Radiation Toxicity Research Articles

Effect of Dose to the Heart and Cardiac Substructures on Cardiac Toxicity after Breast Cancer Radiation

Pre-existing cardiovascular disease, chemotherapy, and higher mean heart dose are known risk factors for cardiac toxicity after breast radiation therapy. However, the relationship between cardiac substructure radiation exposure and toxicity is not well understood. We hypothesized that mean heart dose is a surrogate for global cardiac radiation exposure but that more specific dosimetric thresholds for the heart and its substructures could be identified, which could be used to guide radiation planning for breast cancer patients in the future. In this cohort study, all breast cancer patients who received curative intent breast or chest wall radiotherapy at a single high-volume institution in 2014 and 2017 were included (n = 841). Baseline characteristics included hormone therapy, chemotherapy, menopausal status, diabetes, dyslipidemia, pre-existing cardiac toxicity, and age at diagnosis. Outcomes included any cardiac toxicity, arrhythmia, cardiomyopathy, ischemia, valvular, pericardial disease, and death. The heart and substructures, including left ventricle, right ventricle, left atrium, right atrium, aortic valve, pulmonic valve, mitral valve, tricuspid valve, and left anterior descending artery, were delineated on the simulation CT for each patient. Dosimetric variables, including mean dose, max dose, and V1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, and 70 Gy for the heart and substructures (in cc) were extracted. For each dosimetric variable, multivariable logistic regression was performed using baseline covariates in addition to the single dosimetric variable. Patients with missing data values were excluded. Results were combined and False Discovery Rate p-value correction was performed. Multiple cardiac substructure dosimetric variables were associated with increased risk of mortality on multivariable analysis (p < 0.05). For left atrium and right atrium, V2, 3, 4, and 5 Gy were all significant. For right ventricle, mean dose, V1, 2, 3, 4, 5, 10, 15, 20, 25, 30, and 35 Gy were significant. For mitral valve, mean dose, max dose, V3, 4, and 5 Gy were significant. For tricuspid valve, mean dose was significant. For aortic valve, max dose, mean dose, V4, and V5 Gy were significant. For the whole heart, V1, 2, 3, 4, 5, 10, 15, 20, 25, 30, and 35 Gy were significant. We have identified multiple dosimetric variables for the heart and its substructures which were associated with increased risk of mortality after breast cancer radiation. In fact, for certain structures, there were multiple exposure thresholds which showed increased risk of toxicity, highlighting the complex relationship between substructure dose and outcomes. Further study into these relationships will identify the most critical cardiac substructure constraints that could be used in radiation treatment planning.

Cardiopulmonary Toxicity from Intensity Modulated Proton Therapy for Thymic Malignancies

Use of radiation therapy for thymic malignancies is limited by excess dose to organs at risk (OARs) including heart, lung, and esophagus. Intensity Modulated Proton Therapy with Pencil Beam Scanning (IMPT/PBS) allows the conformality benefits of volumetric modulated arc therapy (VMAT) combined with dosimetry benefits of protons making it an exciting tool to treat thymic tumors. Very limited clinical data are reported with the use of IMPT/PBS to treat thymic malignancies. This study evaluates the incidence of acute and delayed toxicities among patients who underwent IMPT/PBS for thymic tumors. Our single center retrospective study identified 27 patients with diagnosis of either thymic carcinoma or thymoma who received IMPT/PBS between 2015 and 2022. Patient demographics, IMPT treatment details and clinical outcomes (toxicity, recurrence, and survival) were recorded. Frequency distributions are described for primary endpoints of acute (≤ 90 days) and late (>90 days) toxicity graded using CTCAE version 5.0. Specific toxicities assessed were dermatitis, esophagitis, pneumonitis, pulmonary fibrosis, and cardiac toxicity. Recurrence and survival data were analyzed as secondary endpoint using Kaplan-Meier method. Median follow-up was 22 months. Median age of the patients was 59 years (range, 30-87), predominantly female (55%), and white (66%), and stage ¾ (72%). Histologically showed mainly thymoma (59%) and Masaoka stage ¾ (70%). Surgery prior to IMPT was performed in 19 (70%) patients; of whom 5 patients had positive margins. Chemotherapy was used in 12 (44%) patients. Median IMPT dose was 50.4 GyE. Patients were primarily planned with 2 or 3 fields (81%), coplanar distribution (74%), using SFO technique (70%). Robust planning was performed accounting for 5 mm margin and 3.5-5% range uncertainty. All patients required use of range shifter ranging from 2-5 cm. Median of Heart-mean (10.3 GyE), Heart-max (54 GyE), Lung-mean (8.1 GyE), Lung V20 Gy (16.1%), Lung-V30 Gy (11.4%), Esophagus-mean (10.3 GyE) and Cord-Max (1.4 GyE). QACT was performed in 21 (77%) patients with replan needed in 5 of them. Only 1 (3.7%) patient had a grade 3+ acute toxicity (dermatitis) and only 2 (7.4%) patients had a grade 3+ late toxicity (both pulmonary). No patients had any acute or delayed cardiac-related adverse effects following PBT treatment. One (3.7%) patient had an infield recurrence of malignancy and 6 had out-of-field metastatic failure. Local control and overall survival were 74.1% and 85.2%, respectively. In this largest single-institution analysis of IMPT/PBS experience, we note extremely low incidence of grade 3+ acute or late toxicity with excellent local control and overall survival. No marginal failures were noted. In a patient population at high risk of cardiopulmonary radiation toxicities, IMPT/PBS should be strongly explored as a possible treatment option.

Evaluation of Sexual Side Effects in Patients after Chemoradiation and Brachytherapy for Gynecologic Cancers Involving the Lower Vagina and Bulboclitoris

Radiation toxicity to the bulboclitoris has not been previously investigated. This retrospective cohort study aims to report sexual side effects of patients who underwent radiotherapy for tumors involving the lower vagina, periurethra, and bulboclitoris (BC). Patients treated between 2017- 2022 for gynecologic cancer involving the low vagina were included. The high-risk clinical target volume (HR-CTV), bladder, rectum, and urethra were contoured on patient imaging during initial treatment planning. The BC was retrospectively contoured using T2 MRI sequences fused to the pre-treatment and brachytherapy CT simulation. Superiorly, the BC was defined as inferior to the pubic symphysis and attached to the suspensory ligament of the clitoris. Laterally, the crura extend on either side of the corpus. Inferiorly, the vestibular bulbs flank the urethra and vagina on either side, extending posteriorly to mid-vagina. Dosimetric data for the BC, vaginal morbidity using the CTCAE 4.0 for vaginal stenosis, and pain scoring of the BC were obtained via chart review. Patients underwent external beam radiotherapy (IMRT) to the pelvis and bilateral inguinal region (45 Gy in 25 fractions) followed by High Dose Rate Ir-192 interstitial brachytherapy in 5 fractions for a total dose of 25 Gy (22.5 - 27.5 Gy). Patients had a median age of 65 years (49-73) with tumors located in the lower vagina, near the BC and urethra. At the time of brachytherapy, in order to cover the HR-CTV, interstitial brachytherapy needles were placed within the BC structure with 58% (33% - 77%) of total interstitial needles placed within the bulbs of the BC. The mean pre-treatment volume of the BC was 16.6 cc (11.9 - 20.9 cc) and at brachytherapy was 12.66 cc (7.3 - 22.1 cc) with Table 1 summarizing radiation doses. At a median follow up of 19.6 months, all patients had a complete local response, with one patient deceased of metastatic disease. In the acute period, all patients reported severe pain in the clitoral glans region and dysuria that completely resolved after 2 years. Grade 1-2 vaginal stenosis occurred in all patients despite vaginal dilator usage. One patient reported decreased clitoral sensitivity and inability to achieve clitoral-mediated orgasm 5 months after radiotherapy. This study demonstrates that the BC receives a significant radiation dose during vaginal brachytherapy treatment which can cause clitoral pain and dysfunction. Further studies are needed to evaluate the dose response of the BC as well as explore methods to spare the organ during radiation therapy in order to minimize toxicity and preserve sexual function.

A Potential Cause for Unexplained Radiation Toxicity in Proton Therapy

Rare but devastating neurological tissue injury by proton therapy is poorly understood. One consideration is that the transition from passively scattered to pencil beam scanning (PBS) proton radiotherapy over the past decade has affected dose rate. We analyzed clinical data acquired at two institutions on a correlation of voxel-wise dose rates and injury of brain tissue (institution 1) and the optic apparatus (institution 2). All radiation-induced toxicities were delineated (Brain/optic apparatus) on follow-up MRIs. A method to calculate dose rates for PBS plans has been implemented at two institutions independently. Institution 1 reports beam-by-beam time-averaged maximum dose rates per voxel (VMDR) using a 100 ms time interval. Data from four patients who incurred brain tissue injury was included. Dose rate volume histograms were prepared for the target, a 1 cm outer ring to the target, and the necrotic region itself. Prescription doses ranged from 30.6 to 60 Gy delivering either 1.8 or 2.0 Gy per fraction. Tissue injury was generally observed in the dose fall-off at the edge of the target. Additionally, we performed LET weighted dose calculation, robustness analysis, and Monte Carlo calculations. Institution 2 presents voxel-wise dose delivered above a selected dose rate threshold, considering values between 30 and 180 Gy/min. The analysis was performed for 2 cases with optical apparatus injuries and one matching non-toxicity case. Both injuries were observed in the chiasma. Patients received 50.4, 50.4 and 55.8 Gy (non-toxicity) in 1.8 Gy fractions. D1 for chiasma was 51.1, 47.2 and 54 Gy, respectively. Mean and (max) LET in chiasma were 4.02 (4.72), 2.49 (3.16) and 3.44 (4.56) keV/µm accordingly. Institution 1 finds distinct dose rate hot spots in the contoured injured brain regions. Mean VMDR values across all beams are lower in targets than in the 1 cm outer ring (80 Gy/min and 82.8 Gy/min, respectively) and elevated to 113 Gy/min for necrotic regions. Neither of the additional computations showed significant increase of dose in the affected areas. Institution 2 observes that chiasmas, which developed radiation injuries, were exposed to higher dose levels delivered at elevated dose rates (> 72 Gy/min) than the chiasma that did not show any radiation injury. D95 above 72 Gy/min for the two volumes identified as radiation injury was 0.25 and 0.12 Gy/fx, while D98 to chiasmas minus radiation injury or chiasma without any injury for the matching case was 0.06, 0.03 and 0 Gy/fx respectively. Using unique formulations to assess voxel-wise dose rates to brain and optic chiasm, two independent institutions observed that regions with elevated dose rates correlated with radiographic radiation injury. An extended retrospective study including a larger patient cohort with radiation-induced toxicity and asymptomatic patients is under way to confirm or refute the presented observations.

Total Lymphoid Irradiation in the Treatment of Heart Transplant Rejection: Single Institution Long-Term Results

Acute cardiac allograft rejection is a major cause of morbidity and mortality post-transplant. Total lymphoid irradiation (TLI) has been shown to cause long-lasting alterations in lymphocyte sub-sets, and thereby induces a state of partial response that is useful to prevent organ transplant rejection. In our previous report, treatment with TLI resulted in decreased episodes of acute rejection and steroid dosage requirements for up to 9.1 years post cardiac transplantation. In this study, we report an update on the short- and long-term effects of TLI in the treatment of cardiac transplant rejection. We performed a retrospective analysis of patients with intractable cardiac allograft transplantation evaluated in the department of radiation oncology at our institution over 23 years (1998-2021). Cardiac allograft rejection was defined as multiple or persistent episodes of rejection despite aggressive immunosuppressive therapy. The prescribed dose was 8 Gy in 10 fractions to be delivered over 5 weeks. All episodes of pathologic acute cardiac rejection, duration of immunosuppression, and episodes of acute infection requiring treatment before and after TLI were documented. Overall survival (OS) was analyzed using Kaplan-Meier method. The median time to first cardiac allograft rejection and the median time to first acute rejection was monitored. Of the 29 patients included, 21 (72.4%) had ISHLT grade 1R, 5 (17.2%), grade 2R, and 2(6.9%) grade 3R rejection. Rejection grade was unknown for 1 patient. The mean number of acute rejections after transplant was 14.4 episodes per patient (range 1-44) with median time to first rejection of 0.63 months. The median radiation dose was 8 Gy (range 7.2-8 Gy) delivered over a mean of 31 days. Treatment was stopped early in 2 (6.5%) patients (after 7.2 Gy and 7.9 Gy) for severe bone marrow suppression and drop in CD4 counts, respectively. The number of rejections dropped from 14.2 to 3.97 per patient over a median time of 29.0 months vs 28.1 months pre and post TLI (p = 0.01). The frequency of ISHLT acute grade 3R rejections decreased from 0.58 to 0.06 episodes per patient pre and post TLI (p = 0.02). Immunosuppressant requirements decreased from 2.83 before TLI to 2.69 after TLI (p = 0.71). Infection rates per patient were 0.71 pre TLI and remained at 0.63 post TLI. Treatment was well tolerated with 4 (13.8%) grade 2 or higher radiation toxicity. Median follow up was 76.3 months. Median and 3-year OS were 53.4 months and 60.9%, respectively. TLI is a safe and effective treatment for control of intractable cardiac rejection. The episodes of acute rejection and immunosuppressant requirements are decreased, but with long-term follow up, these patients continue to experience rejection. However, TLI lowers the frequency of ISHLT moderate to severe rejection episodes for up to 6.4 years. There was no increased risk of severe infections and there were only minimal short- and long-term grade 2 or higher radiation toxicities.

Radiation Toxicity Profile Difference in p16+ vs. p16- Oropharyngeal Cancer Patients

p16+ oropharyngeal squamous cell carcinoma is radiosensitive and has better prognosis than p16-ve. However, the correlation between p16 reactivity and radiation toxicity profile in these patients has not been studied. Edmonton Symptom Assessment System (ESAS) is a generic patient reported symptom scale validated for patient reported outcome (PRO) assessments in head and neck cancer patients. We sought to review the ESAS and its psychometric properties in oropharyngeal cancer patients treated with concurrent chemoradiation (CCRT) stratified by their HPV status. To evaluate differences in magnitude and temporal trends in PRO before, during and after radiation treatments in both p16+ and p16-ve oropharyngeal cancer patients using ESAS scores. Prospectively collected ESAS scores for oropharyngeal cancer patients treated at a safety net hospital with CCRT were analyzed. Longitudinal variation in pain, depression, appetite and family distress scores before, during and up to 36 weeks after CCRT were evaluated at seven time points: prior to treatment, 1-3, 4-6, 7-10, 11-15, 16-20 and 20-36 weeks. Statistical analysis focused on data collected through repeated measurements for patients using ANOVA mixed regression analysis using p16 status as between subjects factor for each symptom. Three hundred fifty-five ESAS assessments were analyzed for each symptom for 64 oropharyngeal cancer patients treated with CCRT. Subsites identified were 21 (32.8%) tonsil, 15 (23.4%) base of tongue, 22 (34.4%) soft palate, and 6 (9.4%) oropharynx not specified. We identified 35 (54.7%) p16+ and 29 (45.3%) p16-ve patients. The median age of the cohort was 60 (range: min 39 - max 88); the median age was 59 for p16+ and 61 for p16-ve. Median total radiation dose was 6996 Gy. Pain scores peaked at 7-10 weeks for both groups but p16-ve had delayed peak 11-15 weeks as well. Depression scores stayed <4 for both populations but family distress, pain and appetite scores peaked for p16-ve between 11-15 weeks. Mean pain scores were similar for both populations and peak during CCRT for both however p16-ve patients have another peak after completion of CCRT. Family distress and decreased appetite also heighten during this post CCRT time for p16-ve patients which warrants a planned early intervention at 11-15 weeks for these patients to improve their quality of life.

Circulating Growth Differentiation Factor 15 as a Biomarker in Patients with Unresected Locally Advanced Non-Small Cell Lung Cancer Treated with Chemo-Radiotherapy with or without Metformin

Growth differentiation factor 15 (GDF15) is a member of the TGFβ family suggested to have prognostic value in cancer. Plasma GDF15 levels are elevated in humans during cellular stress, chronic diseases, and cancer and in response to cytotoxic (chemotherapy and radiation) or metabolic (metformin) therapies. Currently, the effect of combined metformin and cytotoxic treatment on circulating GDF15 is not known, and it is unclear whether GDF15 can serve as a biomarker in patients receiving such therapy. To examine this question, we analyzed circulating GDF15 levels in stage IIIA or IIIB NSCLC patients that participated in the randomized phase II clinical trial OCOG-ALMERA (NCT02115464). In OCOG-ALMERA patients were randomized to treatment with concurrent platinum-based chemotherapy and chest radiotherapy (60-66 Gy), with or without consolidation chemotherapy (CRT) or the same treatment plus metformin (2000mg/d). Dosimetric parameters and survival outcomes were collected by the trial. EDTA Plasma was collected from patients at baseline, 2 weeks into CRT treatment, at completion of CRT and 6 months after treatment initiation and assayed for GDF15 using an ELISA method. Statistical analyses were conducted to explore potential associations between plasma GDF15 with survival and dosimetric parameters. Fifteen patients from the metformin arm and 18 from the control arms provided EDTA plasma for this analysis. Average baseline GDF15 levels for all participants were elevated compared to those reported for healthy individuals. Baseline plasma GDF15 was statistically prognostic for RFS and OS (hazard ratio = 1.19, 95% CI = 1.06 to 1.34, p = 0.005). GDF15 levels increased during CRT treatment reaching the highest value at the end of cytotoxic therapy. Addition of metformin to CRT treatment was associated with further increase in circulating GDF15 (p<0.001). Plasma GDF15 levels at 2 weeks of CRT were positively correlated with size of the radiotherapy clinical target volume and volumes of esophagus and heart receiving high dose radiotherapy. This work suggests that GDF15 may be a promising prognostic marker to predict response to standard chemoradiation therapy in NSCLC. Future studies should aim to validate these results in larger datasets and examine whether GDF15 may have value as early biomarker of radiation toxicity in lung cancer patients.

Combined Pulsed Radiotherapy (“QUAD SHOT” regimen) with Immune Checkpoint Inhibition (ICI) to Enhance Immune Response for LAHNSCC in Patients Considered Ineligible for Curative Intent Therapy

To utilize pulsed QUAD SHOT as an in-situ vaccine by stimulating the tumor microenvironment (TME) and excluding elective nodal sites, to enhance the immune response with concurrent ICI. Thirty-three patients (20 males and 13 females), with a median age of 81 years, seen at two community hospitals, determined to be ineligible for curative treatment, were treated. All pts received pulsed dose QUAD shot regimen to gross disease (44.4-59.2 Gy) spaced 3 weeks apart with addition of an approved ICI (Pembrolizumab or Cemiplimab). ERT was directed ONLY to Gross Primary + nodal disease. ICI was administered in most pts after the first QUAD shot to enhance immune response. ICI was continued adjuvantly until a > Grade 3 adverse event (AE) or progression of disease (POD). Pts with either advanced cutaneous or mucosal SCC were included (cSCC, mSCC). 39% presented with N1-2 adenopathy, and 24% presented with recurrent disease. PD-L1 status were not routinely obtained. The median number of ICI cycles delivered was 5 (range 2-24). All pts completed at least 3 QUAD shots. Overall LRC for all 33 pts was 69.7%, with a mean follow-up of 11 months (1-39). LRC for 33 pts at 1 and 2 years after the end of radiation were 61.07% and 55.52%, respectively. The percentage of pts free from elective regional recurrences at 1 and 2 years was 87.13% for both cSCC and mSCC groups. Overall, 6 pts (18%) experienced distant failure. Freedom from distant failure at 1 yr after QUAD shot completion by pathology was 100.00% for cSCC and 77.08% for mSCC. DFS for all 33 pts at 1 and 2 yrs were 59.39% and 37.12%, respectively. DFS at 1 year for cSCC was 100% and 53% for mSCC. Median DFS for the mSCC was 13.8 months. Overall survival for all 33 pts was 45.45% with a median OS time of 17.7 months. The 1 and 2 year OS rates were 65% and 33%. Overall toxicity was low and manageable. Gr 3 mucositis occurred in 1 patient and 5 (15%) developed Gr 2 AE's. Gr 3/4 IMAR's were observed in 3 pts and included infusion reaction, colitis, and fatigue/FTT and were discontinued. 4 pts required post QUAD PEG's unrelated to radiation toxicity and due to POD. In elderly, frail, or comorbidly ill patients with LAHNC, the addition of ICI to involved field QUAD shot regimen nearly tripled the median OS rate from prior publications with QUAD shot alone from 5.7 months to 17 months in our series. The low percentage of failure in the elective nodal beds was particularly encouraging based on our hypothesis. This approach represents the next step in an evolution away from conventional RT approaches that engender greater toxicity and warrants further study.

Recent Advances and Adaptive Strategies in Image Guidance for Cervical Cancer Radiotherapy.

The standard of care for locally advanced cervical cancer is external beam radiotherapy (EBRT) with simultaneous chemotherapy followed by an internal radiation boost. New imaging methods such as positron-emission tomography and magnetic resonance imaging have been implemented into daily practice for better tumor delineation in radiotherapy planning. The method of delivering radiation has changed with technical advances in qualitative imaging and treatment delivery. Image-guided radiotherapy (IGRT) plays an important role in minimizing treatment toxicity of pelvic radiation and provides a superior conformality for sparing the organs at risk (OARs) such as bone marrow, bowel, rectum, and bladder. Similarly, three-dimensional image-guided adaptive brachytherapy (3D-IGABT) with computed tomography (CT) or magnetic resonance imaging (MRI) has been reported to improve target coverage and reduce the dose to normal tissues. Brachytherapy is a complementary part of radiotherapy treatment for cervical cancer and, over the past 20 years, 3D-image-based brachytherapy has rapidly evolved and established itself as the gold standard. With new techniques and adaptive treatment in cervical cancer, the concept of personalized medicine is introduced with an enhanced comprehension of the therapeutic index not only in terms of volume (three-dimensional) but during treatment too (four-dimensional). Current data show promising results with integrated IGRT and IGABT in clinical practice and, therefore, better local control and overall survival while reducing treatment-related morbidity. This review gives an overview of the substantial impact that occurred in the progress of image-guided adaptive external beam radiotherapy and brachytherapy.

Immunomodulatory Effects of Histone Variant H2A.J in Ionizing Radiation Dermatitis

Histone variant H2A.J is associated with premature senescence after ionizing radiation (IR) and modulates senescence-associated secretory phenotype (SASP). Using constitutive H2A.J knock-out mice, the role of H2A.J was investigated in radiation dermatitis. H2A.J wild-type (WT) and knock-out (KO) mice were exposed to moderate or high IR doses (≤20 Gy, skinfold IR). Radiation-induced skin reactions were investigated up to 2 weeks post-IR at macroscopic and microscopic levels. H2A.J and other senescence markers, as well as DNA damage and proliferation markers, were studied by immunohistochemistry, immunofluorescence, and electron microscopy. After high-dose IR, protein-coding transcriptomes were analyzed by RNA sequencing, immune cell infiltration by flow cytometry, and gene expression by reverse transcription polymerase chain reaction in (non-) irradiated WT versus KO skin. In WT skin, epidermal keratinocytes showed time- and dose-dependent H2A.J accumulation after IR exposure. Unexpectedly, stronger inflammatory reactions with increased epidermal thickness and progressive hair follicle loss were observed in irradiated KO versus WT skin. Clearly more radiation-induced senescence was observed in keratinocyte populations of KO skin after moderate and high doses, with hair follicle stem cells being particularly badly damaged, leading to follicle atrophy. After high-dose IR, transcriptomic analysis revealed enhanced senescence-associated signatures in irradiated KO skin, with intensified release of SASP factors. Flow cytometric analysis indicated increased immune cell infiltration in both WT and KO skin; however, specific chemokine-mediated signaling in irradiated KO skin led to more neutrophil recruitment, thereby aggravating radiation toxicities. Increased skin damage in irradiated KO skin led to hyperproliferation, abnormal differentiation, and cornification of keratinocytes, accompanied by increased upregulation of transcription-factor JunB. Lack of radiation-induced H2A.J expression in keratinocytes is associated with increased senescence induction, modulation of SASP expression, and exacerbated inflammatory skin reactions. Hence, epigenetic H2A.J-mediated gene expression in response to IR regulates keratinocyte immune functions and plays an essential role in balancing the inflammatory response during radiation dermatitis.

Radiotherapy dose de-escalation in patients with high grade non-Hodgkin lymphoma in a real-world clinical practice.

The standard treatment of non-Hodgkin lymphoma (NHL) comprises combined modality treatment, radiotherapy (RT), and chemotherapy with rituximab which has significantly improved both disease-free survival (DFS) and overall survival (OS). However, there is no uniformity in radiation dose usage in these patients. In this retrospective study, we compared lower radiation dose with higher in patients with aggressive NHL. From 2007 to 2017, treatment records of all high-grade NHL or diffuse large B-cell lymphoma and non-central nervous system NHL were included. We compared response rates, OS and DFS of patients who received ≤30 Gy RT to those with >30 Gy. Univariate and multivariate analyses were done to determine factors affecting prognosis, i.e., age, sex, stage, International Prognostic Index (IPI), adding rituximab, and radiation dose. A total of 184 NHL patients treated with combined modality or radiation alone having complete follow-up details were analyzed. At median follow-up of 66.8 months, 5-year OS was 72.8% in high-dose group versus 69.9% in low-dose group (p = 0.772) and 5-year DFS 64.7% versus 64.1% (p = 0.871). Patients having early-stage disease receiving low dose and those with advanced disease treated with >30 Gy had better OS and DFS though not statistically significant. Adding rituximab was associated with significantly better OS and DFS irrespective of radiation dose delivered. High IPI score and omitting rituximab were the only factors that significantly worsened both OS and DFS. Acute radiation toxicities were comparable in both groups (p = 0.82). Among late toxicities, no patient developed a second malignancy and 5% died due to cardiovascular complications (p = 0.595) though only two patients (1.1%) had received thoracic radiation. The two groups had comparable response rates, acute toxicities, DFS and OS. This study suggests that RT dose reduction may be possible in high-grade NHL without compromising the DFS and OS.

P03.07.B DOSIMETRIC ACCURACY OF CYBERKNIFE STEREOTACTIC RADIOSURGERY FOR BENIGN PERIOPTIC TUMOR

Abstract BACKGROUND The Cyberknife (CK) SRS delivers a highly focused ablative radiation dose to tumors to effectively control tumors with minimized radiation toxicity to surrounding normal tissues. This study aimed to evaluate the dosimetric accuracy of Cyberknife (CK) for benign perioptic tumor using patient specific head phantom. METHODS Patient specific head phantoms was fabricated using a 3D-printer to be dosimetrically equivalent to actual target regions of benign perioptic tumor case treated via Cyberknife radiosurgery. Head phantom QA plan was produced using the original CK contour set (target and optic nerve). The head phantom containing the Gafchromic EBT3 film was irradiated using Cyberknife 6D skull tracking method. The dose distributions calculated by MultiPlan Treatment Planning System (version 5.6) was compared with those measured by film dose using gamma analysis method. After moved rotating (1 degree) and translating (1-5mm) the couch table prior to beam delivery, we checked the 6D skull tracking accuracy according to the beam irradiation. RESULTS Gamma passing rates for the 2%/1 mm and 2%/2 mm criteria was found to be 84.11 ± 2.12% and 93.61±1.39% greater than the acceptance criteria 80% and 90%. The difference between measured and calculated dose to the optic nerve in contact with the tumor was less than 3%. CONCLUSION Dosimetric verification with patient-specific head phantoms could be successfully implemented as the evaluation method for CK perioptic tumor radiosurgery delivery with 6D skull tracking system.

P18.03.A HYPOFRACTIONATION WITH OPTIMIZED STEREOTACTIC RADIOSURGERY PLANNING FOR SKULL BASE PERIOPTIC MENINGIOMAS

Abstract BACKGROUND Skull base perioptic meningiomas are challenging for stereotactic radiosurgery (SRS). The therapeutic window between tumor control and normal tissue complication is extremely narrow in these tumors, especially of large volume and/or in close proximity to the optic apparatus (OA). To minimize the risk of radiation toxicity, we optimized our SRS plans in terms of both steeper dose fall-off and dose-volume constraints for OA and delivered hypofractionation treatment. MATERIAL AND METHODS Thirty-one patients had been treated with hypofractionated SRS using the CyberKnife for perioptic meningiomas &amp;gt; 10 cm3 in volume (median 18.9 cm3). Tumor locations were cavernous sinus (n=7), petroclival (n=6), and tentorial edge (n=6). Optimization in SRS planning was carried in two aspects: 1) for steeper dose fall-off, multiple virtual shells outside the target were introduced and appropriate dose limits (formulated from our own Gamma Knife data) were applied; and 2) to minimize the risk of optic neuropathy, dose-volume constraints for OA (from AAPM TG101) were applied. SRS was delivered in five daily fractions with a median cumulative dose 27.8 Gy. RESULTS With a median follow-up of 33 months, tumor control was achieved in 28 of 31 patients (90.3%). Treatment response on MRI included partial response (volume decrease &amp;gt; 20%) in 17 patients, stable in 11, and progression (volume increase &amp;gt; 20%) in 3. Neurological symptoms improved in 10 patients, unchanged in 20, and worsened in 1. CONCLUSION Our current results show a promising role of hypofractionated SRS with optimization in steeper dose fall-off and dose-volume constraints for OA for large-sized skull base perioptic megningiomas in terms of both tumor control and neurological outcomes.

A Success Story of Cerebral Arteriovenous Malformation (AVM) Treated with Stereotactic Radiosurgery (SRS) in Bangladesh

Purpose: To share a case of cerebral Arteriovenous Malformation (AVM) patient, treated with Stereotactic Radiosurgery (SRS) at Evercare Hospital Dhaka, treatment process and successful outcome. Background: Arteriovenous malformation is an anomaly, mostly congenital due to a misfit in vasculogenic, where arteries and veins come to a direct connection. Treatment options include observation, embolization, microsurgery, Stereotactic Radiosurgery (SRS) either alone or in combination. This report describes our experience in treating a patient of AVM by SRS. Stereotactic Radiosurgery is an established modality to achieve desired nidus obliteration, excellent compliance being noninvasive, and reduced treatment-related morbidity. This case report also reviewed the literature in detail. After a thorough literature search, to the best of our knowledge, this shall be the first published case report of AVM successfully treated with SRS in Bangladesh. Case Presentation: In March 2019, 25-years old male presented in Radiation Oncology OPD as a diagnosed case of AVM, having complaints of headache for two years. Headache was occasional and often associated with vertigo and dizziness. He had no neurologic deficit. A radiological assessment revealed a large (4.6x4.4cm) AVM in the left parieto-occipital lobe showing serpiginous enhancement with IV contrast. After routine workup, he underwent stereotactic Radiosurgery in March’2019. A dose of 23Gy was delivered to the malformation, including all nidus. Acute radiation toxicity was noted as transient hair loss only over the irradiated area and no other side effect. Radiological Assessment was done at six months, 1year, and 2.5 years. After having a stable size at six months, complete nidus obliteration was achieved at one year. His last visit to our OPD was in July 2021, with radiologically complete nidus obliteration without any significant clinical symptoms. Conclusions: Linear Accelerator-based SRS is an excellent treatment option for AVM, encouraging clinical outcomes for carefully selected patients. Bang. J Neurosurgery 2022; 12(1): 53-64

Late Effects of Pelvic Radiation Therapy in the Female Patient: A Comprehensive Review

Abstract Radiation therapy (RT) is a valuable treatment option for gynecologic cancers, but it is also associated with acute and chronic toxicity that can greatly impact a patient’s quality of life. The severity and incidence of these side effects depend on various factors, such as the site, volume of tissue within the radiation field, treatment schedule, total dose, dose per fraction, and type of RT. Gastrointestinal (GI) toxicity is the most common side effect of pelvic radiation and late toxicity can include strictures, lower GI bleeding, and fibrosis. Genitourinary complications may include hemorrhagic cystitis, urethral and ureteral strictures, urge incontinence, fistulas, vaginal stenosis, premature ovarian insufficiency, and secondary malignancies. Outside the visceral tissues, insufficiency fractures, bone marrow suppression, and skin changes are also sporadically seen. Overall, advances in RT techniques and the understanding of patient-related factors influencing toxicity have led to improvements in treatment outcomes and reduced rates of late side effects. Understanding the late side effects associated with pelvic RT is critical for developing strategies to both minimize the risk of long-term complications and improve the quality of life of patients. This review aims to summarize the late side effects associated with RT in the pelvis and the respective interventions that may help treat toxicities.

Late Effects of Pelvic Radiation Therapy in the Female Patient: A Comprehensive Review

Abstract Radiation therapy (RT) is a valuable treatment option for gynecologic cancers, but it is also associated with acute and chronic toxicity that can greatly impact a patient’s quality of life. The severity and incidence of these side effects depend on various factors, such as the site, volume of tissue within the radiation field, treatment schedule, total dose, dose per fraction, and type of RT. Gastrointestinal (GI) toxicity is the most common side effect of pelvic radiation and late toxicity can include strictures, lower GI bleeding, and fibrosis. Genitourinary complications may include hemorrhagic cystitis, urethral and ureteral strictures, urge incontinence, fistulas, vaginal stenosis, premature ovarian insufficiency, and secondary malignancies. Outside the visceral tissues, insufficiency fractures, bone marrow suppression, and skin changes are also sporadically seen. Overall, advances in RT techniques and the understanding of patient-related factors influencing toxicity have led to improvements in treatment outcomes and reduced rates of late side effects. Understanding the late side effects associated with pelvic RT is critical for developing strategies to both minimize the risk of long-term complications and improve the quality of life of patients. This review aims to summarize the late side effects associated with RT in the pelvis and the respective interventions that may help treat toxicities.

Efficacy and Toxicity of Hypofractionated Palliative Radiotherapy for Breast Cancer Patients with Skin Invasion

Objectives: To determine the efficacy and toxicity of palliative radiotherapy for locally advanced breast cancer patients with skin invasion.&#x0D; Study Design: Quasi-experimental study.&#x0D; Place and Duration of Study: Radiotherapy Department Combined Military Hospital, Rawalpindi Pakistan, Jan 2019 to Jun 2020.&#x0D; Methodology: Patients who received palliative radiotherapy for the breast cancer and received radiation of 24 Gray in 3 fractions to the breast/ chest wall were included. Radiation toxicity was assessed using RTOG criteria as the primary outcome of the study. Radiotherapy efficacy in controlling bleeding/discharge and improving pain and odour scores were the secondary outcomes.&#x0D; Results: Twelve (80%) patients reported improvement in pain, 13/18(72.2) patients reported improvement in bleeding and 24/25 (96%) patients a decrease in pain level (p-value &lt; 0.001). 11/25(44%) developed Grade-2 skin toxicity, and 8/25 (32%) developed Grade-3 skin toxicity. No patient experienced Grade-4 skin toxicity.&#x0D; Conclusion: Our study has shown that hypofractionated radiotherapy is effective and safe for palliation of patients with locally advanced breast cancer and skin invasion.

Locally advanced cervical cancer: how the improvement in techniques in external beam radiotherapy and brachytherapy impacts on survival outcomes and long-term toxicities.

Platinum-based chemoradiotherapy and brachytherapy are the standard treatment for locally advanced cervical cancer. Reported long-term outcomes for treated with both IMRT and 3D-Image-guided-adaptive brachytherapy are lacking. This retrospective study included 165 patients with FIGO Stage IB-IVB cervical cancer, treated with chemoradiotherapy in combination with brachytherapy. External beam radiotherapy was delivered as IMRT/VMAT/TOMO helical or 3DCRT. The intracavitary brachytherapy treatment (ICBT) was performed using two different planning system (with or without optimization). Among the patient subgroups, comprising those who received IMRT/VMAT/Tomo helical and 3DCRT, as well as those who underwent ICBT planning optimization and those who did not, homogeneity was observed in terms of age, performance status, T stage, N status, TNM stage, and histology. With a median follow-up time of 60.5months, the 5-year overall survival (OS) in the 3DCRT and IMRT groups was 74.9% and 92.8%, respectively (p = 0.033). The 5-year OS in the ICBT planning optimization group was 93.7%, compared to 75% in the non-optimization group (p = 0.014). Regarding late radiation toxicities, patients in the IMRT group had a lower incidence of chronic rectal toxicity compared to those in the 3DCRT group (6.5% vs. 34.1%, p = 0.001). The group with ICBT planning optimization had a lower incidence of late urinary toxicities (10.4%) compared to the non-optimized ICBT planning group (18.2%, p = 0.012). Similarly, the ICBT planning optimization group had a lower incidence of late rectal toxicity (6.5% with 80% grade 1 and 20% grade 2) compared to the non-optimized ICBT planning group (34.1%, p = 0.001). In this series, the group of patients receiving optimized ICBT had an advantage in terms of OS and CSS suggesting that the use of new Treatment Planning Systems associated with 3D imaging, improves the long-term survival. Additionally, a significant reduction in late rectal and urinary toxicity has been observed.

Locoregional Treatment for Early-Stage Breast Cancer: Current Status and Future Perspectives.

The locoregional recurrence of breast cancer has been reduced due to the multidisciplinary approach of breast surgery, systemic therapy and radiation. Early detection and better surgical techniques contribute to an improvement in breast cancer outcomes. The purpose of this review is to have an overview and summary of the current evidence behind the current approaches to the locoregional treatment of breast cancer and to discuss its future direction. With improved surgical techniques and the use of a more effective neoadjuvant systemic therapy, including checkpoint inhibitors and dual HER2-directed therapies that lead to a higher frequency of pathologic complete responses and advances in adjuvant radiation therapy, breast cancer patients are experiencing better locoregional control and reduced local and systemic recurrence. De-escalation in surgery has not only improved the quality of life in the majority of breast cancer patients, but also maintained the low risk of recurrence. There are ongoing clinical trials to optimize radiation therapy in breast cancer. More modern radiation technologies are evolving to improve the patient outcome and reduce radiation toxicities.

Radiomics based predictive modeling of rectal toxicity in prostate cancer patients undergoing radiotherapy: CT and MRI comparison.

Rectal toxicity is one of the common side effects after radiotherapy in prostate cancer patients. Radiomics is a non-invasive and low-cost method for developing models of predicting radiation toxicity that does not have the limitations of previous methods. These models have been developed using individual patients' information and have reliable and acceptable performance. This study was conducted by evaluating the radiomic features of computed tomography (CT) and magnetic resonance (MR) images and using machine learning (ML) methods to predict radiation-induced rectal toxicity. Seventy men with pathologically confirmed prostate cancer, eligible for three-dimensional radiation therapy (3DCRT) participated in this prospective trial. Rectal wall CT and MR images were used to extract first-order, shape-based, and textural features. The least absolute shrinkage and selection operator (LASSO) was used for feature selection. Classifiers such as Random Forest (RF), Decision Tree (DT), Logistic Regression (LR), and K-Nearest Neighbors (KNN) were used to create models based on radiomic, dosimetric, and clinical data alone or in combination. The area under the curve (AUC) of the receiver operating characteristic curve (ROC), accuracy, sensitivity, and specificity were used to assess each model's performance. The best outcomes were achieved by the radiomic features of MR images in conjunction with clinical and dosimetric data, with a mean of AUC: 0.79, accuracy: 77.75%, specificity: 82.15%, and sensitivity: 67%. This research showed that as radiomic signatures for predicting radiation-induced rectal toxicity, MR images outperform CT images.