Curative-intent Radiotherapy Research Articles

The Importance of Multi-Parametric MRI, PET/CT, and Biopsy for Identifying and Delineating the Extent of Locally Radiorecurrent Prostate Cancer: A Multi-institutional Analysis of the F-SHARP Clinical Trial.

Up to 50% of clinical recurrences after curative-intent radiation are intraprostatic local radiorecurrences (LRR), with improved detection through the recent incorporation of multi-parametric MRI and PET/CT in workup. Salvage local therapy (SLT) is increasingly being offered, particularly focal SLT to try to reduce toxicity due to prior radiation. Limited data exist on the incremental value of each imaging modality and biopsy in defining LRR. The objective of this study is to compare the findings of MRI, PET/CT and biopsy in patients with LRR prostate cancer, and the impact each modality has on identifying recurrence and defining the extent of prostate involvement. This is a secondary analysis of 58 patients enrolled on the ongoing F-SHARP phase I/II clinical trial of salvage HDR brachytherapy from 3 institutions who underwent PSMA or fluciclovine PET/CT, MRI, and biopsy prior to enrollment. Recurrent tumor was delineated on each imaging modality and by inclusion of involved regions on biopsy. Descriptive statistics were used to compare the imaging-defined tumor with biopsy findings to assess the congruence between the imaging modalities and generate the percentage of patients with disease involvement on biopsy outside of the image-defined targets. Initial therapy was conventional/moderately hypofractionated photons in 35 patients, LDR in 13, proton therapy in 7, SBRT in 2, and neutrons in 1. Recurrence Gleason grade groups included 1 (n = 3), 2 (17), 3 (12), 4 (8), 5 (9), and uninterpretable (9). MRI/TRUS sextant + fusion biopsy was performed in 40 patients, TRUS saturation biopsy in 4, and TRUS systematic biopsy in 14. The median number of cores involved and obtained were 6 and 14. The median number of discrete lesions on biopsy in different quadrants of the prostate was 3 (1-6). The median number of discrete lesions seen on MRI was 1 (0-4). MRI did not identity a discrete lesion in 4 patients. The sensitivity of MRI for detection of the LRR was 92.8%. The false negative rate for not detecting the focus of LRR on MRI was 7.2%. 68.4% of patients had biopsy-proven cancer outside of the MRI-defined target. Fluciclovine PET/CT was used in 45 patients, and 13 had PSMA PET/CT. The median number of lesions on PET/CT was 1 (0-2). PET/CT did not identify a discrete lesion in 8 patients. The pooled sensitivity of PET/CT in detecting the focus of LRR was 86.2% (Fluciclovine: 82.2%, PSMA: 100%). PET/CT false negative rate of PET/CT for not detecting the focus of LRR was 13.8% (Fluciclovine: 17.8%, PSMA 0%). 72.41% of patients had biopsy-proven cancer outside of the PET/CT-defined target (Fluciclovine: 77.8%, PSMA: 53.8%). Although mpMRI and PET/CT are valuable tools for identifying LRR and delineating the extent of prostate/SV involvement, a thorough biopsy is mandatory if pursuing focal SLT. Such treatment should optimally be performed on a clinical trial with robust integration of all imaging and histopathologic data.

Patient-Level and Endpoint-Specific Clinico-Dosimetric Analysis of the Cardiac Base as a Mediator of Radiation Cardiotoxicity in Non-Small Cell Lung Cancer

Cardiac disease is a dose-limiting toxicity in non-small cell lung cancer (NSCLC) radiation therapy. Radiation dose to the cardiac base is associated with poor overall survival in several clinical studies, but has not been validated in a non-dose escalated cohort, or with individual patient delineations. In this study we examined the impact of cardiac base dose on overall survival (OS) and cardiac events (CEs), and interrogated the relationships of the substructures comprising the heart base with OS and CEs. Patients with stage I-III NSCLC treated with curative-intent radiation therapy between 2015 and 2020 at a regional cancer center were identified. Clinical notes were examined for baseline patient, tumor and cardiac details, and both cancer and cardiac outcomes. Three cardiologists verified CEs. Cardiac delineations were completed using a validated deep learning-based autosegmentation tool. Cox and Fine and Gray regressions were undertaken for the risk of death and CEs respectively, accounting for pre-specified evidence-based dose metrics and clinically relevant cardiac covariates. Most patients received 55 Gy/20# (n = 461/478, 96%) without chemotherapy (58%), planned with VMAT (51%) or IMRT (20%). Pre-existing cardiovascular morbidity was common, with 78% having ≥2 risk factors, and 46% having >1 established cardiac disease. The median follow-up was 21.1 months. Dichotomized at the median, higher heart base Dmax was associated with poorer survival on Kaplan-Meier analysis (21.6 months (95% CI 19.3-24.9) versus 29.4 months (95% CI 21.6-36.6), p = 0.021), and remained significant when statistically compared in published multivariate models. In a multivariate analysis for pooled acute CEs, heart base Dmax was associated with CEs (HR 1.75, 95% CI 1.01-1.06, p = 0.04), but this was not the case for individual CEs. Using Fine and Gray models to account for the competing risk of death, left main coronary maximum dose was associated with atrial fibrillation (p = 0.024), proximal right coronary artery V15 (p = 0.023) and mean dose (p = 0.032), and the right atrium mean dose (p = 0.029) were associated with heart failure. No dose-volume metrics were significantly associated with acute coronary syndrome. None of the constituent base substructures dose were significantly associated with death. Dose to the heart base was associated with increased mortality and an increased pooled cardiac event rate. Accounting for endpoint-specific clinical covariates, only select constituent substructures of the heart base were associated with CEs and no substructures were independently associated with survival. Together, these findings are suggestive of possible interplay between the constituent base substructures in their mediation of radiation cardiotoxicity.

Safety and Feasibility of the Addition of a Radiosensitizing Methionine-Restricted Diet to Radiation Therapy

Methionine is an amino acid necessary for numerous processes critical for cell growth and survival. While normal cells can tolerate methionine deficiency, most cancer cells are methionine auxotrophs, requiring dietary intake since they cannot synthesize it. In vitro, methionine deficiency causes cancer cells to undergo cell cycle arrest and cell death, and in vivo a methionine restricted diet (MRD) enhances radiosensitization without significant adverse effects. Combining a MRD and radiation therapy (RT) to treat human malignancies has never been evaluated. The hypothesis of this Phase I study was that a MRD would be safe, and feasible to administer concurrently with curative-intent RT. Eligible patients included adults with any non-skin cancer malignancy undergoing standard radiation therapy without concurrent cytotoxic chemotherapy. The MRD consisted of low-protein cereals, grains, and breads; fruits; vegetables; margarines and oils; and simple carbohydrates. A clinical dietician developed a personalized meal plan with each subject to reduce methionine consumption to 5-10 mg/kg body weight/day, while maintaining adequate protein and caloric intake. An unlimited supply of a commercially available methionine-free protein supplement was provided to minimize hunger and weight loss. The MRD extended from 2 weeks before initiation of RT, through 2 weeks beyond completion of RT. The primary endpoint for safety was the rate of grade 3 or higher acute and late toxicities per CTCAE, over 12 months follow-up. Feasibility was assessed with a biweekly quantitative plasma amino acid panel during the MRD. The target accrual was 15 subjects. Over two years, 53 patients were offered enrollment, 9 subjects enrolled, 5 completed the MRD and RT, and 4 withdrew during the MRD. The table summarizes subjects' characteristics and outcomes. There was no grade 3 or higher adverse events attributable to the MRD. Methionine plasma levels varied over the course of treatment, and while no subject achieved the target of 13 μM, two nadired at 14 μM. The trial was closed early due to slow accrual and subjects' difficulty maintaining the diet. This study suggests a MRD is safe with thoracic or abdominopelvic RT, with toxicities comparable to those expected with RT alone. However, the diet was challenging, and unacceptable to most patients with cancer.

Simulation CT Features and Radiation Cardiotoxicity in Non-Small Cell Lung Cancer

Radiation cardiotoxicity is a significant clinical dilemma in non-small cell lung cancer (NSCLC) radiation therapy (RT). Baseline cardiovascular (CV) status may influence the risk of cardiotoxicity, and may be ascertainable from the appearance of the heart on simulation computed tomography (CT). We examined the association of CT features with incidental heart dose and risk of cardiac events in NSCLC. Patients treated with curative-intent RT between 2015 and 2020 at a regional center were identified. Clinical notes were interrogated for baseline patient and CV health details, and follow-up CV events. Cardiac events were verified by a cardiologist. A deep learning-based auto-segmentation tool was applied, allowing extraction of a pre-specified list of volume parameters in a programming environment. CAC was graded as none, mild, moderate and severe in patients with a non-contrast scan. The craniocaudal relationship of the PTV and heart (Feng atlas) were annotated. A total of 478 patients were included, with a median age of 70 and Charlson Index of 5. The median mean heart dose was 6.3 Gy (IQR 2.7-11.4). The median lung V20 was 20.0% (IQR 14.8-27.1). Cardiovascular risk factors were common, with most patients having 2 (39%) or 3 (31%). A history of previous cardiac events was common, including myocardial infarction (14%), arrhythmia (11%) or heart failure (9%). A total of 6.9% and 7.1% patients developed a new atrial arrhythmia (AA) or heart failure (HF) after completing RT. The volume metrics with the highest AUC for AA and HF events were the left atrium (LA) (AUC 0.67, p = 0.0002) and left ventricle:right ventricle (LV:RV) ratio (AUC 0.66, p = 0.0021). Kaplan-Meier analysis for cardiac events dichotomizing at the optimal cut-point for maximum sensitivity and specificity demonstrated significantly different rates for both AA (LA 109cc, HR 3.35, 95% CI 1.64-6.83, p = 0.0009) and HF (LV:RV ratio 1.61, HR 2.37, 95% CI 1.19-4.74, p = 0.0143). Only 2 patients with non-contrast scans developed a myocardial infarction, both had mild CAC. The incidence of pooled cardiac events was not significantly different between patients with no (n = 2/21, 9.5%), mild (n = 10/38, 26.3%), moderate (n = 8/53, 15.1%) and severe (n = 7/24, 29.2%) CAC (p = 0.3916). Where the inferior border of the PTV was above the superior border of the heart, mean heart dose was significantly lower than compared with overlap of levels (1.9 Gy v 9.7 Gy, p<0.0001), and this was true for 3DCRT (n = 139, p<0.001), IMRT (n = 94, p<0.001) and VMAT (n = 145, p<0.001) patients. LA volume and LV:RV volume ratio are predictive for the development of AA and HF respectively. CAC grade did not differentiate patients by risk of cardiac events. Where the craniocaudal level of the PTV doesn't overlap with the level of the heart, the cardiac dose is likely to be very low. Several simulation CT features are associated with cardiac events following treatment for NSCLC and prospective evidence of cardiac risk could enable medical optimization prior to RT.

Predictors of Long-Term Survival in Patients Treated for Oligometastases

The purpose of this work is to report the long-term outcomes of patients with oligometastases treated with curative intent radiotherapy in the context of the recently developed ESTRO EORTC classification schema. This retrospective, single institution study consists of consecutive adult patients with oligometastases from solid tumor malignancy referred to a single high volume radiation oncologist. Oligometastases were defined as 5 or fewer extracranial or intracranial metastatic lesions where all sites of active disease are amenable to treatment. Patients with a history of distant metastases requiring treatment of the primary tumor ± regional lymph nodes were included. Radical local therapies utilized included stereotactic radiotherapy (53% of patients, median dose 27 Gy in 3 fractions), intensity modulated radiotherapy (64% of patients; median dose 50 Gy in 15 fractions), surgery and/or ablation. Overall survival and progression-free survival were estimated using the Kaplan-Meier method. Predictors of survival were assessed using log-rank test for categorical variables and Cox regression for continuous variables for univariable analysis and Cox multivariable analyses. The study population consists of 130 patients with 207 treated distant metastases referred to radiation oncology between 1/2014 and 12/2021. Key patient characteristics include median age 71, median pre-radiation albumin 3.7 g/dl, 72% ECOG 0-1 performance status, 35% lung primary, 12% prostate primary, median of 1 distant metastasis treated, 31% bone metastases, 30% brain metastases, 47% required treatment to primary tumor ± regional lymph nodes and 71% received systemic therapy after radiation. The most frequent ESTRO EORTC oligometastatic groups were synchronous oligometastases (40%) and metachronous oligorecurrence (29%). At a median follow-up of 28.8 months (IQR 16.0 to 56.3 months), the median overall survival is 37.9 months with a 4-year overall survival of 41.1%. The median progression-free survival was 12.3 months with a 4-year progression-free survival of 22.6%. On multivariable analysis, the strongest predictors of overall survival are age (HR 1.05 [1.02-1.08]; CI: 95%; p<0.001), ECOG performance status (HR 1.69 [1.15-2.47]; CI: 95%; p = 0.007), primary prostate, breast or kidney tumor (HR 2.79 [1.29-6.03]; CI: 95%; p = 0.009) and pre-radiation serum albumin (HR 0.55 [0.35-0.87]; CI: 95%; p = 0.01). The strongest predictors of progression free survival on multivariable analysis are albumin (HR 0.59 [0.39-0.88]; CI: 95%; p = 0.009) and primary prostate, breast or kidney tumor (HR 1.90 [1.06-3.38]; CI: 95%; p = 0.03). Long-term overall survival is not uncommon after radical treatment for oligometastases. The ESTRO EORTC classification provides an enriched nomenclature for oligometastases but is not independently predictive of survival.

Improving the Radiation Oncology Alternative Payment Model

The Centers for Medicare and Medicaid Services (CMS) proposed Radiation Oncology Alternative Payment Model (RO-APM) intends to introduce an episode-based compensation model and is currently delayed until further notice. We aimed to investigate cost implications of factors not considered in the initial model. We analyzed data from 10,226 patients who were treated with radiotherapy from 2018-2021 at Mayo Clinic in Minnesota, Florida, and Arizona. Mean total radiotherapy costs were calculated using inflation adjusted standardized Medicare rates for all codes in the RO-APM. Curative intent radiotherapy was delivered for 64.4% of patients while the remaining 35.6% was palliative intent. Patients receiving protons composed of 22.2% of all radiotherapy patients. Median number of fractions was 10. Mean cost for all curative treatments was $31,035 vs. $10,428 for all palliative patients (p<0.01). Mean cost for all patients treated with protons was $45,966 vs. $17,541 with photons (p<0.01). Mean costs for patients treated with 1-5 fractions, 6-10 fractions, 11-20 fractions, and >20 fractions were $11,261, $13,712, $21,793, and $45,672 respectively (p<0.01). Factors not considered in the final CMS RO-APM proposal such as treatment intent, utilization of proton therapy, and fractionation scheme all have significant cost implications and should be accounted for in future national base rate calculations.

Determining the Minimal Clinically Important Difference of the FACT-E to Evaluate the Change in the Quality of Life of Patients with Esophageal Cancer Treated with Curative Radiotherapy

Patients with esophageal cancer (EC) are often treated with radiotherapy (RT). The Functional Assessment of Cancer Therapy-Esophageal (FACT-E) is a health-related quality of life (QOL) instrument validated in patients with EC. The aim of this study was to determine the minimal clinically important difference (MCID) for FACT-E subscales, to allow for meaningful evaluation of the effect of RT on EC patient's QOL. We evaluated patients with EC, treated with curative intent RT, who completed the FACT-E at baseline and end of treatment (EOT). We calculated the MCID for the FACT-E subscales using anchor-based and distribution-based approaches. In the anchor-based approach we determined improvement and deterioration based on the overall health assessment from the PROMIS-10 as the anchor. We modeled the change in domain scores with age-adjusted regressions to determine the difference in classifications. For distribution-based analysis, we considered 0.3 and 0.5 standard deviation (SD). We averaged MCID for improvement and deterioration separately across timepoints, by approach, and we report MCID ranges as the minimum and maximum values across methods. Our cohort included 210 patients with EC, 96.7% white, 85.7% males, and 32.9% treated with photon with a median dose of 50 Gy (IQR 50-50) and a median fraction number of 25(IQR 25,25). The median age at RT was 67.6 years (IQR 60.9,73.7). The social domain had the lowest MCID (deterioration and improvement 0.9-1.9), while the widest MCID range, proportionally to the measure, was associated with the Fact-E total score (2.1-5.6 for improvement, and 3.7-5.6 for deterioration). MCID estimates from 0.3 SD were in exact agreement with the anchor-based deterioration estimates for the physical domain (2.3), and improvement estimates for the Trial Outcome Index (6.1). We determined the MCID for the FACT-E domains, using a combination of anchor- and distribution-based approaches. These findings are critical to determine whether there is meaningful change in the QOL of individuals with EC treated with curative RT.

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.

Natural History and Clinical/Dosimetric Determinants of Osteoradionecrosis in a Large Cohort of Head and Neck Cancer Following Curative Radiotherapy: Debunking the Myth of Decreased Rates of Osteoradionecrosis in the Modern Radiotherapy Era

Osteoradionecrosis (ORN) of the mandible is the most devastating toxicity following head and neck cancer (HNC) radiotherapy (RT). The rate of ORN occurrence has been debatable in the modern era of advanced RT. We aim to determine the natural history and time to ORN development in a large cohort of HNC. After IRB approval, we identified HNC patients treated with curative-intent RT between 2005 and 2020 at MD Anderson Cancer Center. Dental oncology notes were reviewed and all dental procedures were recorded. Available dose volume histograms (DVHs) for the segmented mandibular volumes were extracted. Based on our previously published ORN normal tissue complication probability (NTCP) model, any dental procedure pre-RT is a clinical high-risk factor and, therefore, data were coded as (high vs. low clinical risk) accordingly. We also coded the dosimetric risk factors to (high vs. low dosimetric risk) according to our published DVH thresholds (high dosimetric risk if any applies: V45≥40%, V55≥25%, and/or D30 ≥40 Gy). Finally, patients were classified to four groups according to combined clinical and dosimetric risk factors (No, clinical, dosimetric, and both). We used the Kaplan-Meier method to calculate time to ORN development and ORN-free survival. For time to ORN development, any grade ORN occurrence was coded as event and all others were censored. For ORN-free survival, death and ORN were coded as events and all others were censored. Log-rank test was used to compared curves of different risk groups. One thousand eight hundred sixty-six patients were included. Median follow-up was 38 months (range 4-162). ORN was reported in 252 patients (13.5%). The median time to ORN development was 18.5 months (range 4-145). 95 patients (37.7%) developed ORN after 2-years post-RT. The 1-, 3-, and 5-year ORN rates were 4.7%, 12.7%, and 17.8%, respectively. The 1-, 3-, and 5-year ORN-free survival were 94.3%, 85.5%, and 80.3%, respectively. There were statistically significant differences (P < 0.0001) between ORN-free survival in different clinical/dosimetric risk factors. The patients with no, clinical-only, dosimetric-only, and both clinical and dosimetric risk factors were 35%, 19%, 22%, and 24%, respectively. The 5-year ORN-free survival was 94.3%, 89.8%, 76.3%, and 69.6% for patients with no, clinical-only, dosimetric-only, and both clinical and dosimetric risk factors, respectively. The hazard-ratio (HR) of ORN development in clinical-only, dosimetric-only, and both clinical and dosimetric risk groups was 2.1, 5.4, and 7.5 compared to the no risk group (P<0.05 for all). Our findings indicate that ORN remains a remarkable toxicity hazard for HNC survivors. A prolonged surveillance time is required for the majority of HNC survivor since more than one-third of the ORN events occurred after 2-year follow-up. Patients with combined clinical and dosimetric risk factors have a staggering ORN risk profile and are proper candidates for future prophylactic pharmacotherapy clinical studies.

Adjuvant Radiation Therapy Improves Local Control in the Treatment of Adnexal Carcinoma

Adnexal carcinoma (AC) is a rare subset of cutaneous malignancies derived from skin adnexa. There are limited data on the role of adjuvant radiation therapy (RT). This study investigates outcomes associated with adjuvant RT at our high-volume referral center. Using an institutional pathology database we identified 45 patients with locoregionally-confined AC treated between 2001-2020 with curative intent surgery and RT at initial diagnosis or at the time of locoregionally-confined recurrence. Clinicopathologic variables were described and time to relapse events were assessed by the Kaplan-Meier method. Median age was 64 yrs (IQR 57-71). Primary tumors were in the head and neck (H&N, n = 36, 80%), trunk/extremities (n = 8, 18%) or unknown (n = 1). The most common histologic subtypes were: sebaceous-14 (31%), microcystic adnexal carcinoma-9 (20%), eccrine-6 (13%), and trichilemmal-5 (11%). Twenty-two (50% of known primaries) had PNI. All patients had primary tumor excision. Six had clinically evident lymphadenopathy (13%), all of whom had lymph node dissection (LND). Five patients without evidence of nodal disease (13%) had sentinel lymph node biopsy (SLNB) with one having SLN+ disease. Thirty patients (67%) received adjuvant locoregional RT at initial diagnosis with the following targets: 21 (30%) primary only, 4 (13%) nodal only, and 5 (17%) both. Of those receiving nodal RT, 7 (78%) had LN+ LND with 2 of those receiving concurrent platinum-based chemoradiation. Sixteen were treated at recurrence with the following targets: 4 (25%) primary only (1 having had prior adjuvant nodal RT), 4 (25%) nodal only, and 8 (50%) both. Across the full cohort, median RT dose was 60 Gy in 30 fractions. Median follow-up from initial surgical resection was 60 months (IQR 30-160). 5-year LC, NC, DFS and DSS were 71%, 86%, 66%, and 91% respectively. The only evaluated factor associated with better outcome was adjuvant primary site RT (5-yr LC 83% vs. 56%, p = 0.01 and 5-yr DFS 83% vs. 46%, p = 0.0003). All 15 patients with local recurrence (LR) had salvage surgery with median subsequent follow-up of 75 months (IQR 2-94). Overall, 5 patients receiving adjuvant primary site RT at any time (initial or salvage) developed subsequent local recurrence (13%). Of the 8 patients who developed nodal recurrence (NR) during follow-up, 1 received adjuvant nodal RT at initial diagnosis. Six of 7 who did not receive prior RT then received adjuvant nodal RT after LND and only 1 developed subsequent NR. AC is a rare skin cancer with a primarily locoregional recurrence pattern. In our experience, adjuvant RT was associated with improved LC which, depending on the tumor location, may help prevent morbid or cosmetically-impactful salvage surgery. Patients with AC would benefit from radiation oncology referral to discuss adjuvant treatment.

Longitudinal Monitoring of Quantitative Imaging Kinetics of Primary Tumor and Nodal Volumes Using the MR-Linac Device in Head and Neck Cancer Patients

We aim to characterize the serial quantitative apparent diffusion coefficient (ADC) changes of the target disease volume using diffusion-weighted imaging (DWI) acquired weekly during radiation therapy (RT) on a 1.5T MR-Linac and correlate these changes with tumor response and oncologic outcomes for head and neck squamous cell carcinoma (HNSCC) patients. Thirty patients with pathologically confirmed HNSCC and received curative-intent RT at the University of Texas MD Anderson Cancer Center, were included in this prospective study. Baseline and weekly MRIs (weeks 1-6) were obtained, and various ADC parameters (mean, 5th, 10th, 20th, 30th, 40th, 50th, 60th, 70th, 80th, 90th and 95th percentile) were extracted from the target regions of interest (ROIs). Pre-RT and weekly ADC parameters were correlated with response during RT, loco-regional control, and the development of relapse using the Mann-Whitney U test. The Wilcoxon signed-rank test was used to compare the weekly ADC versus baseline values. Weekly volumetric changes (Δvolume) for each ROI were correlated with ΔADC using Spearman's Rho test. Recursive partitioning analysis (RPA) was performed to identify the optimal ΔADC threshold associated with different oncologic outcomes. There was an overall significant rise in all ADC parameters during different time points of RT compared to baseline values for both GTV-P & GTV-N. The increased ADC values for GTV-P were statistically significant only for primary tumors achieving CR during RT. RPA identified GTV-P ΔADC 5th percentile >13% at the 3rd week of RT as the most significant parameter associated with CR for GTV-P during RT (p <0.001). Baseline ADC parameters didn't significantly correlate with response to RT or other oncologic outcomes. There was a significant decrease in residual volume of both GTV-P & GTV-N throughout the course of RT. Additionally, a significant negative correlation between mean ΔADC and Δvolume for GTV-P at the 3rd and 4th week of RT was detected (r = -0.39, p = 0.044 & r = -0.45, p = 0.019, respectively). Assessment of ADC kinetics at regular intervals throughout RT is potentially able to predict the response to RT and oncologic outcome. Further studies with larger cohorts and multi-institutional data are needed for validation of our results.

Comprehensive Quality of Life Report from a Prospective Clinical Trial of 4DCT-Ventilation Functional Lung Avoidance Radiation Therapy

Functional imaging has been developed that uses 4DCT images and image processing to generate lung ventilation maps (4DCT-ventilation). 4DCT-ventilation functional avoidance uses 4DCT-images to generate plans that avoid functional regions of the lung with the goal of reducing pulmonary toxicity. A 4DCT-ventilation functional avoidance, phase II, multi-center clinical trial was completed, and patient reported outcomes (PRO) measured. PROs are an essential measure of quality-of-life following radiotherapy. The purpose of this work is to quantify PRO changes for lung cancer patients treated with functional avoidance and to compare PROs against clinical pneumonitis. Patients with locally advanced lung cancer receiving curative intent radiotherapy (prescriptions of 45-75 Gy) and chemotherapy were accrued. Each patient had a 4DCT-ventilation image generated using 4DCT data. Favorable arc geometry and optimization techniques were used to generate functional avoidance plans. PRO instruments included the Functional Assessment of Cancer Therapy Lung (FACT-L) questionnaire and the Visual Analog Scale (VAS) administered pre-treatment and 3-, 6-, and 12-months post-treatment to gather data on physical, social, emotional, functional, and pulmonary well-being. The percentage of patients with clinically significant decline was calculated using the FACT-TOI (Trial Outcome Index), FACT-LCS (Lung Cancer Subscale), and VAS instruments. To evaluate the correlation between PROs and clinical toxicity, the percentage of clinically significant FACT-LCS decline was compared (Chi-square test) for patients who did or did not experience grade 2+ pneumonitis. Fifty-nine patients completed baseline PRO surveys. Median age was 65, 83% of patients had non-small-cell lung cancer, with 75% having stage III disease. Clinically significant FACT-TOI decline at, 3, 6, and 12 months was 46.3%, 38.5%, and 26.8%, respectively. The percentage of patients with clinically significant FACT-LCS decline was 33.3%, 33.3%, and 29.3%, at 3 months, 6 months, and 12 months, respectively. The percentage of patients with clinically significant VAS decline at 3, 6, and 12 months was 18.9%, 20.0%, and 18.6%, respectively. Patients who experienced grade 2+ pneumonitis had a greater percentage of clinically significant decline at all time-points with the results reaching significance (p = 0.045) at 6 months. The study presents the first comprehensive evaluation of PROs for patients treated with 4DCT-ventilation functional avoidance. The data show that 20-40% of patients had clinically significant decline and that PROs had a strong correlation with pneumonitis. The PRO data demonstrate that functional avoidance results in low rates of patient reported outcome clinical decline and provide seminal results to be used in phase III studies.

Assessing the Sexual Health of Female Survivors of Pelvic Malignancies after Radiotherapy

To assess patient-reported sexual health outcomes of female survivors of pelvic malignancies after radiotherapy (RT). Female patients treated with curative intent RT for pelvic malignancies between 2013 and 2019 were surveyed electronically post-RT using the PROMIS Sexual Function and Satisfaction Full Profile and Female Sexual Distress Scale-Revised questionnaires. Cervical and vaginal cancers were grouped together due to the similar treatment characteristics. Surveys were sent to 544 patients, and 53 (10%) completed the questionnaires. Respondents included survivors of anal canal (N = 11), cervical or vaginal (N = 10), uterine (N = 30), and vulvar cancers (N = 2). The median age of patients at the time of treatment was 60 years (range 31,77). The median time between RT and survey completion was 6 years (range 3,9). A total of 22 (42%), 17 (32%), and 14 patients (26%) were treated with brachytherapy (BT), external beam RT (EBRT), or a combination of EBRT and BT, respectively. Of respondents, 96% were free of disease recurrence. Sexually active was defined as partaking in sexual activity within 30 days of survey response. Patients were stratified by age greater than or less than 52 at time of RT, representing the average age of menopause. A total of 30 patients (57%) had at least somewhat interest in sex. There was no difference in the proportion of patients who had at least somewhat interest in sex over 52 years compared to those 52 and (54% vs 67%, p = 0.424). A total of 39 patients (74%) were sexually active, and of those 30 (77%) were over the age of 52 at the time of RT. Of sexually active patients, 28 (72%) reported some, quite a bit, or a lot of satisfaction with their sex lives, whereas the remaining 11 (28%) reported having none or a little bit of satisfaction with their sex lives; the proportion of those with at least some satisfaction with their sex lives did not differ between those who were over or under 52 years at the time of RT (73% vs 67%, p = 0.697). Satisfaction with sex life differed by site of malignancy with 71% cervical or vaginal, 44% anal canal, 86% uterine, and 0% vulvar patients reporting at least some satisfaction (p = 0.043). Patients treated for anal canal cancer tended to have quite a bit or a lot of vaginal discomfort during sex (78%), compared to those treated for cervical/vaginal (29%), or endometrial (18%) cancers (p = 0.006). There was no difference in patients feeling frequently or always stressed about sex between those who were sexually active compared to those who were not (13% vs 14%, p = 0.890). Patients 52 or under at the time of RT were more likely to feel frequently or always stressed about sex compared to those receiving RT over the age of 52 (42% vs 5%, p<0.001). In our cohort, the majority of female survivors of pelvic malignancies were sexually active post-RT, and this important topic warrants further investigation.

Dosimetric Impact of Systematic Mediastinal Staging via Endobronchial Ultrasound for Patients with Locally Advanced Lung Cancer: The SEISMIC Trial

The SEISMIC trial aims to find the best method for mediastinal staging in patients with lung cancer receiving chemoradiotherapy. Currently, CT or PET-CT scans are standard in clinical practice, but histological evaluation of the mediastinum is performed on a case-by-case basis. The study will examine the effect of systematic histological evaluation using Endobronchial Ultrasound (EBUS) on radiotherapy target volumes. The hypothesis of this study is that differences in staging between the diagnostic PET-CT and EBUS would result in reduced tumor coverage and/or increased doses to organs at risk (OAR). SEISMIC is a prospective multicenter international cohort study. Patients were enrolled from Australia, the Netherlands, USA and Canada after regional IRB approvals. Patients were treated with 4DCT simulation. Two iGTV and PTV target volumes were delineated for each patient with discordant staging according to both PET-CT and EBUS, as were OARs. Two VMAT plans were generated for each patient based on either PET-CT or EBUS target volumes using knowledge-based planning methodology. Plans aimed to achieve institutional guidelines for target coverage and OAR dose constraints, with a prescribed dose of 60 Gy in 30 fractions. Target coverage and OAR doses for the PET- and EBUS-defined volumes were compared. In 156 patients, EBUS showed a larger extent of disease than PET in 18 (11.5%) and a smaller extent of lymph node (LN) involvement than PET in 49 (31.4%). Out of 67 patients with PET-EBUS discordant results, 25 underwent upfront radiotherapy and were included in the study. EBUS revealed PET-occult LN involvement in 11/25 patients (44%). In these patients, 10/11 patients received <95% of the prescribed dose to PET-occult LN iGTVs; the median [range] minimum dose to the EBUS iGTV was 9.2 Gy [0.1 - 57.9 Gy]. When planning based on EBUS LN involvement, all patients received ≥95% of the prescribed dose to the iGTV (the median [range] minimum dose to the EBUS iGTV was 58.9 Gy [58.1 - 60.5 Gy]). This resulted in increased median [range] doses to OARs; mean lung dose increased by 1.1 Gy [0.3 - 8.4 Gy], esophagus mean dose increased by 3.6 Gy [0.2 - 24.8 Gy], and mean heart dose increased by 0.5 Gy [-0.6 - 8.5 Gy]. Systematic endoscopic evaluation of the mediastinum had a significant effect on tumor coverage in a clinically meaningful proportion of cases and consequent plan adaptation impacted on organ-at-risk (OAR) doses. Results suggest systematic mediastinal LN staging should be considered in all patients prior to curative-intent radiotherapy. ACTRN12617000333314.

A Phase 1 Study of the DNA-PK Inhibitor Peposertib in Combination With Radiation Therapy With or Without Cisplatin in Patients With Advanced Head and Neck Tumors

DNA-dependent protein kinase (DNA-PK) plays a key role in the repair of DNA double strand breaks via nonhomologous end joining. Inhibition of DNA-PK can enhance the effect of DNA double strand break inducing anticancer therapies. Peposertib (formerly "M3814") is an orally administered, potent, and selective small molecule DNA-PK inhibitor that has demonstrated radiosensitizing and antitumor activity in xenograft models and was well-tolerated in monotherapy. This phase 1 trial (National Clinical Trial 02516813) investigated the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, and tolerability of peposertib in combination with palliative radiation therapy (RT) in patients with thoracic or head and neck tumors (arm A) and of peposertib in combination with cisplatin and curative-intent RT in patients with squamous cell carcinoma of the head and neck (arm B). Patients received peposertib once daily in ascending dose cohorts as a tablet or capsule in combination with palliative RT (arm A) or in combination with intensity modulated curative-intent RT and cisplatin (arm B). The most frequently observed treatment-emergent adverse events were radiation skin injury, fatigue, and nausea in arm A (n=34) and stomatitis, nausea, radiation skin injury, and dysgeusia in arm B (n=11). Based on evaluations of dose-limiting toxicities, tolerability, and pharmacokinetic data, RP2D for arm A was declared as 200 mg peposertib tablet once daily in combination with RT. In arm B (n=11), 50 mg peposertib was declared tolerable in combination with curative-intent RT and cisplatin. However, enrollment was discontinued because of insufficient exposure at that dose, and the RP2D was not formally declared. Peposertib in combination with palliative RT was well-tolerated up to doses of 200 mg once daily as tablet with each RT fraction. When combined with RT and cisplatin, a tolerable peposertib dose yielded insufficient exposure.

Time-Dependent ROC Curve Analysis for Assessing the Capability of Radiation-Induced CD8 T-Lymphocyte Apoptosis to Predict Late Toxicities after Adjuvant Radiotherapy of Breast Cancer Patients.

Late fibrosis can occur in breast cancer patients treated with curative-intent radiotherapy. Predicting this toxicity is of clinical interest in order to adapt the irradiation dose delivered. Radiation-induced CD8 T-lymphocyte apoptosis (RILA) had been proven to be associated with less grade ≥2 late radiation-induced toxicities in patients with miscellaneous cancers. Tobacco smoking status and adjuvant hormonotherapy were also identified as potential factors related to late-breast-fibrosis-free survival. This article evaluates the predictive performance of the RILA using a ROC curve analysis that takes into account the dynamic nature of fibrosis occurrence. This time-dependent ROC curve approach is also applied to evaluate the ability of the RILA combined with the other previously identified factors. Our analysis includes a Monte Carlo cross-validation procedure and the calculation of an expected cost of misclassification, which provides more importance to patients who have no risk of late fibrosis in order to be able to treat them with the maximal irradiation dose. Performance evaluation was assessed at 12, 24, 36 and 50 months. At 36 months, our results were comparable to those obtained in a previous study, thus underlying the predictive power of the RILA. Based on specificity and cost, RILA alone seemed to be the most performant, while its association with the other factors had better negative predictive value results.

Radiation Facility Volume and Survival for Men With Very High-Risk Prostate Cancer Treated with Radiation and Androgen Deprivation Therapy

Very high-risk (VHR) prostate cancer is an aggressive substratum of high-risk prostate cancer, characterized by high prostate-specific antigen levels, high Gleason score, and/or advanced T category. Contemporary management paradigms involve advanced molecular imaging and multimodal treatment with intensified prostate-directed or systemic treatment-resources more readily available at high-volume centers. To examine radiation facility case volume and overall survival (OS) in men with VHR prostate cancer. A retrospective cohort study was performed from November 11, 2022, to March 4, 2023, analyzing data from US facilities reporting to the National Cancer Database. Patients included men diagnosed with nonmetastatic VHR prostate cancer by National Comprehensive Cancer Network criteria (clinical T3b-T4 category, primary Gleason pattern 5, >4 cores with grade group 4-5, and/or 2-3 high-risk features) and treated with curative-intent radiotherapy and androgen deprivation therapy between January 1, 2004, to December 31, 2016. Treatment at high- vs low-average cumulative facility volume (ACFV), defined as the total number of prostate radiotherapy cases at an individual patient's treatment facility from 2004 until the year of their diagnosis. The nonlinear association between a continuous ACFV and OS was examined through a Martingale residual plot; an optimal ACFV cutoff was identified that maximized the separation between high vs low ACFV via a bias-adjusted log rank test. Overall survival was assessed between high vs low ACFV using Kaplan-Meier analysis with and without inverse probability score weighted adjustment and multivariable Cox proportional hazards. A total of 25 219 men (median age, 71 [IQR, 64-76] years; 78.7% White) with VHR prostate cancer were identified, 6438 (25.5%) of whom were treated at high ACFV facilities. Median follow-up was 57.4 (95% CI, 56.7-58.1) months. Median OS for patients treated at high ACFV centers was 123.4 (95% CI, 116.6-127.4) months vs 109.0 (95% CI, 106.5-111.2) months at low ACFV centers (P < .001). On multivariable analysis, treatment at a high ACFV center was associated with lower risk of death (hazard ratio, 0.89; 95% CI, 0.84-0.95; P < .001). These results were also significant after inverse probability score weighted-based adjustment. In this cohort study of patients with VHR prostate cancer who underwent definitive radiotherapy and androgen deprivation therapy, facility case volume was independently associated with longer OS. Further studies are needed to identify which factors unique to high-volume centers may be responsible for this benefit.

Long-term outcomes of SBRT for PSMA PET detected oligometastatic prostate cancer

BackgroundOligometastatic disease in prostate cancer (PCa) is a challenging clinical scenario encountered more frequently with the widespread adoption of PSMA-PET. SBRT aims to defer androgen deprivation and may deliver sustained biochemical failure (BF) free survival in selected patients. Little long-term data is currently available regarding the effectiveness of this approach.MethodsA retrospective single institution study of PSMA-PET directed SBRT without initial ADT for oligo-metachronous PCa. Median dose/fractionation was 24 Gy in 2# to bones and 30 Gy in 3# to lymph nodes. The primary endpoint was time to BF (PSA + 0.2 ug/L above nadir). Secondary endpoints included time to ADT for relapse (i.e. palliative ADT), BF defined as PSA nadir + 2 ug/L, toxicity, patterns of failure and survival. Patients were excluded if they received ADT with their SBRT, had short disease-free interval, or > 3 metastases on PSMA-PET.Results103 patients treated from November-2014 to December-2019 were analysed from our prospective database. Median follow-up was 5 years. 64 patients were treated for nodal only disease, 35 bone only and 4 mixed. 15% were free of any BF at 5 years with median time to BF of 1.1 years. 32% (33/103) of patients had further curative-intent radiation treatment following their first BF after SBRT, including subsequent SBRT. Eight patients underwent potentially curative treatment for their second or third relapse. Allowing for salvage treatment, 29/103 (28%) were biochemically disease free at last follow up. At 5 years, 39% of patients had never received any ADT and 55% had not started ADT for relapse with a median time to ADT for relapse of 5.5 years. There were 2 grade 3 toxicities (rib fracture and lymphoedema), and no local failures.ConclusionPSMA-PET guided SBRT for oligo-metachronous PCa recurrence in appropriately triaged patients results in excellent local control, low toxicity and over 50% ADT free at 5 years.

Psycho-oncology/Supportive Care in Head–Neck Cancers Patients Undergoing Radiation Therapy: A Randomized Controlled Trial

An elevated level of distress is associated with poor health-related quality of life (QoL), decreased patient satisfaction, poor treatment compliance, and possible reduced survival. This randomized trial, conducted at a single center in India, enrolled head–neck cancer patients aged &gt; 18 years who were undergoing curative intent radiation therapy, and had significant baseline distress as per the National Comprehensive Cancer Network distress thermometer (distress score ≥ 4). The patients were randomized into the Standard arm (STD), which involved routine assessment by the oncologist, or the Interventional arm (INV), where psycho-oncology/palliative/supportive care referral was done at baseline and every week during treatment. The study's primary endpoint was the proportion of patients having significant distress 6 months' posttreatment. A total of 212 patients were randomized (n = 108 STD, n = 104 INV). At 6 months' post-treatment completion, 90 and 89 were evaluable in the STD and INV, respectively. The median distress score was 2 in both arms at this time point. There was no significant difference in the proportion of patients having significant distress in STD versus INV (9 vs. 15.6%, p = 0.20). There was an improvement in any symptom measured by the Edmonton Symptom Assessment Score (pain, tiredness, drowsiness, nausea, lack of appetite) and the QoL for the entire cohort with no statistically significant difference between arms for symptoms, QoL, or survival endpoints. Psycho-oncology and palliative/supportive care referral did not impact distress, symptom burden, QoL, or survival at 6 months' posttreatment completion significantly in this randomized trial. Clinical Trial Registry of India Registration number: CTRI/2016/01/006549.

Impact of the COVID-19 Pandemic on Outcomes for Patients with Lung Cancer Receiving Curative-intent Radiotherapy in the UK

AimsPrevious work found that during the first wave of the COVID-19 pandemic, 34% of patients with lung cancer treated with curative-intent radiotherapy in the UK had a change to their centre’s usual standard of care treatment (Banfill et al. Clin Oncol 2022;34:19–27). We present the impact of these changes on patient outcomes. Materials and methodsThe COVID-RT Lung database was a prospective multicentre UK cohort study including patients with stage I–III lung cancer referred for and/or treated with radical radiotherapy between April and October 2020. Data were collected on patient demographics, radiotherapy and systemic treatments, toxicity, relapse and death. Multivariable Cox and logistic regression were used to assess the impact of having a change to radiotherapy on survival, distant relapse and grade ≥3 acute toxicity. The impact of omitting chemotherapy on survival and relapse was assessed using multivariable Cox regression. ResultsPatient and follow-up forms were available for 1280 patients. Seven hundred and sixty-five (59.8%) patients were aged over 70 years and 603 (47.1%) were female. The median follow-up was 213 days (119, 376). Patients with stage I–II non-small cell lung cancer (NSCLC) who had a change to their radiotherapy had no significant increase in distant relapse (P = 0.859) or death (P = 0.884); however, they did have increased odds of grade ≥3 acute toxicity (P = 0.0348). Patients with stage III NSCLC who had a change to their radiotherapy had no significant increase in distant relapse (P = 0.216) or death (P = 0.789); however, they did have increased odds of grade ≥3 acute toxicity (P < 0.001). Patients with stage III NSCLC who had their chemotherapy omitted had no significant increase in distant relapse (P = 0.0827) or death (P = 0.0661). ConclusionThis study suggests that changes to radiotherapy and chemotherapy made in response to the COVID-19 pandemic did not significantly affect distant relapse or survival. Changes to radiotherapy, namely increased hypofractionation, led to increased odds of grade ≥3 acute toxicity. These results are important, as hypofractionated treatments can help to reduce hospital attendances in the context of potential future emergency situations.