Role of Brachytherapy in the Postoperative Management of Endometrial Cancer: Decision-Making Analysis among Experienced European Radiation Oncologists.

BACKGROUND: There are various society-specific guidelines addressing adjuvant brachytherapy (BT) after surgery for endometrial cancer (EC). However, these recommendations are not uniform. Against this background, clinicians need to make decisions despite gaps between best scientific evidence and clinical practice. We explored factors influencing decision-making for adjuvant BT in clinical routine among experienced European radiation oncologists in the field of gynaecological radiotherapy (RT). We also investigated the dose and technique of BT. METHODS: Nineteen European experts for gynaecological BT selected by the Groupe Européen de Curiethérapie and the European Society for Radiotherapy & Oncology provided their decision criteria and technique for postoperative RT in EC. The decision criteria were captured and converted into decision trees, and consensus and dissent were evaluated based on the objective consensus methodology. RESULTS: The decision criteria used by the experts were tumour extension, grading, nodal status, lymphovascular invasion, and cervical stroma/vaginal invasion (yes/no). No expert recommended adjuvant BT for pT1a G1-2 EC without substantial LVSI. Eighty-four percent of experts recommended BT for pT1a G3 EC without substantial LVSI. Up to 74% of experts used adjuvant BT for pT1b LVSI-negative and pT2 G1-2 LVSI-negative disease. For 74-84% of experts, EBRT + BT was the treatment of choice for nodal-positive pT2 disease and for pT3 EC with cervical/vaginal invasion. For all other tumour stages, there was no clear consensus for adjuvant treatment. Four experts already used molecular markers for decision-making. Sixty-five percent of experts recommended fractionation regimens of 3 × 7 Gy or 4 × 5 Gy for BT as monotherapy and 2 × 5 Gy for combination with EBRT. The most commonly used applicator for BT was a vaginal cylinder; 82% recommended image-guided BT. CONCLUSIONS: There was a clear trend towards adjuvant BT for stage IA G3, stage IB, and stage II G1-2 LVSI-negative EC. Likewise, there was a non-uniform pattern for BT dose prescription but a clear trend towards 3D image-based BT. Finally, molecular characteristics were already used in daily decision-making by some experts under the pretext that upcoming trials will bring more clarity to this topic.

Education and training for image-guided adaptive brachytherapy for cervix cancer-The (GEC)-ESTRO/EMBRACE perspective.

Image-guided adaptive brachytherapy (IGABT) has been shown to improve local/regional control and survival for cervix cancer patients while reducing morbidity. However, the technique is complex involving several conceptual, methodological, and technical innovations compared to conventional brachytherapy. The delivery of high-quality IGABT which will translate into improved outcomes is therefore critically dependent on effective education and training of all health professionals involved in the brachytherapy treatment process. This paper reviews the (GEC)-ESTRO/EMBRACE initiatives for education and training to promote the dissemination and implementation of IGABT for cervix cancer worldwide. The new skills required in different health professionals for successful implementation of IGABT are described. The achievements and challenges of current educational strategies for disseminating IGABT are discussed. Innovations to improve the effectiveness of current and future educational strategies are explored.

Bilateral Breast Metastases from Vulvar Carcinoma: A Case Report and Literature Review.

Vulvar carcinoma is a rare disease that accounts for 3-5% of all gynecologic malignancies. Breast represents an unusual site of metastasis and only a few cases are reported. We describe the first case of bilateral metastatic breast carcinoma of vulvar origin, at an 80-year-old female patient. Six months after treatment of her primary disease, she presented with bilateral metastatic squamous cell breast carcinoma. Diagnosis was based on clinical, radiological, and histological facts. Breast although rare is another potential site of metastasis in vulvar cancer and thus mammary gland examination should be considered in the follow-up of these patients. Differential diagnosis between primary and metastatic lesions is of utmost importance for appropriate management.

Health related quality of life and patient reported symptoms before and during definitive radio(chemo)therapy using image-guided adaptive brachytherapy for locally advanced cervical cancer and early recovery - a mono-institutional prospective study.

OBJECTIVE: To evaluate health-related quality of life (HR-QoL) and patient reported symptoms (PRS) before, during and early after treatment with external-beam radiotherapy (EBRT), chemotherapy and image-guided adaptive brachytherapy (IGABT) for locally advanced cervical cancer. METHODS: In fifty consecutive patients, HR-QoL and PRS were prospectively assessed with the EORTC-QLQ-C30+CX24 questionnaire prior to and during treatment, one week after IGABT and three months thereafter. HR-QoL was compared to an age-matched, female normative reference population. Prevalence rates of individual PRS are presented and defined as "substantial", if reported as "quite a bit" or "very much". RESULTS: Global health status and physical and role functioning show a highly significant decline during treatment (p≤0.001), before returning to near the baseline levels three months after end of treatment. Compared to the reference population, the global health status and emotional and role functioning remain impaired. The most frequently reported substantial PRS during active treatment are: fatigue (78%), diarrhea (68%), urinary frequency (60%) and nausea (54%); these recover to some degree three months after end of treatment. However, fatigue remains increased (50%) and an onset of hot flashes (44%), sexual worries (38%) and limb edema (22%) is observed. CONCLUSIONS: Several impairments in HR-QoL and PRS were found during definitive radio(chemo)therapy with IGABT, with different patterns of progress over time and signs of recovery three months thereafter, although some aspects of functional HR-QoL remain impaired. These findings support a comprehensive patients' counseling on what to expect and how to organize professional, social and family life and plan additional support during this period.

Posttraumatic stress disorder after high-dose-rate brachytherapy for cervical cancer with 2 fractions in 1 application under spinal/epidural anesthesia: incidence and risk factors.

PURPOSE: To investigate the psychological consequences of high-dose-rate brachytherapy with 2 fractions in 1 application under spinal/epidural anesthesia in the treatment of locally advanced cervical cancer. METHODS AND MATERIALS: In 50 patients with locally advanced cervical cancer, validated questionnaires were used for prospective assessment of acute and posttraumatic stress disorder (ASD/PTSD) (Impact of Event Scale-Revision), anxiety/depression (Hospital Anxiety and Depression Scale), quality of life (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30/Cervical Cancer 24), physical functioning (World Health Organization performance status), and pain (visual analogue scale), before and during treatment and 1 week and 3 months after treatment. Qualitative interviews were recorded in open format for content analysis. RESULTS: Symptoms of ASD occurred in 30% of patients 1 week after treatment; and of PTSD in 41% 3 months after treatment in association with this specific brachytherapy procedure. Pretreatment predictive variables explain 82% of the variance of PTSD symptoms. Helpful experiences were the support of the treatment team, psychological support, and a positive attitude. Stressful factors were pain, organizational problems during treatment, and immobility between brachytherapy fractions. CONCLUSIONS: The specific brachytherapy procedure, as performed in the investigated mono-institutional setting with 2 fractions in 1 application under spinal/epidural anesthesia, bears a considerable risk of traumatization. The source of stress seems to be not the brachytherapy application itself but the maintenance of the applicator under epidural anesthesia in the time between fractions. Patients at risk may be identified before treatment, to offer targeted psycho-social support. The patients' open reports regarding helpful experiences are an encouraging feedback for the treatment team; the reported stressful factors serve as a basis for improvement of patient management, especially regarding pain control.

Magnetic resonance imaging for assessment of parametrial tumour spread and regression patterns in adaptive cervix cancer radiotherapy.

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.

Uncertainty analysis for 3D image-based cervix cancer brachytherapy by repetitive MR imaging: assessment of DVH-variations between two HDR fractions within one applicator insertion and their clinical relevance.

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(αß10) (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(αß3) (1±6%) for bladder, 1.1±2.4 Gy(αß3) (2±4%) for rectum and decreased by 0.8±3.4 Gy(αß3) (1±5%) for sigmoid. For HR CTV the individual approach did not identify any case with a decrease of D(90) >5 Gy(αß10). 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(αß3). For the bladder all dose variations of more than 5 Gy(αß3) 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.

Uncertainties of target volume delineation in MRI guided adaptive brachytherapy of cervix cancer: a multi-institutional study.

BACKGROUND AND AIM: We aimed to quantify target volume delineation uncertainties in cervix cancer image guided adaptive brachytherapy (IGABT). MATERIALS AND METHODS: Ten radiation oncologists delineated gross tumour volume (GTV), high- and intermediate-risk clinical target volume (HR CTV, IR CTV) in six patients. Their contours were compared with two reference delineations (STAPLE-Simultaneous Truth and Performance Level Estimation and EC- expert consensus) by calculating volumetric and planar conformity index (VCI and PCI) and inter-delineation distances (IDD). RESULTS: VCISTAPLE and VCIEC were 0.76 and 0.72 for HR CTV, 0.77 and 0.68 for IR CTV and 0.59 and 0.58 for GTV. Variation was most prominent caudally and cranially in all target volumes and posterolaterally in IR CTV. IDDSTAPLE and IDDEC for HR CTV (3.6±3.5 and 3.8±3.4 mm) were significantly lower than for GTV (4.8±4.2 and 4.2±3.5 mm) and IR CTV (4.7±5.2 and 5.2±5.6 mm) (p<0.05). CONCLUSIONS: Due to lower delineation uncertainties when compared to GTV and IR CTV, HR CTV may be considered most robust volume for dose prescription and optimization in cervix cancer IGABT. Adequate imaging, training and use of contouring recommendations are main strategies to minimize delineation uncertainties.

Comparison of 3D MRI with high sampling efficiency and 2D multiplanar MRI for contouring in cervix cancer brachytherapy.

BACKGROUND: MRI sequences with short scanning times may improve accessibility of image guided adaptive brachytherapy (IGABT) of cervix cancer. We assessed the value of 3D MRI for contouring by comparing it to 2D multi-planar MRI. PATIENTS AND METHODS: In 14 patients, 2D and 3D pelvic MRI were obtained at IGABT. High risk clinical target volume (HR CTV) was delineated by 2 experienced radiation oncologists, using the conventional (2D MRI-based) and test (3D MRI-based) approach. The value of 3D MRI for contouring was evaluated by using the inter-approach and inter-observer analysis of volumetric and topographic contouring uncertainties. To assess the magnitude of deviation from the conventional approach when using the test approach, the inter-approach analysis of contouring uncertainties was carried out for both observers. In addition, to assess reliability of 3D MRI for contouring, the impact of contouring approach on the magnitude of inter-observer delineation uncertainties was analysed. RESULTS: No approach- or observer - specific differences in HR CTV sizes, volume overlap, or distances between contours were identified. When averaged over all delineated slices, the distances between contours in the inter-approach analysis were 2.6 (Standard deviation (SD) 0.4) mm and 2.8 (0.7) mm for observers 1 and 2, respectively. The magnitude of topographic and volumetric inter-observer contouring uncertainties, as obtained on the conventional approach, was maintained on the test approach. This variation was comparable to the inter-approach uncertainties with distances between contours of 3.1 (SD 0.8) and 3.0 (SD 0.7) mm on conventional and test approach, respectively. Variation was most pronounced at caudal HR CTV levels in both approaches and observers. CONCLUSIONS: 3D MRI could potentially replace multiplanar 2D MRI in cervix cancer IGABT, shortening the overall MRI scanning time and facilitating the contouring process, thus making this treatment method more widely employed.

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.

Treatment of locally advanced vaginal cancer with radiochemotherapy and magnetic resonance image-guided adaptive brachytherapy: dose-volume parameters and first clinical results.

PURPOSE: To investigate the clinical feasibility of magnetic resonance image-guided adaptive brachytherapy (IGABT) for patients with locally advanced vaginal cancer and to report treatment outcomes. METHODS AND MATERIALS: Thirteen patients with vaginal cancer were treated with external beam radiotherapy (45-50.4 Gy) plus IGABT with or without chemotherapy. Distribution of International Federation of Gynecology and Obstetrics stages among patients were as follows: 4 patients had Stage II cancer, 5 patients had Stage III cancer, and 4 patients had Stage IV cancer. The concept of IGABT as developed for cervix cancer was transferred and adapted for vaginal cancer, with corresponding treatment planning and reporting. Doses were converted to the equivalent dose in 2 Gy, applying the linear quadratic model (α/ß = 10 Gy for tumor; α/ß = 3 for organs at risk). Endpoints studied were gross tumor volume (GTV), dose-volume parameters for high-risk clinical target volume (HRCTV), and organs at risk, local control (LC), adverse side effects, and survival. RESULTS: The mean GTV (± 1 standard deviation) at diagnosis was 45.3 (±30) cm(3), and the mean GTV at brachytherapy was 10 (±14) cm(3). The mean D90 for the HRCTV was 86 (±13) Gy. The mean D2cc for bladder, urethra, rectum, and sigmoid colon were 80 (±20) Gy, 76 (±16) Gy, 70 (±9) Gy, and 60 (±9) Gy, respectively. After a median follow-up of 43 months (range, 19-87 months), one local recurrence and two distant metastases cases were observed. Actuarial LC and overall survival rates at 3 years were 92% and 85%. One patient with Stage IVA and 1 patient with Stage III disease experienced fistulas (one vesicovaginal, one rectovaginal), and 1 patient developed periurethral necrosis. CONCLUSIONS: The concept of IGABT, originally developed for treating cervix cancer, appears to be applicable to vaginal cancer treatment with only minor adaptations. Dose-volume parameters for HRCTV and organs at risk are in a comparable range. First clinical results indicate excellent LC. Further prospective multicenter studies are needed to establish this method and to confirm these results.

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/ß = 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.

Local recurrences in cervical cancer patients in the setting of image-guided brachytherapy: a comparison of spatial dose distribution within a matched-pair analysis.

PURPOSE: It has been shown that a cumulative dose of ≥87 Gy (EQD2) of external beam radiotherapy (EBRT) and image guided adaptive brachytherapy (IGABT) to the high risk clinical target volume (HR CTV) confer a local control rate >95% in locally advanced cervical cancer. This study examines the dose distribution within the HR CTV and intermediate (IR) CTV in patients with cervical cancer treated with definitive EBRT +/- concomitant chemotherapy and MRI-based IGABT between patients with local recurrence (LR) and patients in continuous complete local remission (CCLR). MATERIAL AND METHODS: From 1998 to 2010, 265 patients were treated with definitive EBRT +/- concomitant chemotherapy and IGABT. Twenty-four LRs were documented. For the statistical analysis all patients with LR were matched to patients in CCLR from our database according to the following criteria: FIGO stage, histology, lymph node status, tumour size and chemotherapy. DVH parameters (D50, D90, D98, D100) were reported for HR CTV and IR CTV. In order to report the minimum dose in the region where the recurrence occurred, the HR CTV/IR CTV were divided into four quadrants on transversal planes. The minimum dose at the HR CTV/IR CTV contour was measured (within the corresponding quadrant closest to the LR) in the treatment planning system. A mean minimum point dose (MPD) was calculated by averaging these measurements on four consecutive slices at the level of the recurrence for each of the 4 brachytherapy fractions. EQD2 doses were calculated by summation of all BT and external beam therapy fractions. For each matched patient in the control group the measurements were performed on the same quadrant and at the same level. RESULTS: Sufficient image data were available for 21 LRs. Eight central failures and 13 non-central failures were observed. The mean D90 and D100 for HR CTV were 77 Gy and 61 Gy for patients with LR and 95 Gy and 71 Gy for patients in CCLR, respectively (p<0.01). The MPD for HR CTV was 72 Gy for patients in the LR arm and 99 Gy for patients in the CCLR arm (p<0.01). In the LR arm seven patients had a D90 for HR CTV ≥87 Gy, however, in only three patients the MPD was ≥87 Gy. CONCLUSION: This study demonstrated significant differences in local outcome according to the delivered dose. In 85% of the LRs systematic low dose regions with less than 87 Gy were found at HR CTV contour. Systematic low dose regions leading to local recurrence could be detected even if a D90 HR CTV ≥87 Gy was applied. In addition to DVH parameters, inspection of the spatial dose distribution remains a key point in dose prescription.

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 45-50.4Gy±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.

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/ß = 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.

Evaluating repetitive 18F-fluoroazomycin-arabinoside (18FAZA) PET in the setting of MRI guided adaptive radiotherapy in cervical cancer.

BACKGROUND: The aim of this pilot study was to assess tumour hypoxia in patients with cervical cancer before, during and after combined radio-chemotherapy and Magnetic Resonance Imaging (MRI) guided brachytherapy (BT) by use of the hypoxia Positron Emission Tomography (PET) tracer (18)F-fluoroazomycin-arabinoside ((18)FAZA ). MATERIAL AND METHODS: Fifteen consecutive patients with locally advanced cervical cancer referred for definitive radiotherapy (RT) were included in an approved clinical protocol. Stage distribution was 3 IB1, 1 IB2, 10 IIB, 1 IIIB, tumour volume was 55 cm(3) (+/- 67, SD). Dynamic and static (18)FAZA -PET scans were performed before, during and after external beam therapy (EBRT) and image guided BT +/- concomitant cisplatin. Dose was prescribed to the individual High Risk Clinical Target Volume (HR CTV) taking into account the dose volume constraints for adjacent organs at risk. RESULTS: Five patients had visually identifiable tumours on (18)FAZA -PET scans performed prior to radio-chemotherapy and four patients before brachytherapy. One of five (18)FAZA PET positive patients had incomplete remission three months after RT, one had regional recurrence. Four of ten (18)FAZA-PET negative patients developed distant metastases. The one patient with incomplete remission received 69 Gy (D90) in the HR CTV, whereas all other patients received mean 99 Gy (+/-12, SD). CONCLUSION: PET imaging with (18)FAZA is feasible in patients with cancer of the uterine cervix. However, its predictive and prognostic value remains to be clarified. This applies in particular for the additional value of (18)FAZA-PET compared to morphologic repetitive MRI within the setting of image guided high dose radiotherapy which may contribute to overcome hypoxia related radioresistance.

Dose volume parameter D2cc does not correlate with vaginal side effects in individual patients with cervical cancer treated within a defined treatment protocol with very high brachytherapy doses.

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.

Is the Roach formula predictive for biochemical outcome in prostate cancer patients with minimal residual disease undergoing local radiotherapy after radical prostatectomy?

PURPOSE: To find out if the risk of biochemical failure can be predicted applying the risk assessment for lymph-node metastases as suggested by the Roach formula for patients with minimal residual disease after radical prostatectomy undergoing adjuvant radiotherapy. MATERIALS AND METHODS: Patients after radical prostatectomy presenting with pT3-tumours or positive surgical margins, negative nodes and with a post-operative and pre-radiotherapy PSA level or=15%. Biochemical recurrence was defined by reaching a PSA level >or=0.2 ng/ml. RESULTS: A total of 55/288 patients could be identified, 26 patients in Group 1 and 29 patients in Group 2. Mean follow-up was 45 months. Biochemical recurrence free survival after 5 years was 78% for all patients and showed a significant difference between Group 1 (100%) and Group 2 with (58%; p=0.004). CONCLUSION: The risk for biochemical failure after adjuvant radiotherapy in post-operative patients presenting with minimal residual disease is significantly influenced by the Roach formula. These findings are considered to provide a rationale for the decision on the volume of post-operative radiotherapy.

A detailed dosimetric comparison between manual and inverse plans in HDR intracavitary/interstitial cervical cancer brachytherapy.

PURPOSE: The purpose of this study was to compare two inverse planning algorithms for cervical cancer brachytherapy and a conventional manual treatment planning according to the MUW (Medical University of Vienna) protocol. MATERIAL AND METHODS: For 20 patients, manually optimized, and, inversely optimized treatment plans with Hybrid Inverse treatment Planning and Optimization (HIPO) and with Inverse Planning Simulated Annealing (IPSA) were created. Dosimetric parameters, absolute volumes of normal tissue receiving reference doses, absolute loading times of tandem, ring and interstitial needles, Paddick and COIN conformity indices were evaluated. RESULTS: HIPO was able to achieve a similar dose distribution to manual planning with the restriction of high dose regions. It reduced the loading time of needles and the overall treatment time. The values of both conformity indices were the lowest. IPSA was able to achieve acceptable dosimetric results. However, it overloaded the needles. This resulted in high dose regions located in the normal tissue. The Paddick index for the volume of two times prescribed dose was outstandingly low. CONCLUSIONS: HIPO can produce clinically acceptable treatment plans with the elimination of high dose regions in normal tissue. Compared to IPSA, it is an inverse optimization method which takes into account current clinical experience gained from manual treatment planning.