Iodine-125 Seed Implantation and Transarterial Chemoinfusion Combined with Immune Checkpoint Inhibitors for a Thoracic SMARCA4-Deficient Undifferentiated Tumor

Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a rare and aggressive malignancy, currently treated by conventional chemotherapy and associated with a dismal prognosis (1Li Y.-M. Guo R.-Q. Bie Z.-X. Li B. Li X.-G. Sintilimab plus bronchial arterial infusion chemotherapy/drug-eluting embolic chemoembolization for advanced non–small cell lung cancer: a preliminary study of 10 patients.J Vasc Interv Radiol. 2021; 32: 1679-1687Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar, 2Chao C. Wei W. Zhe Y. Tian S. Li Y. Wang Y. Combination of computed tomography-guided iodine-125 brachytherapy and bronchial arterial chemoembolization for locally advanced stage III non-small cell lung cancer after failure of concurrent chemoradiotherapy.Lung Cancer. 2020; 146: 290-296Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar). Given limited response to immune checkpoint inhibitors (ICIs), novel treatment options need to be explored for thoracic SMARCA4-UT. This report presents a patient with thoracic SMARCA4-UT who responded to a combination treatment of interventional therapy with ICIs and experienced no severe adverse events. Approval for publication was obtained from the Beijing Hospital ethics committee. A 63-year-old man with 30 pack-years of smoking developed sudden hoarseness. Tumor marker levels (carcinoembryonic antigen 7.4, ng/mL; squamous cell carcinoma antigen, 4.0 ng/mL; cancer antigen125, 59.4 U/mL) were mildly elevated. Laryngoscopy demonstrated paralysis of the left vocal cord. A contrast-enhanced computed tomography (CT) scan of the thorax showed a 2.9 × 4.1 cm irregular mass in the left anterior mediastinum; there was no clear fat plane separating the aortic arch from the mass (Fig 1a). The patient subsequently underwent CT-guided percutaneous transsternal needle biopsy. Immunohistochemical tests demonstrated an absence of SMARCA4 expression. Next-generation sequencing of the biopsy specimen suggested SMARCA4 c.355+1G>T (+), with a mutation frequency of 10.3%, tumor mutational burden of 58.56 muts/Mb, and microsatellite stability. The patient was diagnosed with thoracic SMARCA4-UT with clinical T4N1M0 stage IIIA according to the 8th edition TNM staging system. First, CT-guided percutaneous transthoracic iodine-125 (125I) radioactive seed implantation (n = 30, 0.6 mCi, 80 Gy; Xinke Pharmaceutical, Shanghai, China) was performed (Fig 1b). The next month, the patient started 5 cycles of transarterial chemoinfusion (Fig 2a, b) (nedaplatin, 100 mg; liposomal paclitaxel, 180 mg) administered every 4 weeks. Concurrently, 200 mg of a PD-1 inhibitor (camrelizumab; Jiangsu Hengrui Medicine, Jiangsu, China) was administered intravenously every 3 weeks. Three months after the initial scan, a repeat CT demonstrated a partial response of the thoracic tumor. The patient was placed on maintenance therapy with camrelizumab. Another follow-up CT performed 9 months after start of therapy confirmed a durable partial response and continued decrease in tumor size. There were no obvious adverse effects, except self-limited mild reactive cutaneous capillary endothelial proliferation and skin pigmentation. After 3 cycles of camrelizumab monotherapy maintenance, ICI therapy was discontinued and routine imaging follow-up pursued. A contrast-enhanced CT scan 19 months after start of therapy revealed a nearly complete response of the tumor (Fig 3). To date, the patient remains stable and asymptomatic. Thoracic SMARCA4-UT is most common in men with a long history of heavy smoking and presents with dyspnea, chest pain, and superior vena cava syndrome. Tumors mainly involve the mediastinum, hilum, lung, and/or pleura with or without chest wall invasion. The median expected survival is less than 6 months. Currently, there is no uniform treatment for SMARCA4-UT, which is usually nonresponsive to surgery and chemotherapy. Because of the lack of common driver gene mutations, it is not sensitive to targeted therapy. However, it is worth noting that immunotherapy responses are variable but promising for SMARCA4-UT, either as first-line therapy or after failed chemotherapy. Henon et al. (3Henon C. Blay J.Y. Massard C. et al.Long lasting major response to pembrolizumab in a thoracic malignant rhabdoid-like SMARCA4-deficient tumor.Ann Oncol. 2019; 30: 1401-1403Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar) reported that patients with SMARCA4-UT treated with pembrolizumab showed a partial response and a remarkable clinical improvement with decline of thoracic pain and dyspnea. Kunimasa et al. (4Kunimasa K. Okami J. Takenaka S. et al.Conversion surgery for advanced thoracic SMARCA4-deficient undifferentiated tumor with atezolizumab in combination with bevacizumab, paclitaxel, and carboplatin treatment: a case report.JTO Clin Res Rep. 2021; 2100235PubMed Google Scholar) reported a case of SMARCA4-UT that was successfully converted to surgical candidacy after treatment with atezolizumab, bevacizumab, paclitaxel, and carboplatin. In the present case, the patient had a high tumor mutational burden load, suggesting a high likelihood that he would benefit from ICIs. The combination of immunotherapy and transarterial chemoinfusion resulted in a favorable response, lasting in 19-month progression-free survival for this patient. There may be a synergistic effect in this combination. Accumulating evidence has revealed the clinical benefit of interventional therapies when used to treat thoracic malignancies, but there have been no studies of interventional therapy in patients with thoracic SMARCA4-UT. Considering that this tumor was located in the anterior mediastinum and invaded the aortic arch, percutaneous 125I radioactive seed implantation and transarterial chemoinfusion were specifically selected as local treatment options. Iodine-125 radioactive seeds can continuously emit low-energy gamma rays and provide sustained irradiation within the target tumor. More importantly, the aortic arch is not subjected to a high radiation dosage. Transarterial chemoinfusion delivers chemotherapy locally, avoiding dilutional and metabolic attenuation with milder systemic toxicity than conventional chemotherapy. In this case, a combination of brachytherapy, transarterial chemoinfusion, and ICI therapy achieved good local tumor control, without serious adverse events. Given the paucity of data and limited effective treatment options available for thoracic SMARCA4-UT, this case provides a preliminary signal that interventional locoregional therapy combined with ICI therapy may result in favorable patient outcomes.