SUMMARYBackgroundAfter brain metastasis resection, whole-brain radiation therapy (WBRT) decreases local recurrence but may cause cognitive decline. We performed this study to determine if stereotactic radiosurgery (SRS) to the surgical cavity improved local tumor tumor-free recurrence rates compared to surgical resection alone as an alternative to the need for immediate WBRT.MethodsThe main entry criteria for the study included patients >3 years of age, with a Karnofsky Performance Score ≥ 70, who were able to undergo an MRI scan and who had a complete resection of 1–3 brain metastases (the maximum diameter of the resection cavity had to be ≤4cm). Patients were assigned randomly to either SRS treatment of the resection cavity (within 30 days of surgery) or observation (OBS). Patients were stratified by histology, tumor size, and number of metastases. Patients were recruited at a single tertiary cancer center. The primary endpoint was time to local recurrence in the resection cavity assessed by blinded central review of brain MRI scans in the intention-to-treat population. The trial was registered at clinicaltrials.gov (Trial NCT00950001, status: closed to new participants).FindingsBetween 8/13/2009 and 2/16/2016, 132 patients were randomized to OBS (N=68) or SRS (N=64), with 128 patients available for analysis. We stratified by metastasis size (maximum diameter of ≥3 cm vs. <3 cm), histology (melanoma vs. other), and number of metastases (one vs. two or three). The 12-month local tumor recurrence-free rate was 43% (OBS) (95% CI 31%–59%) and 72% (SRS) (95% CI 60%–87%) (hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.24–0.88, p=0.015).InterpretationThis prospective randomized trial of patients undergoing surgical resection for 1–3 brain metastases indicates that SRS administered to the resection cavity significantly lowers local recurrence compared to observation alone. Thus, the use of SRS after brain metastasis resection is an alternative to WBRT.

Background: When achieved, complete surgical resection improves outcomes in anaplastic thyroid carcinoma (ATC). However, most ATC patients present with advanced inoperable disease, often with impending airway obstruction, increased hemorrhage risk, and significant dysphagia. Novel treatment strategies are critically needed to improve disease control and decrease locoregional morbidity. The objective of this study was to determine the feasibility and effectiveness of a neoadjuvant regimen by using dabrafenib with trametinib followed by surgical resection in patients with initially unresectable BRAF V600E -mutated ATC. Methods: Case series of six consecutive patients with BRAF V600E -mutated ATC diagnosed between January 2017 and February 2018. Pathologic confirmation of ATC was obtained before treatment. BRAF V600E status was ascertained via immunohistochemistry or sequencing of circulating tumor DNA. All patients received dabrafenib and trametinib (DT) followed by surgical resection and adjuvant chemoradiation. Three patients also received pembrolizumab. Results: Complete surgical resection was achieved in all patients. Histopathologic analyses of resected specimens showed high pathologic response rates with significantly decreased ATC viability and residual papillary thyroid carcinoma components. Overall survival at six months and one year was 100% and 83%, respectively. Locoregional control rate was 100%. Two patients died of distant metastases without evidence of locoregional disease at 8 and 14 months from diagnosis. The remaining four patients had no evidence of disease at the last follow-up. Conclusions: We report the first series in the literature of BRAF V600E -mutated ATC patients with locoregionally advanced disease treated with DT followed by surgical resection. We demonstrated feasibility of complete resection, decreased need for tracheostomy, high pathologic response rates, and durable locoregional control with symptom amelioration.

Anaplastic thyroid cancer (ATC) is a devastating disease with a dismal prognosis. Patients who have disease confined to the thyroid and who are able to undergo complete surgery and chemoradiation stand the best chance for survival. Unfortunately, nearly 50% of patients have distant metastases at diagnosis, and most present with locally advanced, unresectable tumors. Nevertheless, BRAF-mutated ATC patients represent a subset of cases who can benefit from a combination therapy with BRAF and MEK inhibitors. Here, a patient is presented with end-stage, locally advanced, unresectable ATC who was treated with this combination. Immunotherapy with pembrolizumab was added at the first sign of progression after which he achieved a partial response to therapy, enabling a complete surgical resection followed by postoperative chemoradiation to be undertaken. This novel neoadjuvant approach to BRAF-mutated ATC should be studied in further in clinical trials.

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