Marginal Failure Research Articles

Recurrent Patterns in Patients With Nasopharyngeal Caricinoma and Risks Leading to Inaccurate Delineation in Marginal Failure in the Era of Intensity-Modulated Radiotherapy.

To investigate the failure patterns of recurrent nasopharyngeal carcinoma (NPC), especially to identify the relationship between the recurrent-prone anatomic structures and the tumor regression sites after the introduction of chemotherapy (IC). A cohort of 1121 non-metastatic patients with NPC was retrospectively enrolled. The pretreatment and recurrent images of each patient were registered to the planning CT. Tumor regression sites after IC (Vicr) overlapped with recurrent tumor (rGTV) were evaluated for the delineation accuracy and dose sufficiency in marginal failure patients. A total of 126 (11.24%) experienced tumor recurrence. Re-evaluation of 12 patients with local marginal recurrence, their rGTV within Vicr predominantly located at choanae, sphenoidal sinus, and cavernous sinus. The regression sites did not receive the full 70 Gy but over half receiving with 60Gy. Analysis from marginal failure that exempts tumor regression sites from GTV or an insufficient prescription dose of less than 70 Gy may contribute to marginal failure.

Outcomes of proton therapy to infradiaphragmatic sites in pediatric patients with Hodgkin lymphoma.

Proton therapy (PT) has potential advantages in pediatric Hodgkin lymphoma (pHL). However, there are limited data on PT, specifically to infradiaphragmatic targets. We report on PT planning details, doses achieved to organs at risk (OARs), and clinical and toxicity outcomes for patients with pHL who received PT to infradiaphragmatic regions. This is a retrospective study including patients treated between 2011 and 2022. Demographic and clinical factors were collected, and toxicity was reported using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Dosimetric and clinical factors associated with key outcomes were assessed via Cox regression. Photon plans were generated for all patients, and the paired t-tests or Wilcoxon signed rank sum tests were used for dosimetric comparisons. Twenty-one patients comprising 22 PT courses were included. Median follow-up was 5.0years, and mean age was 14.2years. Median dose was 21 Gray equivalent (GyE) over 14 fractions. Top acute grade 1 (G1) toxicities included fatigue (59%) and anorexia (36%). Rates of acute G2 and G3+ toxicity were 18% and 0%, respectively. After PT, no local or marginal failures occurred. Five percent experienced disease progression, who were all successfully salvaged, and all patients were alive and disease-free at last follow-up. No secondary malignancies developed. Compared to photon radiotherapy, PT achieved significantly lower doses to the bowels, stomach, spleen, pancreatic tail, liver, kidneys, and pelvic bones. PT is well-tolerated and leads to excellent oncologic and toxicity outcomes with long-term follow-up. PT confers dosimetric advantages when compared to photons.

Effect analysis of 847 nasopharyngeal carcinoma cases treated with intensity modulated radiation: Experience and suggestions

ObjectivesTo identify the failure patterns and prognostic factors of nonmetastatic nasopharyngeal carcinoma (NPC) in the intensity-modulated radiotherapy (IMRT) era. MethodsData on 847 patients with newly diagnosed, non-disseminated NPC treated by IMRT between 2012 and 2016 were retrospectively reviewed. Survival outcome, failure patterns and prognosis factors were analyzed. ResultsThe 5-year local relapse-free survival, nodal relapse-free survival, distant metastasis-free survival, disease-free survival, and overall survival rates were 94.3%, 95.3%, 84.8%, 76.5% and 85.7%, respectively. The major local recurrence sites were the nasopharynx (91.5%, 43/47) and skull base (68.1%, 32/47); 39 patients had in-field failures, four had marginal failures, and four had out-field failures. Level IIb (62.2%, 23/37) was the most frequent regional recurrence site, followed by IIa (35.1%, 13/37) and retropharyngeal region (32.4%, 12/37); 35 cases had in-field failure alone, one had out-field failure alone, and one had both in- and out-field failure. TNM stage was the most significant factor for prognosis prediction. 402 (47.5%) patients had acute adverse events of grade 3 or 4; leukopenia (31.5%) and mucositis (26.7%) was the most common hematological and non-hematological event, respectively. Late complications were slight or moderate damages; xerostomia (647/847, 76.4%) and hearing impairment (422/847, 49.8%) remained the most troublesome. ConclusionNPC patients treated with IMRT obtained satisfactory survival outcomes. The key failure pattern was distant metastasis. The main pattern of local–regional failure was in-field failure. Screening high risk patients with distant metastases and optimizing radiotherapy targets should be studied.

Reduced frequency and severity of radiation esophagitis without marginal failure risk by contralateral esophagus sparing IMRT in stage III non-small cell lung cancer patients undergoing definitive concurrent chemoradiotherapy

PurposeRadiation esophagitis is frequent and annoying toxicity in high dose thoracic radiation therapy. Contalateral esophagus sparing intensity modulated radiation therapy (CES-IMRT) has been proposed to mitigate this problem, and this is to report the impact of CES-IMRT in definitive concurrent chemoradiotherapy (dCCRT) for lung cancer patients. Materials and methodsFrom January 2021 till May 2023, 183 stage III non-small cell lung cancer patients underwent dCCRT. Esophagus was located within 1 cm from internal target volume in 159 patients. We comparatively evaluated the frequency and severity of esophagitis by pain-killer usage, analgesic quantification algorithm (AQA) score, and failure patterns in 159 CES-necessary patients. ResultsAll patients underwent dCCRT (66 Gy in 30 fractions with concurrent chemotherapy). Actual CES-IMRT application was determined based on the discretion of responsible radiation oncologists: CES-applied in 41 patients; and CES-unapplied in 118. CES-applied patients experienced pain events less frequently (pain-killer usage: 53.7 % vs. 77.1 %, p = 0.008) and less severely (AQA score of 2–3: 39.0 % vs. 68.6 %, p = 0.002). On multivariate analyses, overlapping volume of esophagus and planning target (HR = 1.32, 95 % CI 1.12–1.55, p = 0.001) and CES-IMRT application (HR = 0.31, 95 % CI 0.13–0.76, p = 0.010) were associated with AQA score of 2–3 less frequently. There were no differences in failure pattern, progression-free survival, and overall survival. ConclusionsCES-IMRT application resulted in less frequent and less severe pain events without compromising oncologic outcomes. Further studies, preferably in a randomized fashion, would be desired.

Patterns of recurrence after radiotherapy for high-risk neuroblastoma: Implications for radiation dose and field

BackgroundPrognosis for patients with high-risk neuroblastoma (HR-NBL) is guarded despite aggressive therapy, and few studies have characterized outcomes after radiotherapy in relation to radiation treatment fields. MethodsMulti-institutional retrospective cohort of 293 patients with HR-NBL who received autologous stem cell transplant (ASCT) and EBRT between 1997–2021. LRR was defined as recurrence at the primary site or within one nodal echelon beyond disease present at diagnosis. Follow-up was defined from the end of EBRT. Event-free survival (EFS) and OS were analyzed by Kaplan-Meier method. Cumulative incidence of locoregional progression (CILP) was analyzed using competing risks of distant-only relapse and death with Gray’s test. ResultsMedian follow-up was 7.0 years (range: 0.01–22.4). Five-year CILP, EFS, and OS were 11.9 %, 65.2 %, and 77.5 %, respectively. Of the 31 patients with LRR and imaging review, 15 (48.4 %) had in-field recurrences (>12 Gy), 6 (19.4 %) had marginal failures (≤12 Gy), and 10 (32.3 %) had both in-field and marginal recurrences. No patients receiving total body irradiation (12 Gy) experienced marginal-only failures (p = 0.069). On multivariable analyses, MYCN amplification had higher risk of LRR (HR: 2.42, 95 % CI: 1.06–5.50, p = 0.035) and post-consolidation isotretinoin and anti-GD2 antibody therapy (HR: 0.42, 95 % CI: 0.19–0.94, p = 0.035) had lower risk of LRR. ConclusionsDespite EBRT, LRR remains a contributor to treatment failure in HR-NBL with approximately half of LRRs including a component of marginal failure. Future prospective studies are needed to explore whether radiation fields and doses should be defined based on molecular features such as MYCN amplification, and/or response to chemotherapy.

Antibacterial Activity of the Vancomycin and Cefotaxime-Incorporated Total Etch Adhesive System - An In Vitro Study.

Marginal failure at the resin dentin interface promotes biofilm formation, which further leads to secondary caries and hypersensitivity. This likelihood also increases if residual bacteria are present following cavity preparation. In order to achieve a proper biological seal without jeopardizing bonding, efforts were made to functionalize the adhesive system with antibacterial activity. Aim and objectives: To appraise the antibacterial activity of a total-etch adhesive system against S. mutans with and without incorporation of antibiotics Vancomycin and Cefotaxime. A commercially available 5th-generation total-etch bonding agent (Te-Econorm) was used. S. mutans broth had been standardized and streaked over Muller-Hinton agar culture medium and round wells about 6 mm in diameter were made in the centre of the agar plates. Each experimental group comprised 10 samples, which include: Group 1 - 30µg Cefotaxime, Group 2- 30µg Cefotaxime + Bonding agent, Group 3- 30µg Vancomycin, Group 4- 30µg Vancomycin + Bonding agent, Group 5- Bonding agent, and Group 6- No material. Inoculated culture plates were examined for the zone of inhibition after incubation at 37° C for 24 hours. There was a significant difference in the mean diameter of zone of inhibition (p=0.000), with the maximum exhibited by Group 4, followed by Group 3 and Group 2. The least zone of inhibition was exhibited by Groups 1 and 5. The negative control showed no zone of inhibition. The combination of Vancomycin and bonding agent had superior antibacterial activity against S. mutans in comparison to cefotaxime and bonding agent.

Patterns of failure after radiosurgery for WHO grade 1 or imaging defined meningiomas: Long-term outcomes and implications for management

BackgroundWe analyzed long-term control and patterns of failure in patients with World Health Organization Grade 1 meningiomas treated with definitive or postoperative stereotactic radiosurgery at the authors’ affiliated institution. Methods96 patients were treated between 2004 and 2019 with definitive (n = 57) or postoperative (n = 39) stereotactic radiosurgery. Of the postoperative patients, 17 were treated adjuvantly following subtotal resection and 22 were treated as salvage at time of progression. Patients were treated to the gross tumor alone without margin or coverage of the dural tail to a median dose of 15 Gy. Median follow up was 7.4 years (inter-quartile range 4.8–11.3). Local control, marginal control, regional control, and progression-free survival were analyzed. ResultsLocal control at 5 and 10 years was 97 % and 95 %. PFS at 5 and 10 years was 94 % and 90 % with no failures reported after 6 years. Definitive and postoperative local control were similar at 5 (95 % [82–99 %] vs. 100 %) and 10 years (92 % [82–99 %] vs. 100 %). Patients treated with postoperative SRS did not have an increased marginal failure rate (p = 0.83) and only 2/39 (5 %) experienced recurrence elsewhere in the cavity. ConclusionsStereotactic radiosurgery targeting the gross tumor alone provides excellent local control and progression free survival in patients treated definitively and postoperatively. As in the definitive setting, patients treated postoperatively can be treated to gross tumor alone without need for additional margin or dural tail coverage.

Treatment outcomes of single-fraction stereotactic radiosurgery for adenoid cystic carcinoma: a case series of 55 patients.

This study aimed to analyze the treatment outcomes of single-fraction stereotactic radiosurgery (SRS) for adenoid cystic carcinoma patients. Retrospective analysis was conducted for 55 patients with 66 lesions. SRS intentions were categorized as definitive, adjuvant, salvage, and palliative. Tumor control was defined as local (within 50% isodose line), marginal (outside 50% isodose line), and distant (metastasis outside head/neck). The median age was 60 years (range 21-85), with 53% males. Tumor origin was head/neck for 88% and trachea/lung for 12%. 61% were recurrent lesions. Median interval from diagnosis to SRS was 14 months. Preceding surgery was performed in 30%. SRS was administered as definitive (30 lesions), adjuvant (13), salvage (19), and palliative (4). SRS was used as a boost to external beam radiation therapy (EBRT) in 39%. Concurrent chemotherapy was administered in 26%. 5-, 10-, and 15-year local control rates were 60%, 33%, and 27%, respectively; local/marginal control rates were 29%, 13%, and 10%. For recurrent lesions treated with SRS without EBRT, 5-year local control rate was 14%, and local/marginal control rate was 5%. For recurrent lesions treated with SRS and EBRT, 5-year local control rate was 100%, and local/marginal control rate was 40%. The rate of distant failure after SRS was 40%. Older age and distant metastasis before SRS were negative factors for overall survival. SRS provided a high rate of local tumor control, but marginal failure was frequent. Integrating SRS with added EBRT exhibits potential for enhancing local and local/marginal tumor control, particularly in recurrent cases.

Patterns and Prognosis of Local Recurrence of Nasopharyngeal Carcinoma after Intensity-modulated Radiotherapy.

Objective: To investigate the patterns of local failure and prognosis in patients with locally recurrent nasopharyngeal carcinoma (rNPC) after primary intensity-modulated radiotherapy (IMRT). Methods: The data of 298 patients with locally rNPC after IMRT were retrospectively analyzed. Magnetic resonance images of the initial and recurrent tumors were reviewed and, for patients with extra-nasopharyngeal local recurrence, the gross tumor volume of local recurrence was transferred to the original IMRT plan for dosimetry analysis. Significant prognostic factors for overall survival (OS) were selected by multivariate Cox regression analysis. Results: The commonest recurrence sites were the nasopharynx (93%, 277/298) and skull base (53.7%, 160/298). Of the 21 patients with extra-nasopharyngeal recurrence (19 cases valid), 12 had in-field failures, 4 had marginal failures, and 3 had out-field failures. The ethmoid sinus (57.1%, 4/7) and nasal cavity (28.6%, 2/7) were the most frequent sites of marginal and out-field failures. After median follow-up of 37 months, the 3-year and estimated 5-year OS rates were 57.3% and 41.7%, respectively. Multivariate analysis showed that age, recurrence interval, plasma Epstein-Barr virus (EBV) DNA level, and recurrent T stage were independent prognostic factors for OS. Conclusions: Local failure after IMRT occurs most commonly in the nasopharynx and skull base. In patients with extra-nasopharyngeal recurrence, in-field failure remains the main failure pattern, and marginal and out-field failures mainly occur in the ethmoid sinus and nasal cavity. Elder age, shorter recurrence interval, detectable plasma EBV DNA, and advanced recurrent T stage are negative predictors of OS in patients with rNPC.

Patterns of failure for recurrent head and neck squamous cell carcinoma treated with salvage surgery and postoperative IMRT reirradiation

Purpose/ObjectivesThe purpose of this study was to evaluate patterns of locoregional recurrence (LRR) after surgical salvage and adjuvant reirradiation with IMRT for recurrent head and neck squamous cell cancer (HNSCC). Materials/MethodsPatterns of LRR for 61 patients treated consecutively between 2003 and 2014 who received post-operative IMRT reirradiation to ≥ 60 Gy for recurrent HNSCC were determined by 2 methods: 1) physician classification via visual comparison of post-radiotherapy imaging to reirradiation plans; and 2) using deformable image registration (DIR). Those without evaluable CT planning image data were excluded. All recurrences were verified by biopsy or radiological progression. Failures were defined as in-field, marginal, or out-of-field. Logistic regression analyses were performed to identify predictors for LRR. ResultsA total of 55 patients were eligible for analysis and 23 (42 %) had documented LRR after reirradiation. Location of recurrent disease prior to salvage surgery (lymphatic vs. mucosal) was the most significant predictor of LRR after post-operative reirradiation with salvage rate of 67 % for lymphatic vs. 33 % for mucosal sites (p = 0.037). Physician classification of LRR yielded 14 (61 %) in-field failures, 3 (13 %) marginal failures, and 6 (26 %) out-of-field failures, while DIR yielded 10 (44 %) in-field failures, 4 (17 %) marginal failures, and 9 (39 %) out-of-field failures. Most failures (57 %) occurred within the original site of recurrence or first echelon lymphatic drainage. Of patients who had a free flap placed during salvage surgery, 56 % of failures occurred within 1 cm of the surgical flap. ConclusionOur study highlights the role of DIR in enhancing the accuracy and consistency of POF analysis. Compared to traditional visual inspection, DIR reduces interobserver variability and provides more nuanced insights into dose-specific and spatial parameters of locoregional recurrences. Additionally, the study identifies the location of the initial recurrence as a key predictor of subsequent locoregional recurrence after salvage surgery and re-IMRT.

Patterns of Failure, Low-Volume Relapse, and Subsequent Ablative Management in Locally Advanced Non-Small Cell Lung Cancer Treated With Definitive Chemoradiation and Consolidation Immune Checkpoint Inhibitors

The objective of this study was to describe the patterns of failure, frequency of low-volume relapse (LVR), and candidacy for ablative therapy at time of disease progression (PD) after chemoradiation and consolidative immunotherapy (CRT + ICI) in patients with stage III non-small cell lung cancer. We identified 229 consecutive patients with stage III non-small cell lung cancer treated with CRT + ICI between October 2017 and December 2021 at a single institution. PD was classified as isolated locoregional failure (LRF), isolated distant failure (DF), or synchronous LRF + DF. Any LRF was subclassified as in-field failure, marginal failure, or out-of-field failure. LVR was defined as 3 or fewer sites of PD in any number of organs. Ablative candidates were defined as having 5 or fewer sites of PD radiographically amenable to high-dose radiation or surgery. Time-to-event data were calculated using cumulative incidence analysis and Kaplan-Meier methods. Multivariable Cox modeling was used to examine the correlations between characteristics of relapse and postprogression survival. Of the 229 patients, 119 (52%) had PD. Of these 119 patients, 20 (21%) had isolated LRF, 28 (24%) had synchronous LRF + DF, and 71 (60%) had isolated DF. Of the 48 patients with any LRF, 28 (58%) had in-field failure, 10 (21%) marginal failure, and 10 (21%) out-of-field failure. The cumulative incidence of LRF and DF was 13% (95% CI, 9.2%-18%) and 32% (95% CI, 26%-38%) at 1 year and 19% (95% CI, 14%-24%) and 39% (95% CI, 33%-46%) at 2 years, respectively. Overall, 64 patients (54%) were considered to have LVR. At time of PD, 60 patients (50%) were eligible for ablative therapy. Patients with LVR had longer median survival versus with high-volume relapse (37.4 vs 15.2 months, P < .001). On multivariable analysis, LVR (hazard ratio, 0.32; 95% CI, 0.18-0.56; P < .001) was associated with improved postprogression survival. After CRT + ICI, approximately half of patients experience LVR at time of PD and are candidates for ablative therapies. Prospective trials are needed to validate the optimal treatment strategy for LVR.

Clinical Outcomes and Patterns of Failure in Patients with High-Risk Atypical Meningioma Treated with Single Fraction vs. Hypofractionated Gamma Knife Radiosurgery

The recently completed RTOG 0539 supports fractionated radiation therapy for patients categorized as having intermediate (3 yr PFS 93.8%) or high-risk (3 yr LC 68.9%) meningiomas. Stereotactic radiosurgery (SRS) has not been widely established in the treatment of WHO grade 2 atypical meningiomas given concern that there is a greater risk of microscopic infiltration and therefore requires larger margins than safely achievable with SRS. We look to review a consecutive cohort of patients at our institution who have been diagnosed with atypical meningioma treated with either single fraction Gamma Knife SRS (GK-sfSRS) or hypofractionated Gamma Knife SRS (GK-hfSRS). We review both control rates and patterns of failure. Patients diagnosed with intermediate or high-risk WHO grade 2 meningioma per RTOG 0539 classification, without a history of prior radiation (RT) and treated with either GK-sfSRS or GK-hfSRS between 2014 to 2021 at our institution, were included. Patient charts were reviewed, and follow-up data were analyzed for local control (LC) and failure patterns. Local failure was defined as tumor recurrence within the prescription isodose line, marginal was ≤5 mm outside the prescription isodose line, and distant was >5 mm outside of the prescription isodose line Primary outcome was LC, and secondary outcomes were overall survival (OS) and progression free survival (PFS). We identified 47 pathologically confirmed WHO grade 2 meningiomas in 27 patients. 33 lesions were treated with GK-sfSRS and 14 lesions with GK-hfSRS. 6 lesions were intermediate risk, and 41 were high-risk per RTOG 0539. With a median follow up of 36 months (range 2-86 mo), the 3yr LC was 82.7%, PFS was 83.1%, and OS was 96.3%. A total of 4 patients with 8 lesions failed treatment - all with high-risk disease. All failures were local (4) or marginal (4). The 4 local failures were all from a single patient with 4 distinct meningiomas that were treated with GK-sfSRS without surgical resection. The 4 marginal failures were all in patients treated with GK-sfSRS. There were no failures in patients treated with GK-hfSRS. Our institutional data for patients with atypical meningiomas treated with radiosurgical techniques compare favorably to the patients treated with EBRT in RTOG 0539, though longer follow-up is needed to confirm these findings. Outside of one patient, no patients developed recurrence within the prescription volume. There were 4 tumors with marginal failures, suggesting that additional dural margins than what were prescribed may be meaningful. At our institution, we are increasingly moving to hypofractionated radiosurgery with 5 mm of dural margin when using radiosurgical techniques for high-risk atypical meningioma. However, longer term follow-up is needed to validate the use of radiosurgical techniques in atypical meningioma.

Assessment of Local and Regional Control in Atypical (WHO Grade 2) Meningiomas Receiving Fractioned Stereotactic Radiotherapy

The optimal delivery of postoperative radiotherapy to WHO grade 2 or atypical meningiomas (AM) is controversial. The historical standard of care has been high dose fractionated radiation to the resection bed and a 2 cm CTV as in RTOG 0539. Single fraction radiosurgery offers a more conformal alternative with demonstrated local control for smaller AM in less sensitive areas. Though less studied, fractionated stereotactic radiosurgery (FSRT) promises safer treatment of larger AM in more sensitive locations while minimizing the treated volume. This single institution retrospective review examines the hypothesis that local and marginal failure patterns in AM treated with five fraction FSRT remain unacceptably high. Thirty-nine patients received 27.5 - 30 Gy in 5 fractions to their AM from 2009 to 2022 with grading based on the WHO criteria active at the time of treatment. All treatments were frameless VMAT deliveries with no PTV margin. Histological diagnosis of AM, gross disease at time of FSRT, five fraction FSRT, and lack of prior local radiation were required for inclusion. Single fraction treatments were excluded. Local recurrence was defined similar to RECIST criteria as an increase of 20% in the greatest cross-sectional diameter on MRI (or CT if MRI contraindicated) with at least one voxel touching the prescription volume. To examine the role of CTV margin, marginal recurrence was defined as any new lesion outside of the prescription volume but within 2 cm of the resection cavity. High grade toxicity per CTCAE v5 was an irreversible grade 3 or any grade 4 toxicity. Resection for radionecrosis was considered a local failure if any viable tumor was seen on pathology. Median follow up was 32.5 months (range 3.2-147.5 months). The number of AM treated post STR, post GTR recurrence, and definitively were 26, 16, and 5 respectively. 3-year local tumor control was estimated to be 84%. As expected, larger tumors were more likely to fail locally (p >.001). Two (5%) patients experienced high grade toxicity - both symptomatic radionecrosis requiring resection. Three-year marginal control was estimated to be 92.3%. Of the 5 tumors treated to the entire resection cavity, none experienced a marginal failure. Interestingly, recurrent tumors s/p GTR were more likely to recur marginally than tumors treated after STR (p = .009). Only 1 (4%) tumor treated after STR failed marginally while 4 (33%) tumors treated after GTR recurrence failed. The rate of high-grade toxicity in AM receiving FSRT was low. Local control appeared comparable to historical rates which may suggest the need for dose escalation with longer term follow-up. Recurrent tumors appear more prone to marginal failures, however more work is needed to determine which patients may benefit from additional CTV margin and more prolonged fractionated dose schedules. Improved targeting with newer imaging studies (e.g., DOTATATE PET) should be examined to determine if more accurate targeting will improve outcomes.

Five-Fraction Stereotactic Radiation for Head and Neck Paragangliomas

Paragangliomas of the head and neck (HN) are benign, slow-growing neoplasms that are rarely functional. Treatment is often indicated for patients presenting with mass effect, cranial neuropathies, or pulsatile tinnitus. Radiotherapy, traditionally conventionally fractionated, is often used for primary, post-operative, and salvage therapy, given its excellent control rates and reduced risks to adjacent neurovascular structures. Stereotactic ablative radiation (SAbR) offers shorter treatment time, and modern techniques eliminate margins to improve organ-at-risk avoidance. SAbR may offer additional radiobiological sparing of normal structures over single-fraction SAbR. We aimed to evaluate tumor and symptom response, acute and late toxicity rates, and recurrence patterns in HN paraganglioma patients treated with 25 Gy in 5 fractions. Retrospective chart review collected baseline patient and tumor information, treatment and dosimetry details, acute and long-term toxicity grades (per the CTCAE v. 5.0), symptom and tumor response, and survival. Local control was defined as the absence of local enlargement (per RECIST v. 1.1) or marginal failure and was estimated using the Kaplan-Meier method. Between December 2009-March 2020, 39 patients received 25 Gy in 5 fractions to 43 HN paragangliomas, of which 17 were treated in 11 patients with hereditary paraganglioma-pheochromocytoma syndrome. Fifteen targets were post-operative recurrent or residual tumors. There were 27 jugulotympanic tumors, 4 jugular, 1 tympanic, 8 vagal, 5 carotid body, and 2 jugulotympanic or vagal. Median follow-up time was 3.3 years (range 0-11.4 years), and 21 targets had at least 4 years of follow-up. Tumor volume decreased by a median of 37%. Three-year local control was 100%. One patient, known to harbor an SDHD mutation, had 2 out-of-field recurrences within the post-operative bed at 7.1 years. Two patients experienced 2 marginal recurrences within the post-operative bed at 6.1 and 8.4 years: one had an SDHB mutation and developed metastatic disease, and the other did not have genetic testing. The most common grade 1-2 acute toxicities were headache and fatigue; the most common grade 1-2 late toxicities were dysphagia and otalgia. There were no grade >2 acute toxicities. A late grade 3 aspiration event was seen in 1 patient who presented with paralyzed vocal cord requiring multiple medialization laryngoplasties. Within 6 months of SAbR, 18% of symptoms or toxicities improved or resolved; 34% improved or resolved more than 6 months after SAbR. This is the largest series of HN paragangliomas treated with SAbR, detailing a 10-year experience with a 5-fraction regimen that is well-tolerated and achieves excellent local control. Post-SAbR recurrences occurred outside of the radiation field but within the post-operative bed, suggesting that some post-operative patients may benefit from expanded radiation volumes or close surveillance for salvage therapy.

Cardiopulmonary Toxicity from Intensity Modulated Proton Therapy for Thymic Malignancies

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

Results of a Multi-institutional Randomized Phase 3 Trial of Parotid-Sparing Whole Brain Radiotherapy

Observational studies have reported that xerostomia is common after conventional whole brain radiotherapy (WBRT) and associated with parotid dose. In this multi-institutional, single-blind randomized controlled trial, we hypothesized that patient-reported xerostomia is reduced in patients randomized to parotid-sparing vs. standard WBRT fields. Between 2018 and 2021, patients receiving conventional WBRT (30-35 Gy in 10-15 fractions) for any diagnosis were enrolled at 3 academic institutions. Patients were randomized between standard WBRT fields covering the C1 vertebra with no prospective parotid delineation (control) vs. parotid-sparing fields without C1 coverage (experimental). Patients completed the University of Michigan Xerostomia Questionnaire (Scored 0-100, higher is worse) at baseline, EndRT, 2 weeks, 1 month, 3 months, and 6 months. Patients were excluded from toxicity analyses if baseline xerostomia score was >50 or if they did not complete any post-baseline questionnaires. The primary endpoint was proportion of patients with ≥15 point absolute increase in xerostomia score from baseline to 1 month; 108 patients were needed for an 80% power to detect a 22% absolute difference (1-sided significance of 0.05). The secondary endpoint was the rate of marginal failures. The study closed early after 56 patients were randomized. Median survival was 4.6 months. 46 patients (23 in each arm) were eligible for analysis. Mean parotid dose was 17 vs. 10 Gy in the standard vs. parotid-sparing arms, respectively. The table below shows mean xerostomia score and proportion of patients with ≥15 increase in xerostomia score at each time point. There was no difference in the proportion of patients experiencing ≥15 increase in xerostomia score at 1 month, though there was a trend toward lower xerostomia score at 1 month in patients randomized to parotid-sparing fields (p = 0.07, Table). Xerostomia rates were also significantly improved in the parotid-sparing arm at EndRT (p = 0.03), but no longer-term difference was observed with greater attrition at 3 and 6 months. On linear regression, there was a trend toward association between mean parotid dose and xerostomia score at 1 month (p = 0.06). There were no reported marginal failures in either arm. Parotid-sparing without coverage of the C1 vertebra appears safe and may meaningfully reduce acute xerostomia in patients with limited life expectancy who are candidates for conventional WBRT, although the study was underpowered to detect a significant difference at 1 month.

Patterns of Locoregional Pancreatic Cancer Recurrence after Total Neoadjuvant Therapy and Implications on Optimal Neoadjuvant Radiation Treatment Volumes

Neoadjuvant treatment for patients with localized pancreatic adenocarcinoma (PDAC) has improved survival duration. As survival increases, local disease control becomes even more important. We sought to understand the patterns of locoregional recurrence following total neoadjuvant therapy (TNT) and determine the impact of treatment volumes on recurrence. Patients with PDAC managed with neoadjuvant chemotherapy and chemoradiation (TNT) followed by surgery who developed an isolated locoregional or simultaneously locoregional and distant recurrence were identified. Locoregional recurrences were individually contoured utilizing commercially available software. When available, original neoadjuvant dose distributions were registered to the scans on which the locoregional recurrences were contoured. Recurrences where then classified as in-field (> 95% of prescription dose), marginal (50-95% of prescription dose), or out of field (< 50% of prescription dose). Target volumes were created using four commonly utilized PDAC contouring guidelines to characterize the relationship of the local recurrence to the RT dose distribution. Of 474 patients treated with TNT and surgery, 80 (17%) patients developed a locoregional recurrence with or without distant recurrence, visible on diagnostic imaging. Of the 80 patients, 56 (70%) had tumors in the pancreatic head; 46 (57.5%) were borderline resectable, 23 (28.8%) locally advanced, and 11 (13.6%) resectable. The most common initial neoadjuvant therapies were FOLFIRINOX (57.5%) and gemcitabine/nab-paclitaxel (18.8%). Chemoradiation included concurrent gemcitabine (47.5%) or 5-fluorouracil (26.3%). RT dose distributions were available for 38 patients; 22 (57.9%) had in-field failures, 9 (23.7%) marginal failures, and 7 (18.4%) out of field failures. Each published contouring atlas covered a relatively low percentage of recurrences, which are summarized in Table 1. Regions at particularly high likelihood of recurrence that were under covered on existing atlases included: aortic-diaphragmic junction, retro-pancreatic duodenal nodal basin, and the region to the right of the superior mesenteric artery (SMA). We present the largest series (to our knowledge) of mapped locoregional recurrences for patients being treated with TNT in PDAC. These recurrences differ substantially from established atlases and highlight anatomical regions of highest priority for RT coverage. A novel visual contouring volume highlighting these regions will be presented which will strive to advance the use of RT in the TNT setting.

Boron Neutron Capture Therapy Followed by Image-Guided Intensity-Modulated Radiotherapy for Locally Recurrent Head and Neck Cancer: A Prospective Phase I/II Trial.

This trial investigated the efficacy and safety of salvage boron neutron capture therapy (BNCT) combined with image-guided intensity-modulated radiotherapy (IG-IMRT) for recurrent head and neck cancer after prior radiotherapy (RT). BNCT was administered using an intravenous boronophenylalanine-fructose complex (500 mg/kg) in a single fraction; multifractionated IG-IMRT was administered 28 days after BNCT. For BNCT, the mucosa served as the dose-limiting organ. For IG-IMRT, the clinical target volume (CTV) and the planning target volume (PTV) were generated according to the post-BNCT gross tumor volume (GTV) with chosen margins. This trial enrolled 14 patients, and 12 patients received combined treatment. The median BNCT average dose for the GTV was 21.6 Gy-Eq, and the median IG-IMRT dose for the PTV was 46.8 Gy/26 fractions. After a median (range) follow-up period of 11.8 (3.6 to 53.2) months, five patients had a complete response and four had a partial response. One patient had grade 4 laryngeal edema; another patient had a grade 4 hemorrhage. Most tumor progression occurred within or adjacent to the CTV. The 1-year overall survival and local progression-free survival rates were 56% and 21%, respectively. Despite the high response rate (64%) of this trial, there was a high incidence of in-field and marginal failure with this approach. Future studies combining BNCT with modalities other than radiation may be tried.

Clinical Outcomes of Thymic Carcinoma: The Role of Radiotherapy Combined with Multimodal Treatments

We aimed to identify the role of radiotherapy (RT) in the treatment of thymic carcinoma as well as the optimal RT target volume. This single-institution retrospective study included 116 patients diagnosed with thymic carcinoma between November 2006 and December 2021 who received multimodal treatment including RT with or without surgery or chemotherapy. Seventy-nine patients (68.1%) were treated with postoperative RT, 17 patients (14.7%) with preoperative RT, 11 patients (9.5%) with definitive RT, and nine patients (7.8%) with palliative RT. The target volume was defined as the tumor bed or gross tumor with margin, and selective irradiation of the regional nodal area was performed when involved. With a median follow-up of 37.0 (range, 6.7-174.3) months, the 5-year overall survival (OS), progression-free survival, and local recurrence-free survival rates were 75.2%, 47.7% and 94.7%, respectively. The 5-year OS was 51.9% in patients with unresectable disease. Overall, 53 recurrences were observed, of which distant metastasis was the most common pattern of failure (n = 32, 60.4%) after RT. No isolated infield or marginal failures were observed. Thirty patients (25.8%) who had lymph node metastases at the initial diagnosis had regional nodal areas irradiated. There was no lymph node failure inside the RT field. A tumor dimension of ≥5.7 cm (hazard ratio [HR] 3.01; 95% confidence interval [CI] 1.25-7.26; p = 0.030) and postoperative RT (HR 0.20; 95% CI 0.08-0.52; p = 0.001) were independently associated with OS. Intensity-modulated-RT-treated patients developed less overall toxicity (p < 0.001) and esophagitis (p < 0.021) than three-dimensional-conformal-RT-treated patients. A high local control rate was achieved with RT in the primary tumor sites and involved lymph node area in the treatment of thymic carcinoma. A target volume confined to the tumor bed or gross tumor plus margin with the involved lymph node stations seems reasonable. The advanced RT techniques with intensity-modulated RT have led to reduced RT-related toxicity.

Pattern of failure after adjuvant radiation therapy in oral cavity cancer patients: Data from tertiary care institute in North India

Abstract Objectives: To review failure patterns in oral cavity squamous cell carcinoma treated with surgery and adjuvant radiation therapy. Materials and Methods: All patients with biopsy-proven stage I-IVB oral cavity squamous cell carcinoma (OCSCC) treated with surgery and adjuvant therapy between 2018 and 2022 were evaluated. Outcome measures were 3-years loco-regional recurrence (LRR), overall survival (OS), and progression free survival (PFS). LRR was spatially localized in relation to contour and dose distribution. Results: A total of 85 patients treated between years 2018 to 2022 were evaluated with median follow-up of 19 months. Disease subsites were oral tongue (37.6%) and bucco-alveolar complex (62.4%). Of a total of 25.9% failures, 16/85 (18.8%) were local, 9/85 (10.6%) were regional, 18/85 (21.2%) were locoregional, and 10/85 (11.8%) were distant. For LRR, total in-field failure was 11.8%, marginal failure was 4.7%, and out-of-field failure was seen in 2.4% cases. The 3-year actuarial local, regional control, and LRR in our study were 69%, 84%, and 67%, respectively. The cumulative rates of OS were 72% and PFS was 56%. On univariate analysis, independent factors for local failure were perineural invasion (PNI) (OR = 5.89, P = 0.03), lymph vascular space invasion (LVI) (OR = 3.69, P = 0.05), and pathological N3 (OR = 3.69, P = 0.02). For regional, failure was PNI (OR = 4.53, P = 0.038). For locoregional, failure was PNI (OR = 6.13, P = 0.002) and for distant, failure were PNI (OR = 5.80, P = 0.013), pathological N3 (OR = 4.35, P = 0.03) and LVI (OR = 4.66, P = 0.03). On multivariate Cox proportional hazard analysis, for local, failure risk factors were PNI (HR = 4.32, P = 0.01) and pathological N3 (HR = 3.27, P = 0.047), for locoregional, failure was PNI (HR = 4.42, P = 0.006), and for distant, failure was PNI(HR0 = 4.29, P = 0.05). Conclusions: In our cohort of patients, the most common failure was in-field LRR. PNI was significantly associated with local, locoregional, and distant failure on Cox analysis. In addition to PNI, pathological N3 was the cause of local failure.