Early morbidity and dose-volume effects in definitive radiochemotherapy for locally advanced cervical cancer: a prospective cohort study covering modern treatment techniques.

PURPOSE: Predicting morbidity for patients with locally advanced cervix cancer after external beam radiotherapy (EBRT) based on dose-volume parameters remains an unresolved issue in definitive radiochemotherapy. The aim of this prospective study was to correlate patient characteristics and dose-volume parameters to various early morbidity endpoints for different EBRT techniques, including volumetric modulated arc therapy (VMAT) and adaptive radiotherapy (ART). METHODS AND MATERIALS: The study population consisted of 48 patients diagnosed with locally advanced cervix cancer, treated with definitive radiochemotherapy including image-guided adaptive brachytherapy (IGABT). Multiple questionnaires (CTCAE 4.03, QLQ-C30 and EORTC QLQ-CX24) were assessed prospectively for patients treated with different EBRT techniques, including online adaptive VMAT. Contouring and treatment planning was based on the EMBRACE protocols. Acute toxicity, classified as general, gastrointestinal (GI) or genitourinary (GU) and their corresponding dose-volume histograms (DVHs) were first correlated by applying least absolute shrinkage and selection operator (LASSO) and subsequently evaluated by multiple logistic binomial regression. RESULTS: The treated EBRT volumes varied for the different techniques with ~2500 cm3 for 3D conformal radiotherapy (3D-CRT), ~2000 cm3 for EMBRACE­I VMAT, and ~1800 cm3 for EMBRACE-II VMAT and ART. In general, a worsening of symptoms during the first 5 treatment weeks and recovery afterwards was observed. Dose-volume parameters significantly correlating with stool urgency, rectal and urinary incontinence were as follows: bowel V40Gy < 250 cm3, rectum V40Gy < 80% and bladder V40Gy < 80-90%. CONCLUSION: This prospective study demonstrated the impact of EBRT treatment techniques in combination with chemotherapy on early morbidity. Dose-volume effects for dysuria, urinary incontinence, stool urgency, diarrhea, rectal bleeding, rectal incontinence and weight loss were found.

Automated volumetric modulated arc therapy planning for whole pelvic prostate radiotherapy.

BACKGROUND: For several tumor entities, automated treatment planning has improved plan quality and planning efficiency, and may enable adaptive treatment approaches. Whole-pelvic prostate radiotherapy (WPRT) involves large concave target volumes, which present a challenge for volumetric arc therapy (VMAT) optimization. This study evaluates automated VMAT planning for WPRT-VMAT and compares the results with manual expert planning. METHODS: A system for fully automated multi-criterial plan generation was configured for each step of sequential-boost WPRT-VMAT, with final "autoVMAT" plans being automatically calculated by the Monaco treatment planning system (TPS; Elekta AB, Stockholm, Sweden). Configuration was based on manually generated VMAT plans (manualVMAT) of 5 test patients, the planning protocol, and discussions with the treating physician on wishes for plan improvements. AutoVMAT plans were then generated for another 30 evaluation patients and compared to manualVMAT plans. For all 35 patients, manualVMAT plans were optimized by expert planners using the Monaco TPS. RESULTS: AutoVMAT plans exhibited strongly improved organ sparing and higher conformity compared to manualVMAT. On average, mean doses (Dmean) of bladder and rectum were reduced by 10.7 and 4.5 Gy, respectively, by autoVMAT. Prostate target coverage (V95%) was slightly higher (+0.6%) with manualVMAT. In a blinded scoring session, the radiation oncologist preferred autoVMAT plans to manualVMAT plans for 27/30 patients. All treatment plans were considered clinically acceptable. The workload per patient was reduced by > 70 min. CONCLUSION: Automated VMAT planning for complex WPRT dose distributions is feasible and creates treatment plans that are generally dosimetrically superior to manually optimized plans.

Tumor tracking with non-linear internal/external correlation models in the presence of respiratory motion baseline drifts and phase shifts.

PURPOSE: In CyberKnife® respiratory tracking, tumor positions are predicted from external marker positions using correlation models. With available models, prediction accuracy may deteriorate when respiratory motion baseline drifts occur. Previous investigations have demonstrated that for linear models this can be mitigated by adding a time-dependent term. In this study, we have focused on added value of time-dependent terms for the available non-linear correlation models, and on phase shifts between internal and external motion tracks. METHODS: Treatment simulations for tracking with and without time-dependent terms were performed using computer generated respiratory motion tracks for 60.000 patients with variable baseline drifts and phase shifts. The protocol for acquisition of X-ray images was always the same. Tumor position prediction accuracies in simulated treatments were largely based on cumulative error-time histograms and quantified with R95: in 95% of time the prediction error is < R95 mm. RESULTS: For all available correlation models, prediction accuracy improved by adding a time-dependent term in case of occurring baseline drifts, with and without phase shifts present. For the most accurate model and 150 s between model updates, adding time dependency reduced R95 from 3.9 to 3.1 mm and from 5.4 to 3.3 mm for 0.25 and 0.50 mm/min drift, respectively. Tumor position prediction accuracy improvements with time-dependent models were obtained without increases in X-ray imaging. CONCLUSIONS: Using available correlation models with an added time-dependent term could largely mitigate negative impact of respiratory motion baseline drifts on tumor position prediction accuracy, also in case of large phase shifts.

A novel external/internal tumor tracking approach to compensate for respiratory motion baseline drifts.

Objective.Real-time respiratory tumor tracking as implemented in a robotic treatment unit is based on continuous optical measurement of the position of external markers and a correlation model between them and internal target positions, which are established with X-ray imaging of the tumor, or fiducials placed in or around the tumor. Correlation models are created with fifteen simultaneously measured external/internal marker position pairs divided over the respiratory cycle. Every 45-150 s, the correlation model is updated by replacing the three first acquired data pairs with three new pairs. Tracking simulations for >120.000 computer-generated respiratory tracks demonstrated that this tracking approach resulted in relevant inaccuracies in internal target position predictions, especially in case of presence of respiratory motion baseline drifts.Approach.To better cope with drifts, we introduced a novel correlation model with an explicit time dependence, and we proposed to replace the currently applied linear-motion tracking (LMT) by mixed-model tracking (MMT). In MMT, the linear correlation model is extended with an explicit time dependence in case of a detected baseline drift. MMT prediction accuracies were then established for the same >120.000 computer-generated patients as used for LMT.Main results.For 150 s update intervals, MMT outperformed LMT in internal target position prediction accuracy for 93.7 ∣ 97.2% of patients with 0.25 ∣ 0.5 mm min-1linear respiratory motion baseline drifts with similar numbers of X-ray images and similar treatment times. For the upper 25% of patients, mean 3D internal target position prediction errors reduced by 0.7 ∣ 1.8 mm, while near maximum reductions (upper 10% of patients) were 0.9 ∣ 2.0 mm.Significance.For equal numbers of acquired X-ray images, MMT greatly improved tracking accuracy compared to LMT, especially in the presence of baseline drifts. Even with almost 50% less acquired X-ray images, MMT still outperformed LMT in internal target position prediction accuracy.

Tools for large-scale data analytics of an international multi-center study in radiation oncology for cervical cancer.

PURPOSE: To develop and implement a software that enables centers, treating patients with state-of-the-art radiation oncology, to compare their patient, treatment, and outcome data to a reference cohort, and to assess the quality of their treatment approach. MATERIALS AND METHODS: A comprehensive data dashboard was designed, which al- lowed holistic assessment of institutional treatment approaches. The software was tested in the ongoing EMBRACE-II study for locally advanced cervical cancer. The tool created individualized dashboards and automatic analysis scripts, verified pro- tocol compliance and checked data for inconsistencies. Identified quality assurance (QA) events were analysed. A survey among users was conducted to assess usability. RESULTS: The survey indicated favourable feedback to the prototype and highlighted its value for internal monitoring. Overall, 2302 QA events were identified (0.4% of all collected data). 54% were due to missing or incomplete data, and 46% originated from other causes. At least one QA event was found in 519/1001 (52%) of patients. QA events related to primary study endpoints were found in 16% of patients. Sta- tistical methods demonstrated good performance in detecting anomalies, with precisions ranging from 71% to 100%. Most frequent QA event categories were Treatment Technique (27%), Patient Characteristics (22%), Dose Reporting (17%), Outcome 156 (15%), Outliers (12%), and RT Structures (8%). CONCLUSION: A software tool was developed and tested within a clinical trial in radia- tion oncology. It enabled the quantitative and qualitative comparison of institutional patient and treatment parameters with a large multi-center reference cohort. We demonstrated the value of using statistical methods to automatically detect implau- sible data points and highlighted common pitfalls and uncertainties in radiotherapy for cervical cancer.

Multi-center analysis of machine-learning predicted dose parameters in brachytherapy for cervical cancer.

BACKGROUND AND PURPOSE: Image-guided adaptive brachytherapy (IGABT) is a key component in the treatment of cervical cancer, but the nature of the clinical workflow makes it vulnerable to suboptimal plans, as the theoretical optimal plan depends heavily on organ configuration. Patient anatomy-based quality-assurance (QA) with overlap volume histograms (OVHs) is a promising tool to detect such suboptimal plans, and in this analysis its suitability as a multi-institutional clinical QA tool is investigated. MATERIALS AND METHODS: A total of 223 plans of 145 patients treated in accordance with the current state-of-the-art IGABT protocols from UMC Utrecht (UMCU) and Erasmus MC (EMC) were included. Machine-learning models were trained to predict dose D2cm3 to bladder, rectum, sigmoid and small bowel with the help of OVHs. For this strategy, points are sampled on the organs-at-risk (OARs), and the distances of the sampled points to the target are computed and combined in a histogram. Machine-learning models can then be trained to predict dose-volume histograms (DVHs) for unseen data. Single-center model robustness to needle use and applicator type and multi-center model translatability were investigated. Performance of models was assessed by the difference between planned (clinical) and predicted D2cm3 values. RESULTS: Intra-validation of UMCU data demonstrated OVH model robustness to needle use and applicator type. The model trained on UMCU data was found to be robust within the same protocol on EMC data, for all investigated OARs. Mean squared error between planned and predicted D2cm3 values of OARs ranged between 0.13 and 0.40 Gy within the same protocol, indicating model translatability. For the former protocol cohort of Erasmus MC large deviations were found between the planned and predicted D2cm3 values, indicating plan deviation from protocol. Mean squared error for this cohort ranged from 0.84 to 4.71 Gy. CONCLUSION: OVH-based models can provide a solid basis for multi-institutional QA when trained on a sufficiently strict protocol. Further research will quantify the model's impact as a QA tool.

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.

Importance of training in external beam treatment planning for locally advanced cervix cancer: Report from the EMBRACE II dummy run.

BACKGROUND AND PURPOSE: The EMBRACE II study combines state-of-the-art Image-Guided Adaptive Brachytherapy in cervix cancer with an advanced protocol for external beam radiotherapy (EBRT) which specifies target volume selection, contouring and treatment planning. In EMBRACE II, well-defined EBRT is an integral part of the overall treatment strategy with the primary aim of improving nodal control and reducing morbidity. The EMBRACE II EBRT planning concept is based on improved conformality through relaxed coverage criteria for all target volumes. For boosting of lymph nodes, a simultaneous integrated boost and coverage probability planning is applied. Before entering EMBRACE II, institutes had to go through accreditation. MATERIAL AND METHODS: As part of accreditation, a treatment planning dummy-run included educational blocks and submission of an examination case provided by the study coordinators. Seventy-one centers submitted 123 EBRT dose distributions. Replanning was required if hard constraints were violated or planning concepts were not fully accomplished. Dosimetric parameters of original and revised plans were compared. RESULTS: Only 11 plans violated hard constraints. Twenty-seven centers passed after first submission. 27 needed one and 13 centers needed more revisions. The most common reasons for revisions were low conformality, relatively high OAR doses or insufficient lymph node coverage reduction. Individual feedback on planning concepts improved plan quality considerably, resulting in a median body V43Gy reduction of 158 cm3 from first plan submission to approved plan. CONCLUSION: A dummy-run as applied in EMBRACE II, consisting of training and examination cases enabled us to test institutes' treatment planning capabilities, and improve plan quality.

Importance of Technique, Target Selection, Contouring, Dose Prescription, and Dose-Planning in External Beam Radiation Therapy for Cervical Cancer: Evolution of Practice From EMBRACE-I to II.

PURPOSE: To describe the evolution of external beam radiation therapy (EBRT) from EMBRACE-I (general guidelines for EBRT) to the initial phase of the EMBRACE-II study (detailed protocol for EBRT). METHODS AND MATERIALS: EMBRACE-I enrolled 1416 locally advanced cervical cancer patients treated with chemoradiation including image-guided adaptive brachytherapy during 2008 to 2015. From March 2016 until March 2018, 153 patients were enrolled in the ongoing EMBRACE-II study, which involves a comprehensive detailed strategy and accreditation procedure for EBRT target contouring, treatment planning, and image guidance. EBRT planning target volumes (PTVs), treated volumes (V43 Gy), and conformity index (CI; V43 Gy/PTV) were evaluated in both studies and compared. RESULTS: For EMBRACE-I, conformal radiation therapy (60% of patients) or intensity-modulated radiation therapy (IMRT) and volumetric arc therapy (VMAT; 40%) was applied with 45 to 50 Gy over 25 to 30 fractions to the elective clinical target volume (CTV). For pelvic CTVs (82%), median PTV and V43 Gy volumes were 1549 and 2390 mL, respectively, and CI was 1.54. For pelvic plus paraortic nodal (PAN) CTVs (15%), median PTV and V43 Gy volumes were 1921 and 2895 mL, and CI was 1.51. For pelvic CTVs treated with 45 to 46 Gy, the use of conformal radiation therapy was associated with a median V43 Gy volume that was 546 mL larger than with IMRT/VMAT. For pelvic CTVs treated with IMRT, the use of a dose prescription ≥48 Gy was associated with a median V43 Gy volumes that was 428 mL larger than with a dose prescription of 45 to 46 Gy. For EMBRACE-II, all patients were treated with: IMRT/VMAT, daily IGRT, 45 Gy over 25 fractions for the elective CTV, and simultaneously integrated boost for pathologic lymph nodes. For pelvic CTVs (61%), median PTV and V43 Gy volumes were 1388 and 1418 mL, and CI was 1.02. For pelvic plus PAN CTVs (32%), median PTV and V43 Gy volumes were 1720 and 1765 mL, and CI was 1.03. From EMBRACE-I to initial II, median V43 Gy was decreased by 972 mL (41%) and 1130 mL (39%), and median CI decreased from 1.54 to 1.02 and 1.51 to 1.03 for pelvic and pelvic plus PAN irradiation, respectively. CONCLUSIONS: Application of IMRT/VMAT, IGRT, and a 45-Gy dose provides the potential of higher conformality inducing significant reduction of treated volume. Adherence to a detailed protocol including comprehensive accreditation, as in EMBRACE-II, reduces considerably V43 Gy and V50 Gy and improves conformality and interinstitutional consistency.

HDR prostate monotherapy: dosimetric effects of implant deformation due to posture change between TRUS- and CT-imaging.

HDR monotherapy for prostate cancer consists of four fractions. The first fraction is delivered with online TRUS-based treatment planning. For the last three fractions the treatment plan is based on a CT-scan acquired in between fractions 1 and 2. The patient position (high lithotomy, rectal US probe) during TRUS-guided catheter implantation and first fraction differs from the patient position in the CT-scan and the remaining three fractions (lowered legs, no TRUS probe). This study describes the effect of posture changes on dose distributions when a plan designed for the TRUS anatomy is applied to the CT-scan anatomy. The aim is to quantify dosimetrical errors that would result from skipping the use of a planning CT-scan, and rely for all fractions on the TRUS plan. Such a procedure would substantially reduce the involved workload, and would increase patient comfort. For three prostate cancer patients, images were acquired during TRUS-guided catheter implantation. Furthermore, a CT-scan (no US probe in rectum, different position of legs) was acquired and matched with the TRUS set. On both TRUS and CT, prostate, urethra and rectum were delineated and all catheters were traced. For each patient, an optimized treatment plan was designed using TRUS images and contours. Catheters with obtained dwell positions of the TRUS plan were transferred individually to the catheter positions in the CT. Changes in dose distribution due to relocation of catheters were evaluated using DVHs. For all patients the dose distributions changed significantly due to rearrangement of the catheters, having most impact on the urethra (maximum observed change: 32% volume receiving > or = 120% of the prescribed dose) and a reduction of PTV coverage (6-28%). Implant deformation when changing from TRUS patient set-up to CT set-up affected negatively the quality of optimized treatment plans. Inclusion of more patients in this study was planned, but because of the observed strong negative effects it is already concluded that the TRUS plan cannot be used for the last three fractions with a deviating patient set-up.

Dosimetric investigation of lung tumor motion compensation with a robotic respiratory tracking system: an experimental study.

The benefits of using Synchrony Respiratory Tracking System (RTS) in conjunction with the CyberKnife robotic treatment device to treat a "breathing tumor" in an anthropomorphic, tissue-equivalent, thoracic phantom have been investigated. The following have been studied: (a) Synchrony's ability to allow the CyberKnife to deliver accurately a planned dose distribution to the free-breathing phantom and (b) the dosimetric implications when irregularities in the breathing cycle and phase differences between internal (tumor) and external (chest) motion exist in the course of one treatment fraction. The breathing phantom PULMONE (phantom used in lung motion experiments) has been used, which can imitate regular or irregular breathing patterns. The breathing traces from two patients with lung cancer have been selected as input. Both traces were irregular in amplitude, frequency, and base line. Patient B demonstrated a phase difference between internal and external motion, whereas patient A did not. The experiment was divided into three stages: In stage I-static, the treatment was delivered to the static phantom. In stage II-motion, the phantom was set to breathe, following the breathing trace of each of the two patients. Synchrony was switched off, so no motion compensation was made. In stage III-compensation, the phantom was set to breathe and Synchrony was switched on. A linear correspondence model was chosen to allow for phase differences between internal and external motion. Gafchromic EBT film was inserted in the phantom tumor to measure dose. To eradicate small errors in film alignment during readout, a gamma comparison with pass criteria of 3%/3 mm was selected. For a more quantitative approach, the percentage of pixels in each gamma map that exceeded the value of 1 (P1) was also used. For both breathing signals, the dose blurring caused by the respiratory motion of the tumor in stage II was degraded considerably compared with stage I (P1 = 15% for patient A and 8% for patient B). The motion compensation via the linear correspondence model was sufficient to provide a dose distribution that satisfied the set gamma criteria (P1=3% for patient A and 2% for patient B). Synchrony RTS has been found satisfactory in recovering the initial detail in dose distribution, for realistic breathing signals, even in the case where a phase delay between internal tumor motion and external chest displacement exists. For the signals applied here, a linear correspondence model provided an acceptable degree of motion compensation.

Image guided adaptive external beam radiation therapy for cervix cancer: Evaluation of a clinically implemented plan-of-the-day technique.

BACKGROUND: Radiotherapy for cervix cancer is challenging in patients exhibiting large daily changes in the pelvic anatomy, therefore adaptive treatments (ART) have been proposed. The aim of this study was the clinical implementation and subsequent evaluation of plan-of-the-day (POTD)-ART for cervix cancer in supine positioning. The described workflow was based on standard commercial equipment and current quality assurance (QA) methods. MATERIALS AND METHODS: A POTD strategy, which employs a VMAT plan library consisting of an empty bladder plan, a full bladder plan and a motion robust backup plan, was developed. Daily adaption was guided by cone beam computed tomography (CBCT) imaging after which the best plan from the library was selected. Sixteen patients were recruited in a clinical study on ART, for nine POTD was applied due to their large organ motion derived from two computed tomography (CT) scans with variable bladder filling. All patients were treated to 45Gy in 25 fractions. Plan selection frequencies over the treatment course were analyzed. Daily doses in the rectum, bladder and cervix-uterus target (CTV-T) were derived and compared to a simulated non-adapted treatment (non-ART), which employed the robust plan for each fraction. Additionally, the adaption consistency was determined by repeating the plan selection procedure one month after treatment by a group of experts. ART-specific QA methods are presented. RESULTS: 225 ART fractions with CBCTs were analyzed. The empty bladder plan was delivered in 49% of the fractions in the first treatment week and this number increased to 78% in the fifth week. The daily coverage of the CTV-T was equivalent between ART and the non-ART simulation, while the daily total irradiated volume V42.75Gy (95% of prescription dose) was reduced by a median of 87cm3. The median delivered V42.75Gy was 1782cm3. Daily delivered doses (V42.75Gy, V40Gy, V30G) to the organs at risk were statistically significantly reduced by ART, with a median difference in daily V42.75Gy in rectum and bladder of 3.2% and 1.1%, respectively. The daily bladder V42.75Gy and V40Gy were decreased by more than 10 percent points in 30% and 24% of all fractions, respectively, through ART. The agreement between delivered plans and retrospective expert-group plan selections was 84%. CONCLUSION: A POTD-ART technique for cervix cancer was successfully and safely implemented in the clinic and evaluated. Improved normal tissue sparing compared to a simulated non-ART treatment could be demonstrated. Future developments should focus on commercial automated software solutions to allow for a more widespread adoption and to keep the increased workload manageable.

Fully automated, multi-criterial planning for Volumetric Modulated Arc Therapy - An international multi-center validation for prostate cancer.

BACKGROUND AND PURPOSE: Reported plan quality improvements with autoplanning of radiotherapy of the prostate and seminal vesicles are poor. A system for automated multi-criterial planning has been validated for this treatment in a large international multi-center study. The system is configured with training plans using a mechanism that strives for quality improvements relative to those plans. MATERIAL AND METHODS: Each of the four participating centers included thirty manually generated clinical Volumetric Modulated Arc Therapy prostate plans (manVMAT). Ten plans were used for autoplanning training. The other twenty were compared with an automatically generated plan (autoVMAT). Plan evaluations considered dosimetric plan parameters and blinded side-by-side plan comparisons by clinicians. RESULTS: With equivalent Planning Target Volume (PTV) V95%, D2%, D98%, and dose homogeneity autoVMAT was overall superior for rectum with median differences of 3.4 Gy (p < 0.001) in Dmean, 4.0% (p < 0.001) in V60Gy, and 1.5% (p = 0.001) in V75Gy, and for bladder Dmean (0.9 Gy, p < 0.001). Also the clinicians' plan comparisons pointed at an overall preference for autoVMAT. Advantages of autoVMAT were highly treatment center- and patient-specific with overall ranges for differences in rectum Dmean and V60Gy of [-4,12] Gy and [-2,15]%, respectively. CONCLUSION: Observed advantages of autoplanning were clinically relevant and larger than reported in the literature. The latter is likely related to the multi-criterial nature of the applied autoplanning algorithm, with for each center a dedicated configuration that aims at plan improvements relative to its (clinical) training plans. Large variations among patients in differences between manVMAT and autoVMAT point at inconsistencies in manual planning.

The EMBRACE II study: The outcome and prospect of two decades of evolution within the GEC-ESTRO GYN working group and the EMBRACE studies.

The publication of the GEC-ESTRO recommendations one decade ago was a significant step forward for reaching international consensus on adaptive target definition and dose reporting in image guided adaptive brachytherapy (IGABT) in locally advanced cervical cancer. Since then, IGABT has been spreading, particularly in Europe, North America and Asia, and the guidelines have proved their broad acceptance and applicability in clinical practice. However, a unified approach to volume contouring and reporting does not imply a unified administration of treatment, and currently both external beam radiotherapy (EBRT) and IGABT are delivered using a large variety of techniques and prescription/fractionation schedules. With IGABT, local control is excellent in limited and well-responding tumours. The major challenges are currently loco-regional control in advanced tumours, treatment-related morbidity, and distant metastatic disease. Emerging evidence from the RetroEMBRACE and EMBRACE I studies has demonstrated that clinical outcome is related to dose prescription and technique. The next logical step is to demonstrate excellent clinical outcome with the most advanced EBRT and brachytherapy techniques based on an evidence-based prospective dose and volume prescription protocol. The EMBRACE II study is an interventional and observational multicentre study which aims to benchmark a high level of local, nodal and systemic control while limiting morbidity, using state of the art treatment including an advanced target volume selection and contouring protocol for EBRT and brachytherapy, a multi-parametric brachytherapy dose prescription protocol (clinical validation of dose constraints), and use of advanced EBRT (IMRT and IGRT) and brachytherapy (IC/IS) techniques (clinical validation). The study also incorporates translational research including imaging and tissue biomarkers.

Accuracy of tumor motion compensation algorithm from a robotic respiratory tracking system: a simulation study.

The Synchrony Respiratory Tracking System (RTS) is a treatment option of the CyberKnife robotic treatment device to irradiate extra-cranial tumors that move due to respiration. Advantages of RTS are that patients can breath normally and that there is no loss of linac duty cycle such as with gated therapy. Tracking is based on a measured correspondence model (linear or polynomial) between internal tumor motion and external (chest/abdominal) marker motion. The radiation beam follows the tumor movement via the continuously measured external marker motion. To establish the correspondence model at the start of treatment, the 3D internal tumor position is determined at 15 discrete time points by automatic detection of implanted gold fiducials in two orthogonal x-ray images; simultaneously, the positions of the external markers are measured. During the treatment, the relationship between internal and external marker positions is continuously accounted for and is regularly checked and updated. Here we use computer simulations based on continuously and simultaneously recorded internal and external marker positions to investigate the effectiveness of tumor tracking by the RTS. The Cyberknife does not allow continuous acquisition of x-ray images to follow the moving internal markers (typical imaging frequency is once per minute). Therefore, for the simulations, we have used data for eight lung cancer patients treated with respiratory gating. All of these patients had simultaneous and continuous recordings of both internal tumor motion and external abdominal motion. The available continuous relationship between internal and external markers for these patients allowed investigation of the consequences of the lower acquisition frequency of the RTS. With the use of the RTS, simulated treatment errors due to breathing motion were reduced largely and consistently over treatment time for all studied patients. A considerable part of the maximum reduction in treatment error could already be reached with a simple linear model. In case of hysteresis, a polynomial model added some extra reduction. More frequent updating of the correspondence model resulted in slightly smaller errors only for the few recordings with a time trend that was fast, relative to the current x-ray update frequency. In general, the simulations suggest that the applied combined use of internal and external markers allow the robot to accurately follow tumor motion even in the case of irregularities in breathing patterns.

Advanced optimization methods for whole pelvic and local prostate external beam therapy.

PURPOSE: Radiation treatment planning inherently involves multiple conflicting planning goals, which makes it a suitable application for multicriteria optimization (MCO). This study investigates a MCO algorithm for VMAT planning (VMAT-MCO) for prostate cancer treatments including pelvic lymph nodes and uses standard inverse VMAT optimization (sVMAT) and Tomotherapy planning as benchmarks. METHODS: For each of ten prostate cancer patients, a two stage plan was generated, consisting of a stage 1 plan delivering 22Gy to the prostate, and a stage 2 plan delivering 50.4Gy to the lymph nodes and 56Gy to the prostate with a simultaneous integrated boost. The single plans were generated by three planning techniques (VMAT-MCO, sVMAT, Tomotherapy) and subsequently compared with respect to plan quality and planning time efficiency. RESULTS: Plan quality was similar for all techniques, but sVMAT showed slightly better rectum (on average Dmean -7%) and bowel sparing (Dmean -17%) compared to VMAT-MCO in the whole pelvic treatments. Tomotherapy plans exhibited higher bladder dose (Dmean +42%) in stage 1 and lower rectum dose (Dmean -6%) in stage 2 than VMAT-MCO. Compared to manual planning, the planning time with MCO was reduced up to 12 and 38min for stage 1 and 2 plans, respectively. CONCLUSION: MCO can generate highly conformal prostate VMAT plans with minimal workload in the settings of prostate-only treatments and prostate plus lymph nodes irradiation. In the whole pelvic plan manual VMAT optimization led to slightly improved OAR sparing over VMAT-MCO, whereas for the primary prostate treatment plan quality was equal.

Impact of organ shape variations on margin concepts for cervix cancer ART.

BACKGROUND AND PURPOSE: Target and organ movement motivate adaptive radiotherapy for cervix cancer patients. We investigated the dosimetric impact of margin concepts with different levels of complexity on both organ at risk (OAR) sparing and PTV coverage. MATERIAL AND METHODS: Weekly CT and daily CBCT scans were delineated for 10 patients. The dosimetric impact of organ shape variations were evaluated for four (isotropic) margin concepts: two static PTVs (PTV6mm and PTV15mm), a PTV based on ITV of the planning CT and CBCTs of the first treatment week (PTVART ITV) and an adaptive PTV based on a library approach (PTVART Library). RESULTS: Using static concepts, OAR doses increased with large margins, while smaller margins compromised target coverage. ART PTVs resulted in comparable target coverage and better sparing of bladder (V40Gy: 15% and 7% less), rectum (V40Gy: 18 and 6cc less) and bowel (V40Gy: 106 and 15cc less) compared to PTV15mm. Target coverage evaluation showed that for elective fields a static 5mm margin sufficed. CONCLUSION: PTVART Library achieved the best dosimetric results. However when weighing clinical benefit against workload, ITV margins based on repetitive movement evaluation during the first week also provide improvements over static margin concepts.

Intrafractional tumor motion: lung and liver.

Three-dimensional (3D) dose distribution has been improved by 3D conformation and intensity modulation in external radiotherapy. Interfractional uncertainty has been reduced by image-guided setup techniques. Reduction of ambiguity because of intrafractional target motion is the next step forward. Respiratory organ motion is known to be the largest intrafractional organ motion. Radiotherapy techniques controlling, gating, or tracking respiratory motion are under investigation to use smaller safety margins and higher doses for moving tumors. However, data on intrafractional tumor motion are sparse. We developed a fluoroscopic real-time tracking system and implantation techniques of fiducial markers for moving organs and have been accumulating knowledge about internal tumor motion. We also found the importance of 4-dimensional treatment planning to account for tumor motion in precision radiotherapy. This article reviews the current basic knowledge on respiratory physiology and summarizes the accumulating knowledge on internal motion of lung and liver tumors.

Regional differences in lung radiosensitivity after radiotherapy for non-small-cell lung cancer.

PURPOSE: To study regional differences in lung radiosensitivity by evaluating the incidence of radiation pneumonitis (RP) in relation to regional dose distributions. METHODS AND MATERIALS: Registered chest CT and single photon emission CT lung perfusion scans were obtained in 106 patients before curative or radical radiotherapy for non-small-cell lung cancer. The mean lung dose (MLD) was calculated. The single photon-emission CT perfusion data were used to weigh the MLD with perfusion, resulting in the mean perfusion-weighted lung dose. In addition, the lungs were geometrically divided into different subvolumes. The mean regional dose (MRD) for each region was calculated and weighted with the perfusion of each region to obtain the mean perfusion-weighted regional dose. RP was defined as respiratory symptoms requiring steroids. The incidence of RP for patients with tumors in a specific subvolume was calculated. The normal tissue complication probability (NTCP) parameter values for the TD(50), and an offset NTCP parameter for tumor location were fitted for both lungs and for each lung subvolume to the observed data using maximum likelihood analysis. RESULTS: The incidence of RP correlated significantly with the MLD and MRD of the posterior, caudal, ipsilateral, central, and peripheral lung subvolumes (p between 0.05 and 0.002); no correlation was seen for the anterior, cranial, and contralateral regions Similarly, a statistically significant correlation was observed between the incidence of RP and the perfusion-weighted MLD and perfusion-weighted MRD for all regions, except the anterior lung region. For this region, the dose-effect relation improved remarkably after weighting the local dose with the local perfusion. A statistically significant difference (p = 0.01) in the incidence of RP was found between patients with cranial and caudal tumors (11% and 40%, respectively). Therefore, a dose-independent offset NTCP parameter for caudal tumors was included in the NTCP model, improving most correlations significantly, confirming that patients with caudal tumors have a greater probability of developing RP. CONCLUSION: The incidence of RP correlated significantly with the MLD and MRD of most lung regions, except for the anterior, cranial, and contralateral regions. Weighting the local dose with the local perfusion improved the dose-effect relation for the anterior lung region. Irradiation of caudally located lung tumors resulted in a greater risk of RP than irradiation of tumors located in other parts of the lungs.

Precise and real-time measurement of 3D tumor motion in lung due to breathing and heartbeat, measured during radiotherapy.

PURPOSE: In this work, three-dimensional (3D) motion of lung tumors during radiotherapy in real time was investigated. Understanding the behavior of tumor motion in lung tissue to model tumor movement is necessary for accurate (gated or breath-hold) radiotherapy or CT scanning. METHODS: Twenty patients were included in this study. Before treatment, a 2-mm gold marker was implanted in or near the tumor. A real-time tumor tracking system using two fluoroscopy image processor units was installed in the treatment room. The 3D position of the implanted gold marker was determined by using real-time pattern recognition and a calibrated projection geometry. The linear accelerator was triggered to irradiate the tumor only when the gold marker was located within a certain volume. The system provided the coordinates of the gold marker during beam-on and beam-off time in all directions simultaneously, at a sample rate of 30 images per second. The recorded tumor motion was analyzed in terms of the amplitude and curvature of the tumor motion in three directions, the differences in breathing level during treatment, hysteresis (the difference between the inhalation and exhalation trajectory of the tumor), and the amplitude of tumor motion induced by cardiac motion. RESULTS: The average amplitude of the tumor motion was greatest (12 +/- 2 mm [SD]) in the cranial-caudal direction for tumors situated in the lower lobes and not attached to rigid structures such as the chest wall or vertebrae. For the lateral and anterior-posterior directions, tumor motion was small both for upper- and lower-lobe tumors (2 +/- 1 mm). The time-averaged tumor position was closer to the exhale position, because the tumor spent more time in the exhalation than in the inhalation phase. The tumor motion was modeled as a sinusoidal movement with varying asymmetry. The tumor position in the exhale phase was more stable than the tumor position in the inhale phase during individual treatment fields. However, in many patients, shifts in the exhale tumor position were observed intra- and interfractionally. These shifts are the result of patient relaxation, gravity (posterior direction), setup errors, and/or patient movement.The 3D trajectory of the tumor showed hysteresis for 10 of the 21 tumors, which ranged from 1 to 5 mm. The extent of hysteresis and the amplitude of the tumor motion remained fairly constant during the entire treatment. Changes in shape of the trajectory of the tumor were observed between subsequent treatment days for only one patient. Fourier analysis revealed that for 7 of the 21 tumors, a measurable motion in the range 1-4 mm was caused by the cardiac beat. These tumors were located near the heart or attached to the aortic arch. The motion due to the heartbeat was greatest in the lateral direction. Tumor motion due to hysteresis and heartbeat can lower treatment efficiency in real-time tumor tracking-gated treatments or lead to a geographic miss in conventional or active breathing controlled treatments. CONCLUSION: The real-time tumor tracking system measured the tumor position in all three directions simultaneously, at a sampling rate that enabled detection of tumor motion due to heartbeat as well as hysteresis. Tumor motion and hysteresis could be modeled with an asymmetric function with varying asymmetry. Tumor motion due to breathing was greatest in the cranial-caudal direction for lower-lobe unfixed tumors.