Panayiotis Mavroidis

Stricture of the proximal esophagus in head and neck carcinoma patients after radiotherapy

It is well recognized that many patients with head and neck carcinoma have problems with food intake and malnutrition. The objective of the current study was to determine the clinical pattern of patients with nonneoplastic stricture of the upper esophagus after radiotherapy for head and neck carcinoma.

Biologically effective uniform dose (D) for specification, report and comparison of dose response relations and treatment plans

Developments in radiation therapy planning have improved the information about the three-dimensional dose distribution in the patient. Isodose graphs, dose volume histograms and most recently radiobiological models can be used to evaluate the dose distribution delivered to the irradiated organs and volumes of interest. The concept of a biologically effective uniform dose (D) assumes that any two dose distributions are equivalent if they cause the same probability for tumour control or normal tissue complication. In the present paper the D concept both for tumours and normal tissues is presented, making use of the fact that probabilities averaged over both dose distribution and organ radiosensitivity are more relevant to the clinical outcome than the expected number of surviving clonogens or functional subunits. D can be calculated in complex target volumes or organs at risk either from the 3D dose matrix or from the corresponding dose volume histograms of the dose plan. The value of the D concept is demonstrated by applying it to two treatment plans of a cervix cancer. Comparison is made of the D concept with the effective dose (Deff ) and equivalent uniform dose (EUD) that have been suggested in the past. The value of the concept for complex targets and fractionation schedules is also pointed out.

Optimization of the Dose Level for a Given Treatment Plan to Maximize the Complication-free Tumor Cure

During the past decade, tumor and normal tissue reactions after radiotherapy have been increasingly quantified in radiobiological terms. For this purpose, response models describing the dependence of tumor and normal tissue reactions on the irradiated volume, heterogeneity of the delivered dose distribution and cell sensitivity variations can be taken into account. The probability of achieving a good treatment outcome can be increased by using an objective function such as P+, the probability of complication-free tumor control. A new procedure is presented, which quantifies P+ from the dose delivery on 2D surfaces and 3D volumes and helps the user of any treatment planning system (TPS) to select the best beam orientations, the best beam modalities and the most suitable beam energies. The final step of selecting the prescribed dose level is made by a renormalization of the entire dose plan until the value of P+ is maximized. The index P+ makes use of clinically established dose-response parameters, for tumors and normal tissues of interest, in order to improve its clinical relevance. The results, using P+, are compared against the assessments of experienced medical physicists and radiation oncologists for two clinical cases. It is observed that when the absorbed dose level for a given treatment plan is increased, the treatment outcome first improves rapidly. As the dose approaches the tolerance of normal tissues the complication-free cure begins to drop. The optimal dose level is often just below this point and it depends on the geometry of each patient and target volume. Furthermore, a more conformal dose delivery to the target results in a higher control rate for the same complication level. This effect can be quantified by the increased value of the P+ parameter.

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.

Determination and Clinical Verification of Dose-Response Parameters for Esophageal Stricture from Head and Neck Radiotherapy

The purpose of this work is to determine the parameters and evaluate the predictive strength of the relative seriality model. This is accomplished by associating the calculated complication rates with the clinical follow-up records. The study is based on 82 patients who received radiation treatment for head and neck cancer. For each patient the 3D dose distribution delivered to the esophagus and the clinical treatment outcome were available. Clinical symptoms and radiological findings were used to assess the manifestation of radiation-induced esophageal strictures. These data were introduced into a maximum likelihood fitting to calculate the best estimates of the parameters used by the relative seriality model (D50=68.4 Gy, γ=6.55, s=0.22). The uncertainties of these parameters were also calculated and their individual influence on the dose-response curve was demonstrated. The best estimate of the parameters was applied to 58 patients of the study material and their esophageal stricture induction probabilities were calculated to illustrate the clinical utilization of the calculated parameters. The calculation of the biological effective dose (BED) appeared to be significantly sensitive to the applied fractionation correction for complex treatment plans. The relative seriality model was proved suitable in reproducing the treatment outcome pattern of the patient material studied (probability of finding a worse fit=61.0%, the area under the ROC curve=0.84 and χ2test=0.95). The analysis was carried out for the upper 5 cm of the esophagus (proximal esophagus) where all the strictures are formed. Radiation-induced strictures were found to have a strong volume dependence (low relative seriality). The uncertainties of the parameters appear to have a significant supporting role on the estimated dose-response curve.

NTCP modelling and pulmonary function tests evaluation for the prediction of radiation induced pneumonitis in non-small-cell lung cancer radiotherapy

This work aims to evaluate the predictive strength of the relative seriality, parallel and Lyman-Kutcher-Burman (LKB) normal tissue complication probability (NTCP) models regarding the incidence of radiation pneumonitis (RP), in a group of patients following lung cancer radiotherapy and also to examine their correlation with pulmonary function tests (PFTs). The study was based on 47 patients who received radiation therapy for stage III non-small-cell lung cancer. For each patient, lung dose volume histograms (DVHs) and the clinical treatment outcome were available. Clinical symptoms, radiological findings and pulmonary function tests incorporated in a post-treatment follow-up period of 18 months were used to assess the manifestation of radiation induced complications. Thirteen of the 47 patients were scored as having radiation induced pneumonitis, with RTOG criteria grade 3 and 28 of the 47 with RTOG criteria grade 2. Using this material, different methods of estimating the likelihood of radiation effects were evaluated, by analysing patient data based on their full dose distributions and associating the calculated complication rates with the clinical follow-up records. Lungs were evaluated as a paired organ as well as individual lungs. Of the NTCP models examined in the overall group considering the dose distribution in the ipsilateral lung, all models were able to predict radiation induced pneumonitis only in the case of grade 2 radiation pneumonitis score, with the LKB model giving the best results (chi2-test: probability of agreement between the observed and predicted results Pchi(chi2)=0.524 using the 0.05 significance level). The NTCP modelling considering lungs as a paired organ did not give statistically acceptable results. In the case of lung cancer radiotherapy, the application of different published radiobiological parameters alters the NTCP results, but not excessively as in the case of breast cancer radiotherapy. In this relatively small group of lung cancer patients, no positive statistical correlation could be established between the incidence of radiation pneumonitis as estimated by NTCP models and the pulmonary function test evaluation. However, the use of PFTs as markers or predictors for the incidence or severity of radiation induced pneumonitis must be investigated further.

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

Risk factors for development of a stricture of the upper esophagus after radiotherapy for head and neck cancer are poorly defined.

Prediction of AVM obliteration after stereotactic radiotherapy using radiobiological modelling

This study was carried out in order to derive the radiobiological parameters of the dose-response relation for the obliteration of arteriovenous malformation (AVM) following single fraction stereotactic radiotherapy. Furthermore, the accuracy by which the linear Poisson model predicts the probability of obliteration and how the haemorrhage history, location and volume of the AVM influence its radiosensitivity are investigated. The study patient material consists of 85 patients who received radiation for AVM therapy. Radiation-induced AVM obliterations were assessed on the basis of post-irradiation angiographies and other radiological findings. For each patient the dose delivered to the clinical target volume and the clinical treatment outcome were available. These data were used in a maximum likelihood analysis to calculate the best estimates of the parameters of the linear Poisson model. The uncertainties of these parameters were also calculated and their individual influence on the dose-response curve was studied. AVM radiosensitivity was assumed to be the same for all the patients. The radiobiological model used was proved suitable for predicting the treatment outcome pattern of the studied patient material. The radiobiological parameters of the model were calculated for different AVM locations, bleeding histories and AVM sizes. The range of parameter variability had considerable effect on the dose-response curve of AVM. The correlation between the dosimetric data and their corresponding clinical effect could be accurately modelled using the linear Poisson model. The derived response parameters can be introduced into the clinical routine with the calculated accuracy assuming the same methodology in target definition and delineation. The known volume dependence of AVM radiosensitivity was confirmed. Moreover, a trend relating AVM location with its radiosensitivity was observed.

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: