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 symptoms in long-term gynaecological cancer survivors after radiation therapy: a population-based cohort study.

BACKGROUND: We surveyed the occurrence of physical symptoms among long-term gynaecological cancer survivors after pelvic radiation therapy, and compared with population-based control women. METHODS: We identified a cohort of 789 eligible gynaecological cancer survivors treated with pelvic radiation therapy alone or combined with surgery in Stockholm or Gothenburg, Sweden. A control group of 478 women was randomly sampled from the Swedish Population Registry. Data were collected through a study-specific validated postal questionnaire with 351 questions concerning gastrointestinal and urinary tract function, lymph oedema, pelvic bones and sexuality. Clinical characteristics and treatment details were retrieved from medical records. RESULTS: Participation rate was 78% for gynaecological cancer survivors and 72% for control women. Median follow-up time after treatment was 74 months. Cancer survivors reported a higher occurrence of symptoms from all organs studied. The highest age-adjusted relative risk (RR) was found for emptying of all stools into clothing without forewarning (RR 12.7), defaecation urgency (RR 5.7), difficulty feeling the need to empty the bladder (RR 2.8), protracted genital pain (RR 5.0), pubic pain when walking indoors (RR 4.9) and erysipelas on abdomen or legs at least once during the past 6 months (RR 3.6). Survivors treated with radiation therapy alone showed in general higher rates of symptoms. CONCLUSION: Gynaecological cancer survivors previously treated with pelvic radiation report a higher occurrence of symptoms from the urinary and gastrointestinal tract as well as lymph oedema, sexual dysfunction and pelvic pain compared with non-irradiated control women. Health-care providers need to actively ask patients about specific symptoms in order to provide proper diagnostic investigations and management

UK guidelines on oesophageal dilatation in clinical practice

These are updated guidelines which supersede the original version published in 2004. This work has been endorsed by the Clinical Services and Standards Committee of the British Society of Gastroenterology (BSG) under the auspices of the oesophageal section of the BSG. The original guidelines have undergone extensive revision by the 16 members of the Guideline Development Group with representation from individuals across all relevant disciplines, including the Heartburn Cancer UK charity, a nursing representative and a patient representative. The methodological rigour and transparency of the guideline development processes were appraised using the revised Appraisal of Guidelines for Research and Evaluation (AGREE II) tool.Dilatation of the oesophagus is a relatively high-risk intervention, and is required by an increasing range of disease states. Moreover, there is scarcity of evidence in the literature to guide clinicians on how to safely perform this procedure. These guidelines deal specifically with the dilatation procedure using balloon or bougie devices as a primary treatment strategy for non-malignant narrowing of the oesophagus. The use of stents is outside the remit of this paper; however, for cases of dilatation failure, alternative techniques-including stents-will be listed. The guideline is divided into the following subheadings: (1) patient preparation; (2) the dilatation procedure; (3) aftercare and (4) disease-specific considerations. A systematic literature search was performed. The Grading of Recommendations Assessment, Develop-ment and Evaluation (GRADE) tool was used to evaluate the quality of evidence and decide on the strength of recommendations made.</p

Late symptoms in long-term gynaecological cancer survivors after radiation therapy: a population-based cohort study.

BACKGROUND: We surveyed the occurrence of physical symptoms among long-term gynaecological cancer survivors after pelvic radiation therapy, and compared with population-based control women. METHODS: We identified a cohort of 789 eligible gynaecological cancer survivors treated with pelvic radiation therapy alone or combined with surgery in Stockholm or Gothenburg, Sweden. A control group of 478 women was randomly sampled from the Swedish Population Registry. Data were collected through a study-specific validated postal questionnaire with 351 questions concerning gastrointestinal and urinary tract function, lymph oedema, pelvic bones and sexuality. Clinical characteristics and treatment details were retrieved from medical records. RESULTS: Participation rate was 78% for gynaecological cancer survivors and 72% for control women. Median follow-up time after treatment was 74 months. Cancer survivors reported a higher occurrence of symptoms from all organs studied. The highest age-adjusted relative risk (RR) was found for emptying of all stools into clothing without forewarning (RR 12.7), defaecation urgency (RR 5.7), difficulty feeling the need to empty the bladder (RR 2.8), protracted genital pain (RR 5.0), pubic pain when walking indoors (RR 4.9) and erysipelas on abdomen or legs at least once during the past 6 months (RR 3.6). Survivors treated with radiation therapy alone showed in general higher rates of symptoms. CONCLUSION: Gynaecological cancer survivors previously treated with pelvic radiation report a higher occurrence of symptoms from the urinary and gastrointestinal tract as well as lymph oedema, sexual dysfunction and pelvic pain compared with non-irradiated control women. Health-care providers need to actively ask patients about specific symptoms in order to provide proper diagnostic investigations and management

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

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. </jats:sec

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 (