AAPM Task Group Report 267: A joint AAPM GEC-ESTRO report on biophysical models and tools for the planning and evaluation of brachytherapy.

Brachytherapy utilizes a multitude of radioactive sources and treatment techniques that often exhibit widely different spatial and temporal dose delivery patterns. Biophysical models, capable of modeling the key interacting effects of dose delivery patterns with the underlying cellular processes of the irradiated tissues, can be a potentially useful tool for elucidating the radiobiological effects of complex brachytherapy dose delivery patterns and for comparing their relative clinical effectiveness. While the biophysical models have been used largely in research settings by experts, it has also been used increasingly by clinical medical physicists over the last two decades. A good understanding of the potentials and limitations of the biophysical models and their intended use is critically important in the widespread use of these models. To facilitate meaningful and consistent use of biophysical models in brachytherapy, Task Group 267 (TG-267) was formed jointly with the American Association of Physics in Medicine (AAPM) and The Groupe Européen de Curiethérapie and the European Society for Radiotherapy & Oncology (GEC-ESTRO) to review the existing biophysical models, model parameters, and their use in selected brachytherapy modalities and to develop practice guidelines for clinical medical physicists regarding the selection, use, and interpretation of biophysical models. The report provides an overview of the clinical background and the rationale for the development of biophysical models in radiation oncology and, particularly, in brachytherapy; a summary of the results of literature review of the existing biophysical models that have been used in brachytherapy; a focused discussion of the applications of relevant biophysical models for five selected brachytherapy modalities; and the task group recommendations on the use, reporting, and implementation of biophysical models for brachytherapy treatment planning and evaluation. The report concludes with discussions on the challenges and opportunities in using biophysical models for brachytherapy and with an outlook for future developments.

Survival prediction in patients with gynecological cancer irradiated for brain metastases.

BACKGROUND AND PURPOSE: This large population-based, retrospective, single-center study aimed to identify prognostic factors in patients with brain metastases (BM) from gynecological cancers. MATERIAL AND METHODS: One hundred and forty four patients with BM from gynecological cancer treated with radiotherapy (RT) were identified. Primary cancer diagnosis, age, performance status, number of BM, presence of extracranial disease, and type of BM treatment were assessed. Overall survival (OS) was calculated using the Kaplan-Meier method and the Cox proportional hazards regression model was used for multivariable analysis. A prognostic index (PI) was developed based on scores from independent predictors of OS. RESULTS: Median OS for the entire study population was 6.2 months. Forty per cent of patients died within 3 months after start of RT. Primary cancer with the origin in cervix or vulva (p = 0.001),  Eastern Cooperative Oncology Group (ECOG) 3-4 (p < 0.001), and the presence of extracranial disease (p = 0.001) were associated with significantly shorter OS. The developed PI based on these factors, categorized patients into three risk groups with a median OS of 13.5, 4.0, and 2.4 months for the good, intermediate, and poor prognosis group, respectively. INTERPRETATION: Patients with BM from gynecological cancers carry a poor prognosis. We identified prognostic factors and developed a scoring tool to select patients with better or worse prognosis. Patients in the high-risk group have a particular poor prognosis, and omission of RT could be considered.

Chronic fatigue in long-term survivors of head and neck cancer treated with radiotherapy.

BACKGROUND: There is lack of evidence on chronic fatigue (CF) following radiotherapy (RT) in survivors of head and neck cancer (HNC). We aimed to compare CF in HNC survivors > 5 years post-RT with a reference population and investigate factors associated with CF and the possible impact of CF on health-related quality of life (HRQoL). MATERIAL AND METHODS: In this cross-sectional study we included HNC survivors treated in 2007-2013. Participants filled in patient-reported outcome measures and attended a one-day examination. CF was measured with the Fatigue Questionnaire and compared with a matched reference population using t-tests and Cohen's effect size. Associations between CF, clinical and RT-related factors were investigated using logistic regression. HRQoL was measured with the EORTC Quality of Life core questionnaire. RESULTS: The median age of the 227 HNC survivors was 65 years and median time to follow-up was 8.5 years post-RT. CF was twice more prevalent in HNC survivors compared to a reference population. In multivariable analyses, female sex (OR 3.39, 95 % CI 1.82-6.31), comorbidity (OR 2.17, 95 % CI 1.20-3.94) and treatment with intensity-modulated RT (OR 2.13, 95 % CI 1.16-3.91) were associated with CF, while RT dose parameters were not. Survivors with CF compared to those without, had significantly worse HRQoL. CONCLUSIONS: CF in HNC survivors is particularly important for female patients, while specific factors associated with RT appear not to play a role. The high CF prevalence in long-term HNC survivors associated with impaired HRQoL is important information beneficial for clinicians and patients to improve patient follow-up.

Lung cancer reirradiation: Exploring modifications to utilization, treatment modalities and factors associated with outcomes.

BACKGROUND: Patients treated for lung cancer (LC) often experience locoregional failure after initial treatment. Due to technological advances, thoracic reirradiation (re-RT) has become a viable treatment option. We sought to investigate the use of thoracic re-RT in LC patients over a time period characterized by technological advances in a large, multi-center cohort. METHODS AND MATERIALS: LC patients treated with thoracic re-RT in two University Hospitals from 2010-2020 were identified. Clinical variables and RT data were extracted from the medical records and treatment planning systems. Overall survival (OS) was calculated from the last day of re-RT until death or last follow up. RESULTS: 296 patients (small cell LC n=30, non-small cell LC n=266) were included. Three-dimensional conformal radiation therapy was the RT technique used most frequently (63%), and 86% of all patients were referred for re-RT with palliative treatment intent. During the second half of the study period, the use of thoracic re-RT increased in general, more patients received curative re-RT, and there was an increased use of stereotactic body radiation therapy (SBRT). Median time between initial RT and re-RT was 18 months (range 1-213 months). Only 83/296 patients had combined treatment plans that allowed for registration of combined doses to organs at risk (OAR). Most of the combined doses to OAR were below recommendations from guidelines. Multivariate analysis showed superior OS (p<0.05) in patients treated with curative intent, SBRT or intensity modulated radiation therapy or had excellent performance status prior to re-RT. CONCLUSIONS: The use of re-RT increased in the second half of the study period, although 2020 did not follow the trend. The use of SBRT and IMRT became more frequent over the years, yet the majority received palliative re-RT. Combined dose plans were only created for one third of the patients.

MRI-guided dynamic risk assessment in cervical cancer based on tumor hypoxia at diagnosis and volume response at brachytherapy.

BACKGROUND AND PURPOSE: Improvements in treatment outcome for patients with locally advanced cervical cancer (LACC) require a better classification of patients according to their risk of recurrence. We investigated whether an imaging-based approach, combining pretreatment hypoxia and tumor response during therapy, could improve risk classification. MATERIAL AND METHODS: Ninety-three LACC patients with T2-weigthed (T2W)-, dynamic contrast enhanced (DCE)- and diffusion weighted (DW)-magnetic resonance (MR) images acquired before treatment, and T2W- and, for 64 patients, DW-MR images, acquired at brachytherapy, were collected. Pretreatment hypoxic fraction (HFpre) was determined from DCE- and DW-MR images using the consumption and supply-based hypoxia (CSH)-imaging method. Volume regression at brachytherapy was assessed from T2W-MR images and combined with HFpre. In 17 patients with adequate DW-MR images at brachytherapy, the apparent diffusion coefficient (ADC), reflecting tumor cell density, was calculated. Change in ADC during therapy was combined with volume regression yielding functional regression as explorative response measure. Endpoint was disease free survival (DFS). RESULTS: HFpre was the strongest predictor of DFS, but a significant correlation with outcome was found also for volume regression. The combination of HFpre and volume regression showed a stronger association with DFS than HFpre alone. Patients with disease recurrence were selected to either the intermediate- or high-risk group with a 100 % accuracy. Functional regression showed a stronger correlation to HFpre than volume regression. CONCLUSION: The combination of pretreatment hypoxia and volume regression at brachytherapy improved patient risk classification. Integration of ADC with volume regression showed promise as a new tumor response parameter.

Radiation-induced long-term dysphagia in survivors of head and neck cancer and association with dose-volume parameters.

BACKGROUND: Although dysphagia is a common side effect after radiotherapy (RT) of head and neck cancer (HNC), data on long-term dysphagia is scarce. We aimed to 1) compare radiation dose parameters in HNC survivors with and without dysphagia, 2) investigate factors associated with long-term dysphagia and its possible impact on health-related quality of life (HRQoL), and 3) investigate how our data agree with existing NTCP models. METHODS: This cross-sectional study conducted in 2018-2020, included HNC survivors treated in 2007-2013. Participants attended a one-day examination in hospital and filled in patient questionnaires. Dysphagia was measured with the EORTC QLQ-H&N35 swallowing scale. Toxicity was scored with CTCAE v.4. We contoured swallowing organs at risk (SWOAR) on RT plans, calculated dose-volume histograms (DVHs), performed logistic regression analyses and tested our data in established NTCP models. RESULTS: Of the 239 participants, 75 (31%) reported dysphagia. Compared to survivors without dysphagia, this group had reduced HRQoL and the DVHs for infrahyoid SWOAR were significantly shifted to the right. Long-term dysphagia was associated with age (OR 1.07, 95% CI 1.03-1.10), female sex (OR 2.75, 95% CI 1.45-5.21), and mean dose to middle pharyngeal constrictor muscle (MD-MPCM) (OR 1.06, 95% CI 1.03-1.09). NTCP models overall underestimated the risk of long-term dysphagia. CONCLUSIONS: Long-term dysphagia was associated with higher age, being female, and high MD-MPCM. Doses to distally located SWOAR seemed to be risk factors. Existing NTCP models do not sufficiently predict long-term dysphagia. Further efforts are needed to reduce the prevalence and consequences of this late effect.

Investigating survival, quality of life and cognition in PROton versus photon therapy for IDH-mutated diffuse grade 2 and 3 GLIOmas (PRO-GLIO): a randomised controlled trial in Norway and Sweden.

INTRODUCTION: The use of proton therapy increases globally despite a lack of randomised controlled trials demonstrating its efficacy and safety. Proton therapy enables sparing of non-neoplastic tissue from radiation. This is principally beneficial and holds promise of reduced long-term side effects. However, the sparing of seemingly non-cancerous tissue is not necessarily positive for isocitrate dehydrogenase (IDH)-mutated diffuse gliomas grade 2-3, which have a diffuse growth pattern. With their relatively good prognosis, yet incurable nature, therapy needs to be delicately balanced to achieve a maximal survival benefit combined with an optimised quality of life. METHODS AND ANALYSIS: PRO-GLIO (PROton versus photon therapy in IDH-mutated diffuse grade 2 and 3 GLIOmas) is an open-label, multicentre, randomised phase III non-inferiority study. 224 patients aged 18-65 years with IDH-mutated diffuse gliomas grade 2-3 from Norway and Sweden will be randomised 1:1 to radiotherapy delivered with protons (experimental arm) or photons (standard arm). First intervention-free survival at 2 years is the primary endpoint. Key secondary endpoints are fatigue and cognitive impairment, both at 2 years. Additional secondary outcomes include several survival measures, health-related quality of life parameters and health economy endpoints. ETHICS AND DISSEMINATION: To implement proton therapy as part of standard of care for patients with IDH-mutated diffuse gliomas grade 2-3, it should be deemed safe. With its randomised controlled design testing proton versus photon therapy, PRO-GLIO will provide important information for this patient population concerning safety, cognition, fatigue and other quality of life parameters. As proton therapy is considerably more costly than its photon counterpart, cost-effectiveness will also be evaluated. PRO-GLIO is approved by ethical committees in Norway (Regional Committee for Medical & Health Research Ethics) and Sweden (The Swedish Ethical Review Authority) and patient inclusion has commenced. Trial results will be published in international peer-reviewed journals, relevant conferences, national and international meetings and expert forums. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT05190172).

Surface-guided positioning eliminates the need for skin markers in radiotherapy of right sided breast cancer: A single center randomized crossover trial.

BACKGROUND AND PURPOSE: To prospectively investigate whether surface guided setup of right sided breast cancer patients can increase efficiency and accuracy compared to traditional skin marker/tattoo based setup. MATERIAL AND METHODS: Twenty-five patients were included in this study. Each patient was positioned using skin marks and tattoos (procedure A) for half of the fractions and surface guidance using AlignRT (procedure B) for the other half of the fractions. The order of the two procedures was randomized. Pretreatment CBCT was acquired at every fraction for both setup procedures. A total of ten time points were recorded during every treatment session. Applied couch shifts after CBCT match were recorded and used for potential error calculations if no CBCT had been used. RESULTS: In the vertical direction procedure B showed significant smaller population based systematic (Æ©) and random (σ) errors. However, a significant larger systematic error on the individual patient level (M) was also shown. This was found to be due to patient relaxation between setup and CBCT matching. Procedure B also showed a significant smaller random error in the lateral direction, while no significant differences were seen in the longitudinal direction. No significant difference in setup time was found between the two procedures. CONCLUSION: Setup of right sided breast cancer patients using surface guidance yields higher accuracy than setup using skin marks/tattoos and lasers with the same setup time. Patient alignment for this patient group can safely be done without the use of permanent tattoos and skin marks when utilizing surface-guided patient positioning. However, CBCT should still be used as final setup verification.

A Prospective Study of High Dose-Rate Brachytherapy or Stereotactic Body Radiotherapy of Intra-Prostatic Recurrence: Toxicity and Long Term Clinical Outcome.

Background: Up to half of patients with localized prostate cancer experience biochemical relapse within 10 years after definitive radiotherapy. The aim of this prospective study was to investigate the toxicity, dose to the organs at risk (OARs), and efficacy of dose-intensified focal salvage radiotherapy. Methods and Material: Thirty-three patients (median age 68.8 years) with histologically confirmed relapse after primary definitive radiotherapy were enrolled between 2012 and 2019. No patients had metastases at imaging or in bone marrow aspiration. Twenty-three patients were treated with high dose-rate brachytherapy to the recurrent tumor, defined at multiparametric MRI, with 3 fractions of 10 Gy with two weeks interval, and 10 patients by stereotactic body radiotherapy with 35 Gy to the local recurrence and 25 Gy to the whole prostate in 5 fractions. We used the RTOG-scoring system to grade genitourinary (GU) and gastrointestinal toxicity (GI) at three months (acute), and at 12, 24, and 36 months (late). Dose-volume histogram parameters to the local recurrence and the OARs were obtained and 2 Gy equivalent (EQD2) total dose was calculated using the linear-quadratic model with α/ß = 3 Gy. Efficacy was assessed by the progression-free interval and overall survival. Results: Median follow-up time was 81 months (range 21-115). The cumulative moderate to severe GI and GU toxicities were 3.0% (1/33) and 15.2% (5/33). Six patients had grade 1 acute GI toxicity, none had grade 2 or 3. One patient had grade 3 acute GU toxicity, two had grade 2, and fourteen had grade 1. One patient had late GI toxicity grade 2 and eight had grade 1. Four patients had late GU toxicity grade 2 and eight had grade 1. No patients had grade 3 late toxicity. The mean total D90 to the recurrent tumor was 77.7 ± 17.0 Gy. The mean total rectum D2cc was 17.0 ± 7.9 Gy and the mean total urethra D0.1cc was 29.1 ± 8.2 Gy. Twenty-eight patients had re-irradiation without androgen deprivation therapy (ADT). Nine of these are still relapse-free and 10 had a recurrence-free interval longer than 2 years. Conclusion: The toxicity of salvage radiotherapy was mild to moderate. One-third of the patients achieved long-term stable disease without ADT and one-third had a recurrence-free interval longer than 2 years. Some patients progressed rapidly and probably did not benefit from re-irradiation.

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

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

Overall survival after initial radiotherapy for brain metastases; a population based study of 2140 patients with non-small cell lung cancer.

BACKGROUND: Brain metastases (BM) occur in about 30% of all patients with non-small cell lung cancer (NSCLC). BM treatment guidelines recommend more frequent use of stereotactic radiotherapy (SRT). Overall, studies report no difference in overall survival (OS) comparing SRT to whole-brain radiotherapy (WBRT). We examined survival after radiotherapy for BM in a population-based sample from the South-Eastern Norway Regional Health Authority treated 2006-2018. METHODS: We reviewed electronic medical records of 2140 NSCLC patients treated with SRT or WBRT for BM from 2006-2018. Overall survival (OS) was compared to predicted survival according to the prognostic systems DS-GPA and Lung-molGPA. RESULTS: Use of SRT increased during the period, from 19% (2006-2014) to 45% (2015-2018). Median OS for all patients was 3.0 months, increasing from 2.0 (2006) to 4.0 (2018). Median OS after SRT was 7.0 months (n = 435) and 3.0 months after WBRT (n = 1705). Twenty-seven percent of SRT patients and 50% of WBRT patients died within 90 days after start of RT. Age ≥70, male sex, KPS ≤70, non-adenocarcinoma histology, ECM present, multiple BM, and WBRT were associated with shorter survival (p < .001). Actual mOS corresponded best with predicted mOS by DS-GPA and Lung-molGPA for the SRT group. CONCLUSION: Overall survival after radiotherapy (RT) for BM improved during the study period, but only for patients treated with SRT. Survival after WBRT remains poor; its use should be questioned. DS-GPA and Lung-molGPA seem most useful in predicting prognosis considered for SRT.

A Nordic-Baltic perspective on indications for proton therapy with strategies for identification of proper patients.

The beneficial effects of protons are primarily based on reduction of low to intermediate radiation dose bath to normal tissue surrounding the radiotherapy target volume. Despite promise for reduced long-term toxicity, the percentage of cancer patients treated with proton therapy remains low. This is probably caused by technical improvements in planning and delivery of photon therapy, and by high cost, low availability and lack of high-level evidence on proton therapy. A number of proton treatment facilities are under construction or have recently opened; there are now two operational Scandinavian proton centres and two more are under construction, thereby eliminating the availability hurdle. Even with the advantageous physical properties of protons, there is still substantial ambiguity and no established criteria related to which patients should receive proton therapy. This topic was discussed in a session at the Nordic Collaborative Workshop on Particle Therapy, held in Uppsala 14-15 November 2019. This paper resumes the Nordic-Baltic perspective on proton therapy indications and discusses strategies to identify patients for proton therapy. As for indications, neoplastic entities, target volume localisation, size, internal motion, age, second cancer predisposition, dose escalation and treatment plan comparison based on the as low as reasonably achievable (ALARA) principle or normal tissue complication probability (NTCP) models were discussed. Importantly, the patient selection process should be integrated into the radiotherapy community and emphasis on collaboration across medical specialties, involvement of key decision makers and knowledge dissemination in general are important factors. An active Nordic-Baltic proton therapy organisation would also serve this purpose.

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.

GEC-ESTRO/ACROP recommendations for quality assurance of ultrasound imaging in brachytherapy.

Ultrasound (US) is an important imaging modality in brachytherapy (BT). In particular for low-dose-rate (LDR) and high-dose-rate (HDR) prostate implants transrectal ultrasound (TRUS) is widespread. Besides the common use of US for prostate implants, US can also be applied in gynecological and anal cancer therapies as examples amongst others. The BRAPHYQS (BRAchytherapy PHYsics Quality assurance System) and UroGEC (urology) working groups of GEC-ESTRO (GEC: Groupe Européen de Curiethérapie, committee of ESTRO: European SocieTy for Radiotherapy & Oncology) elaborated upon guidelines describing quality assurance (QA) methods for US in BT. The total quality management (QM) for the unit includes acceptance testing, commissioning and periodic image testing. In 2008, the AAPM (American Association of Physicists in Medicine) published the TG (Task group) 128 report. Whereas the TG 128 focuses on US systems and prostate BT, the current recommendations also cover tests for stepping devices and include other interstitial or intracavitary treatment sites in BT, such as anal implants and gynecological BT. The recommendations presented herein do not replace regular maintenance for the US devices performed by the vendor. They are the QA of US in BT but are not sufficient for the whole maintenance of medical US devices. Moreover, national regulations and recommendations should also be followed. For the tests presented in this report tolerances or action limits are given. These recommendations explain practical test procedures of US devices in BT. They will help the clinics to perform a high level of quality in the use of US for BT in Europe.

Dose deviations induced by respiratory motion for radiotherapy of lung tumors: Impact of CT reconstruction, plan complexity, and fraction size.

A thorax phantom was used to assess radiotherapy dose deviations induced by respiratory motion of the target volume. Both intensity modulated and static, non-modulated treatment plans were planned on CT scans of the phantom. The plans were optimized using various CT reconstructions, to investigate whether they had an impact on robustness to target motion during delivery. During irradiation, the target was programmed to simulate respiration-induced motion of a lung tumor, using both patient-specific and sinusoidal motion patterns in three dimensions. Dose was measured in the center of the target using an ion chamber. Differences between reference measurements with a stationary target and dynamic measurements were assessed. Possible correlations between plan complexity metrics and measured dose deviations were investigated. The maximum observed motion-induced dose differences were 7.8% and 4.5% for single 2 Gy and 15 Gy fractions, respectively. The measurements performed with the largest target motion amplitude in the superior-inferior direction yielded the largest dosimetric deviations. For 2 Gy fractionation schemes, the summed dose deviation after 33 fractions is likely to be less than 2%. Measured motion-induced dose deviations were significantly larger for one CT reconstruction compared to all the others. Static, non-modulated plans showed superior robustness to target motion during delivery. Moderate correlations between the modulation complexity score applied to VMAT (MCSv) and measured dose deviations were found for 15 Gy SBRT treatment plans. Correlations between other plan complexity metrics and measured dose deviations were not found.

Ring Versus Ovoids and Intracavitary Versus Intracavitary-Interstitial Applicators in Cervical Cancer Brachytherapy: Results From the EMBRACE I Study.

PURPOSE: The aim of this study was to investigate the influence of brachytherapy technique and applicator type on target dose, isodose surface volumes, and organ-at-risk (OAR) dose. METHODS AND MATERIALS: Nine hundred two patients treated with tandem/ovoids (T&O) (n = 299) and tandem/ring (T&R) (n = 603) applicators from 16 EMBRACE centers were analyzed. Patients received external beam radiation therapy and magnetic resonance imaging guided brachytherapy with dose prescription according to departmental practice. Centers were divided into 4 groups, according to applicator/technique: Ovoids and ring centers treating mainly with the intracavitary (IC) technique and ovoids and ring centers treating routinely with the intracavitary/interstitial (IC/IS) technique. V85Gy EQD210, CTVHR D90% (EQD210), and bladder, rectum, sigmoid, and vaginal 5-mm lateral-point doses (EQD23) were evaluated among center groups. Differences between T&O and T&R were tested with multivariable analysis. RESULTS: For similar point A doses, mean CTVHR D90% was 3.3 Gy higher and V85Gy was 23% lower for ring-IC compared with ovoids-IC centers (at median target volumes). Mean bladder/rectum doses (D2cm3 and ICRU-point) were 3.2 to 7.7 Gy smaller and vaginal 5-mm lateral-point was 19.6 Gy higher for ring-IC centers. Routine use of IC/IS technique resulted in increased target dose, whereas V85Gy was stable (T&R) or decreased (T&O); reduced bladder and rectum D2cm3 and bladder ICRU-point by 3.5 to 5.0 Gy for ovoids centers; and similar OAR doses for ring centers. CTVHR D90% was 2.8 Gy higher, bladder D2cm3 4.3 Gy lower, rectovaginal ICRU-point 4.8 Gy lower, and vagina 5-mm lateral-point 22.4 Gy higher for ring-IC/IS versus ovoids-IC/IS centers. The P values were <.002 for all comparisons. Equivalently, significant differences were derived from the multivariable analysis. CONCLUSIONS: T&R-IC applicators have better target dose and dose conformity than T&O-IC in this representative patient cohort. IC applicators fail to cover large target volumes, whereas routine application of IC/IS improves target and OAR dose considerably. Patients treated with T&R show a more favorable therapeutic ratio when evaluating target, bladder/rectum doses, and V85Gy. A comprehensive view on technique/applicators should furthermore include practical considerations and clinical outcome.

Dose planning variations related to delineation variations in MRI-guided brachytherapy for locally advanced cervical cancer.

PURPOSE: To examine the variability in prescribed dose due to contouring variations in intracavitary image-guided adaptive brachytherapy for cervical cancer. To identify correlations between dosimetric outcomes and delineation uncertainty metrics. METHODS AND MATERIALS: A data set from an EMBRACE sub-study on contouring uncertainties was used, consisting of magnetic resonance images of six patients with cervical cancer delineated by 10 experienced observers (target volumes and organs at risk). Two gold standard contours were generated, an expert consensus and the simultaneous truth and performance level estimation. Plans were individually optimised to all of the contour sets (12 in total). Plans were applied to the gold standard contour sets, and dose volume histogram parameters including D90, D98 and D2cm3 were determined. The variability between plans was assessed. Dose volume histogram parameters and delineation uncertainty metrics were correlated using the Spearman's non-parametric rank correlation. RESULTS: There is a dosimetric variability between observers, patients and the gold standard contour used for analysis. Approximately 3 Gy D90 EQD210 variability (SD) was observed for the CTVHR and 1.2-3.6 Gy D2cm3 EQD23 for the organs at risk. The maximum geometric dimensions of the delineations are most commonly correlated with dosimetry changes. Although the correlations are similar across gold standards, the direction of these correlations differs, indicating that the dosimetric outcomes are dependent on the contour that the plan is optimised to. CONCLUSION: This study highlights the dosimetric differences interobserver uncertainty in contouring can have for cervical cancer brachytherapy. The importance of carefully choosing a gold standard from which to benchmark is reiterated.

Image registration, contour propagation and dose accumulation of external beam and brachytherapy in gynecological radiotherapy.

This review provides an overview of the current status of image registration for image guided gynaecological brachytherapy including combination with external beam radiotherapy. Contour propagation between individual fractions and dose accumulation can be useful for cervix cancer radiotherapy. Contour mapping and applicator reconstruction with rigid registration based on the applicator geometry provide good accuracy. However, deformable image registration is particularly challenging in the pelvic region, due to the large and complex deformations caused by tumor shrinkage, bladder and rectum filling, insertion of a brachytherapy applicator and presence of packing material. This causes substantial limitations and uncertainties when using it in the clinical workflow so that the current generation of deformable image registration algorithms is not yet robust enough to handle complexities involving the dose accumulation of external beam and brachytherapy. The direct addition of doses provides a reasonable estimate of the total absorbed dose. However, in case of significant dose gradients from external beam boosts or midline-shielding adding dose contributions from the different radiotherapy modalities and fractions remains subject to large uncertainties.

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.

Intrafractional motion in stereotactic body radiotherapy of spinal metastases utilizing cone beam computed tomography image guidance.

BACKGROUND AND PURPOSE: Spine stereotactic body radiotherapy (SBRT) requires a high degree of accuracy due to steep dose gradients close to the spinal cord. This study aimed to (1) evaluate intrafractional motion in spine SBRT utilizing flattening filter free (FFF) beam delivery and cone beam computed tomography (CBCT) image guidance and (2) evaluate if adding another CBCT acquisition and corrections prior to treatment improves the overall position accuracy. MATERIALS AND METHODS: Intrafractional motion was retrospectively analyzed for 78 fractions in 54 patients. All patients were immobilized with an evacuated cushion. Before treatment, a CBCT was acquired, a bony fusion with the planning CT was performed and translational and rotational errors were corrected. For 30 of the patients (39 fractions) acquisition of another CBCT and corrections were performed before treatment. A post treatment CBCT was acquired for all patients, and translational and rotational errors measured by fusion of the post treatment CBCT with the planning CT were recorded to calculate means and standard deviations (SDs). RESULTS: The positional errors were significantly smaller in 4 out of 6 error values in the patient group treated with verification CBCT. In this group, translational and rotational SDs ranged from 0.5 to 0.6 mm and 0.3°, respectively. Corresponding values in the group treated without verification CBCT were 0.7-1.0 mm and 0.4-0.7°. CONCLUSION: With proper CBCT image guidance, patient immobilization and FFF-beam delivery, one can obtain very high patient position accuracy in spine SBRT. Inclusion of a verification CBCT prior to treatment increases the overall position accuracy.