A Phase 1 dose-escalation study of disulfiram and copper gluconate in patients with advanced solid tumors involving the liver using S-glutathionylation as a biomarker.

BACKGROUND: Disulfiram and metals inactivate key oncoproteins resulting in anti-neoplastic activity. The goal of this study was to determine the maximum tolerated dose of copper when administered with disulfiram in patients with advanced solid tumors and liver involvement. METHODS: Disulfiram 250 mg was administered daily in 28-day cycles. Four doses of copper gluconate were tested (2, 4, 6, and 8 mg of elemental copper) in a standard 3 + 3 dose escalation design. Patients were evaluated for dose limiting toxicities and response. Protein S-glutathionylation was evaluated as a pharmacodynamic marker. RESULTS: Twenty-one patients were enrolled and 16 patients were evaluable for dose limiting toxicities. Among the 21 patients, there was a median of 4 lines of prior chemotherapy. Five Grade 3 toxicities were observed (anorexia, elevated aspartate aminotransferase or AST, elevated alkaline phosphatase, fever, and fatigue). Response data was available for 15 patients. Four patients had stable disease with the longest duration of disease control being 116 days. The median duration of treatment for evaluable patients was 55 days (range 28-124). Reasons for discontinuation included functional decline, disease progression, and disease-associated death. Increased S-glutathionylation of serum proteins was observed with treatment. CONCLUSION: Disulfiram 250 mg daily with copper gluconate (8 mg of elemental copper) was well-tolerated in patients with solid tumors involving the liver and was not associated with dose limiting toxicities. While temporary disease stabilization was noted in some patients, no objective responses were observed. Treatment was associated with an increase in S-glutathionylation suggesting that this combination could exert a suppressive effect on cellular growth and protein function. TRIAL REGISTRATION: NCT00742911 , first posted 28/08/2008.

Adjuvant therapy for resected high-risk melanoma.

Melanoma is an aggressive cancer that arises from melanocytes that can both locally invade surrounding tissues as well as metastasize systemically. If detected early, melanoma can be curable with surgical resection. However, despite complete removal, high-risk resected melanomas have a significant rate of both local and distant recurrence. Curative treatment options are typically limited for patients who develop distant recurrence after resections of their primary melanoma. Therefore, adjuvant therapy is typically given after complete resection of high-risk melanomas to try and reduce the risk of recurrent disease. Adjuvant therapy for high-risk resected melanoma has changed considerably over the past couple of years due to the availability of new melanoma therapies that are active in the metastatic setting. Here, we review the new treatment options and ongoing clinical research for adjuvant therapy.

Increasing use of nonsurgical therapy in advanced-stage oral cavity cancer: A population-based study.

BACKGROUND: National guidelines support surgical-based treatment and offer nonsurgical therapy as an alternative for advanced-stage oral cavity squamous cell carcinoma (SCC). There are limited data evaluating current utilization of these therapies and their survival outcomes. METHODS: A total of 5856 patients were found in the Surveillance, Epidemiology, and End Results (SEER) database from 1988 to 2008 with resectable advanced-stage oral cavity SCC tumors. Outcomes were disease-specific survival (DSS) and overall survival (OS). RESULTS: Surgical therapy had significantly improved mean DSS and OS (115 and 71 months, respectively) compared to nonsurgical therapy (63 and 35 months, respectively; p < .001). The use of nonsurgical therapy was significantly associated with the hard palate, and patients who were single, divorced, and black, with T3, T4, and N3 tumors, and the percent utilization has significantly increased from 12% to 20% (p < .05). CONCLUSION: Utilization of nonsurgical therapy for advanced-stage oral cavity SCC is increasing and is independently associated with a reduction in survival, as well as patient factors traditionally associated with reduced access to medical care and advanced T and N classifications. © 2016 Wiley Periodicals, Inc. Head Neck 39: 82-91, 2017.