Lara A. Dunn

Background: Re‐irradiation (re‐RT) for recurrent head and neck cancer (HNC) can be potentially curative but is constrained by significant toxicity. Proton therapy may improve the therapeutic ratio. This multicenter phase 2 trial evaluated the safety and efficacy of proton re‐RT in patients with HNC. Methods: Patients received prior HNC radiotherapy at a dose of ≥40 gray (Gy). Salvage surgery and/or systemic therapy before re‐RT were permitted. Considering clinical status, two pragmatic treatment approaches were used: fractionated re‐RT (F‐Re‐RT; 60–70 Gy) or QUAD shot re‐RT (QS‐Re‐RT; 14.8 Gy per cycle, up to four cycles; maximum total, 59.2 Gy). Primary end points were locoregional recurrence–free rates at 12 months for F‐Re‐RT and at 6 months for QS‐Re‐RT, and a fixed‐time, binary proportion analyzed using 90% Clopper–Pearson confidence intervals (CIs) and prespecified success thresholds (lower bound, >55% and >10%, respectively). Secondary end points included overall survival (OS), progression‐free survival, the cumulative incidence of distant metastasis and locoregional recurrence, clinician‐reported toxicity, and patient‐reported outcomes. Results: From July 2017 to November 2022, 85 patients received either F‐Re‐RT ( n = 57) or QS‐Re‐RT ( n = 28), with a median follow‐up of 38 months. The locoregional recurrence–free rates were 71% (90% CI, 59%–81%) at 12 months for F‐Re‐RT and 76% (90% CI, 58%–89%) at 6 months for QS‐Re‐RT, surpassing prespecified success thresholds. The highest late toxicity attributable to re‐RT was grade 3 in 20% of patients, grade 4 in 11%, and grade 5 in 4%. The 5‐year OS rate was 29%, and the 5‐year progression‐free survival rate was 23%. Patient‐reported outcomes were stable at 1 year after F‐Re‐RT and after QS‐Re‐RT. Conclusions: Proton re‐RT demonstrated encouraging locoregional control and survival in heavily pretreated patients, although late toxicities remain important concerns (ClinicalTrials.gov identifier: NCT03217188).

Background: Sinonasal carcinomas are aggressive and often locally invasive at presentation, with no universally accepted treatment approach. Histopathologic IDH2 ‐mutant status appears to be associated with improved treatment response and survival. However, the clinical significance of histopathologic classification among IDH2‐mutant sinonasal carcinomas, as well as that of IDH2 mutation status within SNUC, remains unclear and long‐term clinical outcome data are limited. Methods: Records from a prospectively maintained skull‐base database at a large, tertiary care hospital system from 1986 to 2024 were reviewed. Patients with a diagnosis of SNUC or sinonasal tumor of any histopathology positive for IDH2 R172 mutation were identified. SMARCB1‐deficient, SMARCA4‐deficient, NUT sinonasal carcinomas, and other small round cell mimickers were excluded. After histopathologic confirmation, 22 IDH2 ‐mutant SNUC, 14 IDH2 ‐mutant non‐SNUC, and 8 IDH2 ‐wildtype SNUC cases were amenable to comprehensive clinicopathologic data review. A presence of IDH2 R172 and pathogenic TP53 mutations was determined by molecular testing and/or by immunohistochemistry. Results: The median age at diagnosis was 58 years and 61% of patients were male. The majority of patients presented with T4b disease (41% of IDH2 ‐mutant SNUC; 57% of IDH2 ‐mutant non‐SNUC; 75% of IDH2 ‐wildtype SNUC; p = 0.3). There was no significant difference in the proportion of patients presenting with orbital invasion (55% IDH2 ‐mutant SNUC; 64% IDH2 ‐mutant non‐SNUC; 75% of IDH2 ‐wildtype SNUC; p = 0.7) or intracranial invasion (82% IDH2 ‐mutant SNUC; 79% IDH2 ‐mutant non‐SNUC; 75% of IDH2 ‐wildtype SNUC; p = 0.7). On histopathology, there was no significant difference in perineural invasion and margin status between the three subgroups ( p > 0.6 ). A greater proportion of IDH2 ‐mutant non‐SNUCs had TP53 mutations (67%) than IDH2 ‐mutant SNUC (31%) and IDH2 ‐wildtype SNUC (29%) ( p = 0.13). Across the cohort, 41% of patients received neoadjuvant chemotherapy, with a partial response by RECIST criteria in 94% of patients across the subgroups. Median follow‐up was 28 months (IQR 11–64 months). 5‐year DSS of 73% in IDH2 ‐mutant SNUC, 75% in IDH2 ‐mutant non‐SNUC and 80% in IDH2 ‐wildtype SNUC ( p = 0.78). 5‐year RFS was 53% in IDH2 ‐mutant SNUC, 48% in IDH2 ‐mutant non‐SNUC and 43% in IDH2 ‐wildtype SNUC ( p = 0.78). Conclusion: Upfront assessment of IDH2 mutation status in sinonasal carcinoma patients may be warranted to select patients for clinical trials with IDH‐inhibitors. However, no significant differences in the extent of disease at presentation or response to induction chemotherapy were observed according to histopathologic classification among IDH2‐mutant sinonasal carcinomas or IDH2 mutation status within SNUC. Larger series are required to determine the prognostic significance of IDH2 mutation status in sinonasal carcinoma patients.

Purpose: To evaluate the clinical outcomes and patterns of failure in patients with paranasal sinus cancer treated by proton therapy during 2013–2022. Methods and Materials: This retrospective study included 88 patients with newly diagnosed nonmetastatic paranasal sinus cancer treated by proton therapy at a tertiary academic cancer center from August 2013 to November 2022. Fifteen patients were treated by three‐dimensional conformal proton technique ( 3DCPT ) and 73 patients were treated by intensity modulated proton therapy ( IMPT ). The main outcomes were the long‐term toxicity, patterns of failure and survival outcomes, including cumulative incidence of local or regional failures ( LRF ) and overall survival ( OS ). Results: The median (interquartile range [ IQR ]) follow‐up time for the overall group was 57.3 (38.5–82.6) months. Acute grade 3 radiation dermatitis and late grade 3 nasal congestion occurred significantly more frequently in the 3DCPT group compared to the IMPT group (20.0% vs. 4.1%, p = 0.008; 33.3% vs. 5.6%, p = 0.004, respectively). By the last follow‐up, 33 patients had developed treatment failures. A total of 21 patients (23.9%) developed local failures, 14 were considered in‐field failure; 4 were marginal; 3 were out‐of‐field failure. The 5y‐cumulative incidence of LRF and OS rate of the overall group were 25% [95% confidence interval ( CI ), 16–35] and 79.4% (70.2–89.8), respectively. There were no statistically significant differences following 3DCPT and IMPT in cumulative incidence of LRF and OS . Conclusions: Proton therapy yielded excellent therapeutic outcomes in the management of paranasal sinus cancer. IMPT holds significant potential in enhancing the therapeutic ratio in paranasal sinus cancer and warrants further exploration in clinical settings.

Purpose:There is a significant need for effective therapies to treat recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC). This study evaluated the multitargeted VEGFR tyrosine kinase inhibitor (TKI) regorafenib in patients with R/M ACC.Patients and Methods:Patients with progressive R/M ACC were treated with regorafenib until disease progression, consent withdrawal, or excessive toxicity. The co-primary endpoints were best overall response and 6-month progression-free survival (PFS). Genomic and transcriptomic biomarker analyses were performed in tumors from trial participants.Results:Thirty-eight patients were enrolled, including 7 (18%) patients with prior VEGFR TKIs. No objective responses were observed. The 6-month PFS was 45%, and the median PFS was 7.2 months (95% confidence interval, 5.2–11.9 months). The presence of either activating NOTCH1 (22%) or KDM6A alterations (24%) was associated with decreased PFS [HR 2.6; 95% confidence interval (CI), 1.1–6.1; P = 0.03]. Bulk RNA sequencing of pretreatment tumors revealed that regorafenib clinical benefit (CB; PFS ≥ 6 months; n = 11) was associated with the native enrichment of immune-related signatures. Immune deconvolution revealed a greater degree of macrophage and T-cell infiltration in CB tumors. Tumors from patients with no clinical benefit (NCB; PFS < 6 months; n = 9) had greater expression of signatures related to cell-cycle progression (E2F targets, G2–M checkpoint).Conclusions:The trial failed to meet the prespecified 6-month PFS and best overall response targets. We hypothesize that TKI efficacy may be reliant upon an interplay between kinase inhibition and the ACC immune microenvironment, whereas programs promoting cell-cycle progression may contribute to TKI resistance. These observations suggest that trials evaluating CDK4/6 inhibition plus a VEGFR TKI should be considered.

Purpose: There is a significant need for effective therapies to treat recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC). This study evaluated the multitargeted VEGFR tyrosine kinase inhibitor (TKI) regorafenib in patients with R/M ACC. Patients and Methods: Patients with progressive R/M ACC were treated with regorafenib until disease progression, consent withdrawal, or excessive toxicity. The co-primary endpoints were best overall response and 6-month progression-free survival (PFS). Genomic and transcriptomic biomarker analyses were performed in tumors from trial participants. Results: Thirty-eight patients were enrolled, including 7 (18%) patients with prior VEGFR TKIs. No objective responses were observed. The 6-month PFS was 45%, and the median PFS was 7.2 months (95% confidence interval, 5.2–11.9 months). The presence of either activating NOTCH1 (22%) or KDM6A alterations (24%) was associated with decreased PFS [HR 2.6; 95% confidence interval (CI), 1.1–6.1; P = 0.03]. Bulk RNA sequencing of pretreatment tumors revealed that regorafenib clinical benefit (CB; PFS ≥ 6 months; n = 11) was associated with the native enrichment of immune-related signatures. Immune deconvolution revealed a greater degree of macrophage and T-cell infiltration in CB tumors. Tumors from patients with no clinical benefit (NCB; PFS < 6 months; n = 9) had greater expression of signatures related to cell-cycle progression (E2F targets, G2–M checkpoint). Conclusions: The trial failed to meet the prespecified 6-month PFS and best overall response targets. We hypothesize that TKI efficacy may be reliant upon an interplay between kinase inhibition and the ACC immune microenvironment, whereas programs promoting cell-cycle progression may contribute to TKI resistance. These observations suggest that trials evaluating CDK4/6 inhibition plus a VEGFR TKI should be considered.

Background: We evaluate outcomes of SMARCB1‐deficient sinonasal carcinomas in the largest single‐institution study.Methods: Retrospective cross‐sectional study of patients with SMARCB1‐deficient sinonasal carcinoma between 1998 and 2024. Disease‐specific survival (DSS) and recurrence‐free probability (RFP) at 1 and 5 years were measured by Kaplan–Meier method.Results: There were 47 patients with a median age of 53. Initial pathological diagnosis was altered in 33%. Twelve (34%) patients received neoadjuvant chemotherapy, with one partial response. Curative surgical approach was undertaken in 73%. Definitive chemoradiation was administered in 20%. DSS at 1 and 5 years was 93% and 45%, respectively. RFP at 1 and 5 years was 73% and 33%, respectively. On multivariate analysis, cranial nerve involvement (p = 0.01 for DSS) remained significantly worse for DSS and overall survival.Conclusions: SMARCB1‐deficient tumors had limited response to neoadjuvant chemotherapy. Cranial nerve involvement was associated with worse prognosis. Optimal treatment is unclear. Surgery should be offered to patients with resectable disease.

Background Numerous studies and guidelines suggest an outcome detriment from radiation treatment breaks (rTBs) and the need for compensatory dosing in patients with head and neck cancer. Methods In a consecutive cohort of 521 patients with oropharyngeal squamous cell carcinoma (OPSCC), we investigated the impact of rTBs and prolongation of overall treatment time (OTT) on OS, DFS, LRC, and cancer recurrence using competing risk and multivariate analyses. Results Neither OTT prolongation by <= 2 days nor rTBs of <= 3 days were associated with detriments to clinical outcomes. Consecutive breaks of >= 3 days were also not significantly associated with detriment to clinical outcomes. There was significantly increased competing mortality in those with longer breaks. Conclusions In OPSCC patients treated with definitive concurrent chemoradiotherapy, there is no significant association between disease failure and total rTBs of <= 3 consecutive or scattered days. Further investigation is needed for longer breaks.