Johannes Dimopoulos

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.

Recommendations from Gynaecological (GYN) GEC-ESTRO Working Group (IV): Basic principles and parameters for MR imaging within the frame of image based adaptive cervix cancer brachytherapy.

The GYN GEC-ESTRO working group issued three parts of recommendations and highlighted the pivotal role of MRI for the successful implementation of 3D image-based cervical cancer brachytherapy (BT). The main advantage of MRI as an imaging modality is its superior soft tissue depiction quality. To exploit the full potential of MRI for the better ability of the radiation oncologist to make the appropriate choice for the BT application technique and to accurately define the target volumes and the organs at risk, certain MR imaging criteria have to be fulfilled. Technical requirements, patient preparation, as well as image acquisition protocols have to be tailored to the needs of 3D image-based BT. The present recommendation is focused on the general principles of MR imaging for 3D image-based BT. Methods and parameters have been developed and progressively validated from clinical experience from different institutions (IGR, Universities of Vienna, Leuven, Aarhus and Ljubljana) and successfully applied during expert meetings, contouring workshops, as well as within clinical and interobserver studies. It is useful to perform pelvic MRI scanning prior to radiotherapy (“Pre-RT-MRI examination”) and at the time of BT (“BT MRI examination”) with one MR imager. Both low and high-field imagers, as well as both open and close magnet configurations conform to the requirements of 3D image-based cervical cancer BT. Multiplanar (transversal, sagittal, coronal and oblique image orientation) T2-weighted images obtained with pelvic surface coils are considered as the golden standard for visualisation of the tumour and the critical organs. The use of complementary MRI sequences (e.g. contrast-enhanced T1-weighted or 3D isotropic MRI sequences) is optional. Patient preparation has to be adapted to the needs of BT intervention and MR imaging. It is recommended to visualise and interpret the MR images on dedicated DICOM-viewer workstations, which should also assist the contouring procedure. Choice of imaging parameters and BT equipment is made after taking into account aspects of interaction between imaging and applicator reconstruction, as well as those between imaging, geometry and dose calculation. In a prospective clinical context, to implement 3D image-based cervical cancer brachytherapy and to take advantage of its full potential, it is essential to successfully meet the MR imaging criteria described in the present recommendations of the GYN GEC-ESTRO working group.

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 RADIOTHERAPY FOR CERVIX CANCER: HIGH-TECH EXTERNAL BEAM THERAPY VERSUS HIGH-TECH BRACHYTHERAPY

PURPOSE Many studies comparing external-beam therapy (EBT) and brachytherapy (BT) are biased because advanced EBT is compared with conventional BT. This study compares high-tech EBT against high-tech BT. METHODS AND MATERIALS Nine patients were selected with locally advanced cervix cancer, representing typical clinical situations according to initial tumor extension and response after EBT. Patients were treated either with intracavitary, combined interstitial/intracavitary, or complex interstitial BT. Gross tumor volume, high-risk clinical target volume (CTV), intermediate-risk CTV, bladder, rectum, and sigmoid were delineated. Magnetic resonance-guided BT planning was manually optimized with respect to organ dose limits. Margins (3 and 5 mm) were added to BT CTVs to construct planning target volumes (PTVs) for EBT. Inversely planned EBT with photons (IMRT) and protons (IMPT) was challenged to deliver the highest possible doses to PTVs while respecting D(1cc) and D(2cc) limits from BT, assuming the same fractionation (4 x 7 Gy). The D90 for target structures and normal tissue volumes receiving fractionated doses between 3 and 7 Gy were compared. RESULTS High-risk CTV doses depended on the clinical situation and radiation quality. If IMRT was limited to D(2cc) and D(1cc) from BT, the D90 for high-risk PTV and intermediate-risk PTV was mostly lower. Volumes receiving 60 Gy (in equivalent dose in 20 Gy fractions) were approximately twice as large for IMRT compared with BT. For IMPT, this volume ratio was lower. Planning target volume doses of IMPT plans with 3-mm margins were comparable to those with BT. Gross tumor volume doses were mostly lower for both IMRT and IMPT. CONCLUSION For benchmarking high-tech EBT, high-tech BT techniques have to be used. For cervix cancer boost treatments, both IMRT and IMPT seem to be inferior to advanced BT.

Present status and future of high-precision image guided adaptive brachytherapy for cervix carcinoma

Introduction. Image guided adaptive brachytherapy (IGABT) for cervical cancer, using mainly MRI, is an evolving method, increasingly replacing the 2D approach based on conventional radiography. During the complex 4D chain of this procedure image-assistance is provided for disease assessment, provisional treatment planning (“pre-planning”), applicator placement and reconstruction, as well as for contouring, definitive treatment planning and quality control of dose delivery. With IGABT changes of topography adjacent to the applicator, caused by tumour regression, oedema, organ changes and dilation are identified. Thus, the CTV for IGABT is primarily based on the tumour volume at the time of BT and takes into account both time and spatial domains. IGABT requires systematic concepts for target, OAR, biological modelling, DVH analysis, and dose-volume-adaptation. Methods and Results. This report focuses on the advantages and uncertainties, dose-effect relations and clinical results of the IGABT procedure addressing the current status and future perspectives. Uncertainties during the 4D chain of IGABT are mainly related to target contouring, applicator reconstruction, as well as to inter-fraction, intra-fraction and inter-application variability, as caused by tumour response and organ changes. Different from EBRT where set-up uncertainties are compensated by adding a margin to the CTV, no margins to the lateral and anterior-posterior directions can be used for IGABT. Discussion. By 3D treatment planning for IGABT significant improvement of the DVH parameters is achieved compared to 2D library plans. In small tumours the benefit is primarily obtained by a decrease of dose to nearby OAR while in large tumours the use of supplementary interstitial techniques and optimization may double the target volume that can be treated at a therapeutic dose level. The clinical impact of IGABT could recently be demonstrated by the establishment of some correlations between target- and organ-related DVH parameters versus disease control and side effects, which need further clarification. Overall, a very high local control rate can be achieved with minor treatment related morbidity. This favourable therapeutic ratio seems to be now reproducible under different conditions at various treatment centres. These results have to be validated within the upcoming multi-centre prospective IntErnational study on MRI-guided brachytherapy in locally advanced cervical cancer (EMBRACE).

Inter-observer comparison of target delineation for MRI-assisted cervical cancer brachytherapy: Application of the GYN GEC-ESTRO recommendations

BACKGROUND AND PURPOSE To investigate the inter-observer variation of target contouring when using the GYN GEC-ESTRO recommendations for MR image-guided brachytherapy (IGBT) for cervical cancer. MATERIALS AND METHODS Nineteen cervical cancer patients, treated by radiotherapy at the Institut Gustave Roussy (IGR) in France (n=9) or at the Medical University of Vienna (AKH) in Austria (n=10) were included in this study. IGBT was used for all patients. Two radiation oncologists, one from IGR and the other from AKH, outlined the target volumes on MRI at the time of brachytherapy according to the GYN GEC-ESTRO recommendations. The absolute, common and encompassing volumes and their conformity indices (CIs) were assessed for the GTV, HR CTV and IR CTV. D90 and D100 for each volume were assessed. Visual evaluation was made to assess the reasons for the most frequent inter-observer differences. RESULTS The mean volumes of GTV and HR CTV did not differ significantly between the observers, p>0.05. Significant differences were observed only for the mean volumes of the IR CTV of both centres, p<0.05. CIs ranged from 0.5 to 0.7. DVH-parameter analyses did not reveal any statistical differences, except for the D100 for the GTV at AKH, and the D90 for the IR CTV at IGR, p<0.05. Underlying reasons for inter-observer differences included image contrast adjustment and neglecting to consider anatomical borders. CONCLUSIONS The results of this inter-observer study show that the application of the GYN GEC-ESTRO recommendations for IGBT contouring at two different institutions with two different traditions for applicators, CTV assessment, MR image acquisition and dose prescription is feasible, and it produces acceptable inter-observer variability.

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.