findings suggest that the effect of time be considered at the time of treatment and communication with the patient

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: γ : 1.28, 1.23, 1.32, D : 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

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

<p><b>Background:</b> It is unknown whether smoking; age at time of radiotherapy or time since radiotherapy influence the intensity of late radiation-induced bowel syndromes.</p> <p><b>Material and methods:</b> 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.</p> <p><b>Results:</b> A strong (<i>p</i> < .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 (<i>p</i> = .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.</p> <p><b>Conclusions:</b> 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.</p

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 (

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

<p><b>Purpose:</b> 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.</p> <p><b>Material and methods:</b> 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.</p> <p><b>Results:</b> 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 <i>D₅₀</i>_: 51.3, 51.4, and 51.3 Gy, <i>γ₅₀</i> = 1.19 for all models, <i>s</i> was 7.0e⁻⁰⁹ for RS and <i>n</i> was 9.9 × 10⁷ for LKB. For Sigmoid colon, <i>D₅₀</i> were 51.6, 51.6, and 51.5 Gy, <i>γ₅₀</i> were 1.20, 1.25, and 1.27, <i>s</i> was 2.8 for RS and <i>n</i> was 0.079 for LKB.</p> <p><b>Conclusions:</b> 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.</p