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Purpose: Imaging biomarkers assessed with magnetic resonance imaging (MRI) and/or positron emission tomography (PET) enable non-invasive tumor characterization in cervix cancer patients. We investigated the spatio-temporal stability of hypoxia, perfusion, and the cell density of tumors over time by repetitive imaging prior to, during, and after radio-chemotherapy., Procedures: Thirteen patients were included in this prospective study. The imaging protocol included the following: [ 18 F]fluoromisonidazole ([ 18 F]FMISO)-PET/x-ray computed tomography (CT) and multiparametric (mp)-MRI at four time-points (TP): baseline (BL); and weeks 2 (TP1), 5 (TP2), and 19 after treatment start (follow-up FU). Complete datasets for six patients could be assessed for tumor volume, enhancement kinetics, diffusivity, and [ 18 F]FMISO-avidity (P1-P6). In addition, two patients completed all PET/CT examinations (P7-P8) but not all MR scans; however, one of them had no hypoxia (P8). Descriptive statistics, correlations, and voxel-by-voxel analysis were performed. For various, independent reasons, five patients could not complete the study according to the protocol with all imaging sequences., Results: Median tumor ADCs (in ×10 -3  mm 2 /s) were 0.99 ± 0.10 at BL, 1.20 ± 0.12 at TP1, 1.33 ± 0.14 at TP2, and 1.38 ± 0.21 at FU. The median TBR peak (tumor-to-background) was 2.7 ± 0.8 at BL, 1.6 ± 0.2 at TP1, 1.8 ± 0.3 at TP2, and 1.7 ± 0.3 at FU. The voxel-by-voxel analysis of the [ 18 F]FMISO uptake at BL and TP1 showed no correlation. Between TP2 and TP1 and FU and TP2, weak correlations were found for two patients., Conclusions: Longitudinal mp-MR and PET imaging enables the in vivo tumor characterization over time. While perfusion and cell density decreased, there was a non-uniform change of hypoxia observed during radiotherapy. To assess the potential impact with regard to more personalized treatment approaches, hypoxia imaging-based dose painting for cervix cancer requires further research.

Background and Purpose: Multimodal tissue characterization by combined MRI and PET has high clinical potential in the context of sub-target definition for dose painting and response assessment but its clinical exploration is yet limited. The aim of this study was to prove the potential and feasibility of hybrid PET/MRI to non-invasively measure tumor hypoxia, perfusion and microstructure at one stop in tumors of the uterine cervix during chemoradiotherapy., Material and Methods: Ten cervix cancer patients were subjected to simultaneous multiparametric PET/MRI with [ 18 F]fluoromisonidazole ([ 18 F]FMISO). Imaging was scheduled before, twice during and after chemoradiotherapy. Intra- and inter-time point analyses of the extracted parameters (i.e. ADC, K trans , A Brix , [ 18 F]FMISO-tumor to background ratio (TBR)) were performed. The [ 18 F]FMISO uptake- and ADC-spatio-temporal changes were assessed., Results: Patient averaged ADC values increased from baseline to follow up (1.03 ± 0.11/1.30 ± 0.13 × 10 -3  mm 2 /s), while the TBR decreased (1.73 ± 0.24/1.36 ± 0.19), K trans dropped over time (0.17 ± 0.05/0.05 ± 0.05 min -1 ); for all above p < 0.05. None of these parameters correlated significantly on a voxel-by-voxel basis. Low-ADC regions spatially varied over time. There was pronounced reduction of the [ 18 F]FMISO-avid volumes during treatment., Conclusions: The suggested hybrid PET/MRI protocol to non-invasively investigate tumor hypoxia, perfusion and microstructure at one stop was feasible, revealing spatio-temporal response patterns that could be utilized for comprehensive sub-target definition for dose painting and response assessment., (Copyright © 2017 Elsevier B.V. All rights reserved.)

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 (EQD2 10 ), mean D2cc was: bladder 81±22Gy, rectum 64±9Gy, sigmoid 66±10Gy and bowel 64±9Gy (all EQD2 3 ). 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., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

Background and Purpose: Target and organ movement motivate adaptive radiotherapy for cervix cancer patients. We investigated the dosimetric impact of margin concepts with different levels of complexity on both organ at risk (OAR) sparing and PTV coverage., Material and Methods: Weekly CT and daily CBCT scans were delineated for 10 patients. The dosimetric impact of organ shape variations were evaluated for four (isotropic) margin concepts: two static PTVs (PTV 6mm and PTV 15mm ), a PTV based on ITV of the planning CT and CBCTs of the first treatment week (PTV ART ITV ) and an adaptive PTV based on a library approach (PTV ART Library )., Results: Using static concepts, OAR doses increased with large margins, while smaller margins compromised target coverage. ART PTVs resulted in comparable target coverage and better sparing of bladder (V40Gy: 15% and 7% less), rectum (V40Gy: 18 and 6cc less) and bowel (V40Gy: 106 and 15cc less) compared to PTV 15mm . Target coverage evaluation showed that for elective fields a static 5mm margin sufficed., Conclusion: PTV ART Library achieved the best dosimetric results. However when weighing clinical benefit against workload, ITV margins based on repetitive movement evaluation during the first week also provide improvements over static margin concepts., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

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 (EQD2 3 ). 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 D ICRU , [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 D ICRU 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 (D ICRU ) 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., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objectives: To investigate fused multiparametric positron emission tomography/magnetic resonance imaging (MP PET/MRI) at 3T in patients with locally advanced cervical cancer, using high-resolution T2-weighted, contrast-enhanced MRI (CE-MRI), diffusion-weighted imaging (DWI), and the radiotracers [18F]fluorodeoxyglucose ([18F]FDG) and [18F]fluoromisonidazol ([18F]FMISO) for the non-invasive detection of tumor heterogeneity for an improved planning of chemo-radiation therapy (CRT)., Materials and Methods: Sixteen patients with locally advanced cervix were enrolled in this IRB approved and were examined with fused MP [18F]FDG/ [18F]FMISO PET/MRI and in eleven patients complete data sets were acquired. MP PET/MRI was assessed for tumor volume, enhancement (EH)-kinetics, diffusivity, and [18F]FDG/ [18F]FMISO-avidity. Descriptive statistics and voxel-by-voxel analysis of MRI and PET parameters were performed. Correlations were assessed using multiple correlation analysis., Results: All tumors displayed imaging parameters concordant with cervix cancer, i.e. type II/III EH-kinetics, restricted diffusivity (median ADC 0.80x10-3mm2/sec), [18F]FDG- (median SUVmax16.2) and [18F]FMISO-avidity (median SUVmax3.1). In all patients, [18F]FMISO PET identified the hypoxic tumor subvolume, which was independent of tumor volume. A voxel-by-voxel analysis revealed only weak correlations between the MRI and PET parameters (0.05-0.22), indicating that each individual parameter yields independent information and the presence of tumor heterogeneity., Conclusion: MP [18F]FDG/ [18F]FMISO PET/MRI in patients with cervical cancer facilitates the acquisition of independent predictive and prognostic imaging parameters. MP [18F]FDG/ [18F]FMISO PET/MRI enables insights into tumor biology on multiple levels and provides information on tumor heterogeneity, which has the potential to improve the planning of CRT.

Background: To assess planning aims (PAs) and dose prescription in image-guided adaptive brachytherapy (IGABT) of cervical cancer and investigate potential impact on clinical outcome., Material and Methods: Our study population consists of 225 consecutive cervical cancer patients (FIGO stages IB-IVA) treated between 1998 and 2008 at the Medical University of Vienna by external beam radiotherapy (EBRT) ± chemotherapy and IGABT. For this retrospective study, patients were stratified into two treatment groups: PA+ group, all dose constraints fulfilled for prescription; PA-, one or more dose constraints not fulfilled for prescription. The following dose constraints (EBRT+ IGABT) were applied: clinical target volume (CTV)HR D90 ≥ 85 Gy, D2cm3 Rectum < 70 Gy, D2cm3 Bladder < 90 Gy. Differences in patient, tumor and treatment characteristics and clinical outcome (event: local failure or grade 3 + 4 toxicity) were compared between Group 1 and 2. Further, the impact of learning period (1998-2000) and protocol period (2001-2008) on the fulfillment of PAs for dose prescription and clinical outcome was analyzed., Results: In the PA+ group there were 77 (34%) and in the PA- group 148 (66%) patients. In the PA- group, CTVHR D90 < 85 Gy was prescribed in 82 patients, D2cm3 bladder > 90 Gy was prescribed in 80 patients and D2cm3 Rectum > 70 Gy in 60 patients. Fulfillment of the PA for dose prescription improved from 4% in the learning period to 48% in the protocol period. The five-year event-free interval was 64% in the learning period and 84% in the protocol period (p = 0.008)., Conclusion: Fulfillment of all PAs for dose prescription is challenging - especially in patients with more advanced tumors. However, with growing experience fulfillment of PA for dose prescription can be significantly increased (learning and protocol period). Such increase in fulfilling PA for dose prescription is followed by a significant improvement in clinical outcome.

Purpose: To investigate the impact of magnetic resonance imaging (MRI)-morphologic differences in parametrial infiltration on tumour response during primary radiochemotherapy in cervical cancer., Material and Methods: Eighty-five consecutive cervical cancer patients with FIGO stages IIB (n = 59) and IIIB (n = 26), treated by external beam radiotherapy (± chemotherapy) and image-guided adaptive brachytherapy, underwent T2-weighted MRI at the time of diagnosis and at the time of brachytherapy. MRI patterns of parametrial tumour infiltration at the time of diagnosis were assessed with regard to predominant morphology and maximum extent of parametrial tumour infiltration and were stratified into five tumour groups (TG): 1) expansive with spiculae; 2) expansive with spiculae and infiltrating parts; 3) infiltrative into the inner third of the parametrial space (PM); 4) infiltrative into the middle third of the PM; and 5) infiltrative into the outer third of the PM. MRI at the time of brachytherapy was used for identifying presence (residual vs. no residual disease) and signal intensity (high vs. intermediate) of residual disease within the PM. Left and right PM of each patient were evaluated separately at both time points. The impact of the TG on tumour remission status within the PM was analysed using χ(2)-test and logistic regression analysis., Results: In total, 170 PM were analysed. The TG 1, 2, 3, 4, 5 were present in 12%, 11%, 35%, 25% and 12% of the cases, respectively. Five percent of the PM were tumour-free. Residual tumour in the PM was identified in 19%, 68%, 88%, 90% and 85% of the PM for the TG 1, 2, 3, 4, and 5, respectively. The TG 3-5 had significantly higher rates of residual tumour in the PM in comparison to TG 1 + 2 (88% vs. 43%, p < 0.01)., Conclusion: MRI-morphologic features of PM infiltration appear to allow for prediction of tumour response during external beam radiotherapy and chemotherapy. A predominantly infiltrative tumour spread at the time of diagnosis resulted in a significantly higher rate of residual tumour in the PM at the time of brachytherapy in comparison to a predominantly expansive tumour spread.

Purpose: To investigate dosimetric uncertainties of MRI-based cervix cancer brachytherapy, when applying two HDR fractions for each applicator insertion and their clinical relevance., Methods: 21 patients with 84 MRI-examinations and fractions were investigated. After insertion of the MRI compatible tandem-ring applicator, an MRI-set was recorded and the treatment plan optimised for the first fraction. Prior to the second fraction 16-20 h later a second MRI-set was recorded, and the dose distribution from the plan of the previous day superimposed and analysed. The same procedure was repeated for fractions 3 and 4. Dose from EBRT and brachytherapy was normalised to 2 Gy-fractionation (EQD2), added up to a total dose, and compared to a calculated total dose if only 1 MRI-examination per insertion is available., Results: The total D(90) for High risk (HR) CTV was 1.2±2.7 Gy(αβ10) (1±3%) (mean±1SD) lower by individual MRI-evaluation of each fraction compared to 1 MRI per insertion. The D(2cm(3)) increased by 0.7±4.7 Gy(αβ3) (1±6%) for bladder, 1.1±2.4 Gy(αβ3) (2±4%) for rectum and decreased by 0.8±3.4 Gy(αβ3) (1±5%) for sigmoid. For HR CTV the individual approach did not identify any case with a decrease of D(90) >5 Gy(αβ10). For the bladder 3 cases, for the rectum no case and for the sigmoid 1 case was identified with an increase of D(2cm(3)) >5 Gy(αβ3). For the bladder all dose variations of more than 5 Gy(αβ3) could have been avoided by ensuring a constant bladder filling. Individual MRI-evaluation did not determine any case where dose constraints were not fulfilled., Conclusions: For the treatment schedule as applied in this study, geometric differences between applicator, target and OAR result in overall dosimetric changes, which seem to be of minor relevance in regard to clinical dose volume constraints applied at present., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

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., (Copyright © 2012 Elsevier Inc. All rights reserved.)

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 45-50.4Gy±concomitant cisplatin chemotherapy plus 4×7Gy 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>85Gy), often with inserting additional interstitial needles. Dose volume constraints (D(2cc)) were 70-75Gy for rectum and sigmoid and 90Gy 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 58years) 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 >5cm in 103 patients (66%), lymph node involvement in 75 patients (48%). Median follow-up was 42months for all patients. Interstitial techniques were used in addition to intracavitary brachytherapy in 69/156 (44%) patients. Total prescribed mean dose (D90) was 93±13Gy, D(2cc) 86±17Gy for bladder, 65±9Gy for rectum and 64±9Gy for sigmoid. Complete remission was achieved in 151/156 patients (97%). Overall local control at 3years was 95%; 98% for tumours 2-5cm, and 92% for tumours >5cm (p=0.04), 100% for IB, 96% for IIB, 86% for IIIB. Cancer specific survival at 3years was overall 74%, 83% for tumours 2-5cm, 70% for tumours >5cm, 83% for IB, 84% for IIB, 52% for IIIB. Overall survival at 3years was in total 68%, 72% for tumours 2-5cm, 65% for tumours >5cm, 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 3years 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., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

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., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The study aimed to determine whether post-radiation vaginal side effects in cervical cancer patients can be correlated with DVH parameter D(2cc). The result was negative in that no correlation could be demonstrated between D(2cc) and the presence and grade of side effects in this patients' subset treated with high brachytherapy doses., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

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.

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.

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.

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 D(mean) 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.

Background: To investigate the clinical impact of MRI based cervix cancer brachytherapy combined with external beam radiochemotherapy applying dose volume adaptation and dose escalation in a consecutive group of patients with locally advanced cervix cancer., Methods: In the period 1998-2003, 145 patients with cervix cancer stages IB-IVA were treated with definitive radiotherapy +/- cisplatin chemotherapy. Median age was 60 years. In 67 patients, the tumour size was 2-5 cm, in 78 patients it was >5 cm. In 29 cases the standard intracavitary technique was combined with interstitial brachytherapy. Total prescribed dose was 80-85 Gy (total biologically equivalent dose in 2 Gy fractions). Since 2001, MRI based treatment planning integrated systematic concepts for High Risk Clinical Target Volume (HR CTV) and organs at risk (OAR), biological modelling, Dose-Volume-Histogram analysis, dose-volume-adaptation (D90, D 2 cm(3)), and dose escalation, if appropriate and feasible., Findings: Dose volume adaptation was performed in 130/145 patients. The mean D90 during the whole period was 86 Gy, with a mean D90 of 81 Gy and 90 Gy during the first and second period, respectively (p<<0.01). Median follow-up was 51 months. Complete remission at 3 months was achieved in 138/145 patients (95%). Actuarial continuous complete remission for true pelvis (CCRtp) was 88% at 3 years. For tumours 2-5 cm, CCRtp was 96% both in 1998-2000 and 2001-2003. For tumours >5 cm it was 71% in 1998-2000 and 90% in 2001-2003 (p=0.05). Progression free survival (PFS) for true pelvis (local control) was 85%, PFS for distant metastases was 80%, both at 3 years. Local control for tumours >5 cm was 64% in 1998-2000 and 82% in 2001-2003 (p=0.09) and 100% and 96%, respectively, for tumours 2-5 cm. PFS for distant metastases remained the same during the two treatment periods with 79% and 80%. Overall survival (OS) was 58%, and cancer-specific survival (CSS) was 68% at 3 years. In the two different periods improvement in OS was from 53% to 64% (p=0.03) and in CSS from 62% to 74% (p=0.13). Improvement occurred only in tumours >5 cm: OS 28% versus 58% (p=0.003); CSS 40% versus 62% (p=0.07). Actuarial late morbidity rate (LENT SOMA, grades 3 and 4) at 3 years was gastrointestinal 4%, urinary 4% and vaginal 5% (stage IIA/IIIA). Gastrointestinal and urinary late morbidity (G3,G4) was 10% in 1998-2000 and 2% in 2001-2003., Interpretation: In locally advanced extensive cervix cancer, local control of > or = 85% can be achieved with low treatment related morbidity (G3/G4), when exploiting the potential of MRI based 3D treatment planning including dose volume adaptation and dose escalation and a combined intracavitary/interstitial brachytherapy, if appropriate. A significant impact of this improvement of local control on survival is to be expected. For locally advanced limited disease the MRI based approach will likely result in assuring excellent local control (> or = 95%) and in minimizing treatment related morbidity.

Purpose: The vagina has not been widely recognized as organ at risk in brachytherapy for cervical cancer. No widely accepted dose parameters are available. This study analyzes the uncertainties in dose reporting for the vaginal wall using tandem-ring applicators., Methods and Materials: Organ wall contours were delineated on axial magnetic resonance (MR) slices to perform dose-volume histogram (DVH) analysis. Different DVH parameters were used in a feasibility study based on 40 magnetic resonance imaging (MRI)-based treatment plans of different cervical cancer patients. Dose to the most irradiated, 0.1 cm(3), 1 cm(3), 2 cm(3), and at defined points on the ring surface and at 5-mm tissue depth were reported. Treatment-planning systems allow different methods of dose point definition. Film dosimetry was used to verify the maximum dose at the surface of the ring applicator in an experimental setup., Results: Dose reporting for the vagina is extremely sensitive to geometrical uncertainties with variations of 25% for 1 mm shifts. Accurate delineation of the vaginal wall is limited by the finite pixel size of MRI and available treatment-planning systems. No significant correlation was found between dose-point and dose-volume parameters. The DVH parameters were often related to noncontiguous volumes and were not able to detect very different situations of spatial dose distributions inside the vaginal wall. Deviations between measured and calculated doses were up to 21%., Conclusions: Reporting either point dose values or DVH parameters for the vaginal wall is based on high inaccuracies because of contouring and geometric positioning. Therefore, the use of prospective dose constraints for individual treatment plans is not to be recommended at present. However, for large patient groups treated within one protocol correlation with vaginal morbidity can be evaluated.

Purpose: The aims of this study were to investigate the clinical feasibility and to report on preliminary treatment outcomes of combined intracavitary/interstitial brachytherapy, using a novel applicator and magnetic resonance imaging (MRI)-based treatment planning in patients with locally advanced cervical cancer., Methods and Materials: A total of 22 cervical cancer patients with insufficient response and/or unfavorable topography after external-beam irradiation were included in this study. Parametrial extent of the disease in these patients was judged to exceed the coverage limit of intracavitary brachytherapy alone. A modified tandem/ring (T/R) applicator for guidance of parametrial needles (N) was used to perform high-dose-rate-brachytherapy with MRI-based treatment planning. Clinical feasibility and preliminary treatment outcomes were assessed., Results: A total of 44 interstitial needle implants were performed. The spatial relations between the T/R + N applicator, high-risk clinical target volume, and organs at risk were visible clearly in all cases. Accurate and reproducible needle placement could be achieved in the majority of cases. No severe adverse events were caused by the intervention. The mean follow-up period was 20 months (range, 5-35 months). No G3 to G4 early or persistent late side effects were observed. Complete remission was achieved in 21 patients (95%). One local recurrence was observed within the high-risk clinical target volume area during follow-up., Conclusions: Our preliminary clinical experience indicates that combined intracavitary and interstitial MRI-based brachytherapy in patients with significant residual disease after external-beam therapy extending up to the distal third of parametria is feasible and allows excellent local control and a low rate of morbidity.

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.

Background and Purpose: To evaluate the influence of uterus and bladder size on large and small bowel sparing with intensity modulated whole pelvic radiotherapy (IM-WPRT) in gynecologic patients., Patients and Methods: Twenty patients were selected; 10 women with cervical cancer treated with definitive radiotherapy (group 'DEF') and 10 endometrial cancer patients treated postoperatively (group 'POST'). Bladder, rectal wall, small (SB) and large bowel (LB) were delineated as organs at risk. A conformal four field technique and a seven field IMRT plan (prescription dose 50.4 Gy) were compared in terms of DVH and various target parameters., Results: At doses between 40 and 50.4 Gy statistically significant improvements (P<0.05) were observed for IM-WPRT for irradiated volume of rectal wall and bladder. In both patient groups, with IMRT the average irradiated volume of SB was reduced by a factor of 6 at 50.4Gy. This ratio was 2 for LB. In the DEF group the effect of SB-sparing with IMRT correlated with bladder size (correlation coefficient 0.70) while it did not correlate in the postoperative group. The effect of LB-sparing decreased with increasing bladder size in both groups but the impact of IMRT was larger for postoperative patients., Conclusions: IMRT significantly reduced the absolute volume of rectal wall, bladder and bowel irradiated at the prescribed dose level in gynaecologic patients. Main differences between POST and DEF patients receiving IM-WPRT were absolute volumes of LB irradiated to doses between 35 and 50Gy, suggesting an impact of intact uterus on LB volume in the pelvis. POST patients seem to benefit most from elective nodal IMRT. Bladder filling is an important co-factor influencing the benefit of IMRT with respect to OAR sparing.