External Beam Radiotherapy Dose Research Articles

GSOR18 Presentation Time: 11:55 AM: Obesity and Skin D2cc Predict for Radiation Necrosis After Interstitial Brachytherapy Boost in Locally Advanced Vulvar Cancer

<h3>Background</h3> Interstitial brachytherapy (ISBT) has been increasingly utilized in treating locally advanced as well as locally recurrent vulvar cancer. However, the risk of BT-associated grade 3 or 4 skin necrosis is largely underreported, owing to the rarity of the disease. The purpose of this investigation was to evaluate therapeutic benefit of BT boost and risk of necrosis in a relatively large subset of patients with locally advanced vulvar cancer. <h3>Methods</h3> Patients with vulvar cancer treated with radiation therapy at Upstate Medical University between January 1, 2014 and July 1, 2021 were retrospectively analyzed. Demographics, oncologic history, external beam and BT dosimetry details, clinical outcomes, and CTCAE graded skin toxicities were evaluated and compared across individuals receiving external beam radiation (EBRT) only versus EBRT+brachytherapy (EBRT+BT). <h3>Results</h3> Of the 33 patients with vulvar cancer included, the median age of the cohort was 65.5 years; 97% were non-Hispanic Caucasian. Median follow-up was 31.1 months (2 patients were lost to follow-up and 11 patients were deceased at the time of analysis). The majority of patients had FIGO stage III and IV disease (24/33, 73%); however, stage IV was more frequent among patients treated with EBRT+BT (9/15, 60%; p=0.03). A total of 6 patients were being treated for recurrent disease and 27 with definitive intent. In this cohort, 15 patients received only EBRT and 18 received EBRT+BT. There was a greater proportion of patients with history of smoking in the EBRT+BT group (87% vs. 56%, p=0.05); and the percentage of active smokers was numerically greater in the EBRT+BT group (54% vs. 20%, p=0.09). The median dose of EBRT alone was 6120 cGy (4500-7000 cGy) and the median dose of EBRT for patients receiving BT was 5040 cGy (4500-6750 cGy). Median BT prescription was 2500 cGy over 5 fractions twice daily (1600-3000 cGy). Overall (n=31), there were 6 cases of grade 3 (19%) and 7 of grade 4 (23%) radiation-related skin toxicity including ulceration and/or necrosis. Grade 4 toxicities were exclusively cited among patients treated with BT (7/7, 100%, p=0.014). There were 10 (33%) cases of necrosis: 3 in the EBRT group and 7 in the EBRT+BT group (50%, p=0.07). The odds of developing necrosis were greater among women treated with BT, OR=4.3, CI (0.85-22.23). Obese patients (BMI ≥ 30 kg/m2) had 15 times the odds of developing necrosis from BT as compared to non-obese patients, OR=15.0, 95% CI (1.03-218.3). The risk of BT-related necrosis was even greater in obese smokers, OR=20.0, (1.4-282.5). Patients with grade 4 skin necrosis had a mean skin D2cc of 139%, whereas those with grade 1 or 2 toxicity had a mean D2cc of 79.8% (p=0.001). Overall response to treatment, either partial or complete, appeared to be greater in the BT group (92% vs. 81%, p=0.14). Clinically, a greater proportion of patients receiving BT achieved complete response (77% vs. 65%, p=0.312). Complete responders had a significantly lower BMI (30.3 kg/m²) than non-responders (36.2 kg/m²) and partial responders (37.2 kg/m²) (p=0.05). <h3>Conclusion</h3> ISBT for locally advanced vulvar cancer appears to provide an improvement in overall response to therapy. Toxicity appears greatest in obese patients who are active smokers. Additionally, skin D2cc greater than 130% of prescribed dose appears to correlate with increased risk of grade 4 skin necrosis. These clinical and dosimetric factors should be taken into account when utilizing ISBT for vulvar cancer.

Treatment Toxicities, Response to Treatment and Overall Survival of Cervical Cancer in Women with and without HIV in Botswana: Ipabalele Study U54 CA190158-01

<h3>Purpose/Objective(s)</h3> Cervical cancer is the leading cause of cancer death among women in Botswana. It is well established that persistent human papillomavirus (HPV) infection is the primary risk factor for cervical cancer and that co-infection with human immunodeficiency virus (HIV) further increases the risk for cancer development. Standard of care for locally advanced disease is treatment with chemoradiation (CRT). This study aimed to characterize toxicities, response to treatment, and survival in patients with cervical cancer in Botswana. <h3>Materials/Methods</h3> Patients with histologically confirmed locally advanced cervical cancer eligible for CRT were prospectively enrolled between Jan 2015 and June 2019 to the <i>Ipabalele</i> study in Gaborone, Botswana. Clinical and treatment characteristics, on-treatment toxicities, and treatment response of patients were recorded. Biochemical response to treatment was characterized using SCC-Ag level <2.2ng/ml at the end of treatment and 3 months post treatment. Toxicities were measured during on treatment visits (OTVs) and evaluated using CTCAE 4.0 grading. All patients were followed every 3 months for 2 years. <h3>Results</h3> Of 293 women diagnosed with cervical cancer, 73.7% (n=216) were women living with HIV (WLWH). The mean age of diagnosis for cervical cancer was younger in WLWH vs those without HIV (44.9 vs. 47.5, p<0.001). There was no difference in stage at presentation by HIV status, with the most common stage at presentation among both populations as Stage II (46.3% WLWH, 58.84% without HIV, p=0.349). Median CD4 count among WLWH was 467 cells/μL. WLWH had a lower external beam radiation dose (45.76 Gy) compared to women living without HIV (47.09 Gy), p=0.002; however, HIV status did not impact total EQD2 (median 85.7 Gy). HIV status did not impact number of chemotherapy cycles received (median 4 cycles). Seventy three percent (n=106) of all patients had a complete response to treatment by clinical exam and imaging, 65% (n=82) of all patients had a complete response to treatment by SCC-Ag. HIV status did not impact response to treatment by either SCC-Ag or clinical evidence (p=0.718). Two-year overall survival (OS) probability for the cohort was 77.7%. There was no difference in survival by HIV status (OS 75.8% in WLWH; 82.05% in those without HIV, p=0.31). Treatment response by SCC-Ag was associated with OS. Factors associated with OS in a multivariate analysis included cycles of chemotherapy given and stage at presentation. HIV was not significantly related to overall survival. The most common Grade2+ toxicities included anemia (42.8%, n=125), leukopenia (34.6%, n=101), and radiation dermatitis (39.9%, n=101). Importantly, HIV did not impact prevalence of any of the toxicities measured. <h3>Conclusion</h3> HIV status impacted age of diagnosis of cervical cancer; however, did not impact stage, treatment received for cervical cancer, or OS. There was no difference seen in chemoradiation associated toxicities of treatment for locally advanced cervical cancer by HIV status.

PO04: Clinical and Dosimetric Outcomes with Image-Guided High Dose Rate (HDR) Endoluminal Brachytherapy in Endobronchial Tumours: A Single Institute Experience

<h3>Purpose</h3> Endoluminal brachytherapy is an effective treatment modality for endobronchial tumours. With the advent of image-guidance, target coverage has improved and volume-based target delineation has helped in conformal treatment. In this study, we report our experience with high dose rate endobronchial brachytherapy (HDR-EBBT) and to assess its efficacy and tolerability. <h3>Materials and Methods</h3> Between January 2015 to February 2022, a retrospective review of patients with endobronchial tumours treated at our institution with HDR-EBBT was retrospectively assessed. Analysis of disease characteristics and thereafter, the subjective response and treatment related toxicities were extracted from patient records. The follow-up was undertaken as per the institutional protocol. Local control (LC) and overall survival (OS) were analysed. During each procedure of EBBT, a source-centralizing applicator was used which kept the source-dwelling catheter in the centre of bronchial lumen and reference dose point was placed 5 mm from source axis as per the bronchial diameter. <h3>Results</h3> With a median follow up of 18 months, a total of 8 patients with histopathologically proven endobronchial tumours were identified. The median external beam radiation dose was 45Gy in 25 fractions followed by brachytherapy dose of 14Gy in 2 fractions with treatment a week apart. The commonest symptoms to palliate included dyspnea (5/8), cough (3/8), and hemoptysis (4/8). The median disease-free survival and overall survival was 18 months and 21 months respectively. No grade 3-5 acute or late toxicities were reported and only one patient required further palliation measures to control the symptoms. On dosimetric analysis the PTV V95% and V98% were 95.12% and 93.45% respectively. On assessing the D20 and D5 for lungs, the median dose was 1.32Gy and 0.73Gy respectively. Similarly, the D2cc, 1cc and 0.1cc of oesophagus and heart were 1.63, 1.89 and 2.67Gy and 1.15, 1.37 and 1.69Gy respectively. <h3>Conclusion</h3> HDR-EBBT is a promising treatment with minimal complications and improved outcomes and thus provide curative options. If performed properly, desirable dosimetry can be achieved to improve target coverage and reduced normal tissue doses.

Locoregional Control Following Adjuvant Chemotherapy and Radiotherapy for Treatment of High-Risk Endometrial Cancer

<h3>Purpose/Objective(s)</h3> Patients with locally advanced stage and aggressive histology endometrial cancer are at high risk of relapse, and usually treatment includes surgery, chemotherapy and radiotherapy. The timing and coordination of chemotherapy and radiotherapy remain controversial, though historically we have delivered adjuvant radiotherapy after completion of chemotherapy. The premise being to avoid delaying chemotherapy, which confers an overall survival benefit. We decided to review oncologic outcomes and patterns of recurrence among our patients and compare them with the published literature. <h3>Materials/Methods</h3> A retrospective review was conducted to evaluate patients who underwent primary surgery for endometrial cancer between 2005 and 2017, had a final pathology demonstrating Stage I-II endometrial cancer of serous or clear cell histology, Stage III endometrial cancer of any histology or Stage IV endometrial cancer of endometrioid adenocarcinoma histology, and were considered appropriate for adjuvant chemotherapy and radiotherapy. Kaplan-Meier analysis was used to calculate progression-free survival (PFS) and overall survival (OS). <h3>Results</h3> A total of 140 patients met the eligibility criteria and were included, with a median age of 65. The distribution according to stage was as follows: 41 (29.3%) Stage I, 24 (17.1%) Stage II, 68 (48.6%) Stage III, and 7 (5.0%) Stage IV. Of these patients, 52 (37.1%) had endometrioid, 75 (53.6%) had serous, and 11 (7.9%) had clear cell histology. All patients received chemotherapy with the median start time being 49 days after initial surgery. In total, 120 (92%) completed 6 cycles of chemotherapy. The median start time for radiotherapy was 35 days after chemotherapy and 192 days after surgery, with 129 (92.1%) completing adjuvant radiotherapy. The median dose of external beam radiotherapy (EBRT) was 4500 cGy in 25 fractions and the median dose of vaginal brachytherapy, when used, was 1800 cGy in 3 fractions. In terms of EBRT technique, 54 were treated with traditional conformal fields and 74 with IMRT techniques. The median follow-up was 63.9 months and the 5-year PFS and OS rates were 69% and 66% respectively. A total of 42 patients (30.0%) developed a recurrence; of which 2 (1.4%) were local, 10 (7.1%) were locoregional (any with component of locoregional failure), 8 (5.7%) were isolated para-aortic and 27 (19.3%) were distant. Among the 129 patients receiving radiotherapy, 6 (4.6%) patients had locoregional failure. Only 7 (5.4%) of patients had an "in-field" recurrence after EBRT, with 4 (3.1%) among patients treated with conformal fields and 3 (2.3%) among those treated with IMRT. <h3>Conclusion</h3> Adjuvant radiotherapy given after completion of surgery and adjuvant chemotherapy leads to favorable outcomes with regards to PFS and OS (compared to published randomized studies), and still results in excellent locoregional control.

Accumulated Dose Prediction for Assisting Radiation Treatment in Cervical Cancer

<h3>Purpose/Objective(s)</h3> For cervical cancer treated with combined external beam radiotherapy (EBRT) and brachytherapy (BT), ideally, the treatment optimization and evaluation should take the accumulated dose distribution into account. However, in current clinical practice different treatment parts are linked to different planning images and optimized independently, resulting in multiple dose distributions. In this study, we used a combination of deformable image registration (DIR) and deep learning techniques to predict the accumulated dose for assisting treatment planning and dose estimation. <h3>Materials/Methods</h3> The dose distributions of both EBRT and BT plans from 32 cervical cancer patients were used for this study. Firstly, the BT images were registered to the EBRT images using DIR to obtain the accumulated dose distributions. Then, a deep learning model based on a 101-layers ResNet was trained to predict pixel-wise dose distributions. The input data was combined anatomic maps including the CT images, structure maps and distance maps. The output data was the corresponding accumulated dose maps. We used 5-fold cross-validation to test the performance of the prediction model. The evaluation parameters included the voxel-based mean absolute error (MAE) and dice similarity coefficient (DSC) of isodose volumes for the prescription dose (PD) of EBRT (45/50 Gy) and the summed PD of EBRT and BT (76.25/82 Gy_EQD2). Finally, we randomly selected 10 patients to validate the effect of the dose prediction on treatment planning. For each patient, two EBRT plans were separately designed by a single physicist in the cases of unknowing and knowing the predicted accumulated dose distribution. The resulting two EBRT doses were separately accumulated with BT dose for comparison. <h3>Results</h3> In the comparison between the predicted and original dose distributions, the mean MAE of the whole body, normal tissue, bladder and rectum were 3.73±1.58, 3.27±1.06, 6.55±3.10 and 8.05±4.95 Gy, respectively. The mean DSC of the isodose volumes for 45/50 Gy and 76.25/82 Gy_EQD2 were 0.89±0.02 and 0.69±0.09, respectively. Compared to the planning without knowing the predicted dose, the planning with knowing the predicted dose resulted in a lower D2cc (-1.2±0.80 Gy, p=0.04), V40 (-3.23±2.19%, p=0.002), V50 (-2.19±%1.34, p=0.001) and V60 (-0.79±0.82%, p=0.02) of the rectum. For the bladder, the V40 of were decreased by 1.48±0.58% (p<0.001) but other dosimetric parameters had no significant difference. <h3>Conclusion</h3> The accumulated dose prediction could help to estimate and further decrease the doses to organs at risk. The predicted dose is recommended to be used as a reference during treatment planning in order to pursue a superior accumulated dose distribution for the combined cervical cancer treatment.

Determining Combined Modality Dosimetric Constraints by Integration of IMRT and LDR Prostate Brachytherapy Dosimetry

Determining Combined Modality Dosimetric Constraints by Integration of IMRT and LDR Prostate Brachytherapy Dosimetry <h3>Purpose/Objective(s)</h3> Combined external beam radiation therapy (EBRT) and prostate brachytherapy is one standard of care for men with prostate cancer. Dosimetric correlation of organ at risk (OAR) has been limited by the lack of spatial registration and differences in biological effectiveness between EBRT and brachytherapy dose. This study utilized a validated technique to spatially combine three-dimensional biological effective dose (BED) distributions from different modalities to more accurately depict a composite dose. We use this technique to correlate dosimetry with genitourinary (GU) and gastrointestinal (GI) toxicity in an effort to propose conservative dosimetric tolerances for OARs during combination therapy for prostate cancer. <h3>Materials/Methods</h3> The study cohort consisted of 144 intermediate and high-risk prostate cancer patients treated with combination therapy. Patients received 45 Gy using IMRT, either by static field or modulated arc, and 100 Gy using ¹⁰³Pd. Dosimetry was converted voxel-by-voxel to BED and combined using deformable image or inherent DICOM registration. Acute and late GU and GI toxicity was scored using CTCAE and correlated with combined BED. Biological effective doses for each toxicity group were compared using analysis of variance (α=0.05). <h3>Results</h3> Using dose methodology, the mean prostate BED was 223.5 ± 24.2 Gy. Mean urethral dose and D10 were 182.5 ± 22.8 and 232.0 ± 37.0 respectively. Mean rectal dose and D2cc were 33.2 ± 7.9 and 86.4 ± 24.4 respectively. CTCAE toxicity is reported in Table 1. Overall, there was minimal grade 3+ toxicity. No statistical differences were noted among any of the toxicity grades and there was no correlation between urethral or rectal dose and toxicity. <h3>Conclusion</h3> This study demonstrates the feasibility of using the spatial combination of biologic effective doses for OARs in combination EBRT and brachytherapy for prostate cancer. In this study cohort, the level of toxicity was generally less than reported elsewhere. This dataset serves as an opportunity to propose using combined constraints as a conservative estimate for future studies to estimate OAR tolerances. Initially, we propose conservative combination constraints equal to one standard deviation below our mean patient dosimetry: Urethra D10 < 160 Gy and Rectum D2cc < 60 Gy. The process of establishing a useful BED between two different treatments can help redefine OAR tolerances and has applicability for other treatment sites with combined therapy such as cervix cancer and re-irradiation.

Prospective Evaluation of Role of Hybrid Approach Brachytherapy with MRI Only at First Fraction Followed by CT Based IGBT in Subsequent Sessions in Cervical Cancer Patients

<h3>Purpose/Objective(s)</h3> We evaluated target volume coverage and doses to organ at risks (OARs) using combined MRI and CT based intracavitary brachytherapy (hybrid approach) with MRI only at first fraction and CT in subsequent fractions for cervical cancer. <h3>Materials/Methods</h3> This is a single-arm, prospective, interventional trial (CTRI/2019/01/01691). 22 cervical cancer patients, after external beam radiotherapy (EBRT) by 3D-CRT, underwent IGBT planning at first fraction using MRI and CT in the second (CT-1) and third (CT-2) fractions (7Gy per fraction). The dose received by at least 90% of the volume (D90%) for high-risk clinical target volume (HR-CTV) and the doses to 0.1 cm³, 1 cm³, and 2 cm³ for the OARs were evaluated. <h3>Results</h3> Median age was 50 years. Stage distribution (FIGO 2009) was 6:8:8 for IIB:IIA:IIIB respectively. Median EBRT dose was 50Gy and all received weekly concurrent cisplatin at doses of 40mg/m² (median 5 cycles). HR-CTV volumes (mean ± SD) of MRI, CT-1 and CT-2 were 24.23 cc ± 9.26 cc, 27.82 cc ± 15.37 cc and 24.82 cc ± 11.14 cc respectively. No statistically significant differences in bladder (MRI, 99.0 cc ± 53.4 vs CT-1, 99.1 cc ± 54.2 vs CT-2, 105.6 cc ± 42.8), rectum (MRI, 42.6 cc ± 13.4 vs CT-1, 50.8 cc ± 23.8 vs CT-2, 47.0 cc ± 12.9) and sigmoid (MRI, 25.3 cc ± 12.1 vs CT-1, 25.2 cc ± 12.6 vs CT-2, 34.6 cc ± 16.9) volumes. D90% doses for HR-CTV were significantly higher in MRI based plans as compared to CT-1 (MRI, 108.86% vs CT-1, 98%, p=0.03) but not different than CT-2 (MRI, 108.86% vs CT-2, 106.86%, p=0.07). Doses OARs were not different (Table 1). At a median follow-up of 25 months, loco-regional control was 95.4% and any acute or late toxicities were limited to grade II. <h3>Conclusion</h3> MRI-based IGBT plans deliver higher doses to HR-CTV than CT-based plans and this can be further improved during subsequent fractions. Hybrid approach brachytherapy is feasible and cost-effective approach in limited resources constraint settings.

Superior Post-Treatment Biopsy Outcomes with High Dose SBRT Compared to High-Dose Conventionally Fractionated IMRT for Clinically Localized Prostate Cancer

<h3>Purpose/Objective(s)</h3> To compare post-treatment biopsy outcomes for clinically localized prostate cancer patients treated with high-dose conventionally fractionated intensity modulated radiotherapy (CF- IMRT) versus high-dose stereotactic body radiotherapy (SBRT). <h3>Materials/Methods</h3> 451 patients with low and intermediate risk prostate cancer treated with high dose external beam radiotherapy underwent a post-treatment biopsy which was routinely performed at our institution to assess local control status. Biopsies were performed 2-3 years after completion of radiotherapy. 221 patients were treated with CF-IMRT to a median dose of 75.6 Gy (range: 64.8-86.4) and 230 patients were treated with SBRT to a median dose of 40 Gy in 5 fractions (range: 32.5-42.0). A 6-month course of androgen deprivation therapy (ADT) was used in conjunction CF-IMRT and SBRT in 38% and 17% of patients. The percentage comprising low, favorable intermediate and unfavorable intermediate risk group were similar (CF-IMRT: 23%, 36% and 41%; SBRT: 18%, 49%, 33%). The histological outcome of the prostate biopsy was classified as positive (prostatic adenocarcinoma without typical radiation–induced changes), negative (no evidence of carcinoma) or severe treatment effect. <h3>Results</h3> The incidence of a positive post treatment among the IMRT and SBRT cohorts were 49% and 17%, respectively (p< 0.001). The incidence of a positive biopsy for low risk, favorable- intermediate risk and unfavorable- intermediate risk patients treated with IMRT and SBRT were: IMRT: 40%, 52%, and 52%; SBRT: 7.1%, 17%, and 21%, respectively. Multivariable analysis evaluating co-variates associated with a positive post-treatment biopsy was IMRT (P< 0.001 CI:0.12, 0.33) with 5-fold higher odds of a positive biopsy compared to SBRT. Other variables including the use of ADT and the risk group did not significantly impact on the biopsy outcome. <h3>Conclusion</h3> The use of SBRT in the treatment of low and intermediate risk prostate was associated with improved post-treatment biopsy outcomes compared to conventionally fractionated IMRT. These findings were observed even in the setting of high-dose IMRT to prescribed doses of ≥75.6 Gy. We hypothesize that these findings may be related to the greater ablative potential of high dose SBRT compared to IMRT.

CT-based image-guided brachytherapy in uterine cervical cancer: Effect of tumor dose and volume on local control

To determine the optimal primary tumor dose for cervical cancer treatment using computed tomography (CT)-based image-guided brachytherapy (IGBT). We retrospectively reviewed 171 patients with cervical cancer who underwent both external beam radiation therapy (EBRT) and IGBT between May 2015 and December 2019. Majority of EBRT plan included central shielding technique. CT-based IGBT was performed weekly a median of three times. Magnetic resonance imaging preceded the first and third session of IGBT for target delineation. The median age of the patients was 64 years (range: 30-91 years). The median follow-up time for living patients was 43 months (range: 6-76 months). The 3-year local control rates according to the International Federation of Gynecology and Obstetrics (FIGO, 2008) stages were 89%, 100%, 92%, 89%, 78%, and 100% for stages IB, IIA, IIB, IIIA, IIIB, and IVA, respectively. The median EBRT dose to the central pelvis and parametrium/pelvic wall was 41.4 Gy and 50.4 Gy, respectively. Patients who received a cumulative 2 Gy equivalent dose (EQD2) (α/β = 10 Gy) of high-risk clinical target volume (HR CTV) D90% ≥ 75 Gy achieved a long-term local control rate of 93%, compared with 80% in those who received <75 Gy (p = 0.02). This is one of the largest CT-based IGBT series examining the treatment of cervical cancer based on the tumor dose-volume relationship. An HR CTV D90% ≥75 Gy was significantly associated with favorable local control in this study.

Nomograms Combining Clinical and Imaging Parameters to Predict Recurrence and Disease-free Survival After Concurrent Chemoradiotherapy in Patients With Locally Advanced Cervical Cancer

To investigate the value of nomograms based on clinical prognostic factors (CPF), intravoxel incoherent motion diffusion weighted imaging (IVIM-DWI) and MRI-derived radiomics in predicting recurrence and disease-free survival (DFS) after concurrent chemoradiotherapy (CCRT) for locally advanced cervical cancer (LACC). Retrospective analysis of data from 115 patients with ⅠB-ⅣA cervical cancer who underwent CCRT and had been followed up consistently. All patients were randomized 2:1 into training and validation groups. Pre-treatment IVIM-DWI parameters (ADC-value, D-value, D*-value and f-value) and pre- and post-treatment three-dimensional radiomics parameters (from axial T2WI) of primary lesions were measured. The LASSO algorithm and Logistic regression analysis were used to filter texture features and calculate radiomics score (Rad-score). Multivariate Logistic and Cox regression analysis was used to construct nomograms to predict recurrence and DFS for patients with LACC after CCRT respectively, with internal and external validation. External beam radiotherapy dose, f-value, pre-treatment and post-treatment Rad-score were independent prognostic factors for recurrence and DFS in patients with cervical cancer, forming Model1 and Model2, with OR values of 0.480, 1.318, 3.071, 3.200 and HR values of 0.322, 3.372, 5.138, 7.204. The area under the curve (AUC) of Model1 for predicting recurrence of cervical cancer was 0.977, with internal and external validation C-indexes of 0.977 and 0.962. The AUC for Model2 predicting disease-free survival (DFS) at 1, 3, and 5 years was 0.895, 0.888 and 0.916 respectively, with internal and external C-indexes of 0.860 and 0.892. The decision curves analysis and clinical impact curves further indicate the high predictive efficiency and stability of nomograms. The nomograms based on clinical, IVIM-DWI and radiomics parameters have high clinical value in predicting recurrence and DFS of patients with LACC after CCRT and can provide a reference for prognostic assessment and individualized treatment of cervical cancer patients.

Integrating external beam and prostate seed implant dosimetry for intermediate and high-risk prostate cancer using biologically effective dose: Impact of image registration technique

Combining external beam radiation therapy (EBRT) and prostate seed implant (PSI) is efficacious in treating intermediate- and high-risk prostate cancer at the cost of increased genitourinary toxicity. Accurate combined dosimetry remains elusive due to lack of registration between treatment plans and different biological effect. The current work proposes a method to convert physical dose to biological effective dose (BED) and spatially register the dose distributions for more accurate combined dosimetry. A PSI phantom was CT scanned with and without seeds under rigid and deformed transformations. The resulting CTs were registered using image-based rigid registration (RI), fiducial-based rigid registration (RF), or b-spline deformable image registration (DIR) to determine which was most accurate. Physical EBRT and PSI dose distributions from a sample of 91 previously-treated combined-modality prostate cancer patients were converted to BED and registered using RI, RF, and DIR. Forty-eight (48) previously-treated patients whose PSI occurred before EBRT were included as a "control" group due to inherent registration. Dose-volume histogram (DVH) parameters were compared for RI, RF, DIR, DICOM, and scalar addition of DVH parameters using ANOVA or independent Student's t tests (α = 0.05). In the phantom study, DIR was the most accurate registration algorithm, especially in the case of deformation. In the patient study, dosimetry from RI was significantly different than the other registration algorithms, including the control group. Dosimetry from RF and DIR were not significantly different from the control group or each other. Combined dosimetry with BED and image registration is feasible. Future work will utilize this method to correlate dosimetry with clinical outcomes.

Intraoperative radiation therapy for early-stage breast cancer: a single-institution experience.

BackgroundTo assess outcomes and toxicity after low-energy intraoperative radiotherapy (IORT) for early-stage breast cancer (ESBC).Materials and methodsWe reviewed patients with unilateral ESBC treated with breast-conserving surgery and 50-kV IORT at our institution. Patients were prescribed 20 Gy to the surface of the spherical applicator, fitted to the surgical cavity during surgery. Patients who did not meet institutional guidelines for IORT alone on final pathology were recommended adjuvant treatment, including additional surgery and/or external-beam radiation therapy (EBRT). We analyzed ipsilateral breast tumor recurrence, overall survival, recurrence-free survival and toxicity.ResultsAmong 201 patients (median follow-up, 5.1 years; median age, 67 years), 88% were Her2 negative and ER positive and/or PR positive, 98% had invasive ductal carcinoma, 87% had grade 1 or 2, and 95% had clinical T1 disease. Most had pathological stage T1 (93%) N0 (95%) disease. Mean IORT applicator dose at 1-cm depth was 6.3 Gy. Post-IORT treatment included additional surgery, 10%; EBRT, 11%; adjuvant chemotherapy, 9%; and adjuvant hormonal therapy, 74%. Median total EBRT dose was 42.4 (range, 40.05–63) Gy and median dose per fraction was 2.65 Gy. At 5 years, the cumulative incidence of ipsilateral breast tumor recurrence was 2.7%, the overall survival rate was 95% with no breast cancer-related deaths, and the recurrence-free survival rate was 96%. For patients who were deemed unsuitable for postoperative IORT alone and did not receive recommended risk-adapted EBRT, the IBTR rate was 4.7% versus 1.7% (p = 0.23) for patients who were either suitable for IORT alone or unsuitable and received adjuvant EBRT. Cosmetic toxicity data was available for 83%, with 7% experiencing grade 3 breast toxicity and no grade 4–5 toxicity.ConclusionsIORT for select patients with ESBC results in acceptable outcomes in regard to ipsilateral breast tumor recurrence and toxicity.

A prospective study of radical external beam radiotherapy versus external beam radiotherapy combined with intraluminal brachytherapy for primary esophageal cancer

PURPOSEThis study compared the efficacy and side effects of external beam radiotherapy (EBRT) + intraluminal brachytherapy (IBT) with EBRT alone in patients with primary thoracic esophageal cancer. MATERIALS AND METHODSBetween 2013 and 2020, 64 patients with primary thoracic esophageal cancer without surgery received radiotherapy. Thirty-two patients received EBRT + IBT. EBRT dose was 50 Gy, 2 Gy/f, 5 times a week, and IBT dose was 10 Gy, 5 Gy/f, once a week. Thirty-two patients received EBRT alone, and the total dose was 60 Gy. The median followup was 19 months. RESULTSThe local control rates (LCR) of EBRT + IBT and EBRT alone group at 1, 2, and 3 years after treatment were 88% and 72%, 53% and 22%, 25%, and 9%, respectively. The overall survival (OS) of the EBRT + IBT and EBRT alone group at 3 years after treatment were 38% and 9%. The 3-year local recurrence-free survival (LRFS) rates of EBRT + IBT and EBRT alone group were 25% and 9%. Univariate analysis showed that EBRT + IBT could be the prognostic factor improving OS (p = 0.04), and tumor located in the mid-thoracic region exhibited a poorer prognosis on LRFS (p = 0.03). Grade 3 or higher acute side effects included two cases of dysphagia and three cases of bone marrow suppression. Severe late side effects included three cases of fistula, three cases of radiation pneumonia, and five cases of stenosis requiring treatment. CONCLUSIONSCompared with EBRT alone, EBRT + IBT is an effective treatment modality for T1∼3NanyM0 primary thoracic esophageal cancer with good local control. It can prolong the survival time of patients and has acceptable toxicity.

Abstract 1304: Brachytherapy dose heterogeneity primes response to immune checkpoint blockade to generate anti-tumor immunity

Abstract Purpose: The immunologic effects of radiation (RT) are influenced by dose and each may be optimized over a unique dose range. We used brachytherapy (BT) to deliver a heterogeneous RT dose within a single tumor and compared the relative capacities of BT and homogenous dose external beam radiotherapy (EBRT) to enhance the anti-tumor immune response in combination with immune checkpoint inhibition (ICI). Materials and Methods: We used syngeneic murine models of melanoma (B78) and prostate cancer (Myc-CaP). To evaluate the effect of BT on the microenvironment, mice bearing B78 tumors were randomized to receive BT (192Ir source, 2 Gy to tumor edge), sham insertion, or EBRT (2, 8, or 20 Gy). Tumors were harvested 3 days following RT and in the case of BT, punch excisions were taken from the dissected tumor 1, 3, and 5 mm from the source location for gene expression and immune cell infiltration analysis. To evaluate anti-tumor response, we randomized mice bearing B78 tumors on the right flank (~200 mm3) and left shoulder (~100 mm3) to BT alone, catheter insertion alone, BT + ICI (anti-PD-L1 and anti-CTLA-4, 200 µg IP injection days 3, 6, 9 after RT), EBRT (2 or 8 Gy) + ICI, or ICI alone. Mice bearing MyC-CaP tumors were randomized to sham insertion, BT (2 or 8 Gy to tumor edge), BT + ICI, EBRT (2, 8, or 20 Gy) + ICI, or ICI alone. Immediately following RT, mice were engrafted with a secondary tumor. Results: Using qPCR analysis, we observed statistically significant differences in gene expression of Mhc-1, Ifnβ, and Vcam between tissue locations in BT treated tumors. Furthermore, in a single tumor BT optimally engaged all three pathways while each EBRT dose only optimally engaged one. Bulk RNAseq analysis revealed unique gene expression signatures between tissue locations in BT treated tumors. We observed significant differences in number of CD8+ and FOXP3+ cells between tissue locations. In B78 tumor bearing mice, we observed a greater anti-tumor response at the secondary untreated tumor with BT + ICI (63% CR) compared to EBRT + ICI (12.5% CR). In mice bearing Myc-CaP tumors treated with BT + ICI, we observed a significant reduction in tumor growth compared to other groups and no engraftment at the secondary tumor. This effect was dependent on both CD4+ and CD8+ cells and was sensitive to BT dose. Splenocytes harvested from disease-free mice co-cultured with tumor cells showed significant increases in expression of T cell activation markers in both CD4+ and CD8+ cell populations. Conclusions: We report dose-dependent effects of RT on expression of immune susceptibility markers and immune cell infiltration in a murine tumor model. We observe that a heterogeneous dose of BT results in spatial differences in these effects within a single tumor. This spatial heterogeneity in activation of immune mechanisms may underlie a greater capacity of BT to augment anti-tumor immune response when combined with ICI, as compared to homogenous dose EBRT. Citation Format: Justin C. Jagodinsky, Wonjong Jin, Jessica M. Vera, Raghava N. Sriramaneni, Paul A. Clark, Keng-Hsueh S. Lan, Ishan Chakravarty, Noah Siegel, Raad H. Allawi, Sarah E. Emma, Ian S. Arthur, Rupak K. Das, Irene M. Ong, Jessica R. Miller, Zachary S. Morris. Brachytherapy dose heterogeneity primes response to immune checkpoint blockade to generate anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1304.

High-dose-rate brachytherapy boost for elderly patients with intermediate to high-risk prostate cancer: 5-year clinical outcome of the PROSTAGE cohort

PurposeTo analyze the oncological outcome in elderly (>70 years) prostate cancer after high-dose rate brachytherapy (HDB) boost. Materials/methodsIn this retrospective study, patients with intermediate (IR) and high-risk (HR) prostate cancer underwent external beam radiation therapy (EBRT) followed by HDB boost with/without androgen deprivation therapy (ADT). The impact of age (≤70y vs. > 70y) was investigated. Oncological outcome focused on biochemical relapse-free survival (bRFS), cause-specific (CSS) and overall survival (OS). Late genito-urinary (GU) and gastro-intestinal (GI) toxicities were investigated. ResultsFrom 07/08 to 01/22, 518 pts received a HDB boost, and 380 were analyzed (≤70y:177pts [46.6%] vs. > 70y:203pts [53.4%]). Regarding NCCN classification, 98 pts (≤70y: 53pts; >70y: 45pts; p = 0.107) and 282 pts (≤70y: 124pts; >70y: 158pts; p = NS) were IR and HR pts respectively. Median EBRT dose was 46 Gy [37.5–46] in 23 fractions [14–25]. HDB boost delivered a single fraction of 14/15 Gy (79%). ADT was used in 302 pts (≤70y: 130pts; >70y: 172pts; p = 0.01). With MFU of 72.6 months [67–83] for the whole cohort, 5-y bRFS, 5-y CSS and 5-y OS were 88% [85–92], 99% [97–100] and 94% [92–97] respectively; there was no statistical difference between the two age groups except for 5-y CSS (p = 0.05). Late GU and GI toxicity rates were 32.4% (G ≥ 3 7.3%) and 10.1% (no G3) respectively. ConclusionsFor IR and HR prostate cancers, HDB boost leads to high rates of disease control with few late G ≥ 3 GU/GI toxicities. For elderly pts, HDB boost remains warranted mainly in HR pts, while competing comorbidity factors influence OS.

Long-term versus short-term androgen deprivation combined with EBRT for unfavourable prostate cancer.

Previous mature trials on long-term versus short-term androgen deprivation combined with external beam radiotherapy (EBRT) for prostate cancer were limited to conventional dose radiotherapy (65–70 Gy) leaving some uncertainty as to whether the same conclusions would apply with modern EBRT doses and techniques.1–3 In 2017,1 the 20-year follow-up of RTOG 9202 compared androgen deprivation for 4 months versus 28 months combined with conventional doses of EBRT of 65–70 Gy in 1554 men. Long-term androgen deprivation (LTAD) improved 15-year distant metastasis-free survival from 74·0% (95% CI 70·8–77·1) to 82·6% (79·8–85·3; p<0·0001), biochemical failure-free survival from 38·8% (95% CI 35·4–42·4) to 54·6% (51·0–58·2; p<0·0001), and disease-free survival from 10·0% (95% CI 6·8–12·4) to 15·7% (10·1–18·5).

A feasibility study of a modified treatment strategy combined external beam radiation therapy and brachytherapy for cervical cancer.

PurposeTo evaluate the feasibility of a modified treatment strategy combined external beam radiation therapy (EBRT) and brachytherapy (BT) for cervical cancer through a dosimetry analysis.Material and methodsThis study retrospectively selected 12 cervical cancer patients treated with the conventional treatment strategy, which consisted of 45─50 Gy/25 fractions of EBRT using volumetric‐modulated arc therapy (VMAT) and image‐guided BT with a fraction dose of 5─7 Gy. The modified treatment strategy decreased the central EBRT dose while increasing the number of BT fractions. New target volumes were additionally contoured, and new VMAT EBRT plans were generated for the modified treatment strategy. The dosimetric parameters for evaluation included the doses to the most irradiated 2 cc (D2cc) of the organs at risk (OARs) and doses to at least 90% (D90) of the gross tumor volume (GTV) and high‐risk clinical target volume (HR‐CTV). The total doses to OARs and targets obtained by adding the equivalent doses in 2 Gy fraction (EQD2) from the EBRT and BT plans were used for quantitative comparison between the modified and conventional treatment strategies.ResultsComparison to the conventional treatment strategy, the modified treatment strategy resulted in a higher bladder D2cc, a slightly lower rectal D2cc and a similar HR‐CTV D90, all with no significant differences (p > 0.05). The GTV D90 of the modified treatment strategy was significantly higher than that of the conventional treatment strategy (p < 0.01).ConclusionThe modified treatment strategy can significantly increase the BT dose while remaining the total doses to the bladder and rectum basically unchanged, demonstrating its feasibility and promising prospect in clinical use.

3D-Image-Guided Multi-Catheter Interstitial Brachytherapy for Bulky and High-Risk Stage IIB-IVB Cervical Cancer.

Simple SummaryThe prognosis of locally advanced cervical cancer still remains poor. Recently, image-guided brachytherapy ameliorated local control and pelvic control in these patients. Additionally, concurrent chemoradiotherapy with interstitial brachytherapy (ISBT) demonstrated more favorable outcomes than that with intracavity brachytherapy. The purpose of our study was to evaluate the efficacy and safety of CT-MRI-guided multi-catheter ISBT for bulky (≥4 cm) and high-risk stage IIB-IVB cervical cancer. Total of 18 patients with squamous cell carcinoma received concurrent chemoradiotherapy with ISBT were assessed. Four (22.2%), seven (38.9%), and seven (38.9%) patients were diagnosed with stage II, III, and IV cervical cancer, respectively. The four-year local control, pelvic control, disease-free survival, and overall survival rates were 100%, 100%, 81.6%, and 87.8%, respectively. Although three (16.7%) patients experienced grade 3 late adverse events, no one had procedure-related complications. CT-MRI-guided multi-catheter ISBT could be a promising treatment strategy for locally advanced cervical cancer. This study aimed to evaluate the efficacy and safety of computed tomography-magnetic resonance imaging (CT-MRI)-guided multi-catheter interstitial brachytherapy for patients with bulky (≥4 cm) and high-risk, stage IIB–IVB advanced cervical cancer. Eighteen patients who underwent concurrent chemoradiotherapy with multi-catheter interstitial brachytherapy between September 2014 and August 2020 were enrolled. The prescribed dose of external beam radiotherapy was 45–50.4 Gy, and the brachytherapy high-dose-rate aim was 25–30 Gy per 5 fractions. The endpoints were four-year local and pelvic control rates, four-year disease-free and overall survival rates, and the adverse events rate. The median follow-up period was 48.4 months (9.1–87.5 months). Fifteen patients received concurrent cisplatin therapy (40 mg/m2, q1week). Four (22.2%), seven (38.9%), and seven (38.9%) patients had stage II, III, and IV cervical cancer, respectively. Pelvic and para-aortic lymph node metastases were observed in 11 (61.1%) and 2 (11.1%) patients, respectively. The median pre-treatment volume was 87.5 cm3. The four-year local control, pelvic control, disease-free survival, and overall survival rates were 100%, 100%, 81.6%, and 87.8%, respectively. Three (16.7%) patients experienced grade 3 adverse events, and none experienced grade 4–5 adverse events. CT-MRI-guided multi-catheter interstitial brachytherapy could be a promising treatment strategy for locally advanced cervical cancer.

Quantification of uptake in pelvis F-18 FLT PET-CT images using a 3D localization and segmentation CNN.

The purpose of this work was to develop and validate a deep convolutional neural network (CNN) approach for the automated pelvis segmentation in computed tomography (CT) scans to enable the quantification of active pelvic bone marrow by means of Fluorothymidine F-18 (FLT) tracer uptake measurement in positron emission tomography (PET) scans. This quantification is a critical step in calculating bone marrow dose for radiopharmaceutical therapy clinical applications as well as external beam radiationdoses. An approach for the combined localization and segmentation of the pelvis in CT volumes of varying sizes, ranging from full-body to pelvis CT scans, was developed that utilizes a novel CNN architecture in combination with a random sampling strategy. The method was validated on 34 planning CT scans and 106 full-body FLT PET-CT scans using a cross-validation strategy. Specifically, two different training and CNN application options were studied, quantitatively assessed, and statisticallycompared. The proposed method was able to successfully locate and segment the pelvis in all test cases. On all data sets, an average Dice coefficient of 0.9396 0.0182 or better was achieved. The relative tracer uptake measurement error ranged between 0.065% and 0.204%. The proposed approach is time-efficient and shows a reduction in runtime of up to 95% compared to a standard U-Net-based approach without a localizationcomponent. The proposed method enables the efficient calculation of FLT uptake in the pelvis. Thus, it represents a valuable tool to facilitate bone marrow preserving adaptive radiation therapy and radiopharmaceutical dose calculation. Furthermore, the method can be adapted to process other bone structures as well asorgans.

Quality of Life Implications of Dose-Escalated External Beam Radiation for Localized Prostate Cancer: Results of a Prospective Randomized Phase 3 Clinical Trial, NRG/RTOG 0126

External beam radiation therapy (EBRT) dose escalation has been tested in multiple prospective trials. However, the impact on patient reported outcomes (PROs) associated with higher doses of EBRT remain poorly understood. We sought to assess the differences in PROs between men treated with a dose of 70.2 Gy versus 79.2 Gy of EBRT for prostate cancer. The phase 3 clinical trial RTOG 0126 randomized 1532 patients with prostate cancer between March 2002 and August 2008 to 79.2 Gy over 44 fractions versus 70.2 Gy over 39 fractions. Eligible patients participated in the PRO data collection. PROs completed included the International Index of Erectile Function Questionnaire (IIEF), Functional Alterations due to Changes in Elimination (FACE), and the Spitzer Quality of Life Index (SQLI). The timepoints for the IIEF were collected pre-entry and at 6, 12, and 24 months. The FACE and SQLI were collected pre-entry and at 3, 6, 12, 18, and 24 months. The impact of EBRT dose to normal structures (penile bulb, rectum, and bladder) on PROs was also examined. Mixed effects models were used to analyze trends across time. In total, 1144 patients completed baseline IIEF forms and of these, 56%, 64%, and 61% completed the IIEF at 6, 12, and 24 months, respectively; 1123 patients completed the FACE score at baseline and 50%, 61%, 73%, 61%, and 65% completed all 15 items for the FACE metric at timepoints of 3, 6, 12, 18, and 24 months, respectively. Erectile dysfunction at 12 months based on the single question was not significantly different between arms (38.1% for the standard dose radiation therapy arm vs 49.7% for the dose escalated radiation therapy arm; P=.051). Treatment arm (70.2 vs 79.2) had no significant impact on any PRO metrics measured across all collected domains. Comprehensive dosimetric analyses are presented and reveal multiple significant differences to regional organs at risk. Compliance with PRO data collection was lower than anticipated in this phase 3 trial. Examining the available data, dose escalated EBRT did not appear to be associated with any detriment to PROs across numerous prospectively collected domains. These data, notwithstanding limitations, add to our understanding of the implications of EBRT dose escalation in prostate cancer. Furthermore, these results illustrate challenges associated with PRO data collection.