Multi-center dosimetric predictions to improve plan quality for brachytherapy for cervical cancer treatment.

BACKGROUND AND PURPOSE: Image-guided adaptive brachytherapy (IGABT) is an important modality in the cervical cancer treatment, and plan quality is sensitive to time pressure in the workflow. Patient anatomy-based quality-assurance (QA) with overlap volume histograms (OVHs) has been demonstrated to detect suboptimal plans (outliers). This analysis quantifies the possible improvement of plans detected as outliers, and investigates its suitability as a clinical QA tool in a multi-center setting. MATERIALS AND METHODS: In previous work OVH-based models were investigated for the use of QA. In this work a total of 160 plans of 68 patients treated in accordance with the current state-of-the-art IGABT protocol from Erasmus MC (EMC) were analyzed, with a model based on 120 plans (60 patients) from UMC Utrecht (UMCU). Machine-learning models were trained to define QA thresholds, and to predict dose D2cm3 to bladder, rectum, sigmoid and small bowel with the help of OVHs of the EMC cohort. Plans out of set thresholds (outliers) were investigated and retrospectively replanned based on predicted D2cm3 values. RESULTS: Analysis of replanned plans demonstrated a median improvement of 0.62 Gy for all Organs At Risk (OARs) combined and an improvement for 96 % of all replanned plans. Outlier status was resolved for 36 % of the replanned plans. The majority of the plans that could not be replanned were reported having implantation complications or insufficient coverage due to tumor geometry. CONCLUSION: OVH-based QA models can detect suboptimal plans, including both unproblematic BT applications and suboptimal planning circumstances in general. OVH-based QA models demonstrate potential for clinical use in terms of performance and user-friendliness, and could be used for knowledge transfer between institutes. Further research is necessary to differentiate between (sub)optimal planning circumstances.

Dose-effect relationship between vaginal dose points and vaginal stenosis in cervical cancer: An EMBRACE-I sub-study.

BACKGROUND AND PURPOSE: To evaluate dose-effect relationships between vaginal dose points and vaginal stenosis in patients treated for locally advanced cervical cancer with radio(chemo)therapy and image-guided adaptive brachytherapy. MATERIAL AND METHODS: Patients from six centres participating in the EMBRACE-I study were included. Information on doses to different vaginal dose points, including the Posterior-Inferior Border of Symphysis (PIBS) points and recto-vaginal reference (RV-RP) point, were retrieved from the treatment planning system. In addition, the vaginal reference length (VRL) was evaluated. Vaginal stenosis was prospectively assessed according to the CTCAEv3.0 system at baseline and follow-up. Primary endpoint was grade 2 or higher (G ≥ 2) vaginal stenosis. Impact of dose to the vaginal dose points, and impact of VRL, age, vaginal involvement and applicator on vaginal stenosis G ≥ 2 was evaluated with a Cox proportional-hazard regression model. RESULTS: 301 patients were included. Median follow-up was 49 months. During follow-up, the incidence of G0, G1, G2, and G3 vaginal stenosis was 25% (76), 52% (158), 20% (59) and 3% (8), respectively. Median total doses to PIBS+2 cm, PIBS, PIBS-2 cm and the RV-RP were 52.9 (IQR 49.3-64.7), 41.0 (IQR 15.4-49.0), 4.1 (IQR 2.9-7.0) and 64.6 (IQR 60.0-70.6) Gy EQD23, respectively. Higher doses to the PIBS, PIBS + 2 cm and RV-RP points were significantly associated with increased risk for vaginal stenosis G ≥ 2. Other risk factors for vaginal stenosis were: vaginal involvement at diagnosis, higher age, shorter VRL and use of a tandem-ovoid applicator. CONCLUSION: Higher doses to the PIBS+2 cm, PIBS and RV-RP dose points are associated with vaginal stenosis G ≥ 2.

Risk factors for nodal failure after radiochemotherapy and image guided brachytherapy in locally advanced cervical cancer: An EMBRACE analysis.

OBJECTIVE: To assess risk factors for nodal failure (NF) after definitive (chemo)radiotherapy and image-guided brachytherapy for locally advanced cervical cancer (LACC) for patients treated in the EMBRACE I study. MATERIALS AND METHODS: Data for pelvic NF and para-aortic (PAO) NF (NFPAO) were analysed. After multiple imputation, univariable and multivariable Cox-regression was performed for clinical and treatment-related variables. For patients with affected pelvic nodes but no PAO nodes at diagnosis, additional analyses were performed for two subgroups: 1. 'small pelvis' nodes in internal and external iliac, obturator, parametrial, presacral and/or common iliac (CI) region and 2. any CI nodes (subgroup of 1). RESULTS: 1338 patients with 152 NF and 104 NFPAO events were analysed with a median follow-up of 34.2 months (IQR 16.4-52.7). For the entire group, larger tumour width, nodal risk groups (in particular any CI nodes without PAO nodes), local failure, and lower Hb-nadir increased the risk of NF. Elective PAO-irradiation was independently associated with a decreased risk of NFPAO (HR 0.53, 95%-CI 0.28-1.00, p = 0.05). For subgroup 1, having 'any CI nodes without PAO nodes' and local failure significantly increased NF risk. Additionally, elective PAO-irradiation was associated with less risk of NFPAO (HR 0.38, 95%-CI 0.17-0.86, p = 0.02). For subgroup 2 only local failure was associated with higher risk of NF. CONCLUSION: In this patient cohort, nodal disease and tumour width at diagnosis, as well as local failure, are risk factors for NF after definitive treatment. Having either 'any PAO nodes' (with or without pelvic nodes) or 'any CI nodes' (without PAO nodes) are stronger risk factors than involvement of nodes in the small pelvis alone. Elective PAO-irradiation was associated with significantly less NFPAO, particularly in patients with nodal disease in the 'small pelvis' and/or CI region at time of diagnosis.

Vaginal dose-surface maps in cervical cancer brachytherapy: Methodology and preliminary results on correlation with morbidity.

PURPOSE: The purpose of the study was to develop a methodology for vaginal dose-surface maps (DSMs) in patients with cervix cancer and to investigate dose-surface histogram metrics as predictors for vaginal stenosis (St) and mucositis (Muc). METHODS AND MATERIALS: Thirty-one patients with locally advanced cervix cancer with no vaginal St/Muc (CTCAE-v3) G ≥ 2 at baseline were analyzed. Patients were divided in four morbidity groups: 15 with St/Muc G0/1, 6 with St G ≥ 2, 4 with St/Muc G ≥ 2, and 6 with Muc G ≥ 2. Patients received external beam radiotherapy and 4-fraction intracavitary/interstitial high-dose-rate brachytherapy using tandem and ovoids. DSMs were generated from inner/outer vaginal surfaces. DSMs of external beam radiotherapy and brachytherapy (Gy EQD23) were added based on a system of homologous points, to generate cumulative DSMs. Dose-surface histogram/dose-volume histogram parameters, location of high/intermediate-dose regions, rectovaginal reference point, vaginal lateral 5 mm point doses, and vagina/implant dimensions were investigated for St and Muc prediction. Average/difference DSMs and one-way analysis of variance were used to compare between groups. RESULTS: Best predictors of stenosis were D15-25cm2 and upper-vagina S65-120Gy(%). Cutoffs of ∼90 Gy EQD23 for D20cm2 and ∼80% for S65Gy to top 3 cm inner vaginal surface suitably discriminated for stenosis. Spatial dose location on average/difference DSMs showed significantly higher doses (by > 20 Gy, p < 0.001) over longer parts of the dorsolateral vagina and higher rectovaginal reference point doses for any G ≥ 2 morbidity, over the whole circumference of the upper vagina for G ≥ 2 stenosis. Dose-volume histogram parameters were dependent on vaginal wall thickness. An increase of wall thickness from 2 to 4 mm resulted in an increase of D2cm3 (D4cm3) of 16% (32%). CONCLUSIONS: A novel method was developed to generate vaginal DSMs and spatial-dose metrics. DSMs were found to correlate with vaginal stenosis. The findings of this study are promising and should be further validated on a larger patient cohort, treated with different applicators.

Implementing an online radiotherapy quality assurance programme with supporting continuous medical education - report from the EMBRACE-II evaluation of cervix cancer IMRT contouring.

BACKGROUND AND PURPOSE: EMBRACE-II is an international prospective study of IMRT and MRI-guided adaptive brachytherapy (IGABT) in locally advanced cervix cancer. An online radiotherapy quality assurance (RTQA) programme with minimal data transfer and supporting continuing medical education (CME) was implemented for IMRT contouring. MATERIALS AND METHODS: Participant contours for six volumes-of-interest (VOIs) on one benchmark case were scored (2 = excellent, 1 = fair, 0 = revision required) against a consensus reference contour. For contours receiving a 0 or 1 score, additional qualitative comments were provided. The Jaccard conformity index (JCI) was retrospectively calculated. User interaction with CME content (pre-accreditation questionnaire, contouring atlas, practice cases, quizzes, internal target volume (ITV-T) guide) was analysed. RESULTS: 78 clinicians submitted contours for evaluation. 41% passed at the first attempt, 44% after one revision and 6% after two or more revisions. 9% did not re-submit after failing. The lowest mean scores were for the elective nodal CTV (CTV-E) (1.01/2) and ITV-T (1.06/2). 60 different errors across the six VOIs were identified; five potentially had high impact on loco-regional control. A JCI cut-off of 0.7 would have identified 87% contours that failed expert assessment, but also excluded 54% of passing contours. 39 clinicians responded to the pre-accreditation questionnaire - 36% anticipated difficulties with the ITV-T and 13% with the CTV-E. 35% clinicians contoured on the practice cases, 17% answered a quiz, 96% used the atlas and 38% the ITV-T guide. CONCLUSION: Expert evaluation with qualitative feedback improved contouring compliance. The JCI is not a reliable alternative to expert assessment. Moderate uptake of optional CME content limited evaluation.

Nodal failure after chemo-radiation and MRI guided brachytherapy in cervical cancer: Patterns of failure in the EMBRACE study cohort.

PURPOSE/OBJECTIVE(S): To investigate the patterns of nodal failure in patients enrolled in the international multicentre EMBRACE study. MATERIALS/METHODS: Nodal disease at diagnosis (N-, N+) and nodal failure were analysed per region (NF) (pelvic (parametrial, common iliac, internal/external iliac), inguinal and para-aortic (PAO)) in 1338 patients. Treatment consisted of chemo-radiation and MRI guided brachytherapy. PAO radiotherapy and/or nodal boost was left to the treating centre. At time of diagnosis 52% of patients had pathologic nodes. Frequency analyses were performed in relation to patient, primary tumour and nodal disease characteristics, and treatment related factors. RESULTS: Median follow up was 34 months and 83% of NF occurred within 24 months. At diagnosis 99% of the N+ patients had pathologic nodes in the pelvis and 14% in the PAO. NFpelvic and NFPAO were reported in 55% and 68% of patients with NF, respectively. Overall NF was reported in 152 patients (11%); 7 and 16% for N- and N+ patients. Of the patients with NF, 41% were located outside the elective target (39% PAO), 40% inside and 35% inside the nodal boost target. Twelve percent of N+ patients that received a nodal boost had a NF inside the nodal boost target. CONCLUSION: Within the EMBRACE study cohort the overall number of patients developing nodal failure is low, significantly lower for N- compared to N+ patients. Pathological nodes at diagnosis are mainly located in the pelvis, whereas nodal failures are more often reported in the PAO region. About 40% of all nodal failures were reported outside the treatment targets.

Management of Nodal Disease in Advanced Cervical Cancer.

During the last decade the adoption of image-guided adaptive brachytherapy has dramatically improved local control in patients with locally advanced cervical cancer (LACC) treated with radiotherapy and concomitant chemotherapy; however, nodal failure remains an obstacle. Metastatic lymph nodes can be detected by surgical and imaging approaches with different sensitivities and specificities, that improve the definition of relevant targets for macroscopic and microscopic nodal disease, and that influence our understanding of dose levels of external beam radiotherapy. Systematic use of modern radiotherapy techniques including intensity modulated radiotherapy and simultaneously integrated nodal boosts in combination with daily position verification is emerging as increasingly important for obtaining nodal control in LACC. This review summarizes published and ongoing efforts for optimizing nodal disease treatment in LACC, elaborates the state of the art approach for nodal disease detection, radiotherapy planning and delivery, and discusses future investigational efforts needed for precise optimization.

Cervical cancer apparent diffusion coefficient values during external beam radiotherapy.

BACKGROUND AND PURPOSE: Apparent diffusion coefficient (ADC) reflects micro-enviromental changes and therefore might be useful in predicting recurrence prior to brachytherapy. The purpose of this study is to evaluate change in ADC of the primary tumour and pathologic lymph nodes during treatment and to correlate this with clinical outcome. MATERIAL AND METHODS: Twenty patients were included who received chemoradiation for locally advanced cervical cancer between July 2016 and November 2017. All patients underwent magnetic resonance imaging (MRI) prior to treatment, and three MRIs in weeks 1/2, 3 and 4 of treatment, including T2 and diffusion weighted imaging (b-values 0, 200, 800 s/mm2) for determining an ADC-map. Primary tumour was delineated on T2 and ADC-map and pathologic lymph nodes were delineated only on ADC-map. RESULTS: At time of analysis median follow-up was 15 (range 7-22) months. From MRI one to four, primary tumour on ADC-map showed a significant signal increase of 0.94 (range 0.74-1.46) × 10-3 mm2/s to 1.13 (0.98-1.49) × 10-3 mm2/s (p < 0.001). When tumour was delineated on T2, ADC-value signal increase (in tumour according to T2) was similar. All 46 delineated pathologic lymph nodes showed an ADC-value increase on average from 0.79 (range 0.33-1.12) × 10-3 mm2/s to 1.14 (0.59-1.75) × 10-3 mm2/s (p < 0.001). The mean tumour/suspected lymph node volumes decreased respectively 51/40%. Four patients developed relapse (one local and three nodal), without clear relation with ΔADC. However, the median volume decrease of the primary tumour was substantially lower in the failing patients compared to the group without relapse (19 vs. 57%). CONCLUSIONS: ADC values can be acquired using T2-based tumour delineations unless there are substantial shifts between ADC-mapping and T2 acquisition. It remains plausible that ΔADC is a predictor for response to EBRT. However, the correlation in this study was not statistically significant.

Implementation of state-of-the-art (chemo)radiation for advanced cervix cancer in the Netherlands: A quality improvement program.

PURPOSE: To report on the "Dutch Quality Improvement Project" regarding external beam (EBRT) and brachytherapy (BT) contouring and treatment planning for locally advanced cervical cancer (LACC). MATERIAL AND METHODS: Two rounds of three workshops were organized. Data from two patients with LACC were made available for homework exercises. Contouring and treatment planning was asked for according to the EMBRACE-II protocol. The submissions were analysed and the results were addressed during the workshops. RESULTS: Almost all invited centres participated. EBRT contouring guidelines were followed within acceptable range, with major effort needed with regard to the ITV concept. BT contouring was of good quality, with especially small discrepancies for centres already participating in EMBRACE.EBRT treatment planning results improved between workshops with more centres being able to fulfil the planning aims. Guidance was especially necessary to improve the coverage probability planning for affected nodes.For BT planning prioritizing between target coverage and OAR sparing improved over time; the variation in dose to vaginal points remained considerable, as did variation in loading patterns and spatial dose distribution.The project was highly appreciated by all participants. CONCLUSION: Homework and workshop activities provide a suitable platform for discussion, exchange of experience and improvement of quality and conformity. Due to this project, radiotherapy for LACC can be administered with better and more comparable quality throughout the Netherlands.

Patterns of care survey: Radiotherapy for women with locally advanced cervical cancer.

BACKGROUND AND PURPOSE: Regarding latest developments, the need of a radiotherapy 'Patterns of Care' survey was expressed by the Dutch National Platform Radiotherapy for Gynaecological Cancer (LPRGT). Therefore, this study investigated current practice for cervical cancer in all 16 radiation oncology centres in the Netherlands specialised in gynaecological oncology. MATERIAL AND METHODS: A structured 'patterns of care' questionnaire was completed and followed by an in-depth interview with radiation oncologists from all radiotherapy centres specialised in gynaecological oncology. Specific topics addressed were: definition of target volumes, treatment preparation, imaging for treatment planning, treatment planning, and image-guided adaptive radiotherapy for external beam radiotherapy and brachytherapy. RESULTS: Current radiotherapy practice in the Netherlands for cervical cancer appears to be in accordance with international standards. However, at the time of the survey some differences were revealed that might have relevant clinical impact. For instance: 1) Half of the centres acquired positron emission tomography combined with CT (PET-CT) for staging and target delineation for every patient, 2) The definition of upper border of the para-aortal lymph node area and dose prescription for external beam radiotherapy varied between the centres, and 3) 12 centres used a single treatment plan for delivering EBRT, and four used a plan-of-the-day strategy with a library of 3-4 treatment plans. CONCLUSIONS: Most differences were found at the cutting edge of clinical evidence. However, the majority of these uncertainties are topics being addressed in current and planned (inter)national studies.

The feasibility of semi-automatically generated red bone marrow segmentations based on MR-only for patients with gynecologic cancer.

PURPOSE: For patients with cervical cancer the delivery of chemotherapy with radiotherapy improves survival compared with radiotherapy alone. However, high rates of acute hematologic toxicity occur when combining both therapies due to the damage of the red bone marrow (RBM). This study aimed to reduce the radiation damage to the RBM. A tool has been developed for semi-automatic delineation of the red bone marrow based on MR-only. This delineation can be included into the treatment planning process to reduce the volume of RBM irradiated in patients receiving pelvic radiation therapy. METHODS: 13 patients with cervical cancer were enrolled. All the patients underwent MR, CT and FDG-PET imaging. A tool for RBM determination from water and fat MR images was developed. Our MR-based RBM tool was optimized and validated with the FDG-PET scans of the patients. RESULTS: Our tool identified RBM regions in the pelvic area. The mean total volume of these regions was 34% of the pelvic bone marrow. The corresponding SUV values based on the FDG-PET scans were above the reported threshold of active/red bone marrow. CONCLUSION: This study shows that delineations of the RBM for the radiotherapy with RBM sparing can be generated semi-automatically using MR scans only.

Vaginal dose de-escalation in image guided adaptive brachytherapy for locally advanced cervical cancer.

PURPOSE: Vaginal stenosis is a major problem following radiotherapy in cervical cancer. We investigated a new dose planning strategy for vaginal dose de-escalation (VDD). MATERIALS AND METHODS: Fifty consecutive locally advanced cervical cancer patients without lower or middle vaginal involvement at diagnosis from 3 institutions were analysed. External beam radiotherapy was combined with MRI-guided brachytherapy. VDD was obtained by decreasing dwell times in ovoid/ring and increasing dwell times in tandem/needles. The aim was to maintain the target dose (D90 of HR-CTV⩾85Gy EQD2) while reducing the dose to the surface of the vagina to <140% of the physical fractional brachytherapy dose corresponding to a total EQD2 of 85Gy. RESULTS: The mean vaginal loading (ovoid/ring) was reduced from 51% to 33% of the total loading with VDD, which significantly reduced the dose to the vaginal dose points (p<0.001) without compromising the target dose. The dose to the ICRU recto-vaginal point was reduced by a mean of 4±4Gy EQD2 (p<0.001), while doses to bladder and rectum (D2cm3) were reduced by 2±2Gy and 3±2Gy, respectively (p<0.001). CONCLUSIONS: VDD significantly reduces dose to the upper vagina which is expected to result in reduction of vaginal stenosis.

Impact of radiation dose and standardized uptake value of (18)FDG PET on nodal control in locally advanced cervical cancer.

BACKGROUND: Despite local control now exceeding 90% with image-guided adaptive brachytherapy (IGABT), regional and distant metastases continue to curb survival in locally advanced cervical cancer. As regional lymph nodes often represent first site of metastatic spread, improved nodal control could improve survival. The aim of this study was to examine optimal volume and dose of external beam radiotherapy (EBRT) to maximize regional control including dose contribution from IGABT. MATERIAL AND METHODS: In total 139 patients from the EMBRACE study were analyzed. Individual nodal dose was determined by dose-maps from EBRT and IGABT. All PET/CT scans were re-evaluated and nodal maximal standard uptake value (SUVmax) was determined. Nodal failures were registered to planning scans and related to boosted nodes and treated volume. Relation between SUVmax and nodal control as well as the pattern of regional nodal failure were analyzed. RESULTS: Eighty-four patients were node positive. Nine patients had all metastatic nodes surgically removed. Seventy-five patients had 209 nodes boosted with EBRT. Median nodal boost dose was 62 Gy EQD2 (53-69 Gy EQD2). Median SUVmax was 6 (2-22). No patients had persistent nodal disease, but six patients recurred in a boosted node. SUVmax was significantly higher in nodes that recurred (p = 0.02). However, there was no correlation to nodal dose or volume. Twenty-one patients had a nodal failure including para-aortic nodal (PAN) metastases above the irradiated volume. Nine patients had a PAN-only failure. Patients receiving ≤ 4 cycles of weekly cisplatin had higher risk of nodal failure (p < 0.01). CONCLUSION: Current RT practice provides a high level of control in both boosted nodes and the elective irradiated regional target. However, a high nodal SUVmax is a negative prognostic predictor for nodal control. Attention should be raised to administration of a complete schedule of concurrent chemotherapy as well as treatment of para-aortic nodes.

Intra-fraction uncertainties of MRI guided brachytherapy in patients with cervical cancer.

Dosimetric intra-fraction uncertainties in MRI-guided brachytherapy were analysed for HR-CTV and OARs. While dose differences were generally small, individual outliers occurred. In contrast to HDR, patients treated with PDR show increased mean rectal dose over time. Re-imaging prior to dose delivery helps to detect unfavorable anatomical changes, and allows for intervention.

Position shifts and volume changes of pelvic and para-aortic nodes during IMRT for patients with cervical cancer.

BACKGROUND AND PURPOSE: To evaluate volume changes and position shifts and their contribution to treatment margins of pelvic and para-aortic lymph nodes during Intensity Modulated Radiation Therapy (IMRT) for advanced cervical cancer. MATERIALS AND METHODS: Seventeen patients with visible nodes on MR images underwent T2-weighted MR scans before and weekly during the course of IMRT. Thirty-nine pelvic and para-aortic nodes were delineated on all scans. Margins accommodating for volume and position changes were taken from the boundaries of the nodal volumes in the six main directions. RESULTS: Nodal volume regression from the pre-treatment situation to week 4 was 58% on average (range: 11.7% increase to 100% decrease). Nodal volumes partly increased between the pre-treatment scans and the scans in weeks 1-3, but in week 4 all nodes except one had regressed. Around the nodal volumes manually derived ITV margins accounting for volume changes and position shifts of 7.0, 4.0, 7.0, 8.0, 7.0 and 9.0mm to the medial, lateral, anterior, posterior, superior and inferior directions were needed to cover 95% of all nodes. CONCLUSIONS: We used weekly MR scans to derive inhomogeneous margins that accommodate for nodal volume and position changes during treatment. These margins should be taken into consideration when planning external beam radiotherapy (EBRT) boosts, especially for highly conformal boosting techniques.

Image guided adaptive brachytherapy for cervical cancer: dose contribution to involved pelvic nodes in two cancer centers.

PURPOSE: The goal of this study was to determine the dose contributions from image guided adaptive brachytherapy (IGABT) to individual suspicious pelvic lymph nodes (pLNN) in cervical cancer patients. Data were collected in two cancer centers, University of Pittsburgh Cancer Institute (UPCI) and University Medical Center Utrecht (UMCU). MATERIAL AND METHODS: 27 and 15 patients with node positive cervical cancer treated with HDR (high dose rate) or PDR (pulsed dose rate)-IGABT were analyzed. HDR-IGABT (UPCI) was delivered with CT/MRI compatible tandem-ring applicators with 5.0-6.0 Gy × five fractions. PDR-IGABT (UMCU) dose was delivered with Utrecht tandem-ovoid applicators with 32 × 0.6 Gy × two fractions. Pelvic lymph nodes with short axis diameter of ≥ 5 mm on pre-treatment MRI or PET-CT were contoured for all BT-plans. Dose contributions to individual pLNN expressed as D90 (dose to 90% of the volume) were calculated from dose-volume histograms as absolute and relative physical dose (% of the reference dose) for each fraction. For each node, the total dose from all fractions was calculated, expressed in EQD2 (equivalent total dose in 2 Gy fractions). RESULTS: Fifty-seven (UPCI) and 40 (UMCU) individual pLNN were contoured. The mean D90 pLNN was 10.8% (range 5.7-25.1%) and 20.5% (range 6.8-93.3%), respectively, and therefore different in the two centers. These values translate into 2.7 Gy (1.3-6.6 Gy) EQD2 and 7.1 Gy (2.2-36.7 Gy) EQD2, respectively. Differences are caused by the location of the individual nodes in relation to the spatial dose distribution of IGABT, differences in total dose administered and radiobiology (HDR versus PDR). CONCLUSIONS: The IGABT dose contribution to individual pelvic nodes depends on patient and treatment related factors, and varies considerably.

Clinical outcome and dosimetric parameters of chemo-radiation including MRI guided adaptive brachytherapy with tandem-ovoid applicators for cervical cancer patients: a single institution experience.

PURPOSE: To evaluate dosimetric parameters and clinical outcome for cervical cancer patients treated with chemo-radiation and MR-image guided adaptive brachytherapy (MR-IGABT) using tandem-ovoid applicators for intracavitary or combined intracavitary/interstitial approaches. METHOD: This retrospective analysis includes 46 patients treated between 2006 and 2008. Dose-volume parameters D90 HR-CTV (high-risk clinical target volume) and D(2cc) OARs (organs at risk) were determined and converted into biologically equivalent doses in 2 Gy fractions (EQD2). Clinical outcome parameters (local control (LC), progression free survival (PFS) and overall survival (OS)) were analysed actuarially and late morbidity crude rates were scored using CTCAEv3.0. RESULTS: Mean D90 HR-CTV was 84 (SD9) Gy EQD2 for HR-CTV volumes of mean 57 (SD37) cm(3) at time of first brachytherapy (BT). Median follow-up was 41 (range, 4-67) months. Three year LC, PFS, and OS rates were 93, 71, and 65%, respectively. Node negative patients had significantly higher 3-year survival rates compared to node positive ones (PFS 85 versus 53% (p=0.013), OS 77 versus 50% (p=0.032), respectively) with an even larger difference for patients with FIGO stages IB-IIB (PFS 87 versus 42% (p=0.002), OS 83 versus 46% (p=0.007), respectively). Late grade 3-4 mainly gastrointestinal or vaginal morbidity was observed in 4 patients (9.5%). No correlations were seen between morbidity and D(2cc) OAR values. CONCLUSION: (Chemo-) radiation and MR-IGABT with tandem-ovoid applicators result in high LC and promising survival rates with reasonable morbidity.

Multicentre treatment planning study of MRI-guided brachytherapy for cervical cancer: comparison between tandem-ovoid applicator users.

BACKGROUND AND PURPOSE: To compare MRI-guided treatment planning approaches between four centres that use tandem-ovoid applicators. MATERIAL AND METHODS: Four centres generated three treatment plans for four patients: standard, optimised intracavitary, and optimised intracavitary/interstitial. Prescribed D90 High-Risk CTV (HR-CTV) was 85 Gy EQD2 (external-beam radiotherapy and brachytherapy), while the D(2cc) OAR limit was 90 Gy EQD2 for bladder and 75 Gy EQD2 for rectum, sigmoid, and bowel, respectively. DVH-parameters, source loading patterns and spatial dose distributions of the three treatment plans were compared. RESULTS: The standard plans of the different centres were comparable with respect to the D90 HR-CTV, but differed in OAR doses. MRI-guided intracavitary optimisation resulted in organ sparing and smaller variation in DVH parameters between the centres. Adding interstitial needles led to target dose escalation while respecting the OAR constraints. However, substantial differences in relative weights of the applicator parts resulted in an increased variation in DVH parameters and locations of high dose regions. CONCLUSIONS: MRI-guided brachytherapy treatment planning optimisation provides the possibility to increase the dose to the HR-CTV and spare the OARs. Depending on the degree of conformity the centres make different choices in relative weighting of applicator parts, leading to different dose distributions.

Clinical use of the Utrecht applicator for combined intracavitary/interstitial brachytherapy treatment in locally advanced cervical cancer.

PURPOSE: The aims of this study were to investigate the benefit of the Utrecht interstitial CT/MR applicator for combined intracavitary/interstitial (IC/IS) approach, using magnetic resonance imaging-guided brachytherapy, over the intracavitary approach alone in patients with locally advanced cervical cancer and to analyze the clinical use of needles. METHODS AND MATERIALS: This study includes the first 20 patients treated with the new applicator. Brachytherapy consisted of two pulsed dose rate applications, and the second application was performed with the IC/IS approach. The number of needles, chosen guiding holes through the ovoids, and insertion depths were based on the dose distribution and dosimetric shortcomings of the first application (IC alone). We investigated the dosimetric gain by comparing the clinical interstitial optimized plan (IC/IS(clinical)) with an additionally generated optimized plan without needle use (IC(study)). Furthermore, we studied the relation of the inserted needles and their source loading patterns with the high-risk clinical target volume (HR-CTV). RESULTS: A total of 54 needles (range, 1-6 per application) were applied with an average depth of 25 mm. The chosen needle positions corresponded with the location of the HR-CTV extensions. The total and individual needle treatment times per application were on average 19% (range, 4-35%) and 7% (range, 2-14%) of the implant treatment time, respectively. The total (external-beam radiotherapy + brachytherapy) D90 HR-CTV for the IC(study) and the IC/IS(clinical) were on average 79.5 (SD 7.4) Gy(α/ß10) and 83.9 (SD 6.7) Gy(α/ß10), respectively, with an average gain of 4.4 (SD 2.3) Gy(α/ß10) for the second application. CONCLUSIONS: Needle placement was feasible in all patients and resulted in a gain in dose and better coverage of HR-CTV. Defining the location of HR-CTV protrusions and analyzing the associated needles has given us deeper understanding of the possibilities in magnetic resonance imaging-guided (pre)treatment planning with the IC/IS Utrecht applicator.

The effect of alternative biological modelling parameters (α/ß and half time of repair T ½ ) on reported EQD2 values in the treatment of advanced cervical cancer.

PURPOSE: To evaluate the effect of different α/ß and half-time of repair T(½) on the assessment of clinical treatment plans for patients with cervical cancer. MATERIALS AND METHODS: We used EBRT and BT treatment plans of five patients, planned with MRI guided BT. We computed 3D EQD2 dose distributions of combined EBRT and BT treatments and calculated D90 of high-risk clinical target volume (HR-CTV) and D(2cc) for bladder and rectum, and the ratio D(2cc)(bladder)/D90(HR-CTV). BT was modelled as PDR (two applications of 32×60cGy) and HDR (two applications of 2×7Gy). We assumed a low, standard and high value for the biological parameters: HR-CTV α/ß=5/10/15Gy and T(½)=0.5/1.5/2.5h; OAR α/ß=2/3/4Gy; T(½)=0.5/1.5/4.5h. RESULTS: The chosen variation in modelling parameters had a much larger effect on PDR treatments than on HDR treatments, especially for OAR, thus creating larger uncertainties. The relative mean range of the ratio D(2cc)(bladder)/D90(HR-CTV) is 72% for PDR and 25% for HDR. Out of the 125 modelled combinations 48 PDR plans and 23 HDR plans comply with clinical objectives. CONCLUSION: For HDR brachytherapy, only α/ß has a significant impact on reported EQD2 values, whereas for PDR both α/ß and T(½) are important. Generally, the ratio D(2cc)(bladder)/D90(HR-CTV) is more favourable for PDR, even considering the larger uncertainties in EQD2.