Reddy, Jay P.

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.

Background/Objectives: Stereotactic body radiation therapy (SBRT) for skull base reirradiation is particularly challenging, as patients have already received substantial radiation doses to the region, and nearby normal organs may have approached their tolerance limit from prior treatments. In this study, we reviewed the characteristics and capabilities of four advanced external beam radiation delivery systems and four modern treatment planning systems and evaluated the treatment plan quality of each technique using skull base reirradiation patient cases. Methods: SBRT plans were generated for sixteen skull base reirradiation patients using four modalities: the GK plan for the Elekta Leksell Gamma Knife Perfexion/ICON, the CyberKnife (CK) plan for the Accuray CyberKnife, the intensity-modulated proton therapy (IMPT) plan for the Hitachi ProBeat-FR proton therapy machine, and the volumetric-modulated arc therapy (VMAT) plan for the Varian TrueBeam STx. These plans were evaluated and compared using two novel gradient indices in addition to traditional dosimetry metrics for targets and organs at risk (OARs). The steepest border gradient quantified the percent prescription dose fall-off per millimeter at the boundary between the target and adjacent critical structures. This gradient index highlighted the system’s ability to spare nearby critical OARs. The volume gradient assessed the extent of dose spread outside the target toward the patient’s body. Results: All plans achieved comparable target coverage and conformity, while IMPT and VMAT demonstrated significantly better uniformity. The GK plans exhibited the highest border gradient, up to 20.9%/mm, followed by small-spot-size IMPT plans and CK plans. Additionally, IMPT plans showed the benefit of reduced dose spread in low-dose regions and the lowest maximum and mean doses to the brainstem and carotid artery. Conclusions: The advanced external beam radiotherapy modalities evaluated in this study are well-suited for SBRT in skull base reirradiation, which demands precise targeting of tumors with highly conformal doses and steep dose gradients to protect nearby normal structures.

Objective To identify factors associated with regional recurrence after lymph node dissection ( LND ) for squamous cell carcinoma ( SCC ) to determine which patients might benefit from adjuvant therapy. Patients and Methods Men who underwent LND for penile SCC from 1977 to 2014 were identified from an institutional database. Kaplan–Meier curves estimated recurrence‐free survival ( RFS ) calculated from the date of LND . Cox regression models evaluated the association between RFS and patient and tumour characteristics. Results In all, 182 men who underwent LND for penile SCC were identified. The median patient age was 62 years and the median follow‐up was 4.2 years. After LND 34 men had regional recurrence, of which 24 developed isolated regional recurrences without distant metastasis. The median RFS was 5.7 months, and the 3‐year RFS rate was 70%. On univariate analysis, lymphovascular invasion, clinical and pathological nodal stage, pathological inguinal laterality, pelvic nodal involvement, lymph node density ≥5.2%, ≥3 pathologically involved lymph nodes, and extranodal extension ( ENE ) were associated with worse RFS (all P < 0.05). On multivariate analysis, clinical N3 disease [adjusted hazard ratio ( AHR )] 3.53, 95% confidence interval ( CI ) 1.68–7.45; P = 0.001), ≥3 pathologically involved lymph nodes ( AHR 3.78, 95% CI 2.12–6.65; P < 0.001), and ENE ( AHR 3.32, 95% CI 1.93–5.76; P < 0.001) were associated with worse RFS . The 3‐year RFS for patients with cN 0, cN 1, cN 2, and cN 3 disease was 91.7%, 64.5%, 54.7%, and 38.3%, respectively. For men with ≥3 involved nodes, the 3‐year RFS was 17% vs 82.4% in men with <3 involved nodes. The 3‐year RFS was 29.7% in men with ENE and 85.7% in men without ENE. Conclusion The presence of clinical N3 disease, ≥3 pathologically involved lymph nodes, and ENE was associated with worse RFS . As regional recurrence portends a dismal prognosis with few salvage options, adjuvant therapies should be developed for men with the aforementioned adverse factors.