High-risk Clinical Target Volume Research Articles

Clinical outcomes using a 3D printed tandem-needle-template and the EMBRACE-II planning aims for image guided adaptive brachytherapy in locally advanced cervical cancer

Background Extensive local disease or narrow vagina may compromise brachytherapy (BT) in patients with cervical cancer. This is the first study to analyze long-term outcomes of using 3D printed vaginal tandem-needle templates (3DP TNT) for transvaginal insertion of needles in parallel (P) or parallel and oblique (P&O) direction to the tandem. Material and methods All patients treated with BT using 3DP TNT from 2015-2020 were included. Decision to use a 3DP TNT and preplanning were made after 4-5 weeks of external beam radiotherapy, based on gynecological examination and MRI with a tandem-ring applicator in situ. The TNT was 3D-printed in house consisting of a circular template with P&O holes for guidance of plastic needles and a shaft fitting the uterine tandem. Thus, the radioactive source was never in direct contact with the 3DP TNT. The TNT was 3D printed in a standard or personalized configuration. Planning aims were based on the Embrace II protocol. Results 101 patients (median age of 63 years) were included: 49 with P needles only and 52 with P&O needles. Personalized TNT was used in 19 patients in the P&O group. Performance status (WHO) was > 0 in 48%. FIGO2018 stage III-IV was present in 77%. T-score at diagnosis and BT was 9.1 and 6.3 respectively, with a significantly higher T-score in the P&O compared to P group. The mean high-risk CTV D90 was 93 Gy with no significant difference between the two groups. Three-year local control rates were 85%, 95%, 75% for the overall, P- and P&O group respectively and 68%, 80% and 56% for cancer specific survival. Grade ≥3 treatment related complications were observed in 10 (10%) patients. Conclusions 3DP TNT for BT in cervical cancer provides successful management of very extensive local disease and/or unfavorable anatomy with the possibility for treatment individualization.

Locoregional Treatment in Patients With Metastatic Cervical Cancer: Benefit of Dose Escalation Strategies

The objective of this work was to examine the benefit of an intensive locoregional treatment including an image guided adaptive brachytherapy (IGABT) among patients with cervical cancer and extrapelvic extension. Medical records of consecutive patients with a metastatic cervical cancer and receiving external beam radiation therapy and IGABT boost in Gustave Roussy Institute as part of their first line of treatment were examined. Depending on tumor sites, patients received pelvic ± para-aortic external beam radiation therapy. For those with visceral or supradiaphragmatic lymph node metastases, chemoradiation was delivered after usually 3 cycles of chemotherapy. All patients received a brachytherapy boost, guided by magnetic resonance imaging and aimed at increasing the dose to the high-risk clinical target volume (CTVHR). Local control (LC), patient overall survival (OS), progression-free survival, and radiation therapy-related side effects were examined, and prognostic factors were searched. One hundred sixty-four patients were included; 76.2% had para-aortic lymph node extension without distant metastasis (N2) and 23.8% had distant metastatic sites (M1). There was not a statistically significant difference in survival between both groups. With a median follow-up of 36 months, OS, progression-free survival, and LC at 3 years were 55.5% (95% CI, 48%-64%), 40.6% (95% CI, 38%-54%), and 90% (95% CI, 85%-96%), respectively. In multivariate analysis, a D90CTVHR dose ≥80 Gy was significant for better OS (hazard ratio, 0.96; 95% CI, 0.94-0.98; P < .001). Most toxicities were mild to moderate, with 2% grade 3 late urinary toxicity, 7% late grade 2 vaginal sequelae, and 1 grade 3 proctitis. During follow-up, rectovaginal fistula occurred in 2 patients without local relapse. IGABT permits dose escalation and high LC rates for patients with cervical cancer and extrapelvic extension. Dose/effect relationships for survival were shown. Because of high frequency of distant events, systemic intensification should be tested more specifically among these patients.

Attention-Gated Deep-Learning–Based Automatic Digitization of Interstitial Needles in High-Dose-Rate Brachytherapy for Cervical Cancer

Deep learning can be used to automatically digitize interstitial needles in high-dose-rate (HDR) brachytherapy for patients with cervical cancer. The aim of this study was to design a novel attention-gated deep-learning model, which may further improve the accuracy of and better differentiate needles. Seventeen patients with cervical cancer with 56 computed tomography-based interstitial HDR brachytherapy plans from the local hospital were retrospectively chosen with the local institutional review board's approval. Among them, 50 plans were randomly selected as the training set and the rest as the validation set. Spatial and channel attention gates (AGs) were added to 3-dimensional convolutional neural networks (CNNs) to highlight needle features and suppress irrelevant regions; this was supposed to facilitate convergence and improve accuracy of automatic needle digitization. Subsequently, the automatically digitized needles were exported to the Oncentra treatment planning system (Elekta Solutions AB, Stockholm, Sweden) for dose evaluation. The geometric and dosimetric accuracy of automatic needle digitization was compared among 3 methods: (1) clinically approved plans with manual needle digitization (ground truth); (2) the conventional deep-learning (CNN) method; and (3) the attention-added deep-learning (CNN+AG) method, in terms of the Dice similarity coefficient (DSC), tip and shaft positioning errors, dose distribution in the high-risk clinical target volume (HR-CTV), organs at risk, and so on. The attention-gated CNN model was superior to CNN without AGs, with a greater DSC (approximately 94% for CNN+AG vs 89% for CNN). The needle tip and shaft errors of the CNN+AG method (1.1 mm and 1.8 mm, respectively) were also much smaller than those of the CNN method (2.0 mm and 3.3 mm, respectively). Finally, the dose difference for the HR-CTV D90 using the CNN+AG method was much more accurate than that using CNN (0.4% and 1.7%, respectively). The attention-added deep-learning model was successfully implemented for automatic needle digitization in HDR brachytherapy, with clinically acceptable geometric and dosimetric accuracy. Compared with conventional deep-learning neural networks, attention-gated deep learning may have superior performance and great clinical potential.

CBCT-Based Dose Monitoring and Adaptive Planning Triggers in Head and Neck PBS Proton Therapy.

To investigate the feasibility of using cone-beam computed tomography (CBCT)-derived synthetic CTs to monitor the daily dose and trigger a plan review for adaptive proton therapy (APT) in head and neck cancer (HNC) patients. For 84 HNC patients treated with proton pencil-beam scanning (PBS), same-day CBCT and verification CT (vfCT) pairs were retrospectively collected. The ground truth CT (gtCT) was created by deforming the vfCT to the same-day CBCT, and it was then used as a dosimetric baseline and for establishing plan review trigger recommendations. Two different synthetic CT algorithms were tested; the corrected CBCT (corrCBCT) was created using an iterative image correction method and the virtual CT (virtCT) was created by deforming the planning CT to the CBCT, followed by a low-density masking process. Clinical treatment plans were recalculated on the image sets for evaluation. Plan review trigger criteria for adaptive therapy were established after closely reviewing the cohort data. Compared to the vfCT, the corrCBCT and virtCT reliably produced dosimetric data more similar to the gtCT. The average discrepancy in D99 for high-risk clinical target volumes (CTV) was 1.1%, 0.7%, and 0.4% and for standard-risk CTVs was 1.8%, 0.5%, and 0.5% for the vfCT, corrCBCT, and virtCT, respectively. Streamlined APT has been achieved with the proposed plan review criteria and CBCT-based synthetic CT workflow.

A comparison of loco-regional relapse pattern in HPV positive vs negative oropharyngeal cancers following radiotherapy; relation to pretreatment FDG-PET and radiotherapy target volumes

Background Previous studies have shown that a large proportion of relapses in head-and neck squamous cell carcinoma (HNSCC) following radiotherapy (RT) occur in the pretreatment FDG-PET avid volume (GTV-PET). The aim of the current work was to see if this was valid also in an oropharynx squamous cell carcinoma (OPSCC) only population, and to compare the loco-regional relapse pattern between HPV positive and HPV negative patients. Material and methods Among 633 OPSCC patients treated between 2009 and 2017, 46 patients with known HPV (p16) status and isolated loco-regional relapse were included. Oncologists contoured relapse volumes (RV) on relapse scans (PET/CT, CT or MR), which were thereafter deformed to match the anatomy of the planning CTs. The point of origin (center of volume) of the deformed RVs were determined and analyzed in relation to the RT target volumes (GTV-PET, GTV and CTVs). The relapse pattern was compared between HPV positive and HPV negative patients using Fischer’s exact test. Results Sixty RVs were contoured in the 46 patients. 55% (95% CI 44–67%) of relapses originated in GTV-PET, while the other RT volumes harbored 12% (5–20%) (GTV), 18% (9–28%) (high risk CTV) and 5% (0–11%) (low risk CTV) of relapses. Six relapses were found outside the RT target volumes. No significant difference in relapse pattern between HPV positive and HPV negative patients was found (p = .95). Conclusion There were no signs of difference in loco-regional relapse pattern between HPV positive and HPV negative patients. In agreement with previous findings, GTV-PET was the most frequent RT target volume of relapse.

Boost modalities in cervical cancer: dosimetric comparison between intracavitary BT vs. intracavitary + interstitial BT vs. SBRT.

Purpose / objectiveThis study compares the dosimetric plans of three distinct boost modalities in cervical cancer (CC): intracavitary (IC) with tandem/ovoids brachytherapy (BT), IC + interstitial (IS) BT, and Stereotactic-Body-Radiotherapy (SBRT). The aim is to determine the dosimetric impact in terms of target coverage and organ at risk (OAR) doses.Materials and methods24 consecutive IC + IS BT boost treatment plans were retrospectively identified. For each plan included, two additional plans were created: IC-BT and SBRT. Importantly, no planning target volume (PTV) or planning (organ at) risk volume (PRV) margins were generated, therefore all structures were identical for any boost modality. Two different normalizations were performed: (1) Normalization to the target: prescription of 7.1 Gy to the D90% (defined as the minimum dose covering 90%) of the high-risk clinical target volume (HR-CTV); (2) Normalization to the OARs. HR-CTV coverage and OARs sparing were compared. The equivalent doses in 2 Gy fractions (EQD2) of EBRT and BT for CTV-HR and OARs were calculated using the linear-quadratic model with α/β of 10 (EQD210) and 3 (EQD23), respectivelyResultsA total of 72 plans were investigated. In the first normalization, the mean EQD23−D2cc (defined as the minimal dose of the 2 cc) of OAR was significantly higher in the IC-BT plans, and the bladder D2cc hard constraint could not be reached. IC + IS BT leads to a 1 Gy mean absolute decrease of bladder EQD23-D2cc (relative dose: -19%), allowing to reach the hard constraint. SBRT (without PTV) delivers the lowest EQD23-D2cc to the OAR. In the second normalization, IC-BT provides a significantly lower dose to the EQD210-D90% (6.62 Gy) and cannot achieve the coverage goal. SBRT (without PTV) yields the highest dose to the D90% of HR-CTV and a significantly lower EQD210-D50% and D30%.ConclusionThe key dosimetric benefit of BT over SBRT without PTV is a significantly higher D50% and D30% in the HR-CTV, which increases the local and conformal dose to the target. IC + IS BT vs. IC-BT provides significantly better target coverage and a lower dose to the OARs, making it the preferred boost modality in CC.

Optimal Number of Needle Applicators Inserted in Combined Intracavitary and Interstitial Brachytherapy for Cervical Cancer.

Combined intracavitary and interstitial brachytherapy (IC/IS-BT) is an effective treatment for extensive and bulky cervical cancer. However, the optimum number of interstitial needle applicators ("needles") inserted in IC/IS-BT can be difficult to determine. To examine the number of needles required for adequate dose coverage of cervical tumors, we retrospectively analyzed IC/IS-BT plans. IC/IS-BT plans for cervical cancer patients treated from January 2014 to January 2021 were analyzed. All tumors were controlled locally at the time of analysis (August 2022). The relationship between the number of needles and several volumetric parameters of high-risk clinical target volume (CTVHR) were analyzed, including maximum diameter, maximum cross-sectional area, and the volume of CTVHR Spearman's rank correlation coefficients (r) were used to evaluate correlations. Eighty-two plans in 32 patients were analyzed. The median maximum cross-sectional area and volume of CTVHR were 18.9 (12.3-42.5) cm2 and 53.8 (30.1-152.2) cm3, respectively. The mean D90% and D98% of CTVHR at each BT session were 7.0±0.8 Gy and 5.9±0.8 Gy, respectively. There was a positive correlation between the number of needles and the maximum cross-sectional area of CTVHR (r=0.53). The average numbers of needles were 1.3, 1.9, 2.2, 3.1, and 4.0 when the maximum cross-sectional area of CTVHR were ≤15 cm2, 15-20 cm2, 20-25 cm2, 25-30 cm2, and >30 cm2, respectively. The optimal number of needles can be determined from the maximum cross-sectional area of CTVHR.

Efficacy and safety of camrelizumab in combination with radiation and chemotherapy for recurrent or metastatic cervical cancer.

5542 Background: Cisplatin-based concurrent chemoradiation regimens have been suggested to be beneficial in recurrent or metastatic cervical cancer. Immunotherapy has also shown good therapeutic efficacy in recurrent or metastatic cervical cancer. Among them, Pembrolizumab in combination with chemotherapy has been used for first-line treatment of advanced PD-L1-positive cervical cancer. Meanwhile, Camrelizumab has shown good anti-tumor activity and manageable toxicity in patients with locally advanced cervical cancer. The primary objective of this study is to evaluate the efficacy and safety of Camrelizumab in combination with concurrent chemoradiation in patients with recurrent or metastatic cervical cancer. Methods: Patients diagnosed with recurrent or metastatic cervical cancer received Camrelizumab combined with concurrent chemoradiotherapy, radiotherapy:External beam radiotherapy (EBRT) 1.8-2.15 Gy/f, a total of 28 fractions; Brachytherapy: high-risk CTV using image guidance 28 Gy in 4 fractions (18 Gy in 3 fractions for posthysterectomy recurrent patients); chemotherapy regimen used TP regimen (paclitaxel: 175 mg/m2, cisplatin: 75 mg/m2, Q3W 6 cycles); Camrelizumab 200 mg Q3W 6 cycles. The primary endpoint of this trial was objective response rate (ORR), and secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and incidence of adverse reactions. Results: From September 16, 2020 to September 30, 2022, a total of 29 patients were recruited. 27 of these patients completed 6 cycles of planned treatment. 27 patients had a median age of 53 years (33-73 years), ECOG PS 0 (n = 8), ECOG PS 1 (n = 14), ECOG PS 2 (n = 1). The ORR rate was 96.30% (26/27), including 17 patients with CR, 9 patients with PR, and 1 patient with SD Treatment-related AEs were mainly lymphocyte count decreased, anemia, and white blood cell count decreased, with overall safety manageable and no treatment-related deaths. Conclusions: Camrelizumab combined with concurrent chemoradiation in patients with recurrent or metastatic cervical cancer has good efficacy, low side effects and acceptable toxicity. Clinical trial information: NCT04884906 .

Clinical research of the value of high-risk CTV setting on intensity-modulated radiotherapy for stage IIB-IVA cervical cancer

BackgroundThis study aims to evaluate the clinical efficacy and side effects of setting up a high-risk clinical target volume (CTV-hr) alongside simultaneous integrated boost intensity-modulated radiotherapy (IMRT-SIB) in patients diagnosed with stage IIB-IVA cervical cancer.MethodsThis study retrospectively analysed patients with stage IIB-IVA cervical cancer who received radical radiotherapy at the Affiliated Hospital of Qingdao University between November 2014 and September 2019. The patients were divided into experimental and control groups based on whether CTV-hr was set. All patients received a combined treatment of radiotherapy and chemotherapy. The dosage for paclitaxel was 135 mg/m2, while for cisplatin it was 75 mg/m2 or for carboplatin it was AUC 4–6, given in a cycle of 21 days. Radiotherapy (RT) included external beam radiation therapy (EBRT) and intracavitary brachytherapy (ICBT). In the control group, positive lymph nodes (GTV-n) were treated at a dose of 58–62 Gy/26–28 fractions(f), while clinical target volumes (CTV) were treated with a dose of 46–48 Gy/26-28f. The experimental group received a simultaneous integrated boost (SIB) to CTV-hr at a dose of 54–56 Gy/26-28f, with the same CTV and GTV-n as the control group. Both groups were combined with brachytherapy with a total dose (EQD2, the equivalent dose in 2 Gy/f) of 80-90 Gy. The study measured objective remission rate (ORR), 3-year progression-free survival (PFS) rate, 3-year overall survival (OS) rate, recurrence rate, and side effects as endpoints.ResultsThe study enrolled 217 patients, with 119 in the experimental group and 98 in the control group. Results showed that the experimental group had a higher 3-year OS rate (87.4% vs. 71.4%, p = 0.001) and 3-year PFS rate (72.3% vs. 51.0%, p = 0.000) compared to the control group. Additionally, the experimental group had significantly lower rates of overall recurrence (26.1% vs. 50.0%, p = 0.003), in-field recurrence (15.1% vs. 36.7%, p = 0.000), and out-field recurrence(13.4% vs. 35.7%, p = 0.000) compared to the control group. All observed differences were found to be statistically significant. However, the experimental and control groups had no statistically significant difference in ORR and radiological side effects, such as radiation cystitis and enteritis (p > 0.05).ConclusionsSetting CTV-hr and performing IMRT-SIB on patients with stage IIB-IVA cervical cancer effectively increased the 3-year OS rate, 3-year PFS rate and reduced recurrence rate, with no significant differences in side effects.

Retrospective analysis of local recurrence pattern by computed tomography image-guided intracavitary and interstitial brachytherapy for locally advanced cervical cancer in a single Japanese institution

PURPOSEThe purpose of this study was to investigate the treatment results with focus on local control (LC) by computed tomography (CT)-guided intracavity brachytherapy and interstitial brachytherapy (ICBT/ISBT) for locally advanced cervical cancer (LACC). METHODS AND MATERIALSPatients with LACC undergoing ICBT/ISBT at least once in our institution between January 2017 and June 2019 were analyzed retrospectively. The primary endpoint was local control (LC), and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and late toxicities. Differences between patient subgroups for prognostic factors in LC, PFS, and OS were analyzed using the log-rank test. The recurrence patterns of LC were also investigated. RESULTSForty-four patients were included in the present study. The median high-risk clinical target volume (HR-CTV) at the initial brachytherapy was 48.2 cc. The median total dose of HR-CTV D90 (EQD2) was 70.7 Gy. The median followup period was 39.4 months. The 3-year LC, PFS and OS rates in all patients were 88.2%, 56.6%, and 65.4% (95% CI 50.3–78.0%), respectively. Corpus invasion and large HR-CTV (70 cc or more) were significant prognostic factors in LC, PFS, and OS. Marginal recurrences at the fundus of the uterus were detected in 3 of 5 patients in whom local recurrence was observed. Late toxicities of Grade 3 or higher were detected in 3 patients (6.8%). CONCLUSIONSFavorable LC was achieved by performing CT-guided ICBT/ISBT for LACC. The brachytherapy strategy for patients with corpus invasion or large HR-CTV may need to be reconsidered.

Dose prediction of organs at risk in patients with cervical cancer receiving brachytherapy using needle insertion based on a neural network method

ObjectiveA neural network method was employed to establish a dose prediction model for organs at risk (OAR) in patients with cervical cancer receiving brachytherapy using needle insertion.MethodsA total of 218 CT-based needle-insertion brachytherapy fraction plans for loco-regionally advanced cervical cancer treatment were analyzed in 59 patients. The sub-organ of OAR was automatically generated by self-written MATLAB, and the volume of the sub-organ was read. Correlations between D2cm3 of each OAR and volume of each sub-organ—as well as high-risk clinical target volume for bladder, rectum, and sigmoid colon—were analyzed. We then established a neural network predictive model of D2cm3 of OAR using the matrix laboratory neural net. Of these plans, 70% were selected as the training set, 15% as the validation set, and 15% as the test set. The regression R value and mean squared error were subsequently used to evaluate the predictive model.ResultsThe D2cm3/D90 of each OAR was related to volume of each respective sub-organ. The R values for bladder, rectum, and sigmoid colon in the training set for the predictive model were 0.80513, 0.93421, and 0.95978, respectively. The ∆D2cm3/D90 for bladder, rectum, and sigmoid colon in all sets was 0.052 ± 0.044, 0.040 ± 0.032, and 0.041 ± 0.037, respectively. The MSE for bladder, rectum, and sigmoid colon in the training set for the predictive model was 4.779 × 10−3, 1.967 × 10−3 and 1.574 × 10−3, respectively.ConclusionThe neural network method based on a dose-prediction model of OAR in brachytherapy using needle insertion was simple and reliable. In addition, it only addressed volumes of sub-organs to predict the dose of OAR, which we believe is worthy of further promotion and application.

Developing Next-Generation 3-Dimensional Printing for Cervical Cancer Hybrid Brachytherapy: A Guided Interstitial Technique Enabling Improved Flexibility, Dosimetry, and Efficiency

We developed a 3-dimensionally (3D) printed tandem anchored radially guiding interstitial template (TARGIT) to increase the simplicity of intracavitary/interstitial technique for tandem-and-ovoid (T&O) procedures in cervical cancer brachytherapy. This study compared dosimetry and procedure logistics between T&O implants using the original TARGIT versus the next-generation TARGIT-Flexible-eXtended (TARGIT-FX) 3D-printed template designed for practice-changing ease-of-use with further simplified needle insertion and increased flexibility in needle placement. This single-institution retrospective cohort study included patients undergoing T&O brachytherapy as part of definitive cervical cancer treatment. Procedures used the original TARGIT from November 2019 through February 2022 and the TARGIT-FX from March 2022 through November 2022. The FX design features full extension to the vaginal introitus with 9 needle channels and allows for needle additions or depth adjustments intraprocedure and after computed tomography/magnetic resonance imaging. A total of 148 implants were performed, 68 (46%) with TARGIT and 80 (54%) with TARGIT-FX, across 41 patients. Across implants, the TARGIT-FX achieved higher mean V100% (+2.8%, P=.0019), and across patients, the TARGIT-FX achieved higher D90 (+2.0 Gy, P=.037) and higher D98 (+2.7 Gy, P=.016) compared with the original TARGIT. Doses to organs at risk were overall similar between templates. Procedure times for TARGIT-FX implants were 30% shorter on average than for those using the original TARGIT (P < .0001), and 28% shorter on average for the subset of implants with high-risk clinical target volume ≥30 cc (P=.013). All residents (100%, N=6) surveyed regarding the TARGIT-FX indicated ease-of-use for needle insertion and interest in applying the technique in future practice. The TARGIT-FX achieved shorter procedure times with increased tumor coverage and similar normal tissue sparing compared with the previously applied TARGIT and illustrates the potential of 3D printing to enhance efficiency and shorten the learning curve for intracavitary/interstitial procedure technique in cervical cancer brachytherapy.

Self-configuring nnU-Net for automatic delineation of the organs at risk and target in high-dose rate cervical brachytherapy, a low/middle-income country's experience.

The high-dose rate (HDR) brachytherapy treatment planning workflow for cervical cancer is a labor-intensive, time-consuming, and expertise-driven process. These issues are amplified in low/middle-income countries with large deficits in experienced healthcare professionals. Automation has the ability to substantially reduce bottlenecks in the planning process but often require a high level of expertise to develop. To implement the out of the box self-configuring nnU-Net package for the auto-segmentation of the organs at risk (OARs) and high-risk CTV (HR CTV) for Ring-Tandem (R-T) HDR cervical brachytherapy treatment planning. The computed tomography (CT) scans of 100 previously treated patients were used to train and test three different nnU-Net configurations (2D, 3DFR, and 3DCasc). The performance of the models was evaluated by calculating the Sørensen-dice similarity coefficient, Hausdorff distance (HD), 95th percentile Hausdorff distance, mean surface distance (MSD), and precision score for 20 test patients. The dosimetric accuracy between the manual and predicted contours was assessed by looking at the various dose volume histogram (DVH) parameters and volume differences. Three different radiation oncologists (ROs) scored the predicted bladder, rectum, and HR CTV contours generated by the best performing model. The manual contouring, prediction, and editing times were recorded. The mean DSC, HD, HD95, MSD and precision scores for our best performing model (3DFR) were 0.92/7.5mm/3.0mm/ 0.8mm/0.91 for the bladder, 0.84/13.8mm/5.3mm/1.4mm/0.84 for the rectum, and 0.81/8.5mm/6.0mm/2.2mm/0.80 for the HR CTV. Mean dose differences (D2cc/90% ) and volume differences were 0.08Gy/1.3 cm3 for the bladder, 0.02Gy/0.7 cm3 for the rectum, and 0.33Gy/1.5 cm3 for the HR CTV. On average, 65% of the generated contours were clinically acceptable, 33% requiring minor edits, 2% required major edits, and no contours were rejected. Average manual contouring time was 14.0 min, while the average prediction and editing times were 1.6 and 2.1 min, respectively. Our best performing model (3DFR) provided fast accurate auto generated OARs and HR CTV contours with a large clinical acceptance rate.

Automated treatment planning framework for brachytherapy of cervical cancer using 3D dose predictions

Objective. To lay the foundation for automated knowledge-based brachytherapy treatment planning using 3D dose estimations, we describe an optimization framework to convert brachytherapy dose distributions directly into dwell times (DTs). Approach. A dose rate kernel was produced by exporting 3D dose for one dwell position from the treatment planning system and normalizing by DT. By translating and rotating this kernel to each dwell position, scaling by DT and summing over all dwell positions, dose was computed (D calc). We used a Python-coded COBYLA optimizer to iteratively determine the DTs that minimize the mean squared error between D calc and reference dose D ref, computed using voxels with D ref 80%–120% of prescription. As validation of the optimization, we showed that the optimizer replicates clinical plans when D ref = clinical dose in 40 patients treated with tandem-and-ovoid (T&O) or tandem-and-ring (T&R) and 0–3 needles. Then we demonstrated automated planning in 10 T&O using D ref = dose predicted from a convolutional neural network developed in past work. Validation and automated plans were compared to clinical plans using mean absolute differences () over all voxels (xn = Dose, N = #voxels) and DTs (xn = DT, N = #dwell positions), mean differences (MD) in organ D 2cc and high-risk CTV D90 over all patients (where positive indicates higher clinical dose), and mean Dice similarity coefficients (DSC) for 100% isodose contours. Main results. Validation plans agreed well with clinical plans (MADdose = 1.1%, MADDT = 4 s or 0.8% of total plan time, D 2cc MD = −0.2% to 0.2% and D90 MD = −0.6%, DSC = 0.99). For automated plans, MADdose = 6.5% and MADDT = 10.3 s (2.1%). The slightly higher clinical metrics in automated plans (D 2cc MD = −3.8% to 1.3% and D90 MD = −5.1%) were due to higher neural network dose predictions. The overall shape of the automated dose distributions were similar to clinical doses (DSC = 0.91). Significance. Automated planning with 3D dose predictions could provide significant time savings and standardize treatment planning across practitioners, regardless of experience.

Large anatomical changes in head-and-neck cancers – A dosimetric comparison of online and offline adaptive proton therapy

PurposeThis work evaluates an online adaptive (OA) workflow for head-and-neck (H&N) intensity-modulated proton therapy (IMPT) and compares it with full offline replanning (FOR) in patients with large anatomical changes. MethodsIMPT treatment plans are created retrospectively for a cohort of eight H&N cancer patients that previously required replanning during the course of treatment due to large anatomical changes. Daily cone-beam CTs (CBCT) are acquired and corrected for scatter, resulting in 253 analyzed fractions. To simulate the FOR workflow, nominal plans are created on the planning-CT and delivered until a repeated-CT is acquired; at this point, a new plan is created on the repeated-CT. To simulate the OA workflow, nominal plans are created on the planning-CT and adapted at each fraction using a simple beamlet weight-tuning technique. Dose distributions are calculated on the CBCTs with Monte Carlo for both delivery methods. The total treatment dose is accumulated on the planning-CT. ResultsDaily OA improved target coverage compared to FOR despite using smaller target margins. In the high-risk CTV, the median D98 degradation was 1.1 % and 2.1 % for OA and FOR, respectively. In the low-risk CTV, the same metrics yield 1.3 % and 5.2 % for OA and FOR, respectively. Smaller setup margins of OA reduced the dose to all OARs, which was most relevant for the parotid glands. ConclusionDaily OA can maintain prescription doses and constraints over the course of fractionated treatment, even in cases of large anatomical changes, reducing the necessity for manual replanning in H&N IMPT.

Definitive radiotherapy consisting of external beam radiotherapy without central shielding and 3D image-guided brachytherapy for patients with cervical cancer: feasibility for Japanese patients and dose-response analyses for local control in the low-dose range.

To assess the feasibility of external beam radiotherapy without central shielding in definitive radiotherapy for Japanese patients with cervical cancer. We retrospectively analysed the data of cervical cancer patients treated with definitive radiotherapy consisting of external beam radiotherapy without central shielding and three-dimensional-image-guided brachytherapy. The study included 167 patients (T1+2=108, T3+4=59) from eight Japanese institutions. For three-dimensional-image-guided brachytherapy, intra-cavitary and interstitial brachytherapy was utilized in 33 patients (20%). The median follow-up was 26.6months (interquartile range, 20-43.2). The maximum rectal D2 (75Gy)/bladder D2 (90Gy) constraints were deviated by 6%/10% and 10%/5% for T1+2 and T3+4, respectively. The 2-year incidence of ≥grade 3 proctitis/cystitis was 4%/1% for T1+2 and 10%/2% for T3+4. The 2-year local progression-free survival was 89% for T1+2 and 82% for T3+4. For T1+2, the 2-year local progression-free survival for the high-risk clinical target volume D90≥68Gy (indicated by receiver operating characteristic analysis; area under the curve=0.711) was 92% versus 67% for <68Gy (log-rank; P=0.019). Cox multivariate analysis indicated that the high-risk clinical target volume D90 was one of independent predictors of local failure (P=0.0006). For T3+4, the 2-year local progression-free survival was 87% for the high-risk clinical target volume <82cm3 (area under the curve=0.67) and 43% for ≥82cm3 (P=0.0004). Only the high-risk clinical target volume was an independent predictor of local failure (P=0.0024). Definitive radiotherapy consisting of external beam radiotherapy without central shielding and three-dimensional-image-guided brachytherapy was feasible for Japanese patients with cervical cancer. Dose de-escalation from the current global standards is suggested for patients with T1+2 disease.

Safety and efficacy of single insertion accelerated MR-image guided brachytherapy following chemo–radiation in locally advanced cervix cancer: modifying our EMBRACE during the COVID pandemic

BackgroundUtero-vaginal brachytherapy (BT) is an irreplaceable care component for the curative treatment of locally advanced cervix cancer (LACC). Magnetic Resonance Imaging (MRI)-image guided adaptive BT (IGABT) using the GYN-GEC-ESTRO EMBRACE guidelines is the international care standard. Usually following chemo–radiation therapy (CRT), IGABT has high proven utility in LACC but requires significant health system resources. Timely access was disrupted by the COVID-19 pandemic which challenged us to re-design our established IGABT care pathway.MethodsFrom April 2020 consecutive patients with LACC were enrolled after CRT in a single arm exploratory non-inferiority study of a modified IGABT (mIGABT) protocol. This delivered an iso-effective IGABT dose (39.3 Gy: EQD2: α/β10Gy concept) over a 24-h period during a single overnight hospitalisation.ResultsFourteen LACC patients received mIGABT from April 2020 to March 2022. Median age was 62.5 years (37–82 years). LACC histology was primary squamous (9/14) or adeno-carcinoma (5/14). International Federation of Gynaecology and Obstetrics (FIGO) 2018 stages ranged from IB1/2 (N = 3), IIA1/IIB (5), IIIB (2), IIIC1/2 (4) with mean ± standard deviation (SD) gross tumour volume-at-diagnosis (GTV_D) of 37.7 cc ± 71.6 cc. All patients achieved complete metabolic, clinical, and cytologic cancer response with CRT and IGABT. High-risk HPV was cleared by 6-months. Complete MRI-defined cancer response before mIGABT (GTV_Fx1) was seen in 77% of cases (10/13). Only two women developed metastatic disease and one died at 12-months; 13 patients were alive without cancer at mean 20.3 ± 7.2 months follow-up. Actuarial 2-year overall survival was 93%. Compared with our pre-COVID IGABT program, overall mIGABT cost-saving in this cohort was USD 22,866. Prescribed dose covered at least 90% (D90) of the entire cervix and any residual cancer at time of BT (HRCTV_D90: high-risk clinical target volume) with 3-fractions of 8.5 Gy delivered over 24-h (22.8 ± 1.7 h). Total treatment time including CRT was 38 days. The mIGABT schedule was well tolerated and the entire cohort met EMBRACE recommended (EQD2: α/β10Gy) combined HRCTV_D90 coverage of 87.5 ± 3.7 Gy. Similarly, organ-at-risk (OAR) median: interquartile range D2cc constraints (EQD2: α/β3Gy) were EMBRACE compliant: bladder (65.9 Gy: 58.4–72.5 Gy), rectum (59.1 Gy: 55.7–61.8 Gy), and sigmoid colon (54.6 Gy: 50.3–58.9 Gy). ICRU recto-vaginal point dose was significantly higher (75.7 Gy) in our only case of severe (G4) pelvic toxicity.ConclusionsThis study demonstrated the utility of mIGABT and VMAT CRT in a small cohort with LACC. Loco-regional control was achieved in all cases with minimal emergent toxicity. Single insertion mIGABT was logistically efficient, cost-saving, and patient-centric during the COVID-19 pandemic.

Evaluation of auto-segmentation for brachytherapy of postoperative cervical cancer using deep learning-based workflow

Objective. The purpose of this study was to evaluate the accuracy of brachytherapy (BT) planning structures derived from Deep learning (DL) based auto-segmentation compared with standard manual delineation for postoperative cervical cancer. Approach. We introduced a convolutional neural networks (CNN) which was developed and presented for auto-segmentation in cervical cancer radiotherapy. The dataset of 60 patients received BT of postoperative cervical cancer was used to train and test this model for delineation of high-risk clinical target volume (HRCTV) and organs at risk (OARs). Dice similarity coefficient (DSC), 95% Hausdorff distance (95%HD), Jaccard coefficient (JC) and dose-volume index (DVI) were used to evaluate the accuracy. The correlation between geometric metrics and dosimetric difference was performed by Spearman’s correlation analysis. The radiation oncologists scored the auto-segmented contours by rating the lever of satisfaction (no edits, minor edits, major edits). Main results. The mean DSC values of DL based model were 0.87, 0.94, 0.86, 0.79 and 0.92 for HRCTV, bladder, rectum, sigmoid and small intestine, respectively. The Bland-Altman test obtained dose agreement for HRCTV_D90%, HRCTV_Dmean, bladder_D2cc, sigmoid_D2cc and small intestine_D2cc. Wilcoxon’s signed-rank test indicated significant dosimetric differences in bladder_D0.1cc, rectum_D0.1cc and rectum_D2cc (P < 0.05). A strong correlation between HRCTV_D90% with its DSC (R = −0.842, P = 0.002) and JC (R = −0.818, P = 0.004) were found in Spearman’s correlation analysis. From the physician review, 80% of HRCTVs and 72.5% of OARs in the test dataset were shown satisfaction (no edits). Significance. The proposed DL based model achieved a satisfied agreement between the auto-segmented and manually defined contours of HRCTV and OARs, although the clinical acceptance of small volume dose of OARs around the target was a concern. DL based auto-segmentation was an essential component in cervical cancer workflow which would generate the accurate contouring.

Variations and effects of bladder and rectal volume following uniform preparation procedure in cervical cancer: Five fractions of 6 Gy.

To analyze the effects of different bladder and rectal volumes on the dose of organ at risks (OARs) and primary tumors following uniform preparation procedure. In this retrospective study, a total of 60 patients with cervical cancer treated with external beam radiation therapy (EBRT) combined with chemotherapy and brachytherapy (BT) during 2019-2022 were included (300 insertions). Then, tandem-ovoid applicators were placed and computed tomography (CT) scanning was performed after each insertion. Delineation of OARs and clinical target volumes (CTVs) were done according to GEC-ESTRO group recommendations. Finally, doses of high-risk clinical target volume (HR-CTV) and OARs were obtained from dose volume histogram (DVH) automatically generated by BT treatment planning system. Following a uniform preparation procedure, the median bladder volume of 68.36 cc (range, 29.9-235.68 cc) was in optimal agreement with the recommended bladder volume of ≤ 70 ml, which avoided more manipulation and possible risk of adverse events during general anesthesia. As the bladder filling volume increased, there was no corresponding increase in rectal, HR-CTV, and small bowel volumes, while the sigmoid colon volume decreased. The median rectal volume was 54.95 cc (range, 24.92-168.1 cc), and as the rectal volume increased, HR-CTV, sigmoid colon, and rectum volumes increased, and conversely, small bowel volume decreased. HR-CTV changes with volume affected the rectum, bladder, and HR-CTV, but not the sigmoid colon and small intestine. Following a uniform preparation procedure, the bladder and rectum can also be controlled to an optimal volume (B ≤ 70 cc, R ≈ 40 cc), which is related to the dose of the bladder, rectum, and sigmoid colon.

Dosimetry and plan parameters study of three-dimensional-printed template-based intra-cavitary/interstitial interpolation technology using computed tomography-guided high-dose-rate brachytherapy in locally advanced cervical cancer.

To explore differences in dosimetry and planning parameters between intra-cavitary/interstitial interpolation (IC + ISBT) three-dimensional (3D)-printed template-based (3D-printed) and simple intra-cavity (ICBT) radiation techniques using a fixed Rotterdam three-tube applicator (TT) for computed tomography-guided high-dose-rate brachytherapy in locally advanced cervical cancer. This retrospective study included 100 patients (n = 50 each in 3D-printed and Rotterdam three-tube applicator treatment groups) with FIGO stages IIB-IVB cervical cancer from May 2019 to May 2022. Using high-risk clinical target volume, 377 of 400 plans categorized at intervals of 10 cm3 into 20-30, 30-40, 40-50, 50-60, 60-70, and 70-80 cm3; 23 plans with < 20 and > 80 cm3 volume were excluded. Dosimetry parameters (D90 and D98 of high-risk clinical target volume, and D2cc of organs at risk, including bladder, rectum, sigmoid, and bowel) and planning parameters (homogeneity index [HI], conformation number [CN], and organ at risk sparing factor) were compared between the two groups separately for six high-risk clinical target volume plan categories. For the 3D-printing group, target coverage, organs at risk protection, and plan conformity and uniformity were better than those for the Rotterdam three-tube group. Particularly, in high-risk clinical target volume plans between 50-60 cm3, the mean D90 and D98 of high-risk clinical target volume were approximately 0.35 and 0.3 Gy higher, while the average D2cc of the bladder, rectum, sigmoid, and bowel were approximately 1.3, 0.9, 0.9, and 0.8 Gy significantly lower than those of the Rotterdam three-tube group, respectively (p < 0.05). The above-mentioned planning parameters differed significantly between the groups (p < 0.05). For the 3D-printing group, IC/ISBT reduced the dose for organs at risk while ensuring target coverage and conformation. This was especially noticeable for plans with high-risk clinical target volume of 50-60 cm3.