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.

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.

Density calibrated cone beam CT as a tool for adaptive radiotherapy.

BACKGROUND: Visual inspections of anatomical changes observed on daily cone-beam CT (CBCT) images are often used as triggers for radiotherapy plan adaptation to avoid unacceptable dose levels to the target or OARs. Direct CBCT dose calculations would improve the ability to adapt only those plans where dosimetric changes are observed. This study investigates the accuracy of dose calculations on CBCTs. MATERIALS AND METHODS: Calibration curves were obtained for CBCT imagers at nine identical accelerators. CBCT scans of a phantom with different density inserts were recorded for two scan modes (Head-Neck and Pelvis) and mean calibration curves were calculated. Subsequently, CBCT scans of the phantom with six different density inserts were recorded, the dose distributions on the CBCTs were calculated and compared to dose on the planning CT (pCT). The uncertainty was quantified by the dosimetric difference between the pCT and the CBCT. The two mean calibration curves were used to calculate the daily delivered CBCT dose for ten Head-Neck-, eleven Lung-, and ten pelvic patients. Additional patient calculations were performed using low-HU empirically corrected calibration curves. Patient doses were compared on target coverage and mean dose, and D1cc for OARs. RESULTS: The dose differences between pCT and CBCT for phantom data were small for all DVH parameters, with mean deviations below ±0.6% for both CBCT modes. For patient data, it was found that low-HU corrected calibration curves performed the best. The mean deviations for the mean dose and coverage of the target were 0.2%±0.7% and 0.1%±0.6%, across all patient groups. CONCLUSION: Dose calculation on CBCT images results in target coverage and mean dose with an accuracy of the order of 1%, which makes this acceptable for clinical use. The CBCT mode specific calibration curves can be used at all identical imaging devices and for all patient groups.

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.

Robustness of elective lymph node target coverage with shrinking Planning Target Volume margins in external beam radiotherapy of locally advanced cervical cancer.

BACKGROUND AND PURPOSE: Image-Guidance decreases set-up uncertainties, which may allow for Planning Target Volume (PTV) margins reduction. This study evaluates the robustness of the elective lymph node target coverage to translational and rotational set-up errors in combination with shrinking PTV margins and determines the gain for the Organs At Risk (OARs). MATERIAL AND METHODS: Ten cervix cancer patients who underwent external beam radiotherapy with 45 Gy/25Fx were analysed. Daily Image-Guidance was based on bony registration of Cone Beam CT (CBCT) to planning CT (pCT) and daily couch correction (translation and yaw). On each pCT, four Volumetric Modulated Arc Therapy dose-plans were generated with PTV margins of 0, 3, 5 and 8 mm. The elective clinical target volume (CTV-E) was propagated from daily CBCTs to the pCT to evaluate daily CTV-E dose. Additional systematic translational isocenter shifts of 2 mm were simulated. D98% (dose received by 98% of the volume of interest) and D99.9% were extracted from each CTV-E for all dose-plans and scenarios. Total dose was accumulated by Dose-Volume Histogram addition. The dosimetric impact of PTV margin reduction on the OARs was evaluated through V30Gy (volume included within the 30 Gy isodose), V40Gy and body V43Gy. RESULTS: When decreasing the PTV margin from 5 to 0 mm, bowel V30Gy was decreased by 13% (from 247 cm3 to 214 cm3), body V43Gy by 19% (from 1462 cm3 to 1188 cm3) and PTV by 39% (from 1416 to 870 cm3). The dosimetric impact of combined systematic shifts and residual rotations on the elective target with a 0 mm PTV margin was a decrease of D98% (mean ±â€¯SD) from 44.1 Gy ±â€¯0.4 Gy to 43.7 Gy ±â€¯0.8 Gy and a minimum of 42.4 Gy. CONCLUSION: PTV margin reduction from 5 to 0 mm induced significant OARs dosimetric gains while elective target coverage remained robust to positioning uncertainties.

Cone beam computed tomography-based monitoring and management of target and organ motion during external beam radiotherapy in cervical cancer.

BACKGROUND AND PURPOSE: Organ motion is a challenge during high-precision external beam radiotherapy in cervical cancer, and improved strategies for treatment adaptation and monitoring of target dose coverage are needed. This study evaluates a cone beam computed tomography (CBCT)-based approach. MATERIALS AND METHODS: In twenty-three patients, individualized internal target volumes (ITVs) were generated from pre-treatment MRI and CT scans with full and empty bladders. The target volumes encompassed high-risk clinical target volume (CTV-T HR) (gross tumor volume + remaining cervix) and low risk (LR) CTV-T (CTV-T HR + uterus + parametriae + upper vagina). Volumetric Modulated Arc Therapy (VMAT) was used to deliver a dose of 45 Gy in 25 fractions. CBCTs were used for setup and for radiation therapists (RTTs) to evaluate the target coverage (inside/outside the planning target volume). CBCTs were reviewed offline. Estimates of the dose delivered with minimum (point) doses across all fractions to CTV-T HR (aim 42.75 Gy) and CTV-T LR (aim 40 Gy) were assessed. In patients with insufficient dose coverage, re-plans were generated based on previous imaging. RESULTS: Median (range) of the ITV-margins (mean of anterior-posterior margins) related to uterus and cervix was 1.2 (0.5-2.2 and 1.0-2.1) cm. RTTs were able to assess the target coverage in 90% of all CBCTs (505/563). With re-planning, one patient had considerable benefit (12.7 Gy increase of minimum dose) to CTV-T LR_vagina, four patients had improved dose to the CTV-T LR_uterus (1.2-1.8 Gy), and 3 patients did not benefit from re-planning. CONCLUSIONS: Daily CBCT-based monitoring of target coverage by the RTTs has proven safe with limited workload. It allows for reduction in the treated volumes without compromising the target dose coverage.

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.

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.

Clinical implementation of coverage probability planning for nodal boosting in locally advanced cervical cancer.

PURPOSE: To implement coverage probability (CovP) for dose planning of simultaneous integrated boost (SIB) of pathologic lymph nodes in locally advanced cervical cancer (LACC). MATERIAL AND METHODS: CovP constraints for SIB of the pathological nodal target (PTV-N) with a central dose peak and a relaxed coverage at the perimeter were generated for use with the treatment planning system Eclipse: PTV-N D98 >90%, CTV-N D98 >100% and CTV-N D50 >101.5% of prescribed dose. Dose of EBRT was 45Gy/25 fx with a SIB of 55-57.5Gy depending on expected dose from brachytherapy (BT). Twenty-five previously treated patients with 47 boosted nodes were analysed. Nodes were contoured on cone beam CT (CBCT) and the accumulated dose in GTV-NCBCT and volume of body, pelvic bones and bowel receiving >50Gy (V50) were determined. RESULTS: Nearly all nodes (89%) were visible on CBCT and showed considerable concentric regression during EBRT. Total EBRT and BT D98 was >57 GyEQD2 in 98% of the visible nodes. Compared to treatment plans aiming for full PTV-N coverage, CovP significantly reduced V50 of body, bones and bowel (p<0.001) CONCLUSION: CovP is clinically feasible for SIB of pathological nodes and significantly decreases collateral SIB dose to nearby OAR.

Proof of principle: Applicator-guided stereotactic IMRT boost in combination with 3D MRI-based brachytherapy in locally advanced cervical cancer.

PURPOSE: To describe a new technique involving high-precision stereotactic intensity-modulated radiation therapy (IMRT) boost in combination with intracavitary-interstitial (IC-IS) brachytherapy (BT) in cervical tumors that cannot be sufficiently covered by IC-IS-BT due to extensive residual disease and/or difficult topography at the time of BT. METHODS AND MATERIALS: Three patients with stage IIIB-IVA cervical cancer had significant residual disease at the time of BT. MRI-guided IC-IS-BT (pulsed-dose rate) was combined with a stereotactic IMRT boost guided according to the BT applicator in situ, using cone beam CT. The planning aim dose (total external beam radiotherapy and BT) for the high-risk clinical target volume (HR-CTV) was D90 >70-85 Gy, whereas constraints for organs at risk were D2cm3 <70 Gy for rectum, sigmoid, and bowel and <90 Gy for bladder in terms of equivalent total dose in 2 Gy fractions. An IMRT boost adapted to the BT dose distribution was optimized to target the regions poorly covered by BT. RESULTS: HR-CTV doses of D90 >81 Gy were obtained in the central HR-CTV and D90 >69 Gy in the distal regions of HR-CTV. Image-guided set up of the IMRT boost with the applicator in situ was feasible. The dose plans were robust to intra-fraction uncertainties of 3 mm. Local control with acceptable morbidity was obtained at a followup of 3, 2.5, and 1 year, respectively. CONCLUSIONS: The combination of MRI-guided BT with an applicator-guided stereotactic IMRT boost is feasible. This technique seems to be useful in the few cases where HR-CTV coverage cannot be obtained even with IS-IC-BT.

Parametrial boost using midline shielding results in an unpredictable dose to tumor and organs at risk in combined external beam radiotherapy and brachytherapy for locally advanced cervical cancer.

PURPOSE: Midline-blocked boost (MBB) fields are frequently used in the treatment of locally advanced cervical cancer. The purpose of this study was to evaluate the dose contribution from MBBs to tumor and organs at risk. METHODS AND MATERIALS: Six patients with locally advanced cervical cancer (IIB-IIIB) treated with definitive chemoradiotherapy and magnetic resonance imaging (MRI)-guided brachytherapy were analyzed. A three-phase plan was modeled: 45 Gy (1.8 Gy per fraction) four-field box, 9 Gy (1.8 Gy per fraction) MBB (midline-shielded anteroposterior/posteroanterior fields), and intracavitary MRI-guided brachytherapy boost of 28 Gy (7 Gy per fraction). Midline shields 3, 4, and 5 cm wide were simulated for each patient. Brachytherapy and MBB plans were volumetrically summed. The rectum, sigmoid, and bladder minimum dose in the most exposed 2 cm(3) of an organ at risk (D(2 cc)) and high-risk clinical target volume (HR-CTV) and intermediate-risk clinical target volume (IR-CTV) D90 and D100 were evaluated. The intended HR-CTV D90 was 85 Gy or greater, and the intended IR-CTV D90 was greater than 60 Gy. RESULTS: After a 4-cm MBB, HR-CTV D90 remained lower than 85 Gy in all cases (mean, 74 Gy; range, 64-82 Gy). High-risk clinical target volume (85 Gy) coverage increased slightly from 73% (range, 64-82%) to 78% (range, 69-88%). Mean IR-CTV D90 increased from 56 Gy (range, 53-64 Gy) to 62 Gy (range, 59-67 Gy). Intermediate-risk clinical target volume 60-Gy dose coverage increased from 81% (range, 72-96%) to 96% (range, 90-100%). The mean volume irradiated to 85 Gy increased by 14 cm(3) (range, 10-22 cm(3)), whereas the volume irradiated to 60 Gy increased from 276 cm(3) (range, 185-417 cm(3)) to 592 cm(3) (range, 385-807 cm(3)). Bladder, rectum, or sigmoid D(2 cc) increased by more than 50% of the boost dose in 4 of 6 patients. CONCLUSIONS: Midline-blocked boosts contribute substantial dose to rectum, sigmoid, and bladder D(2 cc). HR-CTV dose and 85-Gy coverage remain compromised in large tumors despite MBB. IR-CTV 60-Gy coverage improved at the expense of a considerable increase in volume of normal tissue irradiated to 60 Gy.

A dose planning study on applicator guided stereotactic IMRT boost in combination with 3D MRI based brachytherapy in locally advanced cervical cancer.

PURPOSE: Locally advanced cervical cancer is usually treated with external beam radiotherapy followed by brachytherapy (BT). However, if response or tumour topography is unfavourable it may be difficult to reach a sufficient BT dose. The purpose of this study was to explore whether an applicator guided stereotactic IMRT boost could be combined with brachytherapy to improve dose volume parameters. MATERIAL AND METHODS: Dose plans of 6 patients with HR CTV volumes of 31-100cc at the time of BT were analysed. MRI was performed with a combined intracavitary (IC)-interstitial (IS) ring applicator in situ. A radiotherapy schedule consisting of 45Gy (1.8Gy x 25) IMRT followed by boost of 28Gy (7Gy x 4fx) was modelled. Four different boost techniques were evaluated: IC-BT, IC/IS-BT, IC-BT+IMRT and IMRT. Dose plans were optimised for maximal tumour dose (D90) and coverage (V85Gy) while respecting DVH constraints in organs at risk: D2cc <75Gy in rectum and sigmoid and <90Gy in bladder (EQD2). In combined BT+IMRT dose plans, the IMRT plan was optimised on top of the BT dose distribution. Volumes irradiated to more than 60 Gy EQD2 (V60Gy) were evaluated. RESULTS: Median dose coverage in IC plans was 74% [66-93%]. By using IC/IS or IC-BT+IMRT boost, the median coverage was improved to 95% [78-99%], and to 96% [69-99%] respectively. For IMRT alone, a median coverage of 98% [90-100%] was achieved, but V60Gy volumes were significantly increased by a median factor of 2.0 [1.4-2.3] as compared to IC/IS. It depended on the individual tumour topography whether IC/IS-BT or IC-BT+IMRT boost was the most favourable technique. CONCLUSION: It is technically possible to create dose plans that combine image guided BT and IMRT. In this study the dose coverage could be significantly increased by adding IS-BT or IMRT boost to the intracavitary dose. Using IMRT alone for boost cannot be advocated since this results in a significant increase of the volume irradiated to 60Gy.