Hypofractionation Research Articles

Non-clinical evaluation of local and systemic immunity induced by different vaccination strategies of the candidate tuberculosis vaccine M72/AS01

A new efficacious tuberculosis vaccine targeting adolescents/adults represents an urgent medical need. The M72/AS01E vaccine candidate protected half of the latently-infected adults against progression to pulmonary tuberculosis in a Phase IIb trial (NCT01755598). We report that three immunizations of mice, two weeks apart, with AS01-adjuvanted M72 induced polyfunctional, Th1-cytokine-expressing M72-specific CD4+/CD8+ T cells in blood and lungs, with the highest frequencies in lungs. Antigen-dose reductions across the three vaccinations skewed pulmonary CD4+ T-cell profiles towards IL-17 expression. In blood, reducing antigen and adjuvant doses of only the third injection (to 1/5th or 1/25th of those of the first injections) did not significantly alter CD4+ T-cell/antibody responses; applying a 10-week delay for the fractional third dose enhanced antibody titers. Delaying a full-dose booster enhanced systemic CD4+ T-cell and antibody responses. Cross-reactivity with PPE and non-PPE proteins was assessed, as Mycobacterium tuberculosis (Mtb) virulence factors and evasion mechanisms are often associated with PE/PPE proteins, to which Mtb39a (contained in M72) belongs. In silico/in vivo analyses revealed that M72/AS01 induced cross-reactive systemic CD4+ T-cell responses to epitopes in a non-vaccine antigen (putative latency-associated Mtb protein PPE24/Rv1753c). These preclinical data describing novel mechanisms of M72/AS01-induced immunity could guide future clinical development of the vaccine.

Study protocol for prospective multi-institutional phase III trial of standard of care therapy with or without stereotactic ablative radiation therapy for recurrent ovarian cancer (SABR-ROC)

BackgroundEfforts have been made to investigate the role of salvage radiotherapy (RT) in treating recurrent ovarian cancer (ROC). Stereotactic ablative radiation therapy (SABR) is a state-of-the-art therapy that uses intensity modulation to increase the fractional dose, decrease the number of fractions, and target tumors with high precision.MethodsThe SABR-ROC trial is a phase 3, multicenter, randomized, prospective study to evaluate whether the addition of SABR to the standard of care significantly improves the 3-year overall survival (OS) of patients with ROC. Patients who have completed the standard treatment for primary epithelial ovarian cancer are eligible. In addition, patients with number of metastases ≤ 10 and maximum diameter of each metastatic site of gross tumor ≤ 5 cm are allowed. Randomization will be stratified by (1) No. of the following clinical factors met, platinum sensitivity, absence of ascites, normal level of CA125, and ECOG performance status of 0–1; 0–3 vs. 4; (2) site of recurrence; with vs. without lymph nodes; and (3) PARP inhibitor; use vs. non-use. The target number of patients to be enrolled in this study is 270. Participants will be randomized in a 1:2 ratio. Participants in Arm 2 will receive SABR for recurrent lesions clearly identified in imaging tests as well as the standard of care (Arm 1) based on treatment guidelines and decisions made in multidisciplinary discussions. The RT fraction number can range from 1 to 10, and the accepted dose range is 16–45 Gy. The RT Quality Assurance (QA) program consists of a three-tiered system: general credentialing, trial-specific credentialing, and individual case reviews.DiscussionSABR appears to be preferable as it does not interfere with the schedule of systemic treatment by minimizing the elapsed days of RT. The synergistic effect between systemic treatment and SABR is expected to reduce the tumor burden by eradicating gross tumors identified through imaging with SABR and controlling microscopic cancer with systemic treatment. It might also be beneficial for quality-of-life preservation in older adults or heavily treated patients.Trial registrationThis trial was registered at ClinicalTrials.gov (NCT05444270) on June 29th, 2022.

Fractionation versus Adaptation for Compensation of Target Volume Changes during Online Adaptive Radiotherapy for Bladder Cancer: Answers from a Prospective Registry.

Online adaptive radiotherapy (ART) allows adaptation of the dose distribution to the anatomy captured by with pre-adaptation imaging. ART is time-consuming, and thus intra-fractional deformations can occur. This prospective registry study analyzed the effects of intra-fraction deformations of clinical target volume (CTV) on the equivalent uniform dose (EUDCTV) of focal bladder cancer radiotherapy. Using margins of 5-10 mm around CTV on pre-adaptation imaging, intra-fraction CTV-deformations found in a second imaging study reduced the 10th percentile of EUDCTV values per fraction from 101.1% to 63.2% of the prescribed dose. Dose accumulation across fractions of a series was determined with deformable-image registration and worst-case dose accumulation that maximizes the correlation of cold spots. A strong fractionation effect was demonstrated-the EUDCTV was above 95% and 92.5% as determined by the two abovementioned accumulation methods, respectively, for all series of dose fractions. A comparison of both methods showed that the fractionation effect caused the EUDCTV of a series to be insensitive to EUDCTV-declines per dose fraction, and this could be explained by the small size and spatial variations of cold spots. Therefore, ART for each dose fraction is unnecessary, and selective ART for fractions with large inter-fractional deformations alone is sufficient for maintaining a high EUDCTV for a radiotherapy series.

A novel, multi-active emollient for the prevention of acute radiation dermatitis in breast cancer patients: a randomized clinical trial.

To investigate the efficacy of a novel, multi-active emollient in preventing and managing acute radiation dermatitis (ARD) in breast cancer patients undergoing moderate hypofractionated (HF) radiotherapy (RT) compared to standard of care. A monocentric, open-label, randomized clinical trial (RCT) with breast cancer patients receiving moderate HF (dose: 40.05-55.86Gy, fractions: 15-21) was conducted between January 2022 and May 2023. The experimental group received the novel emollient, while the control group received the standard skin care. Patients applied the skin care products twice daily during the complete RT course. The primary outcome was the severity of ARD at the final RT session measured by the modified Radiation Therapy Oncology Group (RTOG) criteria. Secondary outcomes included patient symptoms, quality of life (QoL), and treatment satisfaction. A total of 100 patients with 50 patients per group were enrolled. In the control group, 50% of the patients developed RTOG grade 1 ARD and 48% grade 2 or higher, while in the experimental group, the severity of ARD was significantly lower with 82% grade 1 and 16% grade 2 ARD (P = .013, χ2-test). The frequency and severity of xerosis were significantly lower in the experimental compared to the control group (Ps ≤ .036, Mann Whiney U test). The impact of ARD on the QoL was low, and treatment satisfaction was high in both groups, with no significant difference. This RCT shows that the novel, multi-active emollient significantly reduced the ARD RTOG grade. Research in a more diverse patient population is warranted. ClinicalTrials.gov: NCT04929808 (11/06/2021).

Plumbago zeylanica L. exhibited potent anticancer activity in Ehrlich ascites carcinoma bearing Swiss albino mice

ObjectivesWe investigated the anticancer activity of the PzMH fraction (hexane fraction) extracted from the roots of Plumbago zeylanica L., an ethnomedicinally significant plant widely distributed in India. MethodsThe PzMH fraction was obtained through rigorous extraction and purification processes. In vitro cytotoxicity assays were performed to assess its effects on Ehrlich ascites carcinoma (EAC) cells. Acute toxicity studies were conducted to evaluate its safety profile. An in vivo study was carried out on EAC-bearing Swiss albino mice to assess its anticancer efficacy. Flow cytometric and microscopic analyses were done to examine the induction of cell death by the PzMH fraction. Western blot analysis was used to investigate the molecular mechanisms involved. ResultsThe PzMH fraction exhibited a significant cytotoxic effect in vitro, resulting in 50% cell death in EAC cells at low concentrations. The calculated GI50 value for the PzMH fraction was 42.74 µg/ml, demonstrating a comparable efficacy to the standard drug 5-fluoro uracil (GI50 = 43.38 µg/ml). The safety of therapeutic doses was confirmed through acute toxicity studies, which yielded an LD50 value of 500 mg/kg body weight. In the in vivo study, the PzMH fraction demonstrated a substantial 79.05% inhibition in the growth of EAC cells at the 300 mg/kg body weight dose of PzMH fraction. Flow cytometric and microscopic analyses revealed distinct apoptotic features in EAC cells treated with the PzMH fraction. Cell cycle analysis showed a significant arrest at the G0/G1 stage following treatment. PzMH treatment elicited a response characterized by escalated levels of cleaved caspases-3 and −9, while concurrently leading to a decreased expression of the Bcl2 protein, as evidenced by Western blot analysis. ConclusionsThe current research provides empirical evidence supporting the anticancer activity of the PzMH fraction extracted from P. zeylanica. The observed cytotoxicity, safety, and apoptosis-inducing properties make it a promising candidate for further investigation as a potential cancer therapy. Further exploration of its phytochemical composition, including major compounds such as 4-hydroxybenzaldehyde, trans-cinnamic acid, plumbagin and lawsone, contributes to our understanding of its mechanisms of action.

Real-World Toxicity of Conventional Versus Hypofractionated Definitive Prostate Radiotherapy across a Large, Diverse, Academic and Community-Based Enterprise.

Over the past 10-15 years there has been increasing adoption of moderate hypofractionation (HF) for definitive prostate radiotherapy as compared to conventional fractionation (CF). Based on several randomized trials hypofractionation results in equivalent treatment efficacy with similar rates of long-term toxicity. However, some studies suggest higher acute GI toxicity with moderate hypofractionation. We sought to compare the rates of toxicity between these two groups across our enterprise including 16 community-based practices and one academic NCI-designated comprehensive cancer center. We retrospectively extracted radiation treatment intent from our network-wide clinical pathways for patients diagnosed with prostate cancer between 3/2019 and 10/2022. Patients treated after prostatectomy and those treated with brachytherapy or SBRT were excluded. For the remaining 1529 patients treated with either conventional fractionation or moderate hypofractionation, we identified and merged physician-graded toxicity data using CTCAE version 5.0 recorded in their electronic medical record at each weekly on-treatment visit and follow-up. A total of 1051 patients had toxicity data available. Rates of toxicities were then compared between the cohort of patients who received CF and those who HF using the Chi-square test. Of the 1051 patients, 450 (43%) received CF and 601 (57%) received HF. These patients were treated by 40 different radiation oncologists (median patients per physician = 18, interquartile range = 7-35). Median age in the CF and HF cohorts was 71 (IQR: 66-76) and 71 (IQR: 66-77; p = 0.51), respectively. The CF cohort had more patients with Gleason 8+ disease (39% vs 19%; p<0.01), PSA >20 (26% vs 11%; p<0.01), or T3a+ (18% vs 8%; p<0.01). Rates of any grade 2+ toxicity were significantly higher in patients who received HF at 45.8% vs 39.6% for those treated with CF (p = 0.04). However, the respective rates of any grade 3+ toxicity were no different at 2.0% vs. 1.8% (p = 0.80). The difference in grade 2 toxicities appeared to be primarily driven by the rates of urinary frequency at 27.1% vs. 17.8% (p<0.01) and prostatic obstruction 14.8% vs. 10.2%, p = 0.03). Rates of grade 2 diarrhea were worse with MF at 5.3% vs. 2.8% for CF (p = 0.04). There were no significant differences between HF and CF in the rates of grade 2 dysuria (6% vs 5.2%), urinary urgency (6.5% vs. 4.2%), proctitis (3.0% vs. 3.6%), urinary incontinence (0.5% vs. 1.3%), rectal bleeding (0.3% vs. 0%), hematuria (0% vs. 0.4%), and fatigue (14.1% vs. 15.1%). In this large network-wide analysis, toxicity was slightly increased among patients with prostate cancer treated with HF compared to CF, consistent with published randomized data. However, the increased toxicity appeared to be primarily GU rather than GI. This study demonstrates the feasibility of analyzing impacts of treatment decisions on a large scale using real-world data through an integrated network of practices.

Effect of high-dose radiation therapy on positive margins after breast-conserving surgery for invasive breast cancer.

Positive margins after breast-conserving surgery are associated with poor oncological outcomes and warrant additional surgery. This study aimed to evaluate the effectiveness of high-dose radiation therapy for positive margins by comparing local recurrence between patients with positive and negative margins. We retrospectively evaluated 550 patients treated with adjuvant radiation therapy after breast-conserving surgery for invasive breast cancer between 2013 and 2019. The total equivalent dose in 2Gy fractions (EQD2) to the tumor bed ranged from 65.81 to 66.25Gy for positive margins and 59.31-61.81Gy for negative margins. The differences in local recurrence between the positive and negative margin groups were analyzed. After a median follow-up of 58 months, the crude local recurrence rate was 7.3% in the positive margin group (n=55) and 2.4% in the negative margin group (n=495). Positive margins were associated with higher local recurrence without statistical significance in the entire cohort (p=0.062). Among patients aged <60 years, those with positive margins had a significantly lower 5-year local recurrence-free survival rate than those with negative margins (89.16% vs. 97.57%, respectively; p=0.005). In contrast, there was no significant difference in the 5-year local recurrence-free survival rate between patients with positive and negative margins among those aged ≥60 years (100.00% vs. 94.38%, respectively; p=0.426). In this study, positive margins were not associated with poor local control in older patients after a high-dose boosts. Further prospective studies are needed to verify our findings.

Stereotactic Ablative Radiotherapy for the Treatment of Glandular Metastases from Renal Cell Carcinoma.

Glandular metastases including pancreatic and adrenal sites of disease are associated with renal cell carcinoma (RCC) of indolent biology. Adrenal and pancreatic metastases may develop in isolation or involve other organs and are associated with prolonged survival. Glandular metastases can be treated with systemic therapy, stereotactic ablative radiotherapy (SAbR) or surgical resection and the optimal management of these patients is unknown. There is paucity of data on SAbR for RCC glandular metastases. We hypothesize that ablative doses of radiation therapy utilizing SAbR are associated with high rates of local control greater than 90%, with minimal or no acute grade 3 toxicities or higher with this approach. Here, we report local control (LC), progression-free survival (PFS), overall survival (OS) rates as well as toxicities related to SAbR for RCC metastases to the pancreatic and adrenal glands. This IRB-approved, single-institution, retrospective study included patients with RCC metastases to the adrenal glands and pancreas treated with SAbR. Data on patient demographics, functional status, tumor characteristics, International Metastatic RCC Database Consortium (IMDC) risk category, local and systemic treatments, toxicities, and outcomes were collected and analyzed. RECIST 1.1 principals were utilized to determine LC rates and PFS. PFS was determined from the initiation of SAbR to progression (at SAbR-treated or other sites), or death. OS was defined from the start of SAbR to death. Two independent reviewers assessed these measures and analyzed patient electronic health records for toxicities using CTCAE v5 and relatedness scores. A total of 50 RCC patients were included in this study with 36 adrenal and 20 pancreatic metastases treated with SAbR. Median dose fractionation used was 40 Gray delivered in 5 fractions. Sixteen patients (32%) were treatment naïve with oligometastatic disease, and thirty-four (68%) were oligo-progressive on systemic therapy with 1-3 prior lines of systemic therapy. For treated adrenal metastatic lesions at 1 year, patients demonstrated a 75.3% OS, 46.7% PFS, and LC of 93.3%. For treated pancreatic metastatic lesions at 1 year, patients demonstrated a 100% OS, 48.6% PFS, and LC of 100%. At 1 year, there was an OS of 82.2%, PFS of 48.2%, and LC of 95.9 % in the combined cohort. The percentage of patients experiencing an acute grade 2 or 3 toxicity attributed to adrenal or pancreatic gland SAbR was 7.4%. There were no acute grade >3 toxicities. The percentage of patients experiencing a late grade 2 or 3 toxicity was 9.3%. Median time to late adverse events was 37.4 months. SAbR of RCC metastases to the pancreas and adrenal glands is feasible, safe and appears to be effective. Median PFS and OS in this cohort compared favorably to those reported in historical cohorts and is consistent with indolent disease.

Experimental validation of multi-fraction online adaptations in magnetic resonance guided radiotherapy

Background and purposeRadiotherapy plan verification is generally performed on the reference plan based on the pre-treatment anatomy. However, the introduction of online adaptive treatments demands a new approach, as plans are created daily on different anatomies. The aim of this study was to experimentally validate the accuracy of total doses of multi-fraction plan adaptations in magnetic resonance imaging guided radiotherapy in a phantom study, isolated from the uncertainty of deformable image registration. Materials and methodsWe experimentally verified the total dose, measured on external beam therapy 3 (EBT3) film, using a treatment with five online adapted fractions. Three series of experiments were performed, each focusing on a category of inter-fractional variation; translations, rotations and body modifications. Variations were introduced during each fraction and adapted plans were generated and irradiated. Single fraction doses and total doses over five online adapted fractions were investigated. ResultsThe online adapted measurements and calculations showed a good agreement for single fractions and multi-fraction treatments for the dose profiles, gamma passing rates, dose deviations and distances to agreement. The gamma passing rate using a 2%/2 mm criterion ranged from 99.2% to 99.5% for a threshold dose of 10% of the maximum dose (Dmax) and from 96.2% to 100% for a threshold dose of 90% of Dmax, for the total translations, rotations and body modifications. ConclusionsThe total doses of multi-fraction treatments showed similar accuracies compared to single fraction treatments, indicating an accurate dosimetric outcome of a multi-fraction treatment in adaptive magnetic resonance imaging guided radiotherapy.

Practice Patterns and Disparities of Fractionation Schemes for Post-Mastectomy Comprehensive Nodal Irradiation

Hypofractionated (HF) radiotherapy is the established standard of care for whole breast irradiation and is being investigated for comprehensive nodal irradiation, but appropriate patient selection for the latter is currently undefined. This study aims to report national practice patterns and patient selection for HF comprehensive nodal irradiation compared to conventional fractionation (CF). The hypothesis is that the rate of HF for comprehensive nodal irradiation in breast cancer has been increasing over time and is more likely to be offered to disparate demographic populations. We queried the National Cancer Database and identified 128,693 patients who received comprehensive nodal irradiation between 2008-2016 in the United States. No patient who underwent lumpectomy received HF nodal irradiation; therefore, only post-mastectomy patients were included in this study. After the exclusion, 29,053 post-mastectomy patients with adjuvant comprehensive nodal irradiation remained. A multivariable binomial regression analysis between HF and CF patients was performed. Of the patients identified, 1,910 received HF (6.57%), and 27,143 received CF (93.43%) radiotherapy. All patients had locally advanced breast cancer treated with mastectomy, lymph node dissection, adjuvant radiation, and +/- chemotherapy. The median dose in the HF group was 4,256 cGy in 16 fractions, and in the CF group was 6,040 cGy in 33 fractions. HF rate grew from 3.56% in 2004-2007, 5.29% in 2008-2011, 7.42% in 2012-2013, and 12.05% in 2014-2016. HF was favored in older patients (median age 66 vs. 51, OR = 1.16, 95% Cl 1.11-1.22) and those who lived in suburban or rural regions compared to urban or metropolitan regions (OR = 9.48, 95% CI 1.17-76.9). However, there was no correlation when distance from treatment site was evaluated as a continuous variable. A "boost" dose was used in only 10.58% of HF patients compared to 54.6% of CF patients (OR = 0.17, 95% Cl 0.14-0.21). Chemotherapy was delivered in 36.91% of HF patients compared to 78.14% of CF patients (OR = 0.77, 95% Cl 0.59-0.99). There were no statistically significant correlates of either fractionation scheme for breast laterality, stage, grade, or receptor status. Notably, other than population density and age, demographic factors including race, Hispanic origin, insurance type, median income, and education level demonstrated no correlation with radiation fractionation scheme. HF for comprehensive nodal irradiation in breast cancer is still uncommon but growing in popularity. Currently, HF is more likely to be used in elderly patients and lower population density centers and less likely to be used in those determined to benefit from receipt of a boost or chemotherapy.

Adaptive Radiotherapy with Dose Fractionation Painting

Efficacy of dose fractionation is dependent on tumor radiosensitivity. However, due to intra-tumoral dose response heterogeneity, the advantage of fractionation cannot be fully utilized. FDG-PET/CT has been used to assess intra-tumoral dose response during the treatment course. Thus, radiosensitivity of different sub-volumes within the individual tumors can be assessed and used to design dose fractionation. For each patient, the pre-treatment FDG-PET/CT and a feedback FDG-PET/CT obtained within the 3rd week of the chemo-radiotherapy for HN cancer were used to construct tumor voxel dose response matrix, DRM. Biologically equivalent dose EQD2 was determined using the DRM and assuming relative stability of the radiation double-hit effect, meanwhile normal tissue EQD2 was determined assuming the corresponding α/β = 3.0. Tumor voxel EQD2 ratio was calculated with a given limitation of normal tissue EQD2 and used to determine tumor voxel fractionation (Table). Tumor was divided into few sub-volumes based on ranges of the tumor voxel DRM value. Different fractionation doses, but same number of fractions, were selected to ensure that the planning dose distribution can be simultaneously delivered. Table shows the EQD2 of tumor voxel DRM for each given fractionation and normal tissue dose limitation. The treatment dose efficiency increases exponentially as increasing dose per fraction for those of resistant tumor voxels, i.e., DRM > = 0.7. The 2 Gy per fraction was used within the first 3 treatment weeks before tumor voxel dose response assessed. After the 15 fractions, tumor voxel dose fractionation will be adjusted with respect to its DRM and the expected treatment dose. Typically, 3 sub-volumes for each resistant tumor were segmented and designed with 3 fractionation regimens. With respect to normal tissue EQD2 constraint < = 70 Gy, the corresponding EQD2 was 55 ∼ 73 Gy for tumor sub-volume with DRM = 0.1 ∼ 0.6; 77 ∼ 90 Gy for tumor sub-volume with DRM = 0.65 ∼ 0.75; > 101 Gy for tumor sub-volume with DRM > = 0.8 respectively. For very resistant tumor cells i.e., DRM > 0.9, the EQD2 > 160 Gy can be achieved or > 244 Gy if the normal tissue EQD2 constraint can be relaxed to 90 Gy for the small resistant tumor sub-volume. For the study patients, tumor sub-volume with DRM > 0.9 = 0.128 ∼ 7.4cc. Adaptive dose fractionation painting can be achieved followed by the dose response assessment. Dependent on the size and location of resistant tumor sub-volumes, tumor EQD2 could be largely improved without increasing normal tissue dose.

Radiobiological Insights of Staged Brachytherapy Using Eye Plaque for Large Uveal Melanoma

I-125 radioactive seeds embedded in an eye plaque is used to deliver the radiation dose of 85Gy to the apex of the tumor. However, it is challenging to treat a lesion in height (>10 mm) because of a high dose (> 500 Gy) to sclera. A staged radiotherapy (SRT) has been implemented successfully in stereotactic radiosurgery when a single dose is risky for a bigger sized lesion. The hypothesis of this work is that the SRT works for eye plaque brachytherapy of uveal melanoma to break the single fraction into two. To apply the concept of SRT, the following questions need to be answered: What are the two fraction doses? What is the time interval between the two fractions? In this work, the two split fraction doses and time interval are calculated using the "incomplete-repair' model. Equation (1) is the linear-quadratic (LQ) model. f(x) is the cell survival curve (SC). Equation (2) and (3) are radiobiological model developed dealing with the split doses by considering the incomplete repair. Ln(f(x)) = -αx - βx2 (1) Ln(fn(x, Ɵ)) = nLn(f(x))-nβx2hn(Ɵ) (2) hn(Ɵ) = (2/n)[ Ɵ/(1- Ɵ)][n-(1- Ɵn)/(1- Ɵ)] (3) Ɵ = exp(-µΔt) (4) x represents the fraction dose, Ɵx is the initial segment of the survival curve, Ɵ determines the rate at which repair proceeds. n is fraction number and µ represent repair constant which equals to ln2/T1/2. T1/2 is the half-life of I-125. For continuous dose vt delivered at dose rate v for time t, with repair constant µ, the LQ model is modified as Ln (f(vt, µ)) = -α(vt) -β(vt)2g(µt) (5) g(µt) = 2[µt-1+exp(-µt)]/(µt)2 (6) Assuming biological effective dose (BED) is the same for the single fraction and split two fractions, SC when n = 1 should be same as when n = 2. Therefore, the equation (7) is derived. Ɵ = [(α/β)x1 - 2(α/β)(x2)2 + (x1)2]/2(x2)2 - 1 (7) x1 is single fraction dose of 85Gy, x2 is the split dose to two fractions. α/β ratio of 10 Gy is used. By fitting the equation (7), the ranges of doses and time intervals were determined. The fraction doses and time interval to get the same BED as single fraction of 85 Gy are determined from 45 Gy to 50 Gy with time interval of 22 days to 76 days for staged brachytherapy eye plaque (SBEP). Our result is matched the treatment protocol for SBEP reported, e.g., 1st fraction dose of 40Gy and 50 Gy of 2nd fraction with 73 days of time interval are used. The max. dose of scleral dose is 328 Gy compared to the single fraction scleral dose of 543Gy. This work could provide guidelines in SBEP in dosage and time interval. The height of tumor matters the most in the SBEP since the taller the tumor, the higher dose to the sclera is. Reference.

Trends in the Use of Hypofractionation in Treatment of Breast Cancer in Botswana

Clinical trials have shown that moderate hypofractionation (HF) is clinically effective as adjuvant treatment to breast conserving surgery or following mastectomy with advanced disease. ASTRO issued updated guidelines in 2018, expanding the population eligible to receive HF to all patients, regardless of age and tumor stage. Use of HF can promote efficient resource utilization for over-burdened health care systems; however, global adoption of HF has been previously only reported via ESTRO survey of individual physicians. These data note that HF following lumpectomy is 40% in Africa vs. >90% in North America, with limited data on the uptake of HF within individual African countries. In this study, we characterize temporal trends and clinical, socio-demographic factors associated with the use of HF in breast cancer in Botswana. We retrospectively analyzed a cohort of breast cancer patients receiving curative intent radiation between 2015 and 2022 at the only radiation clinic in Botswana. We compared patients' characteristics between those who received HF vs. standard fractionation (SF) and report chi-square statistics when appropriate. We fit a multilevel mixed-effects logistic regression model with a random intercept for district while adjusting for fixed effects such as HIV infection status, laterality, hormone receptor status, and marital status. A total of 234 patients were prescribed curative intent radiation between 2015 and 2022 in Gaborone, Botswana. Median age at diagnosis was 51 years old, and the majority of patients presented with stage III disease (61.9%, 109/234). 26.9% of this population were women living with HIV (WLWH), and 71% lived >100km from the hospital. HF was utilized overall in 59.4% (139/234) of patients. Most common fractionation patterns included: 4005cGy/15fx and 4267cG/16fx. One patient received ultra-HF (2600cGy/5fx). In unadjusted chi-square analysis, a higher proportion of HF was seen in right vs left-sided breast cancer (65.8% vs. 50.9%, p = 0.02), increasing year of diagnosis from 2015 - 2022 (p<0.001), and among patients >/ = 40 years of age vs. those <40 years of age (62.8% vs 42.1%, p = 0.017). Temporal trends show a significant increase in the utilization of HF starting from 23.8% (5/21) in 2015, to 61.5% (32/52) in 2018, and finally 100% (11/11) of cases in 2022. Our regression analysis shows that there is no statistically significant between-district variance or patient-level factors that associate with the uptake of HF. The overall utilization rate for HF between 2015-2022 was 59.4% (95% CI: 53.0%-65.5%). Based on recent survey results the uptake of HF among African countries is lower than that of North America. To our knowledge, this is the first quantitative analysis of the utilization of HF over 5 years in an African country. Further analysis on factors related to physician prescription of hypofractionation is warranted, including influence of breast laterality, age, and primary surgery type.

Predictors of Local Control with Palliative Radiotherapy for Multiple Myeloma

Palliative radiotherapy (RT) is employed for patients with multiple myeloma to improve or prevent symptoms. However, the optimal dose fractionation is not well defined. The role of cytogenetics in informing RT warrants further study. We performed an institutional analysis of patients with multiple myeloma receiving palliative RT and assessed factors associated with local progression, with a focus on dose fractionation and cytogenetic abnormalities. We queried a prospectively maintained, departmental database for consecutive patients who received palliative RT for multiple myeloma at our institution from 2015 to 2020. Double- and triple-hit were defined as the presence of two and three high-risk cytogenetic abnormalities. RT dose fractionation data were extracted from the database. Follow-up imaging was used to evaluate for progression. A total of 239 patients with 362 treated lesions were included. Twenty-five patients (10.4%) with 39 lesions had double-hit cytogenetics, and 4 patients (1.7%) with 7 lesions were triple-hit. Patients had the following number of lesions treated with RT: 1 (156, 65.3%), 2 (53, 22.2%), 3 (17, 7.1%), or >3 (13, 5.4%). The most commonly targeted sites were spine (125, 34.5%), abdomen/pelvis (67, 18.5%), and lower extremity (53, 14.6%). Most lesions received doses of 20 Gy/5 fx (132, 36.5%), 8 Gy/1 fx (93, 25.7%), or 30 Gy/10 fx (48, 13.3%). RT equivalent dose in 2 Gray fractions (EQD2) was <2000 cGy for 126 lesions (34.8%) and ≥2000 cGy for 236 lesions (65.2%). At a median follow-up of 4.3 years, the risk of local progression on a per lesion basis at 1 and 4 years was 7.8% (95% CI: 5.5-11.1) and 13.4% (10.3-17.5), respectively. No cytogenetic abnormalities were correlated with local progression. Factors significant on univariate analysis included female sex [hazard ratio (HR): 1.94 (1.02-3.71), p = .045], LDH at diagnosis [HR per 10 units/liter: 1.04 (1.09-1.08), p = .016], and number of treated lesions [HR per lesion: 1.38 (1.02-1.89), p = .039]. These three covariates were included on multivariable analysis, and the only covariate to approach significance was number of treated lesions [HR for >3 versus 1: 2.43 (0.88-6.74), p = .059]. In the overall cohort, EQD2 did not impact risk of progression. Among those with >3 treated lesions, EQD2 ≥2000 cGy was associated with a significantly lower risk of progression [HR: 0.05 (0.01-0.23), p<.001]. Double- and triple-hit status were not correlated with progression. Median overall survival in all patients was 4.1 years versus 1.5 and 0.6 years in those with double- and triple-hit disease, respectively. In this large, institutional study of patients with multiple myeloma, palliative RT achieves durable long-term local control. Patients with high disease burden may be at increased risk of progression at treated sites. This group may benefit from an EQD ≥2000 cGy. Cytogenetics, including double- and triple-hit status, do not appear to influence RT response.

Radio-Immune Response of Spatially Fractionated Radiotherapy for VMAT Lattice Plans

To evaluate radio-immune response of spatially fractionated radiotherapy (SFRT) for large tumors using VMAT Lattice technique in terms of tumor volume under irradiation and dose fractionation schemes after SFRT. Eleven patients treated with SFRT from a single institution were retrospectively replanned to deliver 15Gy in single fraction using Lattice technique. High dose regions are defined by multiple spheres with the diameter of 1.25 to 1.5cm and their vertex space of 3.0 to 4.0cm inside of GTV. VMAT plans with multiple arcs were developed for SFRT. Four palliative fractionation regimens of 200cGy x 12 (EQD2 = 24Gy with a/b of 10Gy), 400cGy x 5 (23.3Gy), 600cGy x 3 (24Gy) and 800cGy x2 (24Gy) and four definitive regimens of 200cGy x 24 (EQD2 = 48Gy), 400cGy x 10 (46.7Gy), 600cGy x 6 (48Gy) and 800cGy x 4 (48Gy) were considered for radiotherapy to follow SFRT. Linear quadratic (LQ) model is compared with radio-immune (RI) response model in which the activation of cytotoxic T lymphocytes, tumor immune suppression capability and immunotherapy drugs can be considered. Tumor regrowth time (TRT, time to tumor regrowth to the original volume after treatment) from each model was compared as a measure of benefit achieved from the application of SFRT. The average volume of GTVs in this study was 776cc (range 58-2944cc). Three different SFRT plans (2D GRID technique with conventional collimator, 2D GRID with step & shoot IMRT, and 3D Lattice) were developed for each patient but only Lattice plans were considered in this study since they produced comparable dose modulation inside the tumor but only Lattice significantly reduced skin and critical organ dose. Radio-immune response model always expects longer TRT than LQ model. For palliative regimens, TRT of RI model is longer than that of LQ model by 14.5±9.9, 15.1±10.6, 17.2±12.4, 17.5±12.8 days for each fractionation scheme. When Lattice plan of 15Gy is delivered before the palliative treatment, the difference becomes 25.9±15.3, 31.5±23.3, 36.7±27.6, 37.5±28.5 days. The benefit of SFRT from RI response is only about 10-20 days. Interestingly, RI response is inversely proportional to tumor volume. When curative dose is considered, the difference of TRT is drastically changed from 25.9±9.8, 460.7±285.8, 1180.8±985.7, 1512.0±1327.5 days to 20.7±4.4, 449.0±411.7, 1725.4±2171.0, 3517.7±4531.7 days. The benefit of SFRT from RI response appears larger for large tumor with hypo-fractionation in definitive regimens. The benefit of SFRT is significant for large tumors with hypo fractionation in the definitive regimens when radio-immune response model is considered which is not apparent in LQ model. Radio-immune response model may help to guide the development of successful treatment scheme large tumor volumes.

Combined Radiotherapy Using a Method for Biologically Informed IMRT Planning

Radiotherapy (RT) regimens routinely employ multiple courses that vary by delivery modality and/or fractionation schedule as part of initial or follow up treatment. The combination of RTs ideally should consider the biological effect of the total composite dose distribution. Biological effect can be quantified by biological effective dose (BED) which is a function of the RT modality, dose fractionation, and tissue radiosensitivity. This work describes a method of optimizing a follow up intensity modulated RT (IMRT) plan that considers BED from prior RT. Required inputs for this method are the desired composite BED objectives (BEDref) for target volume(s) and organs at risk (OARs). First, the physical dose in each CT voxel from prior RT (Dprior) is converted to BED (BEDprior). The difference between BEDref and BEDprior gives the optimal BED distribution for the follow up IMRT plan (BEDIMRT). Next, the optimal physical dose (DIMRT) corresponding to BEDIMRT is calculated for each voxel as a function of the number of IMRT fractions (nIMRT). Commercial IMRT treatment planning systems require optimization objectives to be specified for contoured structures, not individual voxels, so a workaround is proposed: 1) for each structure, BEDref is converted to physical dose (Dopti) as a function of nIMRT, and 2) for each voxel, the difference of Dopti and DIMRT is calculated. The result is a "base dose distribution" (Dbase) that is used with standard inverse optimization tools to optimize an IMRT plan so that the sum of Dbase and the IMRT dose approaches Dopti for each voxel. This method was implemented using a custom software workflow to calculate Dbase as a function of Dprior and input BEDref values. Validation was performed by comparing the workflow output with hand calculated Dbase values at randomly selected points within clinically significant regions. Satisfactory agreement was considered to be within 5%. Feasibility of the method was demonstrated using an RT trial protocol for glioblastoma multiforme that combines permanent low dose rate brachytherapy (BT) using collagen tiles embedded with 131Cs seeds and follow-up IMRT (20 fractions). The Dbase distribution was obtained from the software as a function of the BT dose and BEDref for one patient model. Comparison of Dbase values from the software and hand calculated values resulted in agreement within 5% for 22/25 points and within 10% for 3/25 points. Discrepancies >5% (max 9.4%) were attributed to data precision resolution effects inherent in the DICOM standard. The resulting IMRT plan was deemed clinically acceptable and the composite dose distribution achieved dosimetric objectives for all target and OARs. A method for optimizing a follow up IMRT plan that considers dose from prior RT to produce a desired composite BED distribution was derived and proof of concept was successfully demonstrated. Further validation of this method with additional patients and multimodality RT protocols will be performed.

Stereotactic Radiosurgery (SRS) for Large Brain Metastases: Dosimetric and Clinical Predictors of Local Progression and Radionecrosis

Stereotactic radiosurgery (SRS) provides high rates of local control for small brain metastases with low rates of radionecrosis (RN). Larger targets are associated with increased risk of both local progression (LP) and RN. In this analysis, we hypothesized that dosimetric and clinical parameters predict for risk of LP and RN in SRS targets larger than two centimeters. We retrospectively reviewed patients with one or more targets with either an intact versus post-operative cavity larger than 2.0 cm treated with LINAC-based SRS between 2017 and 2022 at one institution. We assessed for association between patient, treatment, and disease variables with LP and RN. Variables assessed included tumor resection status, PDL1 positivity, target volume, maximum and minimum target dose, EQD2 and BED (a/b = 2 for necrosis and a/b = 10 for tumor control), as well as receipt of steroids, bevacizumab, or systemic therapy before or after SRS. Radionecrosis was determined by characteristic radiographic changes. Analyses were performed for the entire cohort and within subsets including by resection status and dose fractionation. A total of 178 lesions in 143 patients were included. Targets with volume diameters measuring at least 2 cm were used. Median follow-up was 2.3 years. Overall survival at 1 and 2 years was 56% and 32%, respectively. Most lesions (n = 119) were resected and treated with SRS post-operatively. The most common dose and fractionation schemes used were 30 Gy in 5 fractions (n = 89) and 27 Gy in 3 fractions (n = 63). For the entire cohort, the cumulative incidence of LP 1 and 2 years was 26% and 34%, respectively. The cumulative incidence of radiographic radionecrosis at 1 and 2 years was 12% and 17%, respectively. There was no difference in LP or RN between 27 Gy in 3 fractions versus 30 Gy in 5 fractions (p>0.5 for both). Median planning target volume (PTV) size was 18.5 cc for the 27 Gy in 3 fraction group compared to 21.9 cc in the 30 Gy in 5 fraction group. Minimum or maximum dose within the target was not associated with increased risk of LP or RN. Among patients receiving 27 Gy in 3 fractions, patients treated with resection followed by SRS had lower risk of LP compared to those treated with SRS alone (HR: 0.15, 95% CI: 0.03-0.64, p = 0.011). Among patients receiving 30 Gy in 5 fractions, patients who received corticosteroids prior to SRS had a lower risk of RN (HR: 0.14, 95% CI: 0.03-0.66, p = 0.013). For the entire cohort as well as within all subgroups, PD-L1≥1% was associated with increased risk of RN (p<0.001 for all). Selecting the optimal SRS dose fractionation and planning parameters to minimize both LP and RN remains a challenge for large targets. In this analysis, 27 Gy in 3 fractions appeared to provide equivalent LP and RN compared to 30 Gy in 5 fractions, and may be more convenient for patients. Patients with PD-L1≥1% with large brain targets treated with SRS may be at increased risk of RN; corticosteroid prophylaxis may be considered in this population.

Effect of Daikenchuto Therapy on Risk of Rectal Bleeding after IMRT for Prostate Cancer

Rectal bleeding due to radiation proctitis after treatment in radiation therapy for prostate cancer is a typical late toxicity symptom. The rate of rectal bleeding has been reduced by using IMRT, IGRT and peri-rectal hydrogel spacer. On the other hand, few reports have attempted to reduce the rate of rectal bleeding by medication. It has been reported that Daikenchuto (DKT), a traditional Japanese herbal medicine, has the effects of accelerating gastrointestinal motility and anti-fibrosis. We retrospectively investigated the rate of rectal bleeding in patients between concurrently administered and not administered DKT for bowel control during IMRT for prostate cancer. The subjects were 102 patients who underwent definitive IMRT for prostate cancer between 2014 and 2021 in our hospital. The DKT therapy concurrent use group were included 46 patients (45%), who were administered DKT per 10.0 g / day or 15.0 g / day. The irradiation was carried out, confirming the rectal volume every time by the image-guided radiotherapy using cone beam CT in all cases. The curative doses fractionation of IMRT were 78 Gy in 2 Gy per fraction (40%) or 70 Gy in 2.5 Gy per fraction (60%). We compared the rate of rectal bleeding after IMRT with and without DKT. Late rectal bleeding toxicity was scored using the Common Terminology Criteria for Adverse Events ver. 5.0 criteria. The associated factors of rectal bleeding were examined using the Cox proportional hazard model for multivariate analysis. In the DKT therapy group, the median follow-up period was 31 months (Range: 17-84 months), and the rectal bleeding rate was Grade 1 in 2 patients (4%) and Grade ≥ 2 in none. The median observation period in the non-DKT therapy group was 48 months (Range: 17-101 months), and the rectal bleeding rate was Grade 1 in 12 patients (21%), Grade 2 in 6 patients (10%), and there were no events of Grade ≥ 3. In univariate analysis, DKT therapy, dose fractionation and planned rectal doses (V50, V55, V60, V65, V70 and V75 converted to EQD23) were significant factors for rectal bleeding. Multivariate analysis showed that the DKT therapy was a significant independent factor in reducing the rate of rectal bleeding (HR: 0.105, 95% CI: 0.01-0.50, P = 0.003). It was statistically suggested in this study that the DKT therapy further reduced the rate of rectal bleeding in IMRT for prostate cancer.

Stereotactic Body Radiotherapy (SBRT) for Adrenal Metastases: Practice Patterns at Community-Based Radiotherapy Centers

To analyze SBRT of adrenal metastases at free-standing centers within a large network in the USA, in order to guide institutional recommendations. We interrogated records of patients treated with SBRT to adrenal metastases from January 2019 to June 2022 from a database of 13,363 patients who were treated with SBRT at 21 community-based centers clustered into five regions within a network. We reported patient characteristics, frequency, survival rate, and biologically effective dose (BED10) prescribed, respiratory motion capture according to region and treatment year. Survival was calculated by Kaplan-Meier estimates. A total of 271 patients were treated to metastatic adrenal lesions (2.0% of all SBRT patients). Median age was 69.8 years (range 32-96). Frequency of treatment increased by an average of 4.5% per year over the period. Table 1 gives the frequency of primary tumor sites, histological types, and dose fractionations. It also shows the range of BED10 used. 91% received five fractions, and 6% received 3 fractions. Median BED10 was 72 Gy (mean 68.0 Gy SD = 18.7). The most common regimen was 8 Gy x 5 (n = 75, 28%), but ranged from 5 Gy x 5 (n = 20) to 10 Gy x 5 (n = 34). BED10 varied according to geographic region ranging from 61.2 Gy to 73.0 Gy (p = 0.01). Median BED was 72 or above in 2 of 5 regions and less than 72 in 3 regions. Respiratory motion capture simulation was done in 65.1% of cases and frequency varied across the 5 locations as shown in Table1 from 93.3% in region 1 to 41.7% in region 5 (p<.0001). 4D CT simulation was used in 46.2% of cases and use was relatively stable over time: 52.8% in July to December 2020 and 40.9% from January to June 2022 with no trend over time: p = .7635 At median follow-up 6.6 months (range 0.3-48.5), 203 (74.9%) of patients were alive with a median overall survival of 24.3 months. 1-year and 2-year survival was 72.7% and 51.5% respectively. Use of respiratory motion simulation was not significantly associated with survival p = 0.47. Despite variation in BED10 and respiratory motion management, 2-year overall survival was over 50% in patients treated with SBRT for adrenal metastases in a large community network. Further study will address refinement of recommendations regarding dose and other treatment characteristics and expansion of clinical research in this setting.

Using kV Triggered Imaging and Liver Dome Position to Reduce the Dosimetric Error Caused by Breath Hold Variability for Liver Stereotactic Body Radiation Therapy

In a previous study, we demonstrated that manual gating using kV triggered imaging and liver dome position can reduce targeting errors caused by breath hold variability for liver stereotactic body radiation therapy (SBRT). In this study, we quantified the dosimetric error caused by breath hold variability and investigated the effect of liver dome gating on reducing dosimetric error. Twenty-five liver SBRT patients treated with deep inspiration breath-hold were included in this IRB approved study. Volumetric modulated arc therapy was used to deliver 30-60 Gy in 1-5 fractions. To verify the breath-hold reproducibility during treatment, a KV triggered image was acquired at the beginning of each breath-hold. The liver dome position was visually compared with the expected upper/lower liver boundaries created by expanding/contracting the liver contour 5mm in the superior-inferior direction. If the liver dome position was within the boundaries, delivery continued; otherwise, beam was held manually and the patient was instructed to take another breath hold until the liver dome position was within boundaries. To calculate delivered dose, for each fraction, the treatment plan was divided into sub-beams, each corresponding to one breath hold using delivery log files. The triggered images were registered to the planning CT to determine the liver position during each breath hold. Dose delivered during each breath hold was calculated by shifting the isocenter of the sub-beam according to the liver position. Breath holds discarded by gating were excluded since no dose was delivered during these breath holds. Delivered fractional doses were compared with planned fractional doses using GTV D99 and liver Dmean. To estimate delivered dose without gating, the first "corrective" breath hold taken after the discarded breath holds was replaced with the prior discarded breath hold and dose calculation was repeated. Seven hundred eleven triggered images from 91 treatment fractions were analyzed. Without gating, in 11 of the 91 fractions from 7 of the 25 patients, delivered GTV D99 reduced > 0.50 Gy from planned value (range 0.51-1.68 Gy, 3-10% of planned fractional GTV D99). Liver dome gating was able to detect/exclude irreproducible breath holds in 8 of the 11 fractions, increasing the delivered GTV D99 by 0.70 Gy per fraction on average (range 0.21-1.63 Gy). With liver dome gating, delivered fractional GTV D99 was comparable to planned value for all fractions (12.96 +/- 5.19 Gy vs 13.04 +/- 5.18 Gy, p > 0.05). Liver mean dose was not affected by breath hold variability or gating. Fractional liver Dmean was 2.26 +/- 1.19 Gy from plan, 2.27 +/- 1.21 Gy for delivery with gating and 2.27 +/- 1.20 Gy for delivery without gating. Breath hold variability may cause tumor underdose. Liver dome gating using kV triggered imaging reduces dosimetric error and ensures tumor coverage for liver SBRT.