Utility of TTMV-HPV DNA in resolving indeterminate findings during oropharyngeal cancer surveillance.

OBJECTIVES: Clinical and imaging examinations frequently have indeterminate results during cancer surveillance, which can lead to overtreatment and cause psychological and financial harm to the patient. This study addresses the critical need to enhance diagnostic precision and decision-making in the management of HPV-associated oropharyngeal cancer. This study evaluated the utility of tumor tissue-modified viral (TTMV)-HPV DNA to resolve indeterminate disease status following definitive treatment for HPV-associated oropharyngeal cancer. MATERIALS AND METHODS: In this retrospective cohort, patients treated for HPV-associated oropharyngeal cancer at eight U.S. institutions and who received one or more TTMV-HPV DNA tests during post-treatment surveillance between February 2020 and January 2022 were included. RESULTS: Among 543 patients, 210 patients (38.7%; 210/543) experienced one or more clinically indeterminate findings (CIFs) during surveillance, with 503 CIFs recorded. Of those patients with an "indeterminate" disease status at a point during surveillance, 79 were associated with contemporaneous TTMV-HPV DNA testing. TTMV-HPV DNA testing demonstrated high accuracy (97.5%; 77/79) in correctly determining recurrence status. Patients whose disease status was "indeterminate" at the time of a positive TTMV-HPV DNA test were clinically confirmed to recur faster than those whose disease status was "no evidence of disease." Only 3% of patients (17/543) experienced indeterminate TTMV-HPV DNA tests during surveillance. Discordance between TTMV-HPV DNA tests and clinical results was minimal, with only 0.6% (3/543) of patients showing positive tests without recurrence. CONCLUSION: Our findings support the utility of circulating TTMV-HPV DNA in resolving indeterminate disease status and informing the subsequent clinical course.

Comparative evaluation of outcomes amongst different radiosurgery management paradigms for patients with large brain metastasis.

INTRODUCTION: This study compares four management paradigms for large brain metastasis (LMB): fractionated SRS (FSRS), staged SRS (SSRS), resection and postoperative-FSRS (postop-FSRS) or preoperative-SRS (preop-SRS). METHODS: Patients with LBM (≥ 2 cm) between July 2017 and January 2022 at a single tertiary institution were evaluated. Primary endpoints were local failure (LF), radiation necrosis (RN), leptomeningeal disease (LMD), a composite of these variables, and distant intracranial failure (DIF). Gray's test compared cumulative incidence, treating death as a competing risk with a random survival forests (RSF) machine-learning model also used to evaluate the data. RESULTS: 183 patients were treated to 234 LBMs: 31.6% for postop-FSRS, 28.2% for SSRS, 20.1% for FSRS, and 20.1% for preop-SRS. The overall 1-year composite endpoint rates were comparable (21 vs 20%) between nonoperative and operative strategies, but 1-year RN rate was 8 vs 4% (p = 0.012), 1-year overall survival (OS) was 48 vs. 69% (p = 0.001), and 1-year LMD rate was 5 vs 10% (p = 0.052). There were differences in the 1-year RN rates (7% FSRS, 3% postop-FSRS, 5% preop-SRS, 10% SSRS, p = 0.037). With RSF analysis, the out-of-bag error rate for the composite endpoint was 47%, with identified top-risk factors including widespread extracranial disease, > 5 total lesions, and breast cancer histology. CONCLUSION: This is the first study to conduct a head-to-head retrospective comparison of four SRS methods, addressing the lack of randomized data in LBM literature amongst treatment paradigms. Despite patient characteristic trends, no significant differences were found in LF, composite endpoint, and DIF rates between non-operative and operative approaches.

Tubarial gland sparing with intensity modulated radiation therapy for oropharyngeal cancers: A pilot study of dosimetric feasibility.

BACKGROUND: Tubarial glands are a new organ at risk for head and neck cancer radiation therapy (RT). We aimed to study the feasibility of sparing them using intensity-modulated radiation therapy (IMRT). METHODS: Tubarial glands were delineated for 17 patients with oropharyngeal carcinoma receiving definitive RT, and treatment plans were re-optimized to spare dose to the tubarial glands while maintaining target coverage. A paired t test was performed to compare the mean dose of tubarial glands and target coverage. RESULTS: The difference in mean doses was 4.9 and 7.0 Gy for the ipsilateral and contralateral tubarial glands, respectively (p < 0.01). The mean dose to tubarial gland was ≤39 Gy in 35% versus 47% (ipsilateral) and 70% versus 100% (contralateral) in clinical and re-optimized plans, respectively. Re-optimized ipsilateral tubarial gland mean ≤39 Gy was achieved more commonly in patients with base of tongue versus tonsil primaries (86% vs. 20%, p = 0.02). CONCLUSION: This pilot study demonstrates the dosimetric feasibility of tubarial gland sparing with IMRT. Dosimetric constraints need to be determined with larger studies.

Co-relation of Portal Vein Tumour Thrombus Response With Survival Function Following Robotic Radiosurgery in Vascular Invasive Hepatocellular Carcinoma.

Background/aims: The aim of this study was to prospectively evaluate stereotactic body radiotherapy (SBRT) with robotic radiosurgery in hepatocellular carcinoma patients with macrovascular invasion (HCC-PVT). Materials and methods: Patients with inoperable HCC-PVT, good performance score (PS0-1) and preserved liver function [up to Child-Pugh (CP) B7] were accrued after ethical and scientific committee approval [Clinical trial registry-India (CTRI): 2022/01/050234] for treatment on robotic radiosurgery (M6) and planned with Multiplan (iDMS V2.0). Triple-phase contrast computed tomography (CT) scan was performed for contouring, and gross tumour volume (GTV) included contrast-enhancing mass within main portal vein and adjacent parenchymal disease. Dose prescription was as per risk stratification protocol (22-50 Gy in 5 fractions) while achieving the constraints of mean liver dose <15 Gy, 800 cc liver <8 Gy and the duodenum max of <24 Gy). Response assessment was done at 2 months' follow-up for recanalization. Patient- and treatment-related factors were evaluated for influence in survival function. Results: Between Jan 2017 and May 2022, 318 consecutive HCC with PVT patients were screened and 219 patients were accrued [male 92%, CP score: 5-7 90%, mean age: 63 years (38-85 yrs), Cancer of the Liver Italian Program <3: 84 (40%), 3-6117 (56%), infective aetiology 9.5%, performance status (PS): 0-37%; 1-56%]. Among 209 consecutive patients accrued for SBRT treatment (10 patients were excluded after accrual due to ascites and decompensation), 139 were evaluable for response assessment (>2 mo follow-up). At mean follow-up of 12.21 months (standard deviation: 10.66), 88 (63%) patients expired and 51 (36%) were alive. Eighty-two (59%) patients had recanalization of PVT (response), 57 (41%) patients did not recanalize and 28 (17%) had progressive/metastatic disease prior to response evaluation (<2 months). Mean overall survival (OS) in responders and non-responders were 18.4 [standard error (SE): 2.52] and 9.34 month (SE 0.81), respectively (P < 0.001). Mean survival in patients with PS0, PS1 and PS2 were 17, 11.7 and 9.7 months (P = 0.019), respectively. OS in partial recanalization, bland thrombus and complete recanalization was 12.4, 14.1 and 30.3 months, respectively (P-0.002). Adjuvant sorafenib, Barcelona Clinic Liver Classification stage, gender, age and RT dose did not influence response to treatment. Recanalization rate was higher in good PS patients (P-0.019). OS in patients with response to treatment, in those with no response to treatment, in those who are fit but not accrued and in those who are not suitable were 18.4, 9.34, 5.9 and 2.6 months, respectively (P-<0.001). Thirty-six of 139 patients (24%) had radiation-induced liver disease (RILD) [10 (7.2%) had classic RILD & 26 (19%) had non-classic RILD]. Derangement in CP score (CP score change) by more than 2 was seen in 30 (24%) within 2-month period after robotic radiosurgery. Eighteen (13%) had unplanned admissions, two patients required embolization due to fiducial-related bleeding and 20 (14%) had ascites, of which 9 (6%) patients required abdominocentesis. Conclusion: PVT response or recanalization after SBRT is a statistically significant prognostic factor for survival function in HCC-PVT.

Dose-Escalated Preoperative Proton Therapy for Retroperitoneal Sarcomas: Initial Outcomes of a New Treatment Paradigm.

Purpose: Retroperitoneal sarcomas (RPS) have varied treatment practices with regard to the use of radiation therapy (RT). Preoperative RT ∼50 Gy is commonly used, but the Surgery With or Without Radiation Therapy in Untreated Nonmetastatic Retroperitoneal Sarcoma (STRASS-1) randomized trial demonstrated no improvement in abdominal recurrence-free survival with preoperative RT. Dose escalation has been proposed to improve the efficacy of preoperative RT. We analyzed RPS treated with preoperative intensity modulated proton therapy (IMPT) to an escalated dose of 63 Gy at a single institution. Methods and Materials: Patients who received preoperative RT with IMPT with RPS between January 2015 and October 2021 were reviewed. IMPT 63 Gy in 28 fractions to the clinical target volume high-risk and 50.4 Gy in 28 fractions to clinical target volume low-risk was used. Patient baseline characteristics, RT dose parameters, toxicities, margin status, and recurrence patterns were recorded. Local control was computed by Fine-Gray analysis and overall survival by Kaplan-Meier analysis. Results: Sixteen patients met the study criteria (n = 16): 12 primary and 4 isolated local recurrences. Median age was 62 years (IQR, 43.5-66 years) and 62.5% were male; 10 were liposarcoma. The median maximum tumor diameter was 19.9 cm (IQR, 12-24 cm). With a median follow-up of 18 months (IQR, 11.5-37 months), the estimated 3-year freedom from local failure rate was 68.2% (95% CI, 41.7%-94.7%); 3-year overall survival (OS) rate was 68.8% (95% CI, 41.9%-95.8%). No Radiation Therapy Oncology Group grade ≥3 acute or late toxicities were noted. Conclusions: In our RPS cohort, preoperative dose-escalated RT to 63 Gy demonstrated comparable local control without G3 acute toxicities. Given the high local recurrence rates of RPS, this approach warrants further study to validate these results and identify patients most likely to benefit from therapy.

Accelerated Hypofractionated Magnetic Resonance Guided Adaptive Radiation Therapy for Ultracentral Lung Tumors.

Radiotherapy for ultracentral lung tumors represents a treatment challenge, considering the high rates of high-grade treatment-related toxicities with stereotactic body radiation therapy (SBRT) or hypofractionated schedules. Accelerated hypofractionated magnetic resonance-guided adaptive radiation therapy (MRgART) emerged as a potential game-changer for tumors in these challenging locations, in close proximity to central organs at risk, such as the trachea, proximal bronchial tree, and esophagus. In this series, 13 consecutive patients, predominantly male (n = 9), with a median age of 71 (range (R): 46-85), underwent 195 MRgART fractions (all 60 Gy in 15 fractions) to metastatic (n = 12) or primary ultra-central lung tumors (n = 1). The median gross tumor volumes (GTVs) and planning target volumes (PTVs) were 20.72 cc (R: 0.54-121.65 cc) and 61.53 cc (R: 3.87-211.81 cc), respectively. The median beam-on time per fraction was 14 min. Adapted treatment plans were generated for all fractions, and indications included GTV/PTV undercoverage, OARs exceeding tolerance doses, or both indications in 46%, 18%, and 36% of fractions, respectively. Eight patients received concurrent systemic therapies, including immunotherapy (four), chemotherapy (two), and targeted therapy (two). The crude in-field loco-regional control rate was 92.3%. No CTCAE grade 3+ toxicities were observed. Our results offer promising insights, suggesting that MRgART has the potential to mitigate toxicities, enhance treatment precision, and improve overall patient care in the context of ultracentral lung tumors.

Online adaptive radiotherapy: Assessment of planning technique and its impact on longitudinal plan quality robustness in pancreatic cancer.

BACKGROUND AND PURPOSE: Planning on a static dataset that reflects the simulation day anatomy is routine for SBRT. We hypothesize the quality of on-table adaptive plans is similar to the baseline plan when delivering stereotactic MR-guided adaptive radiotherapy (SMART) for pancreatic cancer (PCa). MATERIALS AND METHODS: Sixty-seven inoperable PCa patients were prescribed 50 Gy/5-fraction SMART. Baseline planning included: 3-5 mm gastrointestinal (GI) PRV, 50 Gy optimization target (PTVopt) based on GI PRV, conformality rings, and contracted GTV to guide the hotspot. For each adaptation, GI anatomy was re-contoured, followed by re-optimization. Plan quality was evaluated for target coverage (TC = PTVopt V100%/volume), PTV D90% and D80%, homogeneity index (HI = PTVopt D2%/D98%), prescription isodose/target volume (PITV), low-dose conformity (D2cm = maximum dose at 2 cm from PTVopt/Rx dose), and gradient index (R50%=50% Rx isodose volume/PTVopt volume).A novel global planning metric, termed the Pancreas Adaptive Radiotherapy Score (PARTS), was developed and implemented based on GI OAR sparing, PTV/GTV coverage, and conformality. Adaptive robustness (baseline to fraction 1) and stability (difference between two fractions with highest GI PRV variation) were quantified. RESULTS: OAR constraints were met on all baseline (n = 67) and adaptive (n = 318) plans. Coverage for baseline/adaptive plans was mean ± SD at 44.9 ± 5.8 Gy/44.3 ± 5.5 Gy (PTV D80%), 50.1 ± 4.2 Gy/49.1 ± 4.7 Gy (PTVopt D80%), and 80%±18%/74%±18% (TC), respectively. Mean homogeneity and conformality for baseline/adaptive plans were 0.87 ± 0.25/0.81 ± 0.30 (PITV), 3.81 ± 1.87/3.87 ± 2.0 (R50%), 1.53 ± 0.23/1.55 ± 0.23 (HI), and 58%±7%/59%±7% (D2cm), respectively. PARTS was found to be a sensitive metric due to its additive influence of geometry changes on PARTS' sub-metrics. There were no statistical differences (p > 0.05) for stability, except for PARTS (p = 0.04, median difference -0.6%). Statistical differences for robustness when significant were small for most metrics (<2.0% median). Median adaptive re-optimizations were 2. CONCLUSION: We describe a 5-fraction ablative SMART planning approach for PCa that is robust and stable during on-table adaption, due to gradients controlled by a GI PRV technique and the use of rings. These findings are noteworthy given that daily interfraction anatomic GI OAR differences are routine, thus necessitating on-table adaptation. This work supports feasibility towards utilizing a patient-independent, template on-table adaptive approach.

Surgically targeted radiation therapy (STaRT) for recurrent brain metastases: Initial clinical experience.

PURPOSE: This study evaluates the outcomes of recurrent brain metastasis treated with resection and brachytherapy using a novel Cesium-131 carrier, termed surgically targeted radiation therapy (STaRT), and compares them to the first course of external beam radiotherapy (EBRT). METHODS: Consecutive patients who underwent STaRT between August 2020 and June 2022 were included. All patients underwent maximal safe resection with pathologic confirmation of viable disease prior to STaRT to 60 Gy to a 5-mm depth from the surface of the resection cavity. Complications were assessed using CTCAE version 5.0. RESULTS: Ten patients with 12 recurrent brain metastases after EBRT (median 15.5 months, range: 4.9-44.7) met the inclusion criteria. The median BED10Gy90% and 95% were 132.2 Gy (113.9-265.1 Gy) and 116.0 Gy (96.8-250.6 Gy), respectively. The median maximum point dose BED10Gy for the target was 1076.0 Gy (range: 120.7-1478.3 Gy). The 6-month and 1-year local control rates were 66.7% and 33.3% for the prior EBRT course; these rates were 100% and 100% for STaRT, respectively (p < 0.001). At a median follow-up of 14.5 months, there was one instance of grade two radiation necrosis. Surgery-attributed complications were observed in two patients including pseudomeningocele and minor headache. CONCLUSIONS: STaRT with Cs-131 presents an alternative approach for operable recurrent brain metastases and was associated with superior local control than the first course of EBRT in this series. Our initial clinical experience shows that STaRT is associated with a high local control rate, modest surgical complication rate, and low radiation necrosis risk in the reirradiation setting.

Negative Predictive Value of Circulating Tumor Tissue Modified Viral (TTMV)-HPV DNA for HPV-driven Oropharyngeal Cancer Surveillance.

PURPOSE: Human papillomavirus (HPV) is causally linked to oropharyngeal squamous cell carcinoma (OPSCC). Consensus guidelines recommend clinical exams and imaging in decreasing frequency as part of posttreatment surveillance for recurrence. Plasma tumor tissue modified viral (TTMV)-HPV DNA testing has emerged as a biomarker which can inform disease status during surveillance. EXPERIMENTAL DESIGN: This retrospective observational cohort study involved 543 patients who completed curative-intent therapy for HPV-associated OPSCC between February 2020 and January 2022 at eight U.S. cancer care institutions. We determined the negative predictive value (NPV) of TTMV-HPV DNA for recurrence when matched to physician-reported clinical outcome data (median follow-up time: 27.9 months; range: 4.5-154). RESULTS: The cohort included mostly men with a median age of 61 who had locoregionally advanced disease. HPV status was determined by p16 positivity in 87% of patients, with a positive HPV PCR/ISH among 55%; while pretreatment TTMV-HPV DNA status was unknown for most (79%) patients. Patients had a mean of 2.6 tests and almost half had three or more TTMV-HPV DNA results during surveillance. The per-test and per-patient sensitivity of the assay was 92.5% [95% confidence interval (CI): 87.5-97.5] and 87.3% (95% CI: 79.1-95.5), respectively. The NPV for the assay was 99.4% (95% CI: 98.9-99.8) and 98.4% (95% CI: 97.3-99.5), respectively. CONCLUSIONS: TTMV-HPV DNA surveillance testing yields few false negative results and few missed recurrences. These data could inform decisions on when to pursue reimaging following first disease restaging and could inform future surveillance practice. Additional study of how pretreatment TTMV-HPV DNA status impacts sensitivity for recurrence is needed.

Hepatocellular carcinoma patients with portal vein thrombosis treated with robotic radiosurgery: Interim results of a prospective study.

BACKGROUND: This is a prospective study evaluating the role of stereotactic body radiotherapy (SBRT) with CyberKnife (CK) in Indian patients suffering from hepatocellular carcinoma with portal vein thrombosis (HCC-PVT). METHODS: Patients with inoperable HCC-PVT, good performance score (PS), and liver function are accrued for treatment on CK (version M6) and planned with Multiplan (iDMS V2.0). Triple-phase contrast computed tomography (CT) scan was done for contouring, and the gross tumor volume (GTV) included contrast-enhancing mass within main portal vein and adjacent parenchymal disease. Dose prescription was as per-risk stratification protocol (22-50 Gy in 5 fractions) while achieving the constraints of mean liver dose <15 Gy, 800 cc liver <8 Gy, and the duodenum max of ≤24 Gy). RESULTS: Seventy-two HCC-PVT accrued till date (mean age 63 years [38-76 years], 96% male; Child-Pugh [CP] A 84%, B 9%; Barcelona-Clinic Liver Cancer [BCLC] C 96%; PS0-1: 80%, Karnofsky performance score [KPS]>70: 88%; co-morbidities 42%; infective 12%, alcohol intake 31%, adjuvant sorafenib 39%). CP scores 5, 6, 7, and 8 were in 35%, 32%, 8%, and 18%, respectively. Focal disease with portal vein thrombus (PVT) in 21%, liver involvement >50% and <50% in 46% and 32%. Liver cancer study group of Japan staging-based portal vein invasion VP2, VP3, and VP4 in 22%, 29%, and 40%. Cancer of the Liver Italian Programm (CLIP) scores 1, 2, 3, 4, and 5 were in 8%, 26%, 31%, 26%, and 7%, respectively. Mean follow-up was 7.3 months (median 6 months, standard deviation [SD] 6; range 3-30 months). Mean actuarial overall survival (OS) was 11.4 months (SE 1.587; 95% CI: 8-14.2 months). Six months and 12 months actuarial OS 55% and 38%, respectively. At last follow-up, 25/69 (36%) were alive and 44/69 (64%) were dead. Among 54 patients evaluated for response assessment, 23 (30%) had radiological confirmed PVT response, 1 (3%) had response of IVC thrombus, and 30 (42%) had no or minimal response to SBRT. Actuarial OS in responders and non-responders were 14.4 months (95% CI 9.4-19.2) and 7.4 months (95% CI 4.9-9.7), p-value: 0.022. Six and 12 months survival in responders and non-responders were 65.7% and 37% and 49% and 24.6%, respectively. Post-SBRT, 4 (12%) patients underwent transarterial chemoembolization (TACE) 3 patients (8%) and 1 patient (4%) transarterial radioembolization (TARE). Post-CK, (<4 weeks) 2 patients (4%) had decompensation. CONCLUSIONS: PVT response or recanalization after SBRT is a statistically significant prognostic factor for survival function in HCC-PVT.