Helena Lind

Dose-Response Relations for Anal Sphincter Regarding Fecal Leakage and Blood or Phlegm in Stools after Radiotherapy for Prostate Cancer

Background:The estimation of the parameters that describe the dose-response relations of anal sphincter regarding the clinical endpoints of fecal leakage and blood or phlegm in stools is important in the optimization of prostate cancer radiotherapy. Also, the validity of the relative seriality model for this clinical case needs to be examined by associating the clinical follow-up results with the predicted complication rates.Patients and Methods:In this study, 65 patients who received radiation therapy for clinically localized prostate adenocarcinoma are analyzed. The clinical treatment outcome and the three-dimensional dose distribution delivered to anal sphincter were available for each patient. A questionnaire was used for assessing the clinical bowel and urinary symptoms. A maximum likelihood fitting was performed to calculate the best estimates of the parameters used by the relative seriality model. The clinical utilization of the calculated parameters in predicting anal sphincter complication probabilities was illustrated by applying the best estimate of the parameters to a subset of the patient population.Results:The estimated values of the parameters for the two clinical endpoints are D50 = 70.2 Gy, γ = 1.22, s = 0.35 for fecal leakage and D50 = 74.0 Gy, γ = 0.75, s ≈ 0 for blood or phlegm in stools. The standard deviations of the parameters were also calculated together with the confidence intervals of the dose-response curves. The analysis proved that the treatment outcome pattern of the patient material can suitably be reproduced by the relative seriality model (probability of finding a worse fit = 60.2%, the area under the receiver operating characteristic curve = 0.72 and 0.69 and χ2-test = 0.97 and 0.86, respectively).Conclusion:Fecal leakage is characterized by a medium relative seriality whereas blood or phlegm in stools was found to have strong volume dependence (low relative seriality). Diminishing the biologically effective uniform dose to anal sphincter < 40–45 Gy may significantly reduce the risk of fecal leakage or blood or phlegm in stools for patients irradiated for prostate cancer.Hintergrund:Um die Strahlenbehandlung des Prostatakarzinoms optimieren zu können, ist ein Modell der Dosis-Wirkungs-Beziehung für die Analsphinkterfunktion notwendig, dessen Parameter verlässlich geschätzt werden können. Es sollte die klinischen Endpunkte Stuhlinkontinenz und Blut oder Schleim im Stuhl beschreiben. Zusätzlich sollte die Gültigkeit des Relative-Seriality-Modells überprüft werden, indem die Befunde des klinischen Follow-up mit den prognostizierten Komplikationsraten verglichen werden.Patienten und Methodik:Diese Studie umfasst 65 Patienten, die wegen eines klinisch manifesten lokalisierten Adenokarzinoms der Prostata eine Strahlenbehandlung erhalten hatten. Das klinische Ergebnis und die Dosisverteilung im Analsphinkter waren für jeden Patienten verfügbar. Klinische Symptome des Darms und der Harnwege wurden mittels eines Fragebogens erfasst. Die Parameter des Relative-Seriality-Modells wurden mit Hilfe der Maximum-Likelihood-Methode bestimmt. Bei einer Untergruppe der Patienten wurden die besten Schätzwerte der Parameter angewendet. Der klinische Nutzen für die Prognose von Komplikationen des Analsphinkters konnte dargestellt werden.Ergebnisse:Die Schätzwerte der Parameter der zwei klinischen Endpunkte sind D50 = 70,2 Gy, γ = 1,22, s = 0,35 für Stuhlinkontinenz und D50 = 74,0 Gy, γ = 0,75, s ≈ 0 für Blut oder Schleim im Stuhl. Die Standardabweichungen der Parameter wurden ebenso berechnet wie die Konfidenzintervalle. Die Analyse (untersucht wurden: Probability of Finding worse Fit = 60,2%, die Fläche unter ROC-Kurven 0,72 bzw. 0,69 und χ2 = 0,97 und 0,86) beweist, dass das Behandlungsergebnis bei den untersuchten Patienten mit Hilfe des Relative-Seriality-Modells gut wiedergegeben wird.Schlussfolgerungen:Die Stuhlinkontinenz zeigt eine mittlere Relative Seriality, während für Blut oder Schleim im Stuhl eine starke Volumenabhängigkeit gefunden wurde (geringe Relative Seriality). Eine Reduktion der biologisch effektiven, uniformen Dosis des Analsphinkters unter 40-45 Gy könnte die Risiken der Stuhlinkontinenz und von Blut oder Schleim im Stuhl für Prostatakarzinom-Patienten signifikant senken.

Dose-Response Relations for Anal Sphincter Regarding Fecal Leakage and Blood or Phlegm in Stools after Radiotherapy for Prostate Cancer Radiobiological Study of 65 Consecutive Patients

Background:The estimation of the parameters that describe the dose-response relations of anal sphincter regarding the clinical endpoints of fecal leakage and blood or phlegm in stools is important in the optimization of prostate cancer radiotherapy. Also, the validity of the relative seriality model for this clinical case needs to be examined by associating the clinical follow-up results with the predicted complication rates.Patients and Methods:In this study, 65 patients who received radiation therapy for clinically localized prostate adenocarcinoma are analyzed. The clinical treatment outcome and the three-dimensional dose distribution delivered to anal sphincter were available for each patient. A questionnaire was used for assessing the clinical bowel and urinary symptoms. A maximum likelihood fitting was performed to calculate the best estimates of the parameters used by the relative seriality model. The clinical utilization of the calculated parameters in predicting anal sphincter complication probabilities was illustrated by applying the best estimate of the parameters to a subset of the patient population.Results:The estimated values of the parameters for the two clinical endpoints are D50 = 70.2 Gy, γ = 1.22, s = 0.35 for fecal leakage and D50 = 74.0 Gy, γ = 0.75, s ≈ 0 for blood or phlegm in stools. The standard deviations of the parameters were also calculated together with the confidence intervals of the dose-response curves. The analysis proved that the treatment outcome pattern of the patient material can suitably be reproduced by the relative seriality model (probability of finding a worse fit = 60.2%, the area under the receiver operating characteristic curve = 0.72 and 0.69 and χ2-test = 0.97 and 0.86, respectively).Conclusion:Fecal leakage is characterized by a medium relative seriality whereas blood or phlegm in stools was found to have strong volume dependence (low relative seriality). Diminishing the biologically effective uniform dose to anal sphincter < 40–45 Gy may significantly reduce the risk of fecal leakage or blood or phlegm in stools for patients irradiated for prostate cancer.Hintergrund:Um die Strahlenbehandlung des Prostatakarzinoms optimieren zu können, ist ein Modell der Dosis-Wirkungs-Beziehung für die Analsphinkterfunktion notwendig, dessen Parameter verlässlich geschätzt werden können. Es sollte die klinischen Endpunkte Stuhlinkontinenz und Blut oder Schleim im Stuhl beschreiben. Zusätzlich sollte die Gültigkeit des Relative-Seriality-Modells überprüft werden, indem die Befunde des klinischen Follow-up mit den prognostizierten Komplikationsraten verglichen werden.Patienten und Methodik:Diese Studie umfasst 65 Patienten, die wegen eines klinisch manifesten lokalisierten Adenokarzinoms der Prostata eine Strahlenbehandlung erhalten hatten. Das klinische Ergebnis und die Dosisverteilung im Analsphinkter waren für jeden Patienten verfügbar. Klinische Symptome des Darms und der Harnwege wurden mittels eines Fragebogens erfasst. Die Parameter des Relative-Seriality-Modells wurden mit Hilfe der Maximum-Likelihood-Methode bestimmt. Bei einer Untergruppe der Patienten wurden die besten Schätzwerte der Parameter angewendet. Der klinische Nutzen für die Prognose von Komplikationen des Analsphinkters konnte dargestellt werden.Ergebnisse:Die Schätzwerte der Parameter der zwei klinischen Endpunkte sind D50 = 70,2 Gy, γ = 1,22, s = 0,35 für Stuhlinkontinenz und D50 = 74,0 Gy, γ = 0,75, s ≈ 0 für Blut oder Schleim im Stuhl. Die Standardabweichungen der Parameter wurden ebenso berechnet wie die Konfidenzintervalle. Die Analyse (untersucht wurden: Probability of Finding worse Fit = 60,2%, die Fläche unter ROC-Kurven 0,72 bzw. 0,69 und χ2 = 0,97 und 0,86) beweist, dass das Behandlungsergebnis bei den untersuchten Patienten mit Hilfe des Relative-Seriality-Modells gut wiedergegeben wird.Schlussfolgerungen:Die Stuhlinkontinenz zeigt eine mittlere Relative Seriality, während für Blut oder Schleim im Stuhl eine starke Volumenabhängigkeit gefunden wurde (geringe Relative Seriality). Eine Reduktion der biologisch effektiven, uniformen Dosis des Analsphinkters unter 40-45 Gy könnte die Risiken der Stuhlinkontinenz und von Blut oder Schleim im Stuhl für Prostatakarzinom-Patienten signifikant senken.

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.

Self-reported symptoms of faecal incontinence among long-term gynaecological cancer survivors and population-based controls.

AIM OF THE STUDY To make a comprehensive, detailed inventory of gastrointestinal symptoms reported by gynaecological cancer survivors and control women from the general population. METHOD We identified a cohort of 789 eligible women in the Stockholm and Gothenburg areas, treated with pelvic radiotherapy during the period 1991-2003, alone or as combined treatment, for gynaecological cancer. As controls, we randomly recruited 478 women, frequency matched by age and residence from the Swedish Population Registry. We collected data in 2006 by means of a study-specific, validated, postal questionnaire including 351 questions covering symptoms from the pelvic region. We asked about demographics, psychological and quality-of-life issues as well as social functioning. RESULTS Participation was 78% for cancer survivors and 72% for controls. Mean follow-up was 7.2 years. In this large, population-based study, the greatest age-adjusted absolute risk difference between cancer survivors and control women was observed for the symptom defaecation urgency with faecal leakage and the highest age-adjusted relative risk for emptying of all stools into clothing without forewarning. CONCLUSIONS Cancer survivors having undergone pelvic radiotherapy alone or as part of combined treatment between the period 1991-2003 for a gynaecological malignancy had a higher occurrence of long-lasting gastrointestinal symptoms as compared to population controls.

Fecal incontinence affecting quality of life and social functioning among long-term gynecological cancer survivors.

Introduction: Fecal incontinence is a symptom reported by cancer survivors after pelvic radiotherapy and is recognized to be one of the most troubling symptom-induced sources of distress to patients. Objective: To investigate how fecal incontinence, patient-reported as emptying of all stools into clothing without forewarning, impact self-assessed quality of life from a social, psychological, sexual, and functional aspect among gynecological cancer survivors treated with pelvic radiotherapy. Methods: We identified a cohort of 789 eligible women in the Stockholm and Gothenburg areas treated with pelvic radiotherapy alone or as combined treatment of gynecological cancer. From the Swedish Population Registry, we identified 478 control women. Data were collected using a study-specific, validated, postal questionnaire including questions covering symptoms from the pelvic region, demographics, social functioning, psychological, and quality-of-life issues. Results: Participation was 78% for cancer survivors and 72% for control women. The fecal incontinence symptom emptying of all stools into clothing without forewarning was reported by 70 cancer survivors (12%), with lowered quality of life in 74% of the 70 cancer survivors. This symptom kept the survivors from going to parties (relative risk [RR], 11.8; 95% confidence interval [CI], 6.6-21.1), kept the survivors from traveling (RR, 9.3; 95% CI, 5.3-16.5), affected their work ability (RR, 7.9; 95% CI, 3.8-16.4), hindered their sexual life (RR, 9.2; 95% CI, 4.8-17.6), and changed them as persons (RR, 4.9; 95% CI, 2.9-8.1). The prevalence of the symptom emptying of all stools into clothing without forewarning among control women was 3 (1%) of 344. Conclusions: Among gynecological cancer survivors having undergone pelvic radiotherapy alone or as part of a combined treatment, fecal incontinence is associated with social, psychological, sexual, and functional consequences.

Dose to the anal sphincter region and risk of fecal leakage

From the Clinical Cancer Epidemiology, Department of Oncology and Pathology, Karolinska Institutet, (M. al-Abany, A´ .R. Helgason, G. Steineck), the Stockholm Center for Public Health (A´ .R. Helgason), Department ofMedical Hospital Radiation Physics, So¨der Hospital (A.-K. A˚ gren Cronqvist), Department of Medical RadiationPhysics, Karolinska Institutet (B. Lind, P. Mavroidis), Uro-oncology, Radiumhemmet, Karolinska Hospital (P.Wersa¨ll), Department of Oncology, Radiumhemmet, Karolinska Hospital (H. Lind) and the Department ofRadiology, Karolinska Hospital (E. Qvanta), Stockholm, SwedenCorrespondence to: Professor Gunnar Steineck, Clinical Cancer Epidemiology, Karolinska Hospital Z6:01, SE-17176 Stockholm, Sweden. Tel:

Pain and Mean Absorbed Dose to the Pubic Bone After Radiotherapy Among Gynecological Cancer Survivors

PURPOSE To analyze the relationship between mean absorbed dose to the pubic bone after pelvic radiotherapy for gynecological cancer and occurrence of pubic bone pain among long-term survivors. METHODS AND MATERIALS In an unselected, population-based study, we identified 823 long-term gynecological cancer survivors treated with pelvic radiotherapy during 1991-2003. For comparison, we used a non-radiation-treated control population of 478 matched women from the Swedish Population Register. Pain, intensity of pain, and functional impairment due to pain in the pubic bone were assessed with a study-specific postal questionnaire. RESULTS We analyzed data from 650 survivors (participation rate 79%) with median follow-up of 6.3 years (range, 2.3-15.0 years) along with 344 control women (participation rate, 72 %). Ten percent of the survivors were treated with radiotherapy; ninety percent with surgery plus radiotherapy. Brachytherapy was added in 81%. Complete treatment records were recovered for 538/650 survivors, with dose distribution data including dose-volume histograms over the pubic bone. Pubic bone pain was reported by 73 survivors (11%); 59/517 (11%) had been exposed to mean absorbed external beam doses <52.5 Gy to the pubic bone and 5/12 (42%) to mean absorbed external beam doses ≥ 52.5 Gy. Thirty-three survivors reported pain affecting sleep, a 13-fold increased prevalence compared with control women. Forty-nine survivors reported functional impairment measured as pain walking indoors, a 10-fold increased prevalence. CONCLUSIONS Mean absorbed external beam dose above 52.5 Gy to the pubic bone increases the occurrence of pain in the pubic bone and may affect daily life of long-term survivors treated with radiotherapy for gynecological cancer.

Loose stools lead to fecal incontinence among gynecological cancer survivors

Abstract Background. Many patients treated with radiotherapy to the pelvic region report a change in bowel habits. Loose stools, urgency and fecal incontinence may have a significant impact on daily life and social functioning. Material and methods. We attempted to follow up 789 women, treated with pelvic radiotherapy for a gynecological cancer during 1991 to 2003 at two departments of gynecological oncology in Sweden. A control group of 478 women from the Swedish Population Registry was also included. As a preparatory study, we made in-depth interviews with 26 women previously treated for gynecological cancer. Based on their narratives, we constructed a study-specific questionnaire including 351 questions and validated it face-to-face. The questionnaire covered questions of physical symptoms originating in the pelvis, demographics, psychological and quality of life factors. In relation to bowel symptoms, 60 questions were asked. Results. Six-hundred and sixteen (78%) gynecological cancer survivors and 344 (72%) control women participated. Two-hundred and twenty-six (37%) cancer survivors reported loose stools at least once a week. Eighty-three percent of the survivors with loose stools every day reported defecation urgency with fecal leakage, compared to 20% of cancer survivors without loose stools. Cancer survivors with loose stools at least once a week were 7.7 times more likely to suffer from defecation urgency with fecal leakage (95% CI 4.4–13.3) compared to those who had loose stools once a month or less. In order to avoid loose stools affected survivors with loose stools often skipped meals (13%), made an active choice of food (47%) and preferentially used prescribed medication (36%). Discussion. There is a relation between loose stools and defecation urgency with fecal leakage among long-term gynecological cancer survivors treated with pelvic radiotherapy. Targeting loose stools can possibly help survivors to decrease frequency of fecal leakage.

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

Abstract 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.

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.