Standard Fractionation Research Articles

Comparison of Acute and Chronic Toxicities with Daily vs. QOD Partial Breast Radiation Therapy

<h3>Purpose/Objective(s)</h3> Radiation therapy for breast cancer has evolved from standard fractionation over 5-6 weeks to regimens that allow for completion in 1 week or less; additionally, the target of therapy for patients following breast conserving surgery has evolved from whole breast to partial breast for appropriately selected patients. One such regimen is a 5-fraction partial breast approach; while originally given every other day, questions regarding delivery daily have emerged. We therefore aimed to characterize the acute and chronic toxicities of daily or every-other-day (QOD) 5 fraction PBI. <h3>Materials/Methods</h3> The charts of 273 patients treated from 2017-2021 were identified from an institutional registry and retrospectively reviewed to assess for acute (within 90 days of treatment) and chronic toxicities. All patients received 30 Gy in 5 fractions. Their age, BMI, comorbidities, follow up time, tumor stage, adjuvant therapies, and type of toxicity were recorded. Toxicity related to radiation treatment includes fatigue, dermatitis, desquamation, telangiectasia, lymphedema, and cosmesis. Clinical variables were summarized using descriptive statistics and compared using the Chi-square test. <h3>Results</h3> Of the 273 patients, 64 were treated daily with APBI and 209 were treated QOD. Median follow up was 0.8 years in the daily and 1.2 years in the QOD group. With respect to stage, Tis (11% daily, 19% QOD), T1 (86% daily, 76% QOD), and T2 (3% daily, 5.8% QOD) were relatively well balanced between groups. Comorbidities in both groups were comparable and included obesity (p=0.77), COPD (p=1), CAD (p=1), asthma (p=0.79), HTN (p=0.47), diabetes (p=0.49), and dyslipidemia (p=0.38). 1.6% of patients in the daily group and 1.5% patients in the QOD group received HER2 targeted therapy. 1% of patients in the QOD group and no patients in the daily group received anthracycline. 78% of patients in the daily group and 76% of patients in the QOD group were treated with endocrine therapy. Patients who received QOD therapy had higher rates of acute grade 1 dermatitis (34% QOD vs 19% daily, p = 0.02) and grade 1 fatigue (15% QOD vs 6% daily, p = 0.11). Overall, the majority of patients in both groups did not experience any acute fatigue (93.8% daily, 84% QOD). There were very few instances of chronic toxicity overall, only 1 patient (1.7%) in the daily group with chronic dermatitis vs. 7 (3.6%) in the QOD group. 12% of QOD patients experienced chronic toxicities including hyperpigmentation or fibrosis vs. 3.4% from the daily group (p = 0.051). <h3>Conclusion</h3> Overall, there are few acute and chronic toxicities related to 5 fraction APBI, with significantly less acute toxicity among the daily group. Daily APBI treatment can be considered for patients as an alternative to QOD 5 fraction PBI.

Does the European Society of Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS v1 .1) Apply to Radiation Oncology? A Constructive Critique

<h3>Purpose/Objective(s)</h3> There is an ongoing desire to define "value" in clinical research. ESMO-MCBS is a commonly used framework, endorsed by ESMO and used by several governments in their health technology assessments in various settings. Such value frameworks have not been validated for assessing benefit derived from radiotherapy (RT). We herein assess the applicability of the ESMO-MCBS in radiation oncology, using breast cancer as a test-case. <h3>Materials/Methods</h3> We reviewed the supportive literature used by the ASTRO Evidence-Based Guideline on Radiation Therapy for the Whole Breast for adjuvant whole breast Radiation Therapy. We delineated a pool of "core" (112 studies) and "supplemental" articles (additional 65 studies). Among these, we identified a subset of 15 randomized trials, 1 systematic review and 1 big data study. The goals of our exercise were (1) to evaluate the "scorability" of data, (2) to evaluate the reasonableness of the generated grades for clinical benefit using the current version of the ESMO-MCBS tool, and (3) to identify shortcomings in the instrument when applied to RT approaches, and suggest amendments to improve the efficacy and validity of the ESMO-MCBS tool. <h3>Results</h3> Few studies met the ESMO-MCBS criteria for crediting clinical benefit; i.e., in (1) superiority of the trials in overall survival (OS) or disease-free survival (DFS), or, (2) non-inferiority in OS or DFS with benefit in either life quality (QOL) or toxicity or reduced treatment costs as secondary end-points. OS was the primary end point in only one trial (which was a negative study). However, that study (EORTC boost trial) was practice-changing because it showed a significant improvement in local control (LC) which was a secondary outcome. Since the ESMO-MCBS does not credit local control (i.e., "local DFS"), superiority studies using this endpoint were not scoreable. Arguably, the 4 non-inferiority studies and one meta-analysis comparing hypo-fractionation with standard fractionation (that demonstrated non-inferior disease control with reduced acute and late toxicity) could be scored. Finally, reports describing cosmetic, clever technical or dosimetric advances, without verification of improved patient outcomes nor associated with clinical benefit, were not scoreable. <h3>Conclusion</h3> Currently, ESMO-MCBS does not credit LC as distinct from DFS or RFS. Since local recurrence results in a cascade of adverse events for patients, this is a clinically meaningful outcome, albeit often not always a good surrogate for OS. For consistency in research design and description of results, we propose replacing the conventional nomenclature of LC with Local-DFS (L-DFS)- a subtype of DFS most-relevant to local treatments (e.g., RT and surgery). The utility of the ESMO-MCBS in studies involving RT and surgery would be improved by incorporation of credit for statistically and clinically significant improvements in L-DFS.

Ten-Year Follow-Up on 160 Patients Treated with Hypofractionated Prostate Salvage Radiation Therapy

<h3>Purpose/Objective(s)</h3> Patients with biochemical failure after prostatectomy are commonly treated with standard fractionation radiotherapy requiring 6.5-8 weeks of treatment. GU003 recently reported favorable short-term efficacy and acceptable toxicity using hypofractionated salvage radiotherapy after prostatectomy. However, follow-up for the study is short and questions remain regarding whether late toxicities will remain acceptable. Here, we report on long term outcomes of patients treated with a similar regimen. <h3>Materials/Methods</h3> We evaluated a consecutive cohort of patients treated from 2003-2013 with salvage RT to 65-70 Gy in 25-28 fractions using image-guided IMRT. Freedom from biochemical recurrence (FFBR), prostate cancer specific survival (PCSS), and overall survival (OS) were assessed using Kaplan-Meier analysis. Factors associated with biochemical failure were assessed using Cox regression analysis (surgical margins, Gleason score ≥8, PSA nadir, time to detectable PSA, PSA doubling time, and presalvage PSA). Late GU toxicities were scored based on a modified LENT/RTOG grading system. <h3>Results</h3> A total of 160 patients were identified with a median follow-up of 155 months. Twenty-six patients (16.3%) received androgen deprivation therapy following surgery or concurrently with radiation and 20 patients (12.5%) had lymph nodes electively treated. FFBR was 63% at 5 years and 56% at 10 years; PCSS was 99% at 5 years and 93% at 10 years; OS was 97% at 5 years and 85% at 10 years. Factors associated with increased biochemical recurrence included negative surgical margin status and higher pre-salvage PSA (p =0.025, 0.050). Total incidence grade ≥3 late toxicities was 21.9% (n=35, 33 GU, 1 GI, 1 lymphovascular) which were observed a median of 101 months after the end of radiation. There were four late grade 4 toxicities and three observed deaths potentially associated with radiation (urothelial cancer, urosepsis related to a suprapubic catheter, and pelvic sarcoma). <h3>Conclusion</h3> Prostate cancer has a long natural history as do many late RT toxicities. This cohort of patients with >10 years follow-up treated with hypofractionated salvage RT shows long-term control comparable to that seen in other salvage RT series with long-term follow-up. Although we do not have a comparator group treated with standard fractionation, these data illustrate the importance of long-term follow-up when considering toxicity from salvage RT.

Prospective Single-Arm Trial of Preoperative 42.75 Gy in 15 Fractions for Soft Tissue Sarcoma of the Extremity/Trunk

<h3>Purpose/Objective(s)</h3> The standard pre-operative radiation therapy (RT) dose of 50 Gy in 25 daily fractions for soft tissue sarcoma (STS) contributes to excellent local control and is associated with major wound complications (MWC) in approximately 35% of patients. We sought to prospectively investigate whether a radiobiologically equivalent dose given in a 3-week course of 42.75 Gy in 15 daily fractions confers a higher risk of MWC. <h3>Materials/Methods</h3> We conducted a prospective, single-arm, non-randomized trial of hypofractionated pre-operative RT consisting of 42.75 Gy in 15 once-daily fractions followed by surgery 4-8 weeks after RT completion for adult patients with biopsy-confirmed, non-metastatic, previously un-irradiated STS of the extremity or superficial trunk. Patients (n=120) were enrolled from December 2018 to January 2021. The primary outcome of the study was to determine the rate of MWC within 120 days of surgery among patients treated with the trial regimen. Safety was monitored using a Bayesian stopping rule One-Arm Time-To-Event Simulator which compared development of MWC at 120 days post-surgery among patients on study to the historical rate of 35%. The Kaplan-Meier method was used to estimate outcomes. <h3>Results</h3> Median follow-up from surgery was 23 months (interquartile range [IQR] 15-29). Median age was 60 years (IQR 48-69) and median maximum tumor size was 7.6 cm (IQR 4.5-12.8). A majority of the patients had lower extremity (LE) tumors (n=78, 65%; upper extremity (UE), n=20, 17%; trunk, n=22, 18%). Tumor grade was: high in 51% (n=61), intermediate in 23% (n=27), low in 8% (n=9), or not gradable in 19% (n=23). All patients received 42.75 Gy (or CGE) in 15 once-daily fractions with either: IMRT (n=57, 48%), 3D-RT (n=55, 46%), electrons (n=5, 4%), or protons (n=3, 3%). None experienced acute skin toxicity of CTCAE v4.0 > or = grade 3. Thirty-seven (31%, 95% CI: 24-40%) patients developed MWC within 120 days of surgery (median, 37 days (IQR 25-59)). Six patients (5%) developed local recurrence at a median 16 mos (IQR 7-17); 4 in the RT field, 1 at the field margin, and 1 wide of field. Actuarial 2-year local control is 93% (95% CI: 85-97%). <h3>Conclusion</h3> Our prospective non-randomized clinical trial revealed that a hypofractionated pre-operative radiotherapy dosing regimen of 42.75 Gy in 15 once-daily fractions resulted in a MWC rate that was not higher than accepted historical rates. Early analyses show rates of local recurrence that are consistent with those observed with standard fractionation. These data support that this 3-week regimen may offer a safe, effective, and more convenient alternative to 50 Gy in 25 daily fractions for patients undergoing pre-operative RT for STS.

High-Dose Spatially Fractionated Radiotherapy, Lattice Radiotherapy in Bulky Tumors: Results after One Year Follow-Up

<h3>Purpose/Objective(s)</h3> Spatially Fractionated Radiotherapy (SFRT) or Lattice Radiotherapy (LRT) is a radiotherapy technique that allows to deliver a very high radiation doses spheres inside the tumor in a single fraction, maintaining low dose in OAR, generating an inhomogeneous dose distribution inside the GTV and maintains the PTV marginal dose within planned dose within a multifraction treatment. This can be an option for bulky unresectable tumors with poor local control with standard radiotherapy. The main objective of this study is to assess LTR toxicity in patients with tumors greater than 45 cc and poor candidates for other treatment modalities. <h3>Materials/Methods</h3> From 1 January 2020 to 31 December 2020, 21 patients were treated in our institution. We prescribe 1 cm spheres with a maximum dose over 15 Gy in a single fraction and at least 4 vertices distributed inside of GTV. PTV dose continues as standard dose fractionation of 2.5-3Gy in the LRT session as prescribed in conventional or hypofractionated treatment. Simulation and treatment delivery is as SBRT. LTV (Lattice Tumor Volume) is the structure inside GTV where the VTV spheres (Vertex Tumor Volume), overdose volumes, are located, separated by 2.5-3.0 cm. VV (Valley Volume) is the subtraction of GTV-VTV that must be under 5 Gy. <h3>Results</h3> 21 patients (66,6% of tumors were in the thorax, 28,6% abdomen/pelvis and 4,8% head and neck) were treated. The median follow-up was 12 months (3-25). The median age of the patients was 64 years old (42-84). The median GTV volume was 236cc (80-896cc) and 73 mm (47– 123mm) in greatest axial diameter. The analysis of the results showed 4 patients with complete response (20%), 12 with partial response (57%) and 5 with stable disease (23%). Tumor reduction bigger than 50% has been observed in 75% of cases 2 weeks after LTR session. Local control was 75% at 6 months. Cumulative probability of survival was 76% (95% CI 51-89%) and 59% (95% CI 33-77%) at 6 and 12 months respectively. No additional toxicity has been related. No major grade 3 toxicities were reported according to CTCAE v5.0 grading. <h3>Conclusion</h3> Our experience with LTR protocol is feasible as a technique to be included in radiotherapy treatments for poor prognosis bulky tumors, with reproducibility and adaptability. Our early results confirm good local response and no added toxicity. Further large prospective studies are required to validate these results.

Early Experience of Online Adaptive Radiation Therapy of Definitive Head and Neck Cancer Patients

<h3>Purpose/Objective(s)</h3> Advent of cone beam computed tomography (CBCT) based online adaptive radiotherapy (OnART) systems has reduced the barriers of adaptation by allowing rapid generation of new plans. However, due to the complexity of head and neck cancer (HNC) treatment planning, there is a paucity of OnART data on HNC patients. We present our early OnART experience in definitive radiation of HNC with the hypothesis that OnART would improve target coverage and reduce dose to organs at risk (OAR). <h3>Materials/Methods</h3> Patients with HNC receiving definitive (chemo)radiation who underwent at least one OnART were enrolled on a prospective registry study between 7/2021 and 1/2022. The same OnART software was used for on-couch adaptation for all patients. The frequency of adaptation was at the discretion of the treating physician. Physicians were given the option of delivering one of two plans during adaptation: the original radiation plan transposed onto the CBCT with adapted contours (scheduled) and a new adapted plan generated from the updated contours (adapted). Paired t-test was used to compare the mean doses between scheduled and adapted plans. <h3>Results</h3> Sixteen patients (12 oropharynx, 2 larynx/hypopharynx, 1 sinus, and 1 salivary gland primary) underwent 38 adaptation sessions (median 2; range 1 – 8). Most patients (14/16) were treated in 33 or 35 standard fractions, with SABR delivered to the other two patients. The mean new plan generation and approval time was 22 minutes (median 21; range 9 – 39), the mean physician time at the console was 26 minutes (median 23; range 14 – 45), and the mean patient time in the vault was 44 minutes (median 42; range 28 – 96). The adapted plan was chosen 89.5% (34/38) of the time. The scheduled plan vs adapted plan mean V100% for high-risk PTVs was 87.8% vs 92.4% (p = 0.07), intermediate-risk PTVs was 86.6% vs 98.2% (p = 0.02), and low-risk PTVs was 96.3% vs 98.1% (p < 0.01). The mean hotspot was also lower with adaptation, 108.7% vs 106.7% (p < 0.01). Doses to OARs saw heterogeneous changes from the scheduled to the adapted plan (Table). Most OARs (9/12) showed a decrease in the mean relative difference in dose with the adapted plans, with the larynx (p = 0.045), spinal cord (p < 0.01), mandible (p < 0.01), and brainstem (p = 0.03) reaching significance. <h3>Conclusion</h3> OnART is feasible for HNC patients. Early results show significant improvement in target coverage and homogeneity. On average, OARs saw a modest decrease in dose.

Ensemble Machine Learning Algorithm Using Clinical and Dosimetric Features to Predict Radiation Pneumonitis after Stereotactic Body Radiation Therapy (SBRT) for Lung Cancer

<h3>Purpose/Objective(s)</h3> Radiation pneumonitis (RP) is a significant cause of toxicity in patients receiving radiation therapy (RT) for lung cancer. Machine learning techniques have been utilized to develop models to predict RP, but prior efforts have largely focused on conventionally fractioned RT. The current study's aim is to add to the growing body of literature using machine learning to identify and verify important features related to RP post-RT and to generate an algorithm capable of predicting this adverse outcome. Additionally, this study is differentiated from prior efforts by focusing on SBRT rather than conventionally fractionated RT and using a combination of accessible dosimetric and clinical features, with the goal of creating a clinically useful model to predict RP risk. <h3>Materials/Methods</h3> The study utilized data from 201 lung cancer patients that were treated with SBRT between 2005 and 2015. Patient data including demographics, tumor characteristics, and dosimetric features were analyzed for association with symptomatic RP, defined as CTCAE v. 4.0 ≥ Grade 2. Prior to data modeling the chi-square test was used to rank important features. Data imbalance was corrected for using the Synthetic Minority Oversampling Technique (SMOTE), and commercial software was used to generate classification machine learning models based on the balanced dataset. Models were tested on the original dataset for classification accuracy, area under the curve (AUC), sensitivity, and specificity. The performance of several different algorithms was evaluated including Decision Trees, Discriminant Analysis, Logistic Regression, Naive Bayes Classifiers, Support Vector Machines, Nearest Neighbor Classifiers and Ensemble Classifiers. Each model utilized 10-fold cross-validation to prevent overfitting. <h3>Results</h3> Out of 201 patients receiving SBRT, 24 patients (11.9%) developed symptomatic RP. Based on chi-square test results, increased lung V12.5 (volume receiving 12.5 Gy), multiple tumor sites, prior RT to the thorax or lung surgery, right-sided tumor laterality, and former smoking status were selected as predictors in the machine learning models. After testing, Ensemble classifiers were found to be the most accurate overall. Of the Ensemble models, a Bagged Trees classifier had the most impressive results, correctly classifying 23 out of 24 cases of symptomatic RP. The model had an AUC of 0.93, overall accuracy of 91.5%, sensitivity of 95.8% and specificity of 91.0%. <h3>Conclusion</h3> A machine learning algorithm was developed to predict RP, utilizing a combination of 5 ranked dosimetric and clinical features. The model has an overall accuracy of 91.5% and an AUC of 0.93. The advantage of this model when compared to others is that it was generated using SBRT patient data, as opposed to standard fractionation RT, and easily accessible clinical and tumor characteristics. Future research will test the model's accuracy on an independent dataset and executing prospective studies to verify the model's clinical utility.

The Impact of Implementing Hypofractionation Prescription Regimens and Modernizing Delivery Technique on Treatment Resources in Breast Radiotherapy

<h3>Purpose/Objective(s)</h3> To determine the change in treatment resources due to the implementation of hypofractionated prescription regimen <h3>Materials/Methods</h3> All patients between January 1, 2012 and December 31, 2021 receiving curative intent breast radiotherapy at a tertiary cancer center were included. Plan and patient data were extracted from the patient database with the treatment planning system and direct database query. Treatment plan categorization was completed using data elements to include only curative intent. Treatment plans for seroma boost or supraclavicular irradiation were excluded to ensure this analysis did not double-count regional nodal irradiation contribution or confound boost with hypofractionation. Treatment delivery time is recorded in the database for each patient treatment delivered. Average patient treatment time per year was estimated by multiplying the average fractions each year by average time in the same year. The standard fractionation regimens (95% of patients) are 42.56 Gy in 16, 40 Gy in 16, 27 Gy in 5 (accelerated partial breast irradiation), and 26 Gy in 5 (FAST-Forward). In the analysis, implementation milestones are indicated for new prescription regimens and delivery technique changes including deep inspiration breath hold (DIBH) for left-sided patient treatments and daily verification imaging. <h3>Results</h3> A total of 6505 patients were included. Table 1 details the total number of patients per year, the average number of fractions treated per patient, and the average treatment time of each patient plan. The average total fractions per treatment decreased from 17.5 in 2012 to 10.9 in 2021. The average treatment delivery time increased from 12.9 minutes to 21.4 minutes. <h3>Conclusion</h3> In considering total treatment resources, the interplay between hypofractionation and modernization delivery techniques is complex. The impact of hypofractionation reduced the average number of fractions but total treatment resources are offset with the implementation of modern treatment delivery techniques. Hypofractionated prescription regimens reduce the time and travel commitment required of patients on an individual basis, contributing to person-centered care.

Institutional Outcomes for Patients Receiving Adjuvant Radiotherapy with a Remote History of Augmentation Mammoplasty with Implants

<h3>Purpose/Objective(s)</h3> Postmastectomy radiotherapy (RT) in patients with immediate breast reconstruction has well known risks of late complications including delayed wound healing, capsular contracture and poor cosmesis. For patients with a remote history of augmentation mammoplasty with implants (AMI) receiving adjuvant RT for breast cancer, the risk of complications is not well documented. At our institution, due to concerns about cosmesis, patients receiving adjuvant RT with remote AMI receive standard fractionation rather than hypofractionation. The purpose of this quality assurance project is to review outcomes for patients who received RT with remote AMI. <h3>Materials/Methods</h3> Using our radiation treatment planning interface, patients were identified who underwent adjuvant RT to the breast and/or regional nodes in 25 to 28 fractions between January 1, 2013, and December 31, 2019. Chart review was performed to determine demographics, type of reconstruction, complications, subsequent unexpected re-operations due to cosmesis, and dosimetry. EQD2 calculations were generated assuming an α/β=3.4 for normal breast tissue. Patients with and without cosmetic complication were compared for significance using the Mann Whitney U-test (two tailed, p<0.05). <h3>Results</h3> Thirty-two patients underwent RT with remote AMI. Four patients (12.5%) had documented cosmetic complications after adjuvant RT requiring reoperation. Complications included rupture (n=1), contracture (n=2), asymmetry (n=1). The mean time from radiation to reoperation was 697 days (353-1045 days). For patients with cosmetic complications, 75% received chemotherapy prior to RT while 32.1% of patients without complications received chemotherapy prior to RT. Doses ranged from 45-50 Gy in 25 fractions vs 50.4 Gy in 28 fractions. Boost doses ranged 10-16 Gy in 5-8 fractions. In addition to whole breast irradiation (WBI), one patient (25%) with cosmetic complications also received regional nodal RT while 6 patients without complications (21.5%) received adjuvant nodal RT. Of the patients with cosmetic complications, all received boost with electrons and none of the patients had bolus. The total EQD2 for WBI and boost was statistically higher in the group of patients requiring reoperation for cosmesis (57.8 Gy vs 52.3 Gy, p=0.02). <h3>Conclusion</h3> For our cohort of patients receiving RT after remote AMI, the rate of cosmetic complications requiring reoperation was low (12.5%). This rate is significantly lower than institutional and documented rates of cosmetic complications for patients with immediate reconstruction followed by adjuvant RT. While the sample size was small, it is worthwhile to note that patients receiving chemotherapy, boost, and a higher EQD2 were more likely to experience cosmetic complications. Future investigation should include prospective review of a larger cohort of patients with remote AMI and the risk profile of boost.

AESOP: Phase 2 Open-Label Trial of Avasopasem Manganese (GC4419) for Reduction of Esophagitis in Patients Receiving Chemoradiotherapy for Nonmetastatic Lung Cancer

<h3>Purpose/Objective(s)</h3> National Cancer Institute (NCI) grade 3+ esophagitis has been reported in up to 20% of advanced lung cancer patients receiving standard fractionation radiotherapy with concurrent chemotherapy (Provencio 2011, Curran 2011). Avasopasem (GC4419) is an investigational selective dismutase mimetic that rapidly and selectively converts superoxide to hydrogen peroxide, interrupting the initiation of radiation-induced mucosal injury (Thompson 2010, Sonis 2021). Avasopasem demonstrated the potential to reduce severe oral mucositis due to chemoradiotherapy for head and neck cancer in a randomized phase 2 clinical trial (Anderson 2019), supporting the hypothesis that avasopasem might reduce severe radiation-induced esophagitis in patients with lung cancer. <h3>Materials/Methods</h3> In a single-arm open-label trial, patients with stage 3 or post-operative stage 2B non-small cell lung cancer (NSCLC) or limited stage small-cell lung cancer (LS-SCLC) received 90 mg avasopasem by 60-minute infusion prior to radiation therapy (1.8–2.0 Gy 5 days/week up to 60 Gy total), in combination with investigator's choice of chemotherapy other than gemcitabine. Primary objective to assess the incidence of acute (NCI ≥gr 2) radiation esophagitis, with observed incidence of grade 3–4 radiation esophagitis as a secondary endpoint. <h3>Results</h3> A total of 39 patients were enrolled and received at least 1 dose of avasopasem: median age 64 (range 38–85); 22 (56.4%) were male; 95% performance status (PS) 0 or 1. Thirty-two (82.1%) had NSCLC and 7 (17.9%) had LS-SCLC. Median duration of exposure to avasopasem was 43.0 days (range 2–54). Preliminary results with data analysis ongoing showed 14 of 29 evaluable patients (48.3%) experienced acute esophagitis at week 6 (95% confidence interval [CI], 29.5–67.5). Of these, 13 (44.8%) were grade 2 and 1 (3.4%) was grade 3; there were no grade 4 events. Adverse events (AEs, all grades) considered possibly related to avasopasem occurring in at least 15% of patients were nausea (36%), paresthesia (26%), dizziness, fatigue (21% each), and hypotension (15%). Three patients had grade 3 AEs (7 events) possible related to avasopasem (nausea, vomiting, dehydration, hypokalemia, dysphagia, muscular weakness, hypoxia). <h3>Conclusion</h3> In this phase 2 open-label study, grade 3 esophagitis was infrequent with avasopasem at an unscheduled interim analysis. The AE profile appeared consistent with expectations for standard therapy and avasopasem appeared well tolerated. Final data will be presented at the conference. This study (NCT04529850) is funded by Galera Therapeutics, Inc.

Comparison of different treatments for HPV+ oropharyngeal carcinoma: a network meta-analysis.

Treatment of human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) is rapidly evolving. Despite either surgery or radiotherapy (RT), with or without chemotherapy (CT), being acceptable in intermediate and locally advanced diseases, there is uncertainty regarding the best treatment option for these patients. Therefore, we performed a network meta-analysis (NMA) to compare the relative efficacy of different treatments for HPV+ oropharyngeal carcinoma. Randomized clinical trials that enrolled adults with non-metastatic HPV+ oropharynx cancer and provided data about overall survival (OS) and/or progression-free survival (PFS) and/or locoregional control and distant metastases (LRC and DM) were included. Fixed- or random-effects models were fit using a Bayesian approach to NMA. Between-group comparisons were estimated using hazard ratios (HRs) with 95% credible intervals (CrIs). The primary outcome was OS. A total of 844 citations were screened; 11 randomized clinical trials were included (HPV+ stage III-IV cancer, mainly oropharynx carcinomas). Nine treatment arms were compared. Radiotherapy (altered or standard fractionation) + triweekly cisplatin (HR 3.8; 95% CrIs 0.29-65 and 0.3; 95% CrIs 0.03-2.51) was superior to RT in term of OS (P score = 0.42 and 0.16). Radiotherapy with low and high cisplatin doses appeared similar (HR 1.57; 95% CrIs 0.19-12.72). Altered fractionation or standard RT + 3-weekly cisplatin are the 2 highest-ranked options in terms of PFS (P score = 0.35 and 0.34). This meta-analysis confirms the role of cisplatin added to RT as the best option for HPV+ oropharyngeal carcinoma. RT+ 3-weekly cisplatin is likely to be the best radical treatment in terms of OS and PFS.

Osteoradionecrosis rate in oropharynx cancer treated with dose volume histogram based constraints

ObjectivesMandibular dose constraints are designed to limit high dose to small volumes to avoid osteoradionecrosis (ORN). Based upon a published experience, intermediate-dose constraints were introduced but have not been independently validated. We hypothesize that these constraints lower ORN rate without compromising other organs at risk (OAR). MethodsOropharyngeal cancer patients treated with standard fractionation adjuvant/definitive VMAT from 01/2014–08/2020 were included. In 09/2017, mandibular dose constraint was changed from historical constraint (HC) of D 0.1 cc < 70 Gy to modified constraints (MC) of V 44 Gy < 42%, V 58 Gy < 25%, D 0.5 cc < 70 Gy. OAR dosimetric changes and ORN development were evaluated. Regression modelling predicted long-term ORN cases in MC group. ResultsThere were 174 patients, 71 in MC group. Seven cases of ORN in HC group at a median follow up (FU) of 39 months and 1 case of ORN in MC group at a median FU of 11 months were observed. More patients in the MC group met V 44 Gy (87% vs 62%, p < 0.01) and V 58 Gy constraints (92% vs 73%, p < 0.01). Mean doses to OARs did not rise. Mandible V 44 Gy and V 58 Gy were significantly associated with ORN (p < 0.01 and p = 0.03, respectively) across all patients. In the HC group, V 44 Gy was independently associated with ORN (p = 0.01). To account for shorter FU in MC group, logistic regression of ORN based on V 44 Gy in HC patients was performed. This predicts 3.2 ORN cases in the MC group (95% CI: 0.00–6.4). ConclusionAchieving V 44 Gy and V 58 Gy was successful in 87% of cases without sacrificing target coverage or OARs and resulted in non-significant ORN decrease.

The case against IORT in the management of early stage breast cancer

Since the development of breast conserving therapy (BCT) that incorporated standard fractionation whole breast irradiation (WBI) delivered daily over 5–7 weeks, there has been a concerted effort to shorten the duration of adjuvant radiation therapy as a way to improve convenience and compliance, reduce costs, and potentially reduce toxicities. Over the past decade, an unprecedent shift in breast radiation techniques and regimens has led to the emergence of shorter courses of WBI (5–15 fractions) as well as partial breast approaches which also reduce treatment duration to 1–3 weeks.

Inhibitory Effect of Standardized Extract and Fractions of Nigella sativa L. on Nystatin Susceptible and Clinically Nystatin Resistant Candida albicans.

Candidiasis infection is caused by different species of Candida, which are characterized by host immunologic weakness. Black cumin seeds (Nigella sativa) have shown an inhibitory effect against Candida albicans. In this work, the inhibitory effect of standardized extract and different fractions of Nigella sativa seeds has been evaluated on both nystatin-susceptible and resistant strain of C. albicans. Canadida albicans (NSCA) with ATCC 76645 and nystatin-resistant Candida albicans (NRCA) were prepared from oral samples of HIV individuals. Total extract and different fractions of N. sativa were prepared using maceration and sonication methods. Thymoquinone (TQ) content of the plant was determined by spectrophotometric method. Total extract (TTE) and the fractions along with TQ were evaluated on NSCA and NRCA by the microdilution method. TQ content of the plant was 0.92 ± 0.37g/100g dried extract. The least MIC and MFC (62.5 and 125 μg/ml, respectively) were due to petroleum ether fraction (PEF) against both NSCA and NRCA, followed by chloroform fraction (CHF) with MIC and MFC of 125 and 250 μg/ml, respectively. TQ exhibited MIC of 0.78 and 3.12 μg/ml against NSCA and NRCA, stronger than nystatin (MIC of 2 and 16 μg/ml, respectively). Thymoquinone was detected in the PEF and CHF. Considering more inhibitory effects of PEF and CHF than TTE, we can conclude that active components of the plant belong to non-polar compounds. PEF showed identical inhibitory effects on NRCA and NSCA, which is a valuable result for finding novel medicaments against NRCA infections.

Relationship of dose to vascular target volumes and local failure in pancreatic cancer patients undergoing neoadjuvant chemoradiation.

ObjectiveThe objectives of this study were to evaluate whether dose to the vasculature is associated with local control after surgery in patients with borderline resectable (BLR) and resectable pancreatic cancer (PCA) receiving neoadjuvant radiation therapy (RT) and to identify a dose threshold for clinical use.MethodsPatients with BLR and resectable PCA treated with neoadjuvant RT were retrospectively reviewed. During this period, the institutional paradigm shifted from standard fractionation to hypofractionation/stereotactic body radiation therapy (SBRT). A vasculature clinical target volume (Vasc CTV) was contoured for each patient and defined as a 5-mm margin around the superior mesenteric artery (SMA) from its origin to the pancreatic head, the celiac artery from its origin to the level of the trifurcation and any involved vein. The Vasc CTV D95 was normalized to a 2-Gy equivalent dose to determine the optimal dose associated with optimal local failure-free survival (LFFS).ResultsForty-seven patients were included in the analysis. A Vasc CTV D95 of 32.7 Gy was the optimal cutoff for LFFS. Patients with Vasc CTV D95 Equivalent dose in 2 Gy per fraction (EQD2) >32.7 Gy had significantly longer LFFS compared to patients with Vasc CTV D95 EQD2 ≤32.7 Gy at 12 months (91% vs. 51%, respectively) and 24 months (86% vs. 12%, respectively). The median disease-free survival (DFS) for patients with EQD2 >32.7 Gy was 30.4 months compared to 14.0 months in patients with EQD2 ≤32.7 Gy (p = 0.01). There was no significant difference in overall survival (OS) between the two groups.ConclusionsDuring neoadjuvant treatment, dose to the Vasc CTV is associated with durability of local control (LC) after resection and should be intentionally included in the treatment volume with an EQD2 goal of 31–33 Gy.

Patient-reported outcomes for patients with breast cancer undergoing radiotherapy: A single-center registry experience.

BackgroundWe present Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) for patients undergoing adjuvant radiotherapy for breast cancer with curative intent. We describe the frequency and severity of PRO-CTCAE and analyze them with respect to dose fractionation.MethodsPatients were included in this study if they were treated with curative intent for breast cancer and enrolled on a prospective registry. Patients must have completed at least one baseline and one post-radiation survey that addressed PRO-CTCAE. For univariate and multivariate analysis, categorical variables were analyzed by Fisher’s exact test and continuous variables by Wilcoxon rank sum test. PRO-CTCAE items graded ≥2 and ≥3 were analyzed between patients who received hypofractionation (HF) versus standard conventional fractionation (CF) therapy by the Chi-square test.ResultsThree hundred thirty-one patients met inclusion criteria. Pathologic tumor stage was T1–T2 in 309 (94%) patients. Eighty-seven (29%) patients were node positive. Two hundred forty-seven patients (75%) experienced any PRO-CTCAE grade ≥2, and 92 (28%) patients experienced any PRO-CTCAE grade ≥3. CF was found to be associated with an increased risk of grade ≥3 skin toxicity, swallowing, and nausea (all p < 0.01). HF (OR 0.48, p < 0.01) was significant in the multivariate model for decreased risk of any occurrence of PRO-CTCAE ≥3.ConclusionsOur study reports one of the first clinical experiences utilizing multiple PRO-CTCAE items for patients with breast cancer undergoing radiation therapy with curative intent. Compared with CF, HF was associated with a significant decrease in any PRO-CTCAE ≥3 after multivariate analysis.

The splenic T cell receptor repertoire during an immune response against a complex antigen: Expanding private clones accumulate in the high and low copy number region.

Large cellular antigens comprise a variety of different epitopes leading to a T cell response of extreme diversity. Therefore, tracking such a response by next generation sequencing of the T cell receptor (TCR) in order to identify common TCR properties among the expanding T cells represents an enormous challenge. In the present study we adapted a set of established indices to elucidate alterations in the TCR repertoire regarding sequence similarities between TCRs including VJ segment usage and diversity of nucleotide coding of a single TCR. We combined the usage of these indices with a new systematic splitting strategy regarding the copy number of the extracted clones to divide the repertoire into multiple fractions for separate analysis. We implemented this new analytic approach using the splenic TCR repertoire following immunization with sheep red blood cells (SRBC) in mice. As expected, early after immunization presumably antigen-specific clones accumulated in high copy number fractions, but at later time points similar accumulation of specific clones occurred within the repertoire fractions of lowest copy number. For both repertoire regions immunized animals could reliably be distinguished from control in a classification approach, demonstrating the robustness of the two effects at the individual level. The direction in which the indices shifted after immunization revealed that for both the early and the late effect alterations in repertoire parameters were caused by antigen-specific private clones displacing non-specific public clones. Taken together, tracking antigen-specific clones by their displacement of average TCR repertoire characteristics in standardized repertoire fractions ensures that our analytical approach is fairly independent from the antigen in question and thus allows the in-depth characterization of a variety of immune responses.

Production of mini potato tubers in two rotations of protected ground in the conditions of North Ossetia-Alania

The aim of the research was to grow potato mini-tubers in two crop rotations of protected ground using micro-plants and micro-tubers in vitro as planting material. The experiments were carried out in 2019-2021 in the Republic of North OssetiaAlania (the North Caucasus). The initial in vitro material was planted in spring (April-June) and summer (August-October) rotations in 5 L pots filled with peat substrate. The pots were placed in polycarbonate-lined greenhouses. The objects for the research were the potato varieties Gulliver, Sadon and Kumach. Microplants (control), standard (&gt; 9 mm) and non-standard (5-9 mm) micro-tubers were used as variants for laying the experiment. According to the results of biometric observations in the period from sprouting to the plants reaching 20 cm, the presence of unevenness in plant height was noted in the variants with the use of micro-tubers. In the spring rotation, the cultivation of mini-tubers from microplants contributed to the formation of 6.9-8.0 pcs/plant with a standard fraction yield of 6.1-7.2 pcs. Productivity in variants with planting micro-tubers of 5-9 mm in size decreased by 1.6-1.9 times compared with micro-plants. In the summer rotation, the plants formed from 3.5 to 6.5 minitubers with a standard seed fraction yield of 53-72 %. Microtubers &gt; 9mm (potato varieties: Gulliver and Kumach) in summer planting were more productive than micro-plants. On average, they formed 6.1-6.7 pcs/plant, which exceeded the control variant by 0.8-2.1 pcs. According to the results of the research, the total number of formed mini-tubers during summer rotation was 1.2-1.4 times lower than during spring rotation. The use of two rotations in the process of growing mini-tubers in protected ground contributed to an increase in the quantitative yield of produced seed material for the growing season by 1.7 times.

Patterns of Care and Utilization of Radiation for Women With Good-Risk Ductal Carcinoma In Situ: A National Cancer Database Analysis.

Purpose/objective(s)Lumpectomy followed by whole-breast radiation therapy (WBRT) provides a 50% recurrence rate reduction in ductal carcinoma in situ (DCIS) patients when compared to lumpectomy alone. Certain factors increase the risk of recurrence, including higher nuclear grade, large size, age less than 50, and close margins. RTOG 9804 demonstrated a reduction in local failure after WBRT with the use of adjuvant radiation in women with "good-risk disease" (mammographically detected, measuring less than or equal to 2.5 cm, with a predominant nuclear grade of 1 or 2, and a margin of greater than or equal to 1 cm, or a negative re-excision). The purpose of this study is to retrospectively identify the patterns of care in women with low-risk DCIS utilizing the National Cancer Database (NCDB). We hypothesize that with the utilization of hypofractionation, there may be an increase in the delivery of RT for these "good-risk" patients.Materials/methodsThe National Cancer Database was queried to identify women treated with lumpectomy for <2.5 cm, nuclear grade 1 or 2 DCIS of the breast from 2004 to 2016. Data were collected regarding age, tumor size, endocrine therapy use, ER receptor status, race, insurance type, and distance from the treatment center. The distance was stratified into quartiles consisting of 0-3.9, 4-8, 8.1-15.8, and > 15.8 miles, respectively. Radiation fractionation was collected and categorized as hypofractionation, standard fractionation, or other if fractionation could not be ascertained. Clinical and patient-related factors were compared between patients who received radiation and those who received no radiation. The frequency distributions between categorical variables were compared using the Chi-square test. Multivariable logistic regression was used to identify covariables that impacted the receipt of radiation.ResultsThe eligibility criteria were met by a total of 12,846 patients. Of those, 6,600 (51.4%) received adjuvant WBRT. On multivariable regression, patients whose tumors were ER (OR 1.24, P<0.001) and those who had not received endocrine therapy (OR 2.24, P<0.001) were more likely to receive WBRT. Factors less likely to receive WBRT included increasing age over 50 (age 50-65 OR 0.83, P<0.001; age>65 OR 0.58, P<0.001), and distance of >15.8 miles (OR 0.78, P<0.001). The fractionation technique was categorized as standard or hypofractionated in 52.2% of patients. Of those, the use of hypofractionation increased from 0.4% in 2004 to 8.9% in 2010 and to 53.8% in 2016.ConclusionThis NCDB analysis demonstrated that patients who meet the RTOG 9804 criteria for "good-risk" DCIS are less likely to receive RT as time progresses despite an increase in the utilization of hypofractionation techniques. Overall, slightly more than half of these patients receive adjuvant RT.

Comparison between Automatic and Semiautomatic System for the 3D Echocardiographic Multiparametric Evaluation of RV Function and Dimension.

Background: The right ventricle (RV) plays a pivotal role in cardiovascular diseases and 3-dimensional echocardiography (3DE) has gained acceptance for the evaluation of RV volumes and function. Recently, a new artificial intelligence (AI)–based automated 3DE software for RV evaluation has been proposed and validated against cardiac magnetic resonance. The aims of this study were three-fold: (i) feasibility of the AI-based 3DE RV quantification, (ii) comparison with the semi-automatic 3DE method and (iii) assessment of 2-dimensional echocardiography (2DE) and strain measurements obtained automatically. Methods: A total of 203 subject (122 normal and 81 patients) underwent a 2DE and both the semi-automatic and automatic 3DE methods for Doppler standard, RV volumes and ejection fraction (RVEF) measurements. Results: The automatic 3DE method was highly feasible, faster than 2DE and semi-automatic 3DE and data obtained were comparable with traditional measurements. Both in normal subjects and patients, the RVEF was similar to the two 3DE methods and 2DE and strain measurements obtained by the automated system correlated very well with the standard 2DE and strain ones. Conclusions: results showed that rapid analysis and excellent reproducibility of AI-based 3DE RV analysis supported the routine adoption of this automated method in the daily clinical workflow.