Co-occurrence of symptoms after radiochemotherapy in locally advanced cervix cancer patients: a cluster analysis.

BACKGROUND: State of the art combined radiochemotherapy and image-guided brachytherapy for locally advanced cervical cancer (LACC) has shown improved disease control and survival as well as a significant reduction of organ related morbidity. However, LACC cancer survivors are still experiencing a spectrum of symptoms. The aim of this study was to identify co-occurring symptoms in cervix cancer survivors by using patient-reported outcome and physician assessed morbidity. MATERIALS AND METHOD: EMBRACE I is a multicenter prospective observational study with 1416 LACC patients (2008-2015). Information on physician-assessed morbidity and patient-reported outcome was assessed at baseline and at regular follow-ups up with the CTCAE v.3 and EORTC-C30/CX24, respectively. Patients with at least 2 years of follow-up were included and data from 3 months to 2 years was used in the analysis. Factor analysis was used on both EORTC and CTCAE data with symptoms and follow-ups as observations. The extracted factors represent clusters of symptoms. Subsequently, regression models were built to investigate associations between the symptom clusters and QOL. RESULTS: The analysis included 742 patients. Despite the differences in the definition of physician-assessed and patient-reported symptoms, similar clusters are identified by the two assessment methods. Three main organ-related clusters are recognized for urinary, gastro-intestinal and vaginal morbidity. Furthermore, a general symptoms cluster where fatigue, pain, insomnia, neuropathy, and hot flashes have large weights is found. Lastly, a cluster with nausea, vomit and lack of appetite is also identified. The general, gastrointestinal and nausea clusters show significant associations with general QOL. CONCLUSIONS: This analysis on both PRO and physician-assessed morbidity found a cluster associated with general symptoms and organ-related symptom clusters (urinary, gastrointestinal, vaginal). This shows that LACC survivors experience a variety of co-occurring symptoms. Our analysis also shows that the cluster of general symptoms is associated with a decrease in QOL.

ESGO/ESTRO quality indicators for radiation therapy of cervical cancer.

BACKGROUND: The European Society of Gynaecological Oncology (ESGO) has previously defined and established a list of quality indicators for the surgical treatment of cervical cancer. As a continuation of this effort to improve overall quality of care for cervical cancer patients across all aspects, ESGO and the European SocieTy for Radiotherapy and Oncology (ESTRO) initiated the development of quality indicators for radiation therapy of cervical cancer. OBJECTIVE: To develop a list of quality indicators for radiation therapy of cervical cancer that can be used to audit and improve clinical practice by giving to practitioners and administrators a quantitative basis to improve care and organizational processes, notably for recognition of the increased complexity of modern external radiotherapy and brachytherapy techniques. METHODS: Quality indicators were based on scientific evidence and/or expert consensus. The development process included a systematic literature search for identification of potential quality indicators and documentation of scientific evidence, consensus meetings of a group of international experts, an internal validation process, and external review by a large international panel of clinicians (n=99). RESULTS: Using a structured format, each quality indicator has a description specifying what the indicator is measuring. Measurability specifications are detailed to define how the quality indicators will be measured in practice. Targets were also defined for specifying the level which each unit or center should be aiming to achieve. Nineteen structural, process, and outcome indicators were defined. Quality indicators 1-6 are general requirements related to pretreatment workup, time to treatment, upfront radiation therapy, and overall management, including active participation in clinical research and the decision making process within a structured multidisciplinary team. Quality indicators 7-17 are related to treatment indicators. Quality indicators 18 and 19 are related to patient outcomes. DISCUSSION: This set of quality indicators is a major instrument to standardize the quality of radiation therapy in cervical cancer. A scoring system combining surgical and radiotherapeutic quality indicators will be developed within an envisaged future ESGO accreditation process for the overall management of cervical cancer, in an effort to support institutional and governmental quality assurance programs.

Coverage probability planning for simultaneously integrated boosts of inguinal lymph nodes in vulvar cancer.

BACKGROUND AND PURPOSE: Strategies for minimizing irradiation of organs at risk (OARs) from pathological inguinal lymph node (PILN) boosting are needed to minimize the risk of morbidity. Coverage probability (CovP) is a conformal planning strategy for simultaneously integrated boost (SIB). Our aim was to investigate if SIB of PILN using CovP can be delivered safely in vulvar cancer. MATERIALS AND METHODS: Ten consecutive patients treated with definitive radiotherapy (RT) including SIB of PILN and with daily cone beam CT (CBCT) were included. Dose prescription was 51.2/32 fx to the elective target and 64 Gy/32 fx to the gross disease at the vulva and to positive lymph nodes (LN). PILN were contoured on both planning CT and MRI (GTV-N) and combined to form ITV-N. Each PILN GTV-N was contoured on every third CBCT, in total 11 CBCT for each patient. OARs were subcutaneous tissue (SC), inguinal vessels, skin rim, bowel, and body contour. Three plans were created for every patient: A) Standard CT-based planning; PTV-N based on GTV-NCT with a 10 mm isotropic margin. B) CT and MRI-based planning with smaller margins: PTV-N based on ITV-N with a 5 mm isotropic margin. C) CovP. The total delivered dose to GTV-Ns was estimated by accumulating dose across all fractions based on GTV-Ns contoured on CBCT. RESULTS: Thirty-five PILNs were boosted. There was no significant difference in accumulated GTV-N D98% between the three plans. CovP delivered a higher mean dose to the GTV-N D50% and D2% (p < 0.001). The planned mean doses to the OARs were reduced when applying CovP. CONCLUSIONS: SIB of PILN in vulvar cancer based on CovP and a 5 mm PTV margin does not compromise target coverage during RT and reduces the dose to normal tissues in the groin.

MRI-guided adaptive brachytherapy in locally advanced cervical cancer (EMBRACE-I): a multicentre prospective cohort study.

BACKGROUND: The concept of the use of MRI for image-guided adaptive brachytherapy (IGABT) in locally advanced cervical cancer was introduced 20 years ago. Here, we report on EMBRACE-I, which aimed to evaluate local tumour control and morbidity after chemoradiotherapy and MRI-based IGABT. METHODS: EMBRACE-I was a prospective, observational, multicentre cohort study. Data from patients from 24 centres in Europe, Asia, and North America were prospectively collected. The inclusion criteria were patients older than 18 years, with biopsy-proven squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix, The International Federation of Gynecology and Obstetrics (FIGO) stage IB-IVA disease or FIGO stage IVB disease restricted to paraaortic lymph metastasis below the L1-L2 interspace, suitable for curative treatment. Treatment consisted of chemoradiotherapy (weekly intravenous cisplatin 40 mg/m2, 5-6 cycles, 1 day per cycle, plus 45-50 Gy external-beam radiotherapy delivered in 1·8-2 Gy fractions) followed by MRI-based IGABT. The MRI-based IGABT target volume definition and dose reporting was according to Groupe Européen de Curiethérapie European Society for Radiation Oncology recommendations. IGABT dose prescription was open according to institutional practice. Local control and late morbidity were selected as primary endpoints in all patients available for analysis. The study was registered with ClinicalTrials.gov, NCT00920920. FINDINGS: Patient accrual began on July 30, 2008, and closed on Dec 29, 2015. A total of 1416 patients were registered in the database. After exclusion for not meeting patient selection criteria before treatment, being registered but not entered in the database, meeting the exclusion criteria, and being falsely excluded, data from 1341 patients were available for analysis of disease and data from 1251 patients were available for assessment of morbidity outcome. MRI-based IGABT including dose optimisation was done in 1317 (98·2%) of 1341 patients. Median high-risk clinical target volume was 28 cm3 (IQR 20-40) and median minimal dose to 90% of the clinical target volume (D90%) was 90 Gy (IQR 85-94) equi-effective dose in 2 Gy per fraction. At a median follow-up of 51 months (IQR 20-64), actuarial overall 5-year local control was 92% (95% CI 90-93). Actuarial cumulative 5-year incidence of grade 3-5 morbidity was 6·8% (95% CI 5·4-8·6) for genitourinary events, 8·5% (6·9-10·6) for gastrointestinal events, 5·7% (4·3-7·6) for vaginal events, and 3·2% (2·2-4·5) for fistulae. INTERPRETATION: Chemoradiotherapy and MRI-based IGABT result in effective and stable long-term local control across all stages of locally advanced cervical cancer, with a limited severe morbidity per organ. These results represent a positive breakthrough in the treatment of locally advanced cervical cancer, which might be used as a benchmark for clinical practice and all future studies. FUNDING: Medical University of Vienna, Aarhus University Hospital, Elekta AB, and Varian Medical Systems.

Dosimetric impact of edema on inguinal lymph node boost in locally advanced vulvar cancer.

We aimed to evaluate the extent of groin edema and its dosimetric effect in boosted inguinal lymph nodes (LN) for vulvar cancer patients. The level of edema was determined in 10 patients treated with radical radiotherapy. A dosimetric evaluation of six LNs in the patient with the maximum level of edema was performed. The accumulated dose across CBCT fractions was acceptable for all six LNs (>94% of prescribed dose) even with the development of up to 13 mm of edema. The major contributor to fractional dose degradation was geographical displacement of the nodes. We suggest evaluation of edema on daily CBCT.

Are complex DCE-MRI models supported by clinical data?

PURPOSE: To ascertain whether complex dynamic contrast enhanced (DCE) MRI tracer kinetic models are supported by data acquired in the clinic and to determine the consequences of limited contrast-to-noise. METHODS: Generically representative in silico and clinical (cervical cancer) DCE-MRI data were examined. Bayesian model selection evaluated support for four compartmental DCE-MRI models: the Tofts model (TM), Extended Tofts model, Compartmental Tissue Uptake model (CTUM), and Two-Compartment Exchange model. RESULTS: Complex DCE-MRI models were more sensitive to noise than simpler models with respect to both model selection and parameter estimation. Indeed, as contrast-to-noise decreased, complex DCE models became less probable and simpler models more probable. The less complex TM and CTUM were the optimal models for the DCE-MRI data acquired in the clinic. [In cervical tumors, Ktrans, Fp, and PS increased after radiotherapy (P = 0.004, 0.002, and 0.014, respectively)]. CONCLUSION: Caution is advised when considering application of complex DCE-MRI kinetic models to data acquired in the clinic. It follows that data-driven model selection is an important prerequisite to DCE-MRI analysis. Model selection is particularly important when high-order, multiparametric models are under consideration. (Parameters obtained from kinetic modeling of cervical cancer clinical DCE-MRI data showed significant changes at an early stage of radiotherapy.) Magn Reson Med 77:1329-1339, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Comparison of linear and nonlinear implementation of the compartmental tissue uptake model for dynamic contrast-enhanced MRI.

PURPOSE: Fitting tracer kinetic models using linear methods is much faster than using their nonlinear counterparts, although this comes often at the expense of reduced accuracy and precision. The aim of this study was to derive and compare the performance of the linear compartmental tissue uptake (CTU) model with its nonlinear version with respect to their percentage error and precision. THEORY AND METHODS: The linear and nonlinear CTU models were initially compared using simulations with varying noise and temporal sampling. Subsequently, the clinical applicability of the linear model was demonstrated on 14 patients with locally advanced cervical cancer examined with dynamic contrast-enhanced magnetic resonance imaging. RESULTS: Simulations revealed equal percentage error and precision when noise was within clinical achievable ranges (contrast-to-noise ratio >10). The linear method was significantly faster than the nonlinear method, with a minimum speedup of around 230 across all tested sampling rates. Clinical analysis revealed that parameters estimated using the linear and nonlinear CTU model were highly correlated (ρ ≥ 0.95). CONCLUSION: The linear CTU model is computationally more efficient and more stable against temporal downsampling, whereas the nonlinear method is more robust to variations in noise. The two methods may be used interchangeably within clinical achievable ranges of temporal sampling and noise. Magn Reson Med 77:2414-2423, 2017. © 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Impact of bowel gas and body outline variations on total accumulated dose with intensity-modulated proton therapy in locally advanced cervical cancer patients.

INTRODUCTION: Density changes occurring during fractionated radiotherapy in the pelvic region may degrade proton dose distributions. The aim of the study was to quantify the dosimetric impact of gas cavities and body outline variations. MATERIAL AND METHODS: Seven patients with locally advanced cervical cancer (LACC) were analyzed through a total of 175 daily cone beam computed tomography (CBCT) scans. Four-beams intensity-modulated proton therapy (IMPT) dose plans were generated targeting the internal target volume (ITV) composed of: primary tumor, elective and pathological nodes. The planned dose was 45 Gy [Relative-Biological-Effectiveness-weighted (RBE)] in 25 fractions and simultaneously integrated boosts of pathologic lymph nodes were 55-57.5 Gy (RBE). In total, 475 modified CTs were generated to evaluate the effect of: 1/gas cavities, 2/outline variations and 3/the two combined. The anatomy of each fraction was simulated by propagating gas cavities contours and body outlines from each daily CBCT to the pCT. Hounsfield units corresponding to gas and fat were assigned to the propagated contours. D98 (least dose received by the hottest 98% of the volume) and D99.9 for targets and V43Gy(RBE) (volume receiving ≥43 Gy(RBE)) for organs at risk (OARs) were recalculated on each modified CT, and total dose was evaluated through dose volume histogram (DVH) addition across all fractions. RESULTS: Weight changes during radiotherapy were between -3.1% and 1.2%. Gas cavities and outline variations induced a median [range] dose degradation for ITV45 of 1.0% [0.5-3.5%] for D98 and 2.1% [0.8-6.4%] for D99.9. Outline variations had larger dosimetric impact than gas cavities. Worst nodal dose degradation was 2.0% for D98 and 2.3% for D99.9. The impact on bladder, bowel and rectum was limited with V43Gy(RBE) variations ≤3.5 cm3. CONCLUSION: Bowel gas cavities and outline variations had minor impact on accumulated dose in targets and OAR of four-field IMPT in a LACC population of moderate weight changes.

Early clinical outcome of coverage probability based treatment planning for simultaneous integrated boost of nodes in locally advanced cervical cancer.

INTRODUCTION: More than 50% of patients with locally advanced cervical cancer (LACC) have pathological nodes. Coverage probability (CovP) is a new planning technique allowing for relaxed dose at the boost periphery minimising collateral irradiation. The aim was to report the first early clinical outcome data for CovP based simultaneous integrated boost (SIB) in LACC. MATERIAL AND METHODS: Twenty-three consecutive node positive patients were analysed. FIGO stage IB2/IIB/IIIB/IVA/IVB was 1/14/3/1/4. Treatment was radio(chemo)therapy (RT) delivering 45 Gy/25 fx whole pelvis ± para-aortic region (PAN) using volumetric arc therapy (VMAT) followed by magnetic resonance imaging (MRI) guided brachytherapy. PAN RT (13 pts) was given if >2 nodes or if node(s) were present at the common iliac vessels or PAN. Nodal gross tumour volumes (GTV-N) were contoured on both PET-CT and MRI. Clinical target volume (CTV-N) was formed by fusion of GTV-NCT and GTV-NMRI. A 5-mm isotropic margin was used for planning target volume (PTV-N). Nodes in the small pelvis were boosted to 55.0 Gy/25 fx. Common iliac and para-aortic nodes received 57.5 Gy/25 fx. Planning aims for CovP were PTV-N D98 ≥ 90%, CTV-N D98 ≥ 100% and CTV-N D50 ≥ 101.5%. RESULTS: Seventy-four nodes were boosted. A consistent 5.0 ± 0.7 Gy dose reduction from CTV-N D98 to PTV-N D98 was obtained. In total, 73/74 nodes were in complete remission at 3 months PET-CT and MRI. Pelvic control was obtained in 21/23 patients. One patient (IB2, clear cell) had salvageable local disease, while another (IIB) failed in a boosted node. Two patients failed in un-irradiated PAN. One patient age 88 (IIIB) did not receive PAN RT, despite a common iliac node. The other (IIB) recurred above L1. Two further patients (IVB) failed systemically. CONCLUSION: Since complete remission at 3 months is predictive for favourable long-term nodal control, our study indicates that CovP for SIB is promising.

Adaptive radiotherapy strategies for pelvic tumors - a systematic review of clinical implementations.

UNLABELLED: Introdution: Variation in shape, position and treatment response of both tumor and organs at risk are major challenges for accurate dose delivery in radiotherapy. Adaptive radiotherapy (ART) has been proposed to customize the treatment to these motion/response patterns of the individual patients, but increases workload and thereby challenges clinical implementation. This paper reviews strategies and workflows for clinical and in silico implemented ART for prostate, bladder, gynecological (gyne) and ano-rectal cancers. MATERIAL AND METHODS: Initial identification of papers was based on searches in PubMed. For each tumor site, the identified papers were screened independently by two researches for selection of studies describing all processes of an ART workflow: treatment monitoring and evaluation, decision and execution of adaptations. Both brachytherapy and external beam studies were eligible for review. RESULTS: The review consisted of 43 clinical studies and 51 in silico studies. For prostate, 1219 patients were treated with offline re-planning, mainly to adapt prostate motion relative to bony anatomy. For gyne 1155 patients were treated with online brachytherapy re-planning while 25 ano-rectal cancer patients were treated with offline re-planning, all to account for tumor regression detected by magnetic resonance imaging (MRI)/computed tomography (CT). For bladder and gyne, 161 and 64 patients, respectively, were treated with library-based online plan selection to account for target volume and shape variations. The studies reported sparing of rectum (prostate and bladder cancer), bladder (ano-rectal cancer) and bowel cavity (gyne and bladder cancer) as compared to non-ART. CONCLUSION: Implementations of ART were dominated by offline re-planning and online brachytherapy re-planning strategies, although recently online plan selection workflows have increased with the availability of cone-beam CT. Advantageous dosimetric and outcome patterns using ART was documented by the studies of this review. Despite this, clinical implementations were scarce due to challenges in target/organ re-contouring and suboptimal patient selection in the ART workflows.

Clinical outcome of interstitial pulsed dose rate brachytherapy in multimodality treatment of locally advanced primary or recurrent rectal and sigmoid cancer with high risk of incomplete microscopic resection.

OBJECTIVE: To evaluate the role of interstitial pulsed dose rate brachytherapy (PDR-BT) in multimodality treatment of locally advanced primary or recurrent rectal and sigmoid cancer with high risk of microscopic incomplete resection (R1). METHODS AND MATERIAL: A total of 73 consecutive patients (recurrent/primary: 40/33) were treated with PDR-BT between 2001 and 2010. Patients received preoperative external beam radiotherapy (EBRT) and concomitant chemotherapy. Following resection of the tumor and the involved pelvic organs, a median of four (3-8) catheters were sutured to the tumor bed with a distance of approximately 1 cm between the catheters. A target respecting the catheters with a margin of 5 mm was contoured on computed tomography (CT) and three-dimensional (3D) dose planning with a planning aim for BT of D90 > 30 Gy, (0.6 Gy/pulse, 1 pulse/h) was performed. Previously irradiated patients (27%) underwent surgery that was directly followed by PDR-BT. Postoperative EBRT was then applied to the tumor bed 3-5 weeks after PDR-BT. RESULTS: A total of 23 patients (31%) received a radical resection (R0) and 45 patients (62%) received an R1 resection. Five patients (7%) received a macroscopic incomplete resection (R2). The five-year overall survival was 33%. Local control at five years was 67% for patients who received a R0 resection and 32% for patients who received an R1 resection. The five-year actuarial risk of a grade 3-4 BT-related complication was 5%. CONCLUSIONS: Meaningful disease control and survival can be obtained at an acceptable rate of late morbidity in selected patients with locally advanced primary and recurrent rectal or sigmoid cancer using (chemo) RT, extensive surgery and PDR-BT when a high risk of an R1 resection is expected.

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.

Diffusion-weighted magnetic resonance imaging during radiotherapy of locally advanced cervical cancer--treatment response assessment using different segmentation methods.

BACKGROUND: Diffusion-weighted magnetic resonance imaging (DW-MRI) and the derived apparent diffusion coefficient (ADC) value has potential for monitoring tumor response to radiotherapy (RT). Method used for segmentation of volumes with reduced diffusion will influence both volume size and observed distribution of ADC values. This study evaluates: 1) different segmentation methods; and 2) how they affect assessment of tumor ADC value during RT. MATERIAL AND METHODS: Eleven patients with locally advanced cervical cancer underwent MRI three times during their RT: prior to start of RT (PRERT), two weeks into external beam RT (WK2RT) and one week prior to brachytherapy (PREBT). Volumes on DW-MRI were segmented using three semi-automatic segmentation methods: "cluster analysis", "relative signal intensity (SD4)" and "region growing". Segmented volumes were compared to the gross tumor volume (GTV) identified on T2-weighted MR images using the Jaccard similarity index (JSI). ADC values from segmented volumes were compared and changes of ADC values during therapy were evaluated. RESULTS: Significant difference between the four volumes (GTV, DWIcluster, DWISD4 and DWIregion) was found (p < 0.01), and the volumes changed significantly during treatment (p < 0.01). There was a significant difference in JSI among segmentation methods at time of PRERT (p < 0.016) with region growing having the lowest JSIGTV (mean± sd: 0.35 ± 0.1), followed by the SD4 method (mean± sd: 0.50 ± 0.1) and clustering (mean± sd: 0.52 ± 0.3). There was no significant difference in mean ADC value compared at same treatment time. Mean tumor ADC value increased significantly (p < 0.01) for all methods across treatment time. CONCLUSION: Among the three semi-automatic segmentations of hyper-intense intensities on DW-MR images implemented, cluster analysis and relative signal thresholding had the greatest similarity to the clinical tumor volume. Evaluation of mean ADC value did not depend on segmentation method.

Correction of diffusion-weighted magnetic resonance imaging for brachytherapy of locally advanced cervical cancer.

BACKGROUND: Geometrical distortion is a major obstacle for the use of echo planar diffusion-weighted magnetic resonance imaging (DW-MRI) in planning of radiotherapy. This study compares geometrical distortion correction methods of DW-MRI at time of brachytherapy (BT) in locally advanced cervical cancer patients. MATERIAL AND METHODS: In total 21 examinations comprising DW-MRI, dual gradient echo (GRE) for B0 field map calculation and T2-weighted (T2W) fat-saturated MRI of eight patients with locally advanced cervical cancer were acquired during BT with a plastic tandem and ring applicator in situ. The ability of B0 field map correction (B0M) and deformable image registration (DIR) to correct DW-MRI geometric image distortion was compared to the non-corrected DW-MRI including evaluation of apparent diffusion coefficient (ADC) for the gross tumor volume (GTV). RESULTS: Geometrical distortion correction decreased tandem displacement from 3.3 ± 0.9 mm (non-corrected) to 2.9 ± 1.0 mm (B0M) and 1.9 ± 0.6 mm (DIR), increased mean normalized cross-correlation from 0.69 ± 0.1 (non- corrected) to 0.70 ± 0.10 (B0M) and 0.77 ± 0.1 (DIR), and increased the Jaccard similarity coefficient from 0.72 ± 0.1 (non-corrected) to 0.73 ± 0.06 (B0M) and 0.77 ± 0.1 (DIR). For all parameters only DIR corrections were significant (p < 0.05). ADC of the GTV did not change significantly with either correction method. CONCLUSION: DIR significantly improved geometrical accuracy of DW-MRI, with remaining residual uncertainties of less than 2 mm, while no significant improvement was seen using B0 field map correction.

Tracer kinetic model selection for dynamic contrast-enhanced magnetic resonance imaging of locally advanced cervical cancer.

BACKGROUND: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) offers a unique capability to probe tumour microvasculature. Different analysis of the acquired data will possibly lead to different conclusions. Therefore, the objective of this study was to investigate under which conditions the Tofts (TM), extended Tofts (ETM), compartmental tissue uptake model (C-TU) and 2-compartment exchange model (2CXM) were the optimal tracer kinetic models (TKMs) for the analysis of DCE-MRI in patients with cervical cancer. MATERIAL AND METHODS: Ten patients with locally advanced cervical cancer (FIGO: IIA/IIB/IIIB/IVA - 1/5/3/1) underwent DCE-MRI prior to radiotherapy. From the two-parameter TM it was possible to extract the forward volume transfer constant (K(trans)) and the extracellular-extravascular volume fraction (ve). From the three-parameter ETM, additionally the plasma volume fraction (vp) could be extracted. From the three-parameter C-TU it was possible to extract information about the blood flow (Fp), permeability-surface area product (PS) and vp. Finally, the four-parameter 2CXM extended the C-TU to include ve. For each voxel, corrected Akaike information criterion (AICc) values were calculated, taking into account both the goodness-of-fit and the number of model parameters. The optimal model was defined as the model with the lowest AICc. RESULTS: All four TKMs were the optimal model in different contiguous regions of the cervical tumours. For the 24 999 analysed voxels, the TM was optimal in 17.0%, the ETM was optimal in 2.2%, the C-TU in 23.4% and the 2CXM was optimal in 57.3%. Throughout the tumour, a high correlation was found between K(trans)(TM) and Fp(2CXM), ρ = 0.91. CONCLUSION: The 2CXM was most often optimal in describing the contrast agent enhancement of pre-treatment cervical cancers, although this model broke down in a subset of the tumour voxels where overfitting resulted in non-physiological parameter estimates. Due to the possible overfitting of the 2CXM, the C-TU was found more robust and when 2CXM was excluded from comparison the C-TU was the preferred model.

Evaluation of an application for intensity-based deformable image registration and dose accumulation in radiotherapy.

BACKGROUND: Methods to accurately accumulate doses in radiotherapy (RT) are important for tumour and normal tissues being influenced by geometric uncertainties. The purpose of this study was to investigate a pre-release deformable image registration (DIR)-based dose accumulation application, in the setting of prostate RT. MATERIAL AND METHODS: Initially accumulated bladder and prostate doses were assessed (based on 8-9 repeat CT scans/patient) for nine prostate cancer patients using an intensity-based DIR and dose accumulation algorithm as provided by the Dynamic Adaptive Radiation Therapy (DART) software. The accumulated bladder and prostate dose-volume histograms (DVHs) were compared on a range of parameters (paired Wilcoxon signed-rank test, 5% significance level) to DVHs derived using an in-house developed dose accumulation method based on biomechanical, contour-driven DIR (SurfaceRegistration). Finally, both these accumulated dose distributions were compared to the 'static' DVH, assessed from the planning CT. RESULTS: Over the population, doses accumulated with DART were overall lower than those from SurfaceRegistration (p < 0.05: D2%, gEUD and NTCP (bladder); Dmin (prostate)). The magnitude of these differences peaked for the bladder gEUD with a population median of 47 Gy for DART versus 57 Gy for SurfaceRegistration. Across the ten bladder dose/volume parameters investigated, the most pronounced individual differences were observed between the 'accumulated' DVHs and the 'static' DVHs, with deviations in mean dose up to 22 Gy. CONCLUSION: Substantial and significant differences were observed in the dose distributions between the two investigated DIR-based dose accumulation applications. The most pronounced individual differences were seen for the bladder and relative to the planned dose distribution, encouraging the use of repeat imaging data in RT planning and evaluation for this organ.

A simple calibration routine for small inorganic scintillation detectors for in vivo dosimetry during brachytherapy.

BACKGROUND: In vivo dosimetry (IVD) is rarely performed in brachytherapy (BT), allowing potential dose misadministration to go unnoticed. This study presents a clinical routine-calibration method of detectors for IVD in high (HDR) and pulsed dose rate (PDR) Ir-192 BT. PURPOSE: To evaluate the dosimetric precision and feasibility of an in-clinic calibration routine of detectors for IVD in afterloading BT. METHODS: Calibrations were performed in a PMMA phantom with two needles inserted 20 mm apart. The source was loaded in one of the needles at 15 dwells for 10 s. The detector was placed in the other needle, and its signal was recorded. The mean signal at each dwell position was fitted to the expected dose rate with the calibration factor and the detector's longitudinal position being free parameters. The method was tested with an inorganic scintillation detector using one Ir-192 FlexiSource HDR and two Ir-192 GammaMedPlus PDR sources and followed by validation measurements in water. RESULTS: The standard measurement uncertainty (k = 1) of the calibration factor in absolute terms (Gy/s) was 3.2/3.4% for the HDR/PDR source. The uncertainty was dominated by source strength uncertainty, and the precision of the method was <1%. The mean ± 1SD of the difference in measured and expected dose rate during validation was 1.5 ± 4.7% (HDR) and 0.0 ± 4.1% (PDR) with a positional uncertainty in the setup of 0.33/0.23 mm (HDR/PDR) (k = 1). CONCLUSION: A precise and feasible in-clinic calibration method for IVD and source strength consistency tests in BT was presented.

MRI-guided adaptive radiotherapy in locally advanced cervical cancer from a Nordic perspective.

BACKGROUND: The first Nordic protocol for three-dimensional (3D) planned radiotherapy in locally advanced cervical cancer was the prospective NOCECA study (1994-2000). NOCECA consisted of computed tomography (CT)-based 3D conformal external beam radiotherapy (EBRT) with a simultaneous integrated boost (SIB) to the primary tumour combined with brachytherapy (BT) based on x-ray imaging. In NOCECA the planning aim was to achieve 80 Gy at point A from EBRT and BT combined. However, the balance of dose between EBRT and BT was determined by tumour size at diagnosis with more EBRT dose given to point A and less by BT in more advanced stages. In 2005 image-guided adaptive brachytherapy (IGABT) based on magnetic resonance imaging (MRI) and optimisation of the BT dose distribution to the remaining tumour and cervix at time of BT (HR CTV) was introduced in Aarhus. EBRT remained like in NOCECA until 2008 when the SIB to the primary tumour was abandoned and IMRT was introduced as routine technique. In this study, we report outcome of our first five-year experience with IGABT using our NOCECA cohort as reference. MATERIAL AND METHODS: The NOCECA cohort comprising 99 patients was compared with 140 consecutive patients treated by IGABT. Patients with para-aortic nodes were excluded in NOCECA but were present in 9% of the patients treated with IGABT. No patient in NOCECA received chemotherapy whereas concomitant cisplatin was given to 79% of the IGABT patients. RESULTS: With IGABT actuarial local control was 91% at three years. When comparing NOCECA with IGABT overall survival was significantly improved from 63% to 79% (p = 0.005). In parallel, both moderate and severe late morbidity were reduced by about 50% (p = 0.02). CONCLUSION: Introduction of IGABT reduced morbidity and generated a very high rate of local control, which likely has improved survival by at least as much as concomitant chemotherapy.

Voxelwise comparison of perfusion parameters estimated using dynamic contrast enhanced (DCE) computed tomography and DCE-magnetic resonance imaging in locally advanced cervical cancer.

PURPOSE: Dynamic contrast enhanced (DCE) imaging has gained interest as an imaging modality for assessment of tumor characteristics and response to cancer treatment. However, for DCE-magnetic resonance imaging (MRI) tissue contrast enhancement may vary depending on imaging sequence and temporal resolution. The aim of this study is to compare DCE-MRI to DCE-computed tomography (DCE-CT) as the gold standard. MATERIAL AND METHODS: Thirteen patients with advanced cervical cancer were scanned once prior to chemo-radiation and during chemo-radiation with DCE-CT and -MRI in immediate succession. A total of 22 paired DCE-CT and -MRI scans were acquired for comparison. Kinetic modeling using the extended Tofts model was applied to both image series. Furthermore the similarity of the spatial distribution was evaluated using a Γ analysis. The correlation between the two imaging techniques was evaluated using Pearson's correlation and the parameter means were compared using a Student's t-test (p < 0.05). RESULTS: A significant positive correlation between DCE-CT and -MRI was found for all kinetic parameters. The results showing the best correlation with the DCE-CT-derived parameters were obtained using a population-based input function for MRI. The median Pearson's correlations were: volume transfer constant K(trans) (r = 0.9), flux rate constant kep (r = 0.77), extracellular volume fraction ve (r = 0.58) and blood plasma volume fraction vp (r = 0.83). All quantitative parameters were found to be significantly different as estimated by DCE-CT and -MRI. The Γ analysis in normalized maps revealed that 45% of the voxels failed to find a voxel with the corresponding value allowing for an uncertainty of 3 mm in position and 3% in value (Γ3,3). By reducing the criteria, the Γ-failure rates were: Γ3,5 (37% failure), Γ3,10 (26% failure) and at Γ3,15 (19% failure). CONCLUSION: Good to excellent correlations but significant bias was found between DCE-CT and -MRI. Both the Pearson's correlation and the Γ analysis proved that the spatial information was similar when analyzing the two sets of DCE data using the extended Tofts model. Improvement of input function sampling is needed to improve kinetic quantification using DCE-MRI.

EviGUIDE - a tool for evidence-based decision making in image-guided adaptive brachytherapy for cervical cancer.

PURPOSE: To develop a novel decision-support system for radiation oncology that incorporates clinical, treatment and outcome data, as well as outcome models from a large clinical trial on magnetic resonance image-guided adaptive brachytherapy (MR-IGABT) for locally advanced cervical cancer (LACC). METHODS: A system, called EviGUIDE, was developed that combines dosimetric information from the treatment planning system, patient and treatment characteristics, and established tumor control probability (TCP), and normal tissue complication probability (NTCP) models, to predict clinical outcome of radiotherapy treatment of LACC. Six Cox Proportional Hazards models based on data from 1341 patients of the EMBRACE-I study have been integrated. One TCP model for local tumor control, and five NTCP models for OAR morbidities. RESULTS: EviGUIDE incorporates TCP-NTCP graphs to help users visualize the clinical impact of different treatment plans and provides feedback on achievable doses based on a large reference population. It enables holistic assessment of the interplay between multiple clinical endpoints and tumour and treatment variables. Retrospective analysis of 45 patients treated with MR-IGABT showed that there exists a sub-cohort of patients (20%) with increased risk factors, that could greatly benefit from the quantitative and visual feedback. CONCLUSION: A novel digital concept was developed that can enhance clinical decision- making and facilitate personalized treatment. It serves as a proof of concept for a new generation of decision support systems in radiation oncology, which incorporate outcome models and high-quality reference data, and aids the dissemination of evidence-based knowledge about optimal treatment and serve as a blueprint for other sites in radiation oncology.