Petra Georg

Clinical outcome of protocol based image (MRI) guided adaptive brachytherapy combined with 3D conformal radiotherapy with or without chemotherapy in patients with locally advanced cervical cancer

Background To analyse the overall clinical outcome and benefits by applying protocol based image guided adaptive brachytherapy combined with 3D conformal external beam radiotherapy (EBRT) ± chemotherapy (ChT). Methods Treatment schedule was EBRT with 45–50.4 Gy ± concomitant cisplatin chemotherapy plus 4 × 7 Gy High Dose Rate (HDR) brachytherapy. Patients were treated in the “protocol period” (2001–2008) with the prospective application of the High Risk CTV concept (D90) and dose volume constraints for organs at risk including biological modelling. Dose volume adaptation was performed with the aim of dose escalation in large tumours (prescribed D90 > 85 Gy), often with inserting additional interstitial needles. Dose volume constraints (D2cc) were 70–75 Gy for rectum and sigmoid and 90 Gy for bladder. Late morbidity was prospectively scored, using LENT/SOMA Score. Disease outcome and treatment related late morbidity were evaluated and compared using actuarial analysis. Findings One hundred and fifty-six consecutive patients (median age 58 years) with cervix cancer FIGO stages IB–IVA were treated with definitive radiotherapy in curative intent. Histology was squamous cell cancer in 134 patients (86%), tumour size was >5 cm in 103 patients (66%), lymph node involvement in 75 patients (48%). Median follow-up was 42 months for all patients. Interstitial techniques were used in addition to intracavitary brachytherapy in 69/156 (44%) patients. Total prescribed mean dose (D90) was 93 ± 13 Gy, D2cc 86 ± 17 Gy for bladder, 65 ± 9 Gy for rectum and 64 ± 9 Gy for sigmoid. Complete remission was achieved in 151/156 patients (97%). Overall local control at 3 years was 95%; 98% for tumours 2–5 cm, and 92% for tumours >5 cm (p = 0.04), 100% for IB, 96% for IIB, 86% for IIIB. Cancer specific survival at 3 years was overall 74%, 83% for tumours 2–5 cm, 70% for tumours >5 cm, 83% for IB, 84% for IIB, 52% for IIIB. Overall survival at 3 years was in total 68%, 72% for tumours 2–5 cm, 65% for tumours >5 cm, 74% for IB, 78% for IIB, 45% for IIIB. In regard to late morbidity in total 188 grade 1 + 2 and 11 grade 3 + 4 late events were observed in 143 patients. G1 + 2/G3 + 4 events for bladder were n = 32/3, for rectum n = 14/5, for bowel (including sigmoid) n = 3/0, for vagina n = 128/2, respectively. Interpretation 3D conformal radiotherapy ± chemotherapy plus image (MRI) guided adaptive intracavitary brachytherapy including needle insertion in advanced disease results in local control rates of 95–100% at 3 years in limited/favourable (IB/IIB) and 85–90% in large/poor response (IIB/III/IV) cervix cancer patients associated with a moderate rate of treatment related morbidity. Compared to the historical Vienna series there is relative reduction in pelvic recurrence by 65–70% and reduction in major morbidity. The local control improvement seems to have impact on CSS and OS. Prospective clinical multi-centre studies are mandatory to evaluate these challenging mono-institutional findings.

Dose–effect relationship for local control of cervical cancer by magnetic resonance image-guided brachytherapy

BACKGROUND AND PURPOSE To analyse dose-response relationships for local control of cervical cancer after MR image-guided brachytherapy (IGBT) based on dose-volume histogram parameters. METHODS AND MATERIALS The analysis includes 141 patients with cervix cancer (stages IB-IVA) treated with 45-50.4 Gy EBRT+/-cisplatin plus 4 x 7 Gy IGBT. Gross tumour volume (GTV), high risk clinical target volume (HR CTV) and intermediate risk CTV (IR CTV) were delineated and DVH parameters (D90, D100) were assessed. Doses were converted to the equivalent dose in 2 Gy (EQD2) using linear-quadratic model (alpha/beta=10 Gy). Groups of patients were formed according to tumour size at diagnosis (GTV(D)) of 2-5 cm (group 1) or >5 cm (2), with subgroups of the latter for HR CTV size at first IGBT 2-5 cm (2a) or >5 cm (2b). Dose-response dependence for local recurrence was evaluated by logit analysis. RESULTS Eighteen local recurrences in the true pelvis were observed. Dose-response analyses revealed a significant effect of HR CTV D100 (p=0.02) and D90 (p=0.005). The ED50-values for tumour control were 33+/-15 Gy (D100) and 45+/-19 Gy (D90). ED90-values were 67 Gy (95% confidence interval [50;104]) and 86 Gy [77;113], respectively. CONCLUSIONS A significant dependence of local control on D100 and D90 for HR CTV was found. Tumour control rates of >90% can be expected at doses >67 Gy and 86 Gy, respectively.

Dose–Volume Histogram Parameters and Local Tumor Control in Magnetic Resonance Image–Guided Cervical Cancer Brachytherapy

PURPOSE To investigate the value of dose-volume histogram (DVH) parameters for predicting local control in magnetic resonance (MR) image-guided brachytherapy (IGBT) for patients with cervical cancer. METHODS AND MATERIALS Our study population consists of 141 patients with cervical cancer (Stages IB-IVA) treated with 45-50 Gy external beam radiotherapy plus four times 7 Gy IGBT with or without cisplatin. Gross tumor volume (GTV), high-risk clinical target volume (HRCTV), and intermediate-risk clinical target volume (IRCTV) were contoured, and DVH parameters (minimum dose delivered to 90% of the volume of interest [D90] and D100) were assessed. Doses were converted to the equivalent dose in 2 Gy (EQD2) by applying the linear quadratic model (alpha/beta = 10 Gy). Groups were defined for patients with or without local recurrence (LR) in the true pelvis for tumor size at diagnosis (GTV at diagnosis [GTVD] of 2-5 cm (Group 1) or greater than 5 cm (Group 2) and for tumor size response at IGBT (HRCTV) of 2-5 cm (Group 2a) or greater than 5 cm (Group 2b). RESULTS Eighteen LRs were observed. The most important DVH parameters correlated with LR were the D90 and D100 for HRCTV. Mean D90 and D100 values for HRCTV were 86 +/- 16 and 65 +/- 10 Gy, respectively. The D90 for HRCTV greater than 87 Gy resulted in an LR incidence of 4% (3 of 68) compared with 20% (15 of 73) for D90 less than 87 Gy. The effect was most pronounced in the tumor group (Group 2b). CONCLUSIONS We showed an increase in local control in IGBT in patients with cervical cancer with the dose delivered, which can be expressed by the D90 and D100 for HRCTV. Local control rates greater than 95% can be achieved if the D90 (EQD2) for HRCTV is 87 Gy or greater.

Dose Effect Relationship for Late Side Effects of the Rectum and Urinary Bladder in Magnetic Resonance Image-Guided Adaptive Cervix Cancer Brachytherapy

PURPOSE To establish dose-response relationships for late side effects of the rectum and bladder in cervix cancer patients after magnetic resonance image-guided adaptive brachytherapy (IGABT). METHODS AND MATERIALS A cohort of 141 patients was treated with 45 to 50.4 Gy with or without cisplatin plus 4 fractions of 7 Gy IGABT. Doses for the most exposed 2, 1, and 0.1-cm(3) (D(2 cc), D(1 cc), D(0.1 cc)) volumes of the rectum and bladder were converted into the equivalent dose in 2 Gy fractions (EQD2), using a linear quadratic model (α/β = 3 Gy). Late side effects were prospectively assessed (using late effects in normal tissues subjective, objective, management and analytic [LENT SOMA]) scales. Dose-response relationships were determined by logit analyses. RESULTS Eleven patients developed rectal side effects, and 23 patients had urinary side effects. A significant dose effect was found for all rectal dose-volume histogram (DVH) parameters for patients with side effect grades of 1 to 4 but was only significant for D(2 cc) and D(1 cc) for grades ≥ 2. The ED10 values for D(2 cc) were 73 Gy for grades 1 to 4 and 78 Gy for grades 2 to 4 rectal morbidity. For bladder side effects, a significant dose effect was shown for all DVH parameters for complication grades ≥ 2; the respective ED10 was 101 Gy. CONCLUSIONS Well-defined dose-response curves could be established for D(2 cc) in the rectum and the urinary bladder.

Dose-volume histogram parameters and late side effects in magnetic resonance image-guided adaptive cervical cancer brachytherapy.

PURPOSE To evaluate the predictive value of dose-volume histogram (DVH) parameters for late side effects of the rectum, sigmoid colon, and bladder in image-guided brachytherapy for cervix cancer patients. METHODS AND MATERIALS A total of 141 patients received external-beam radiotherapy and image-guided brachytherapy with or without chemotherapy. The DVH parameters for the most exposed 2, 1, and 0.1 cm(3) (D(2cc), D(1cc), and D(0.1cc)) of the rectum, sigmoid, and bladder, as well as International Commission on Radiation Units and Measurements point doses (D(ICRU)) were computed. Total doses were converted to equivalent doses in 2 Gy by applying the linear-quadratic model (α/β = 3 Gy). Late side effects were prospectively assessed using the Late Effects in Normal Tissues-Subjective, Objective, Management and Analytic score. The following patient groups were defined: Group 1: no side effects (Grade 0); Group 2: side effects (Grade 1-4); Group 3: minor side effects (Grade 0-1); and Group 4: major side effects (Grade 2-4). RESULTS The median follow-up was 51 months. The overall 5-year actuarial side effect rates were 12% for rectum, 3% for sigmoid, and 23% for bladder. The mean total D(2cc) were 65 ± 12 Gy for rectum, 62 ± 12 Gy for sigmoid, and 95 ± 22 Gy for bladder. For rectum, statistically significant differences were observed between Groups 1 and 2 in all DVH parameters and D(ICRU). Between Groups 3 and 4, no difference was observed for D(0.1cc). For sigmoid, significant differences were observed for D(2cc) and D(1cc), but not for D(0.1cc) in all groups. For bladder, significant differences were observed for all DVH parameters only comparing Groups 3 and 4. No differences were observed for D(ICRU). CONCLUSIONS The parameters D(2cc) and D(1cc) have a good predictive value for rectal toxicity. For sigmoid, no prediction could be postulated because of limited data. In bladder, DVH parameters were predictive only for major toxicity.

Image guided brachytherapy in locally advanced cervical cancer: Improved pelvic control and survival in RetroEMBRACE, a multicenter cohort study

PURPOSE Image guided brachytherapy (IGBT) for locally advanced cervical cancer allows dose escalation to the high-risk clinical target volume (HRCTV) while sparing organs at risk (OAR). This is the first comprehensive report on clinical outcome in a large multi-institutional cohort. PATIENTS AND METHODS From twelve centres 731 patients, treated with definitive EBRT±concurrent chemotherapy followed by IGBT, were analysed. Kaplan-Meier estimates at 3/5years were calculated for local control (LC, primary endpoint), pelvic control (PC), overall survival (OS), cancer specific survival (CSS). In 610 patients, G3-4 late toxicity (CTCAEv3.0) was reported. RESULTS Median follow up was 43months, percent of patients per FIGO stage IA/IB/IIA 22.8%, IIB 50.4%, IIIA-IVB 26.8%. 84.8% had squamous cell carcinomas; 40.5% lymph node involvement. Mean EBRT dose was 46±2.5Gy; 77.4% received concurrent chemotherapy. Mean D90 HRCTV was 87±15Gy (EQD210), mean D2cc was: bladder 81±22Gy, rectum 64±9Gy, sigmoid 66±10Gy and bowel 64±9Gy (all EQD23). The 3/5-year actuarial LC, PC, CSS, OS were 91%/89%, 87%/84%, 79%/73%, 74%/65%. Actuarial LC at 3/5years for IB, IIB, IIIB was 98%/98%, 93%/91%, 79%/75%. Actuarial PC at 3/5years for IB, IIB, IIIB was 96%/96%, 89%/87%, 73%/67%. Actuarial 5-year G3-G5 morbidity was 5%, 7%, 5% for bladder, gastrointestinal tract, vagina. CONCLUSION IGBT combined with radio-chemotherapy leads to excellent LC (91%), PC (87%), OS (74%), CSS (79%) with limited severe morbidity.

Correlation of dose–volume parameters, endoscopic and clinical rectal side effects in cervix cancer patients treated with definitive radiotherapy including MRI-based brachytherapy

PURPOSE Correlation of dosimetric parameters for MRI-based 3D treatment planning with rectoscopic findings and clinical rectal side effects. METHODS AND MATERIALS Rectosigmoidoscopy and rectal morbidity assessment were performed on 35 cervical cancer patients treated with external beam radiotherapy (EBRT) and HDR-intracavitary brachytherapy (ICB). The total doses, normalised to 2 Gy fractions (EQD2, alpha/beta=3 Gy), in 0.1, 1.0 and 2.0 cm(3) (D(0.1 cc), D(1 cc), D(2 cc)) of rectum were determined by summation of EBRT and ICB plans. Correlation analysis between clinical symptoms (LENT/SOMA) and rectoscopic changes (Vienna Rectoscopy Score, VRS) was performed. For dose-response analyses, the logit model was applied. RESULTS Mean follow-up was 18 months. LENT/SOMA score was 1 in 4 patients, 2 in 8 patients, 4 in 1 patient. Telangiectasia was found in 26 patients (74%), five of them had ulceration corresponding to the 0.1 cm(3) volume (anterior wall). Mean values D(0.1 cc), D(1 cc), and D(2 cc) were 81+/-13, 70+/-9 and 66+/-8 Gy, respectively. The ED50 values for VRS > or = 3 and for LENT/SOMA > or = 2 significantly increased with decreasing volumes. D(2 cc) was higher in patients with VRS > or = 3 compared to VRS<3 (72+/-6 vs 62+/-7 Gy; p<0.001) and in symptomatic vs asymptomatic patients (72+/-6 vs 63+/-8 Gy; p<0.001). VRS correlated with the LENT/SOMA score. CONCLUSIONS Rectosigmoidoscopy is sensitive in detecting mucosal changes, independent of clinical symptoms. The localization of these changes corresponds to the high dose volumes as defined by imaging. The development of mucosal and clinical changes in the rectum follows a clear dose-effect and volume-effect. DVH parameters could be established.

Dose–volume effect relationships for late rectal morbidity in patients treated with chemoradiation and MRI-guided adaptive brachytherapy for locally advanced cervical cancer: Results from the prospective multicenter EMBRACE study

PURPOSE To establish dose volume-effect relationships predicting late rectal morbidity in cervix cancer patients treated with concomitant chemoradiation and MRI-guided adaptive brachytherapy (IBABT) within the prospective EMBRACE study. MATERIAL AND METHOD All patients were treated with curative intent according to institutional protocols with chemoradiation and IGABT. Reporting followed the GEC-ESTRO recommendations ( [Formula: see text] , [Formula: see text] ), applying bioeffect modeling (linear quadratic model) with equieffective doses (EQD23). Morbidity was scored according to the CTC-AE 3.0. Dose-effect relationships were assessed using comparisons of mean doses, the probit model and log rank tests on event-free periods. RESULTS 960 patients were included. The median follow-up was 25.4months. Twenty point one percent of the patients had grade 1 events, 6.0% grade 2, 1.6% grade 3 and 0.1%, grade 4. The mean DICRU, [Formula: see text] , and [Formula: see text] were respectively: 66.2±9.1Gy, 72.9±11.9Gy, and 62.8±7.6Gy. Increase of dose was associated with increase in severity of single endpoints and overall rectal morbidity (grade 1-4) (p<0.001-0.026), except for stenosis (p=0.24-0.31). The probit model showed significant relationships between the [Formula: see text] , [Formula: see text] , and DICRU and the probability of grade 1-4, 2-4, and 3-4 rectal events. The equieffective [Formula: see text] for a 10% probability for overall rectal grade⩾2 morbidity was 69.5Gy (p<0.0001). After sorting patients according to 6 [Formula: see text] levels, less favorable outcome was observed in the high dose subgroups, for bleeding, proctitis, fistula, and overall rectal morbidity. A [Formula: see text] ⩾75Gy was associated with a 12.5% risk of fistula at 3years versus 0-2.7% for lower doses (p>0.001). A [Formula: see text] <65Gy was associated with a two times lower risk of proctitis than [Formula: see text] ⩾65Gy. CONCLUSIONS Significant correlations were established between late rectal morbidity, overall and single endpoints, and dose-volume ( [Formula: see text] , [Formula: see text] ) and dose-point (DICRU) parameters. A [Formula: see text] ⩽65Gy is associated with more minor and less frequent rectal morbidity, whereas a [Formula: see text] ⩾75Gy is associated with more major and more frequent rectal morbidity.

Assessment of Improved Organ at Risk Sparing for Advanced Cervix Carcinoma Utilizing Precision Radiotherapy Techniques

Purpose:To evaluate the potential benefit of proton therapy and photon based intensity-modulated radiotherapy in comparison to 3-D conformal photon radiotherapy (3D-CRT) in locally advanced cervix cancer.Patients and Methods:In five patients with advanced cervix cancer 3D-CRT (four-field box) was compared with intensity modulated photon (IMXT) and proton therapy (IMPT) as well as proton beam therapy (PT) based on passive scattering. Planning target volumes (PTVs) included primary tumor and pelvic and para-aortic lymph nodes. Dose-volume histograms (DVHs) were analyzed for the PTV and various organs at risk (OARs) (rectal wall, bladder, small bowel, colon, femoral heads, and kidneys). In addition dose conformity, dose inhomogeneity and overall volumes of 50% isodoses were assessed.Results:All plans were comparable concerning PTV parameters. Large differences between photon and proton techniques were seen in volumes of the 50% isodoses and conformity indices. DVH for colon and small bowel were significantly improved with PT and IMPT compared to IMXT, with Dmean reductions of 50–80%. Doses to kidneys and femoral heads could also be substantially reduced with PT and IMPT. Sparing of rectum and bladder was superior with protons as well but less pronounced.Conclusion:Proton beam RT has significant potential to improve treatment related side effects in the bowel compared to photon beam RT in patients with advanced cervix carcinoma.Ziel:Im Rahmen einer planungstechnischen Studie wurden die potentiellen Vorteile der Protonentherapie und der intensitätsmodulierten Photonentherapie (IMXT) im Vergleich zur konformalen Photontherapie bei der Behandlung des fortgeschrittenen Zervixkarzinoms bewertet.Patienten und Methodik:Bei fünf Patientinnen mit fortgeschrittenem Zervixkarzinom wurde eine konformale Vier-Felder-Photonentechnik mit einer Photonen basierten intensitätsmodulierten Radiotherapietechnik sowie Protonentherapie basierend auf Scanning (IMPT) bzw. passiver Aufstreuung (PT) verglichen. Die Planungszielgebiete (PTV) umfassten Lymphknotenstationen im Beckenbereich sowie in der Paraaortalregion. Mittels Dosis-Volumen-Histogramm-(DVH-)Analysen wurde die Belastung der Risikoorgane (Rektumwand, Harnblase, Hüftköpfe und Nieren, Dick- und Dünndarm) sowie die Auslastung des PTV bewertet. Zusätzlich wurden die Gesamtvolumina der 50%-Isodose sowie die Dosiskonformität und Dosishomogenität im PTV bewertet.Ergebnisse:Alle Bestrahlungspläne zeigten hinsichtlich der PTV-Auswertungsparameter vergleichbare Werte. Die größten Unterschiede zwischen den Photon- und Protonentechniken ergaben sich für die Volumina der 50%-Isodose und die Konformitätsindices. Im Vergleich zur Photonentherapie ergaben sich für PT und IMPT signifikant niedrigere gemittelte Dosiswerte (~ 50–80%) für den Dickdarm sowie den Dünndarm. Die Dosisbelastung der Nieren und der Hüftköpfe konnte mit Hilfe beider Protonentechniken ebenfalls wesentlich verringert werden. Die Unterschiede zwischen den Photonen- und Protonentechniken waren für die Risikoorgane Rektum und Blase weniger ausgeprägt.Schlussfolgerung:Im Vergleich zur Photonentherapie konnte mit Hilfe der Protonentherapie die Dosisbelastung am Darm signifikant reduziert werden. Diese verbesserte Darmschonung könnte zu einer Reduktion therapieassoziierter Nebenwirkungen bei der Behandlung des fortgeschrittenen Zervixkarzinoms führen.

Inverse Planning – a Comparative Intersystem and Interpatient Constraint Study

Purpose:To compare commercial treatment-planning systems (TPS) for inverse planning (IP) and to assess constraint variations for specific IMRT indications.Material and Methods:For IP, OTP, XiO and BrainSCAN were used and step-and-shoot intensity-modulated radiotherapy (IMRT) delivery was assumed. Based on identical constraints, IP was performed for a prostate, head and neck, brain, and gynecologic case. IMRT plans were compared in terms of conformity/homogeneity, dose-volume histograms (DVHs), and delivery efficiency. For ten patients each of a class of indications, constraint variations were evaluated.Results:IMRT plans were comparable concerning minimum target dose, homogeneity, conformity, and maximum doses to organs at risk. Larger differences were seen in dose gradients outside the target, monitor units, and segment number. Using help structures proved efficient to shape isodoses and to reduce segmentation workload. For IMRT class solutions, IP constraint variations depended on anatomic site.Conclusion:IP systems requiring doses as input and having objective functions based on physical parameters had a very similar performance. Constraint templates can be established for a class of IMRT indications.Ziel:Die Funktionalität der inversen Planung (IP) von kommerziellen Bestrahlungsplanungssystemen (TPS) sowie die Unterschiede von Dosiszielgrößen bei typischen IMRT-Indikationen (intensitätsmodulierte Strahlentherapie) wurden untersucht.Material und Methodik:Für die IP fanden OTP, XiO und BrainSCAN Verwendung, und eine „Step-and-shoot“-IMRT wurde angenommen. Basierend auf gleichen Zielgrößenvorgaben wurde für je einen Fall mit Prostatakarzinom, Hirntumor, HNO-Tumor sowie gynäkologischem Tumor eine IP durchgeführt. Die IMRT-Pläne wurden anhand von Dosis-Volumen-Histogrammen (DVHs), Konformität, Homogenität und Bestrahlungseffizienz bewertet. Für je zehn Patienten mit bestimmten Indikationen wurde die Schwankung der IP-Zielgrößen untersucht.Ergebnisse:Mit allen drei TPS konnten ähnliche IMRT-Pläne mit vergleichbarer Zielgebietsauslastung, Dosishomogenität, Konformität und maximaler Dosisbelastung der Risikoorgane erstellt werden. Größere Unterschiede wurden hinsichtlich des Dosisgradienten außerhalb des Zielgebiets, der Monitoreinheiten sowie der Segmentzahlen beobachtet. Die Verwendung von Hilfsstrukturen erwies sich als zeitsparend. Für eine IMRT-Indikation schwanken die Zielgrößenvorgaben in Abhängigkeit von der Patientenanatomie.Schlussfolgerung:Mit TPS, deren Zielgrößen und Zielfunktionen auf physikalischen Dosen beruhen, konnten ähnliche IMRT-Pläne erzielt werden. Für IMRT-Konzepte lassen sich Standardzielvorgaben festlegen.