External Beam Radiotherapy Dose Research Articles

Direction Modulated Brachytherapy Tandem Model Applicators for Treatment Planning of Multi-Institutional Cervical Cancer Cases

Direction Modulated Brachytherapy (DMBT) offers a means of utilizing an anisotropic source to create more conformal dose distributions when integrated with image-guided adaptive brachytherapy (IGABT). Authors sought to validate the implementation of nine unique six-channeled, MRI-compatible, novel DMBT tandem applicators of varying physical dimensions within Varian's BrachyVision® (v16.1) treatment planning system (BV-TPS). A total of 110 retrospective clinically delivered high-dose-rate (HDR) cervical cancer brachytherapy plans, from three institutions, were re-planned for each of the nine DMBT tandem models within the BV-TPS, using the latest VEGO® inverse optimization algorithm, with dose heterogeneity accounted for through AcurosBV®. Plans consisted of both intracavitary (77 plans) and interstitial (33 plans) cases with an average prescription dose and high-risk clinical target volumes (CTVHR) of 607±113 cGy and 26.96±14.95 [range 6.70-69.58] cm3, respectively. During re-planning, the conventional tandems were replaced by one of the nine DMBT tandem models while leaving ovoids or rings, and needles (if present), in place. A two-step inverse optimization process was performed such that the lowest possible organs at risk (OAR) D2cc doses could be achieved while 1) keeping equivalent target coverage (ΔCTVHR-D90 to within ±0.5%) and, at the same time, 2) maintaining the general pear-shape dose distribution of the original plans. Noteworthy improvements in plan quality were achieved by all nine DMBT tandem models, which are presented in Table 1. Irrespective of the model, about ∼50 cGy reduction in D2cc across all OARs appear feasible. There is also a general trend of D2cc reductions' magnitude becoming smaller as the CTVHR volume increased due to loss in modulation at distance. Additionally, D2cc reductions in terms of EQD2 [Gy] were calculated assuming each re-plan was delivered throughout the course of treatment, which includes the external beam radiotherapy dose of 45 Gy and showed significant reductions of -6.29±4.38 Gy, -3.80±2.06 Gy, and -4.86±3.02 Gy for the bladder, rectum, and sigmoid, respectively, for DMBT model #9 for example. We have successfully incorporated nine DMBT tandem models into a commercial TPS and re-planned 110 cases, to a total of 990 plans. All nine DMBT tandem models were each able to generate notable D2cc reductions to OARs (∼50 cGy), without compromising target coverage, across plans from multiple institutions with various clinical/optimization practices. The results indicate both a promising impact and smooth integration of DMBT tandem technology into modern clinical IGABT workflow.

Direction Modulated Brachytherapy Tandem Model Applicators for Treatment Planning of Multi-Institutional Cervical Cancer Cases: Removing Needles in Intracavitary-Interstitial Techniques

To evaluate the potential of nine direction modulated brachytherapy (DMBT) tandem applicator models of various designs to obviate the need for needles during intracavitary-interstitial (IC-IS) cervical cancer brachytherapy. A cohort of 33 retrospective clinical high dose-rate (HDR) brachytherapy plans, from three institutions, were re-planned with Varian's BrachyVision® (v16.1) treatment planning system (BV-TPS), using the latest VEGO® inverse optimization algorithm, with dose heterogeneity accounted for through the AcurosBV® model-based dose calculation algorithm. All plans consisted of IC-IS cases, with a range of 2-4 freehand-loaded needles, with an average prescription dose of 706±54 cGy and average high-risk clinical target volume (HRCTV) of 36.0±17.4 [range 9.8-69.6] cm3. Nine novel DMBT tandem models of varying physical dimensions were integrated for the first time into the BV-TPS, with thicknesses (4-8 mm). During re-planning, the conventional tandems and all of the needles were replaced by one of the nine DMBT tandem models while leaving the ovoids/rings in place. An optimization process was performed such that the lowest possible organs at risk (OAR) D2cc doses could be achieved while keeping equivalent target coverage (ΔHRCTV-D90 to within ±0.5%) and maintaining a pear-shape dose distribution. The process was repeated for each of the nine DMBT tandem models resulting in (33 × 9 =) 297 plans. Average ΔHRCTV-D90 was +0.35±0.39% (+2.8±3.1 cGy). OAR D2cc reductions were achieved by all models for all plans. The performance of the thickest DMBT model (8 mm) was the best in terms of achieving the lowest D2cc for all OARs, with 31 out of 33 plans (94%) achieving lower D2cc doses for all three OARs. The two cases in which the D2cc doses could not be reduced had HRCTV volumes ranging between 50 cm3 and 60 cm3. Additionally, D2cc reductions in terms of EQD2 [Gy] were calculated assuming each re-plan was delivered throughout the entire course of a patient's treatment, which included the external beam radiotherapy dose of 45 Gy, showed significant reductions of -2.64±2.67 Gy, -1.65±1.97 Gy, and -2.80±2.20 Gy for bladder, rectum, and sigmoid, respectively. According to the results, it is clinically feasible to replace the conventional IC-IS cases, with 2-4 freehand-loaded needles, with the DMBT tandem technology, effectively avoiding the need for needle involvement.

Disease Control and Toxicity Outcomes after Intraoperative HDR Brachytherapy for Neck Recurrences in Patients Previously Irradiated Head and Neck Cancer

Despite recent advances in local and systemic therapies for head and neck squamous cell carcinomas (HNSCC), the most common types of treatment failure remain local and regional. Patients with HNSCC also have a higher risk of developing secondary head and neck tumors due to a field cancerization phenomenon. Treatment of these recurrences poses a challenge, particularly in patients having previously received full dose external beam radiotherapy (EBRT) to the head and neck region. This study evaluates the clinical outcomes of intraoperative Harrison-Anderson-Mick applicator (HAM) HDR brachytherapy (BT) after salvage neck dissection for neck recurrences in patients previously irradiated for HNSCC. All patients having received HAM BT for HNSCC neck recurrences at a single institution were identified. Demographic, treatment, disease control and toxicity data were collected retrospectively. Toxicity was graded as per Common Terminology Criteria for Adverse events version 5. The Kaplan Meier method was used to assess overall survival (OS) and ipsilateral regional control (IRC) from the time of HAM BT. Nineteen patients with regional recurrence of HNSCC were treated with HAM BT Ir-192 between July 2006 and June 2022, with a median follow-up for survival of 51.4 months (range: 2.5-186.7). The median BT dose was 12.5 Gy delivered intraoperatively at 5 mm tissue depth/1 cm from source. Fifteen patients (78.9%) also received postoperative EBRT to a median dose of 46 Gy in 23 fractions and 13 (68.4%) received systemic therapy. Six patients (31.6%) developed ipsilateral neck recurrences (4 who had adjuvant EBRT and 2 who did not), 2 patients had primary site recurrences and 5 patients developed distant metastases. In terms of acute toxicity, 4 patients had grade 3 dysphagia requiring feeding tube (FT) placement and one patient required surgical intervention for wound necrosis. In terms of late toxicity, 2 additional patients required FT placement and 1 was able to have it removed. No grade 4+ late toxicities were noted. The IRC at the site of HAM BT at 1 year was 71.5% and 63.6% at 5 years. The 1-year OS was 81.3% and 5-year OS was 40.9%. Intraoperative HAM BT resulted in favorable rates of IRC with acceptable toxicity in the reirradiation setting for HNSCC.

A comparative study of the effectiveness of multiagent platinum based concurrent plus adjuvant versus conventional single agent platinum based concurrent chemotherapy in carcinoma cervix.

85 Background: Cervical cancer is the 4th most common cancer in females worldwide. Combination of external beam radiotherapy (EBRT) and intracavitary brachytherapy (BT) with concurrent chemotherapy is the current standard of care for locally advanced cervical cancer. Even though the trials used separate combinations, the common end point suggested that platinum is single most effective chemotherapy agent. Since the latest data on platinum based polychemotherapy globally indicates its overall benefit, further trials are required to determine what regimens would be ideal for treatment of cervical cancer with maximum benefits and least toxicities. Objectives: 1. To compare the response to doublet polychemotherapy with conventional chemotherapy in carcinoma cervix treated with chemoradiation. 2. To compare toxicity profile of doublet polychemotherapy with conventional chemotherapy. Methods: 66 patients of carcinoma cervix were enrolled in this study and were randomized to two arms. Arm A (n=34) was the experimental arm and the patients received concurrent weekly cycles of cisplatin(40mg/m2) plus gemcitabine (125mg/m2) along with EBRT followed by HDR brachytherapy, after 2-3 weeks of which they received 2 adjuvant cycles (21 days each) of gemcitabine (1000mg/m2 on Day1 and Day 8) and cisplatin (50mg/m2 on Day 1). Arm B(n=32) was the control arm and the patients received standard treatment which is concurrent weekly cycles single agent cisplatin(40mg/m2) with EBRT followed by HDR brachytherapy. EBRT doses ranged from 45Gy to 50.4 Gy at 1.8 to 2 Gy per fraction .BT application was either ICBT or ISBT depending on tumour response to EBRT, assessed by MRI. Patients were followed up for response assessment and late toxicities within 6 months of completion of treatment by clinical examination and MRI which was reported using RECIST 1.1 criteria. Results: On 6 month follow up MRI, number of patients achieving CR was 10% higher in the experimental arm (Arm A, n=33;97.06%) than the control arm (Arm B, n=28;87.5%).PR was seen in 2 patients, both from Arm B. Of the 3 patients presenting with PD at follow up 1 belonged to Arm A and 2 to Arm B (2.94% vs 6.25%). On pre-brachytherapy MRIs, the size reduction was better in Arm A and this reduction allowed a majority of patients in said arm to undergo ICBT instead of ISBT. The number of patients achieving >50% reduction post EBRT was 40% higher in Arm A. Acute GI and Hematological toxicities were seen in both arms but were higher in Arm A. as was Grade 3 neutropenia. Late toxicities were similar in both arms. Conclusions: The study concluded that the use of multiagent platinum-based chemotherapy in concurrent plus adjuvant setting can be advantageous. Improved tumour reduction can be achieved & disease can be made more amenable for ICBT. The accompanying toxicities were transient and clinically manageable.

Ten years survival results of randomized study comparing weekly vs. triweekly cisplatin with concurrent radiation in locally advanced carcinoma cervix.

The current standard of treatment for locally advanced cervical cancer is concurrent chemo-radiation with improved overall survival (OS) by 6% with manageable toxicities. The cisplatin 40 mg/m2 given weekly is the widely practiced regimen for 4-6 cycles concurrently with irradiation. Two hundred and twelve patients with histologically proven squamous cell carcinoma of cervix with stages IIB to IIIB were enrolled between 2007-2011. External beam radiation dose of 45 Gy in 25 fractions was delivered over 5 weeks. Brachytherapy was delivered by manual afterloading cesium-137 (Cs137) low dose brachytherapy (LDR) using modified Fletcher suit intracavitary applicators to a total dose of 30 Gy to Point A or interstitial template to dose of 21 Gy/3 fractions with remote afterloading iridium-192 (Ir192) high dose brachytherapy (HDR). Patients were randomized to arm A receiving 40 mg/m2 of concurrent cisplatin weekly and arm B receiving 100 mg/m2 of concurrent cisplatin triweekly. One hundred and nine patients were randomized to weekly cisplatin and one hundred and three patients to triweekly cisplatin at the end of recruitment. At ten years, the OS was higher in the weekly arm (79.8%) compared to triweekly arm (70.9%). Disease free survival (DFS) was almost equal (76.1% and 73.8%) in the weekly and three-weekly arms. There is definite significance in overall DFS with patients receiving the cumulative cisplatin doses of more than 250 mg (p = 0.028). The patients with more than 45 years of age had better overall survival (OS) (79%) with statistical significance 31 (p = 0.020). Both cisplatin based triweekly and weekly concurrent chemotherapy are equally effective in terms of OS and DFS.

Factors affecting local control of bone metastases from radioresistant tumors treated with palliative external beam radiotherapy

BackgroundThis study aimed to evaluate the factors that affect the local control (LC) of bone metastases from radioresistant carcinomas (renal cell carcinoma, hepatocellular carcinoma [HCC], and colorectal carcinoma [CRC]) treated with palliative external-beam radiotherapy (EBRT).Methods and materialsBetween January 2010 and December 2020, 211 bone metastases in 134 patients were treated with EBRT in two hospitals (a cancer center and university hospital). Based on follow-up CT, these cases were reviewed retrospectively to evaluate LC at the EBRT site.ResultsThe median EBRT dose (BED10) was 39.0 Gy (range, 14.4–66.3 Gy). The median follow-up time of the imaging studies was 6 months (range, 1–107 months). The 0.5-year overall survival and LC rates of the EBRT sites were 73% and 73%, respectively. Multivariate analysis revealed that the primary sites (HCC/CRC), low EBRT dose (BED10) (≤ 39.0 Gy), and non-administration of post-EBRT bone modifying agents (BMAs) and/or antineoplastic agents (ATs) were statistically significant factors that negatively affected the LC of EBRT sites. In the absence of BMAs or ATs, the EBRT dose (BED10) escalation from 39.0 Gy improved the LC of EBRT sites. Based on ATs administration, the LC of EBRT sites was significantly affected by tyrosine kinase inhibitors and/or immune checkpoint inhibitors.ConclusionsDose escalation improves LC in bone metastases from radioresistant carcinomas. Higher EBRT doses are needed to treat patients for whom few effective systemic therapies remain available.

Tolerance limit of external beam radiotherapy combined with low-dose rate brachytherapy in normal rabbit tissue.

Dosage-optimized multimodal radiotherapies that are safe for head and neck cancer patients are desirable. In this study, we investigated tissue tolerance to varying doses of external beam radiotherapy (EBRT) combined with low-dose rate brachytherapy in the neck of a rabbit model. Twenty rabbits were used in the four test groups (five each) with iodine-125 seeds implanted in the neck treated with EBRT in four doses at 50, 40, 30 and 20Gy each. Twelve rabbits for three control groups (four each). Three months after implantation, all rabbits were euthanized, and target tissues were collected. Analyses included seed implantation assessment, histopathological evaluation, immunohistochemistry staining, terminal deoxynucleotidyl transferase dUTP nick end labeling assay, electron microscopy and statistics with the SPSS software. Five rabbits died in the four test groups, and three rabbits died in the three control groups (one per group), which showed no significant difference by survival analysis. The calculated minimum peripheral dose was 17.6Gy, the maximum dose near the seed was 1812.5Gy, the D90 was 34.5Gy and the mean dose was 124.5Gy. In all groups that received radiation, apoptosis occurred primarily in the esophageal mucosa and corresponded to the dose of radiation; a higher dose caused a greater apoptosis, with significant difference between groups (P < 0.05). Electron microscopy of carotid arteries revealed that endothelial cells were swollen and some were shed from basement membrane, but no other noticeable tissue damages. Limited EBRT at maximal dose (50Gy) combined with the brachytherapy interstitially applied to the neck was tolerated well in the rabbit model.

Outcomes following brachytherapy boost for intermediate- and high-risk prostate cancer: A retrospective bicenter study by the SFRO brachytherapy group

IntroductionRadiotherapy dose escalation improves biochemical control in intermediate- or high-risk prostate cancer. Brachytherapy boost was shown to further improve biochemical control compared to radiotherapy alone in three randomized trials. The SFRO brachytherapy group sought to evaluate the efficacy and toxicity of BT-boost for intermediate and high-risk prostate cancer in real life, and to determine prognostic factors for efficacy and toxicity. Material and methodA retrospective study was conducted, including all patients with intermediate- or high-risk prostate cancer treated with a combination of external beam radiotherapy (EBRT) and high dose-rate brachytherapy boost (HDR-BB), from 2006 until December 2019 at two centers. Patient characteristics, initial disease, treatment and follow-up were collected. Results709 patients from two centers were analyzed given a short follow-up in the other centers. Out of those, 277 were intermediate risk (170 favorable and 107 unfavorable) and 432 were high risk. The median EBRT and HDR-BB doses were 46 Gy (35–50) and 14 Gy (10–20). After a median follow-up of 62 months, biochemical control at 5 years was 87.5 % for the overall population, 91 % and 85 % for intermediate- and high-risk cancers, respectively. At 5 years, biochemical and clinical relapse-free survival, metastasis-free survival and local control rates were 83 %, 90 % and 97 % respectively. 5-years overall survival was 94 %. Late grade 2 or higher GU or GI toxicity was found in 36 patients (5 %) and 9 patients (1.3 %). ConclusionThis bicenter analysis shows the efficacy and tolerability of HDR-BB as a complement to external radiotherapy. Further improvements such as combination with new hormonal agents or new brachytherapy-radiotherapy fractionation regimens are warranted to improve further the outcomes and therapeutic ratio.

Biochemical outcomes and toxicities in young men with prostate cancer after permanent iodine-125 seed implantation: Prospective cohort study in 6662 patients

PURPOSEWe evaluated the effect of age, <60 and ≥60 years, on biochemical outcomes and toxicities in patients with prostate cancer who underwent permanent seed implantation (PI) ± external beam radiation therapy ± hormone therapy in a national Japanese prospective cohort study (J-POPS). METHODS AND MATERIALSThe safety and efficacy analyses included 6721 and 6662 patients, respectively. We categorized patients into two age groups: <60 (n = 716) and ≥60 (n = 6,005) years. We used propensity score matching (PSM) to estimate the marginal effect of age on biochemical freedom from failure (bFFF) using a Phoenix definition and Cox proportional hazard models. RESULTSThe median followup period was 60.0 months. Without PSM, men <60 years demonstrated similar 5-year bFFF (96.3%) compared with men ≥60 years (95.6%; p = 0.576); percent positive biopsies, biologically effective dose, Gleason score, risk classification, and supplemental external beam radiation therapy (p <0.001, <0.001, <0.001, 0.008, and <0.001) were significantly associated with bFFF while age was not (p = 0.576). With PSM, bFFF was not significantly different between age groups (p = 0.664); however, men <60 years showed a significantly lower incidence of declining erectile function, grade ≥2 all urinary toxicities, urinary frequency/urgency, and rectal bleeding (p <0.001, 0.024, 0.031, and 0.010) than men ≥60 years. CONCLUSIONSAfter PI, men <60 years achieved a comparable 5-year biochemical control rate and showed a lower incidence of several toxicities compared to men ≥60 years. This suggests that PI should be an excellent treatment option for men <60 years with prostate cancer.

Trans-rectal ultrasound-guided hybrid intra-cavitary and interstitial brachytherapy in carcinoma cervix: A feasibility study from a tertiary cancer center in India.

To report the feasibility of performing hybrid intra-cavitary and interstitial (IC/IS) brachytherapy in patients with carcinoma cervix under trans-rectal ultrasound (TRUS) guidance. All patients who received an external beam radiotherapy (EBRT) dose of 50 Gy in 25 fractions with weekly chemotherapy, followed by a brachytherapy boost (21 Gy in 3 fractions) were prospectively included for analysis. IC/IS brachytherapy was performed using Fletcher style tandem and ovoid applicator with interstitial component under TRUS guidance. Parameters of implant quality analyzed included ability to insert tandem, ratio of needles loaded to the number of needles inserted, and incidence of uterine or organ at risk (OARs) perforation. Dosimetric parameters evaluated were dose to point A*, TRAK, D90 high-risk clinical target volume (HR-CTV), and D2cc to OARs (bladder, rectum, and sigmoid). Width and thickness of the target was compared between TRUS (TRUSw and TRUSt) and MRI (MRIw and MRIt). Twenty carcinoma cervix patients treated with IC/IS brachytherapy were included for analysis. The mean HR-CTV volume was 36 cc. The median number of needles used were 6 (range, 2-10 needles). None of the patients had uterine perforation. Two patients had bowel and bladder perforation. The mean D90 HR-CTV and D98 HR-CTV were 87.3 Gy and 82 Gy EQD2, respectively. The mean D2cc to the bladder, rectum, and sigmoid were 80 Gy, 70 Gy, and 64 Gy EQD2, respectively. The mean dose to point A* was 70.4 Gy EQD2. The mean TRAK was 0.40. The mean TRUSw (±SD) and MRIw (±SD) were 4.58 cm (±0.44) and 4.49 cm (±0.50), respectively. The mean TRUSt (±SD) and MRIt (±SD) were 2.7 cm (±0.59) and 2.62 cm (±0.59), respectively. On statistical analysis, there was a significant correlation between TRUSw and MRIw (r = 0.93), and TRUSt and MRIt (r = 0.98). TRUS-guided IC/IS brachytherapy is feasible and provides adequate coverage of the target, with acceptable doses to OARs.

Impact of timing of adjuvant radiotherapy on locoregional control in patients with high-risk endometrial cancer

Aim: High-risk endometrial cancer has a higher risk of regional and distant recurrence. We sought to examine our institutional experience regarding the timing of adjuvant radiotherapy and local failure (LF), locoregional failure (LRF), distant failure (DF), and overall survival (OS). Methods: We retrospectively reviewed a database of patients with high-risk endometrial cancer treated with sequential chemotherapy followed by adjuvant external beam radiation therapy (EBRT) with or without brachytherapy from 2012 to 2019. Results: One hundred thirty-one patients were identified. The median age at diagnosis was 65 (range 32-81). The most prevalent FIGO stages were IIIB (28.2%, n = 37), IIIC1 (19.8%, n = 26), and IIIA (17.6%, n = 23). Of the patients, 29% (n = 38) had positive lymph nodes and 71% (n = 93) had negative lymph nodes. The most prevalent histology was endometrioid (71%, n = 93), serous (12.2%, n = 16), clear cell (9.2%, n = 12), and other (7.6%, n = 10). Moreover, 100% (n = 131) of the patients completed EBRT. The mean EBRT dose was 49.6 Gy (range 45-50.4). The median number of days between surgery and EBRT was 212.4 days (range 103-219). The mean brachytherapy dose was 14.7 Gy (range 12-30). The cumulative incidence of LF was 6.1%, LRF was 19%, DF was 19%, and the median survival was 33.4 months. For patients who completed EBRT 180 days after surgery, LRF (HR 3.55 [1.23-10.2], P = 0.013), LF (HR 1.91 [0.4-8.9], P = 0.429), DF (HR 0.91 [0.41-2], P = 0.806), and OS (HR 0.92 [0.33-2.6], P = 0.87). Conclusion: In our cohort of patients with high-risk endometrial cancer treated with chemotherapy followed by radiotherapy, delaying RT was associated with an increased risk of LRF but no differences in DF or OS.

A Fifteen Years Audit of Endometrial Cancer Referred for Adjuvant Treatment to a Tertiary Care Hospital in Northern India

Introduction: Endometrial cancer is the seventh most common cancer in women worldwide with Age Standardised Incidence Rate (ASIR) of 8.4 per lac. In Indian subcontinent, the incidence is lesser and the ASIR is 2.1/100,000 women. However, its incidence is on the steady rise in developing part of the world including India. Surgery is the primary treatment and adjuvant radiotherapy is given in patients with high-risk of recurrence and significant change has happened in the management in the last 20 years. From India limited literature is available for management practices for endometrial cancer. Aim: To assess the referral patterns, demography, staging, surgical practices, adjuvant treatment and follow-up policies for endometrial cancer in a tertiary care hospital in northern India. Materials and Methods: A retrospective cross-sectional study was done for patients having endometrial cancer treated between January 2000- December 2015 in a tertiary care hospital in northern India in January 2022. A total of 93 patients having endometrial cancer were referred for radiotherapy. For these patients, their referral patterns, demography, staging, surgical practices, adjuvant treatment and follow-up policies were analysed, retrospectively. Disease Free Survival (DFS) and Overall Survival (OS) were computed by Kaplan-Meier method. Results: The median age at presentation was 55 years. Postmenopausal vaginal bleeding was the commonest symptom 78 (83.87%). Ultrasonography 23 (24.73%) was the preferred first imaging modality. Type 1 endometroid carcinoma was 75 (80.64%) and total abdominal hysterectomy with bilateral salpingo-oophrectomy was done in 82 (88.17%). Adjuvant External Beam Radiotherapy (EBRT) with Brachytherapy (BT) was given in 61 (65.59%), EBRT alone in 7(7.52%) and BT alone given in 11 (11.83%). Median EBRT dose was 50.4 Gy. Vaginal cylinder applicator was used in 69 (95.83%) out of 72 patients receiving BT. A 6.0 Gy/# to a total of 2 fractions were given in 57 (79.16%). Median treated length of vagina was 3 cm (range 2-8 cm). Five year DFS and OS was 25% and 25% and 64% and 62% respectively in worst and best case scenario. Ten (10.75%) patients, all having high-risk had multiple visceral and local recurrence. Conclusion: In patients with endometrial cancer, total abdominal hysterectomy with bilateral salpingo-oophrectomy is commonest surgical practice with adjuvant radiotherapy in high-risk patients. In a developing country like India, assuring uniformity of treatment protocols is a challenging task.

Quality Assurance in Clinical Trials Requiring Radiation Therapy in Sub-Saharan Africa

Given the increasing availability of radiation therapy in sub-Saharan Africa, clinical trials that include radiation therapy are likely to grow. Ensuring appropriate delivery of radiation therapy through rigorous quality assurance is an important component of clinical trial execution. We reviewed the process for credentialing radiation therapy sites and radiation therapy quality assurance through the Imaging and Radiation Oncology Core (IROC) Houston Quality Assurance Center for AIDS Malignancy Consortium (AMC)-081, a multicenter study of cisplatin and radiation therapy for women with locally advanced cervical cancer living with HIV, conducted by the AIDS Malignancy Consortium at 2 sites in South Africa and Zimbabwe. Women living with HIV with newly diagnosed stage IB2, IIA (>4 cm), IIB-IVA cervical carcinoma (per the 2009 International Federation of Gynecology and Obstetrics [FIGO] staging classifications) were enrolled in AMC-081. They received 3-dimensional conformal external beam radiation therapy (EBRT) to the pelvis (41.4-45 Gy) using a linear accelerator, high-dose-rate brachytherapy (6-9 Gy to point A with each fraction and up to 4 fractions), and concurrent weekly cisplatin (40 mg/m2). IROC reviewed EBRT and brachytherapy quality assurance records after treatment. All of the 38 women enrolled in AMC-081 received ±5% of the protocol-specified prescribed dose of EBRT. Geometry of brachytherapy applicator placement was scored as per protocol in all implants. Doses to points A and B, International Commission on Radiation Units and Measurements (ICRU) bladder, or ICRU rectum required correction by IROC in >50% of the implants. In the final evaluation, 58% of participants (n=22) were treated per protocol, 40% (n=15) had minor protocol deviations, and 3% (n=1) had major protocol deviations. No records were received within 60 days of treatment completion as requested in the protocol. Major radiation therapy deviations were low, but timely submission of radiation therapy data did not occur. Future studies, especially those that include specialized radiation therapy techniques such as stereotactic or intensity-modulated radiation therapy, will require pathways to ensure timely and adequate quality assurance.

IMMU-37. ANTI-CD47 TREATMENT POTENTIATES PHAGOCYTOSIS OF MEDULLOBLASTOMA BY M1 POLARIZED MACROPHAGES FOLLOWING IRRADIATION

Abstract Medulloblastoma (MB) is the most common malignant brain tumor of childhood and accounts for 15–20% of all pediatric brain tumors. Despite significant advancements over the last decade in our understanding of the molecular underpinnings of MB, the overall risk of recurrence remains high, prognosis remains poor, and available treatment modalities remain limited for patients with this disease. Accordingly, the area of targeting tumor immune resistance has garnered increasing interest as a potentially safe and effective adjunctive therapy. CD47 is a cell surface protein that acts as a primary “don’t eat me” signal to the innate immune system and has been shown to be crucial in allowing tumor cells to evade phagocytosis by tumor-associated macrophages. Several preclinical studies aimed at blocking this “don’t eat me signal” through the application of a mouse anti-human monoclonal antibody (Ab) to CD47 (anti-CD47) have shown promise in pediatric brain tumor models. Further, chemotherapy and irradiation have been shown to increase the expression of pro-phagocytic signals on the surfaces of tumor cells. The authors examined the use of anti-CD47 Ab on the rates of phagocytosis of MB cells undergoing different single-fraction doses of external beam irradiation in vitro. The use of anti-CD47 Ab in the D425 MB cell line phagocytosis assay significantly increased rates of phagocytosis for 0 Gy (4.1% without vs. 20.3% with anti-CD47 Ab; p &amp;lt; 0.0001), 2 Gy (7.4% without vs. 23.4% with anti-CD47 Ab; p &amp;lt; 0.0001), 5 Gy (11.9% without vs. 27.3% with anti-CD47 Ab; p &amp;lt; 0.0001), 10 Gy (21.7% without vs. 34% with anti-CD47 Ab; p &amp;lt; 0.0001), and 20 Gy treatment groups (27.2% without vs. 43.9% with anti-CD47 Ab; p &amp;lt; 0.0001). A similar pattern of phagocytosis potentiation through use of anti-CD47 Ab with increasing doses of radiation was seen in D458 and D341 MB cell lines.

Impact of Adjuvant Pelvic External Beam Radiotherapy or Vaginal Brachytherapy on Clinical Outcomes for Early-Stage Uterine Carcinosarcoma

<h3>Purpose/Objective(s)</h3> Uterine carcinosarcoma (UCS) is an uncommon but aggressive malignancy with poor prognosis. There is no clear consensus regarding adjuvant radiotherapy (RT) following surgical management for patients (pts) with early stage UCS. We compared outcomes for pts with early stage UCS who underwent adjuvant pelvic external beam RT (EBRT) vs. vaginal brachytherapy (VBT) alone. <h3>Materials/Methods</h3> We conducted an Institutional Review Board-approved single institution retrospective study of 98 pts diagnosed with FIGO stage I-II UCS from 2002 to 2020 and received adjuvant RT, with or without chemotherapy (CT), following definitive surgery. EBRT dose was 45-50.4 Gy alone or followed by VBT boost of 10-18 Gy in 2-4 fractions (fx). Dose for adjuvant VBT alone was 21 Gy in 3 fx or 24 Gy in 6 fx, prescribed to the vaginal surface. We recorded clinical and treatment characteristics and clinical outcomes, including dates and location of progression. Fisher exact tests were used for categorical variables. PFS and OS were analyzed by Kaplan-Meier method and log-rank test. Univariate analyses (UVA) were performed using Cox proportional hazards modeling. <h3>Results</h3> 38 received CT+EBRT, 31 received CT+VBT, and 29 received RT alone (18 EBRT, 11 VBT). Fewer pts in the CT+EBRT and RT-alone groups received nodal sampling compared to pts in the CT+VBT group (<i>P</i>=0.02). Other factors including age, comorbidities, FIGO stage, and pathology were not different between the three groups. Median follow up was 93.5, 50.2, and 143.0 months for CT+EBRT, CT+VBT, and RT-alone groups, respectively. 3-year PFS was 78.7%, 67.6%, and 58.2% for CT+EBRT, CT+VBT, and RT alone, respectively. EBRT+CT significantly improved PFS (P=0.01) compared to RT alone (P=0.01), but not compared to CT+VBT (P=0.22). In terms of locoregional recurrences, 1 pt had a vaginal recurrence and 3 had pelvic nodal recurrences after CT+EBRT. In the CT+VBT cohort, 4 pts had vaginal recurrences, 3 had pelvic nodal recurrences, and 1 had a pelvic soft-tissue recurrence. In the RT-alone group, 1 pt receiving VBT suffered a vaginal recurrence, and 4 pts receiving EBRT had pelvic nodal recurrences. UVA showed that compared to CT+EBRT, RT alone was associated with shorter time to progression (HR 2.50, 95% CI 1.08-5.79, <i>P</i>=0.03) but CT+VBT was not (HR 1.82, 95% CI 0.74-4.50, <i>P=</i>0.20). Other factors including age, stage, nodal sampling, and lymphovascular invasion were not significant on UVA. <h3>Conclusion</h3> In one of the largest retrospective cohorts of early stage UCS, we found adjuvant EBRT+CT improved outcomes compared to RT alone, but not CT+VBT. There were 5 vaginal recurrences in pts undergoing VBT, suggesting that VBT alone at the doses prescribed in this study may not be sufficient. Larger prospective studies and longer follow up are needed to further investigate differences in radiation modalities for the treatment of early-stage UCS. †In Memoriam: LJL, deceased June 23, 2021.

MSS07 Presentation Time: 4:15 PM: National Trends in Palliative Esophageal Radiotherapy: External Beam Radiotherapy versus Brachytherapy

<h3>Purpose</h3> In patients with incurable esophageal cancer, dysphagia secondary to an advanced primary is a common occurrence. Different palliative treatment options exist including stenting, laser therapy, and radiotherapy, both in the form of external beam radiotherapy (EBRT), as well as, intraluminal brachytherapy. The optimal palliative approach remains a matter of debate and often varies based on institutional preference. In regard to randomized data, the Dutch SIREC trial (reported in 2004) compared single fraction HDR brachytherapy to metal stent placement and found better long term dysphagia relief and quality-of-life associated with receipt of brachytherapy. Despite these results, practice patterns in the United States regarding palliative radiotherapy utilization for esophageal cancer remain poorly defined. To better characterize management approaches and associated clinicopathologic factors in the United States, we analyzed the national cancer database (NCDB). <h3>Materials/Methods</h3> We queried the NCDB for patients diagnosed with esophageal carcinoma receiving either brachytherapy or palliative doses of EBRT (30 Gy in 10 fractions or 20 Gy in 5 fractions). Patients were grouped according to year of treatment receipt (2004-2007; 2008-2011; 2012-2015). Multivariable logistic regression was performed to identify clinicopathologic variables associated with each treatment modality (Brachytherapy vs EBRT). <h3>Results</h3> Ultimately 140,238 patients with esophageal cancer were identified, of which 2,624 patients met inclusion criteria. Of the included patients, 8% (n=204) received brachytherapy versus 92% (n=2,420) received EBRT. Median age was 67 years old and 72% were male and 28% were female with the following T stage breakdown: T1/T2=17%, T3=30%, T4=15%, unknown T stage=38%. Node positive disease was documented in 38%, while 26% of patients were N0 and 36% had unknown nodal status. Of the 204 brachytherapy patients, 53% (n=109) received treatment from 2004-2007, 30% (n=60) received treatment from 2008-2011, and 17% (n=35) received treatment from 2012-2015. Comparatively, of the 2,420 EBRT patients, 25% (n=606) received treatment from 2004-2007, 29% (n=698) received treatment from 2008-2011, and 46% (n=1,116) received treatment from 2012-2015. Of these patients 13% (n=315) received 20Gy in 5 fractions whereas 87% (n=2,105) received 30 Gy in 10 fractions. When examining the receipt of treatment by year grouping: 2004-2007 (n=715) 15% received brachytherapy vs 84% received EBRT 2008-2011 (n=758) 8% received brachytherapy vs 92% received EBRT 2012-2015 (n=1,151)3% received brachytherapy vs 97% received EBRT On multivariable logistic regression, brachytherapy receipt was associated with greater distance to treatment facility, absence of nodal disease, non-metastatic disease, <cT4 disease, more recent treatment year, white race (p<0.05 for all). <h3>Conclusion</h3> Compared to palliative EBRT, brachytherapy utilization in the United States for palliative esophageal treatment has decreased significantly since 2004 and likely represents <5% of palliative radiation treatments nationwide.

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.