Jay Paul Reddy

Background: Perineural spread (PNS) in head and neck cancer (HNC) is technically challenging due to complex target volumes adjacent to critical organs. Data on stereotactic body radiation therapy (SBRT) for PNS is scarce. Methods: This retrospective study included patients treated with SBRT for PNS across two centers in the USA and Canada from 2015 to 2025. Endpoints included overall survival (OS), progression‐free survival (PFS), local control (LC), and treatment‐related toxicity. Results: Thirty‐six patients were included, with median follow up of 47.5 months. Two‐year OS, PFS, and LC were 79%, 54%, and 72% respectively. Patients with cutaneous squamous cell carcinoma (cSCC) had superior PFS and LC compared with non‐cSCC histologies. Adenoid cystic carcinoma (ACC) accounted for the only in‐field failures. Grade ≥ 3 toxicity occurred in 22% (8/36), including grade ≥ 3 osteoradionecrosis in 6% (2/36). Temporal lobe necrosis was solely Grade 1–2 (32%). Conclusions: SBRT demonstrated durable LC for selected patients with PNS, particularly cSCC, while ACC may warrant a dose‐escalated approach.

PURPOSE: We tested the hypothesis that adding metastasis-directed therapy (MDT) to standard-of-care (SOC) systemic therapy improves progression-free survival (PFS) among patients with oligometastatic disease. METHODS: EXTEND was a multicenter randomized phase II trial. Patients with 1-5 metastases were randomly assigned to MDT + SOC versus SOC in one of the six baskets (breast, pancreas, kidney, two prostate baskets, and an other basket) with basket-specific stratification and powering. PFS, the primary end point, was prespecified in the per-protocol set within each basket, across all baskets, and across all baskets excluding the prostate baskets. Exploratory end points included circulating tumor DNA (ctDNA) and immune profiling. RESULTS: From 2018 through 2023, 521 patients were screened, 350 were randomly assigned, and 334 were analyzed per protocol (MDT + SOC, n = 166; SOC, n = 168). Radiotherapy was used as MDT for 98% of metastases (370/379). Overall, after a median follow-up of 53 months, PFS was improved with MDT + SOC (hazard ratio [HR], 0.54 [95% CI, 0.41 to 0.72], P < .001). Similarly, PFS was improved when excluding the prostate baskets (HR, 0.60 [95% CI, 0.40 to 0.89]). Within each basket, PFS superiority was identified for the pancreas, prostate, and other baskets, whereas the breast and kidney baskets were inconclusive. At enrollment, detectable ctDNA correlated with shorter PFS and survival; by contrast, ctDNA clearance 3 months postenrollment correlated with improved survival. MDT + SOC-induced systemic immune activation was most pronounced among baskets demonstrating PFS superiority. CONCLUSION: The phase II EXTEND trial supports the addition of MDT to SOC for oligometastatic disease. Histology-specific efficacy signals were identified for phase III testing. Translational insights suggest the potential for optimizing the definition of oligometastasis using ctDNA and point to systemic immune responses as a possible mechanism of benefit from MDT.

Sample-level cell counts of CD8 clusters

Statistical test for association of lymphocyte cluster proportion with progression

Fig. S1. Patient disposition and characteristics. Fig. S2. Timing of OI biopsy collection did not correlate with response. Fig. S3. Major cell types identified in the tumor immune microenvironment. Fig. S4. CD4+ T cells identified in the tumor immune microenvironment. Fig. S5. Effector Treg cells in the HPV-positive OPC TIME highly express activation markers. Fig. S6. Treatment-induced changes in Treg proportions and clonotype frequencies. Fig. S7. CD8+ T cells in MHRs have different transcriptional programs vs those in nMHRs. Fig. S8. CD8+ T cells identified in the tumor immune microenvironment. Fig. S9. T cell clusters did not vary by anatomic site. Fig. S10. TRM CD8+ T cells had high expression of tumor-reactive, cytotoxic and checkpoint genes. Fig. S11. Fluorescent imaging of antigen-experienced, memory CD8+ T cells in baseline tumors. Fig. S12. Clonality of CD4+ T-cell TCR repertoire. Fig. S13. CD8+ T-cell TCR repertoire clonality and dynamics. Fig. S14. Phenotypes of treatment-altered CD8 clonotypes varied by response. Fig. S15. Predominant phenotypes of treatment-responsive CD8+ T-cell clonotypes. Fig. S16. Identification of HPV-specific TCRs. Fig. S17. NK cells that express Fc gamma receptor IIIa (CD16) are more activated than those that do not. Fig. S18. Increase in proportion of Effector1(IFNG+) cells associated with reduction in tumor viability.

Table S1. Patient and tumor characteristics. Table S2. Representativeness of study participants. Table S3. Clinical and histopathologic characteristics of individual patients. Table S4. Treatment related adverse events that occurred after first dose. Table S5. Adverse events related to immune checkpoint blockade. Table S6. Serious adverse events.

Clinical and single-cell features used in multivariable regression models

Single-cell RNA and TCR sequencing information and metrics

Differentially expressed genes of CD8+ T cells from MHRs vs non-MHRs at baseline

Differentially expressed genes of CD8 clusters