Discussion
SAEs, lung cancer, toxicity, pain
LUNG CANCER
In this open-labeled, multicenter, randomized clinical trial there was no significant survival benefit of SOC plus disulfiram and copper compared with SOC in patients with recurrent GB. No significant between-group difference was seen in HRQoL. There were significantly more AEs and SAEs in patients treated with SOC plus disulfiram and copper. Despite very promising preclinical reports, disulfiram and copper does not have a clinical benefit in patients with recurrent GB.Our results are in accordance with the previous clinical studies of disulfiram in patients with GB.We were not able to translate the numerous encouraging preclinical results to the clinical setting.Recent preclinical data suggest lack of therapeutic effect of disulfiram if there is interference by cannabidiol and related drugs, not infrequently used by patients to mitigate pain. Cannabidiol induces expression of metallothioneins that bind CuET, the active copper-containing anticancer metabolite of disulfiram, thereby undermining the antitumoral effect of disulfiram.Currently it is difficult to envision a future role of disulfiram and copper in treatment of GB, although new combinations and potential clinical useful synergies with other treatments cannot be ruled out. Concerning combined treatments, disulfiram is “the backbone” of the CUSP9 regimen which seems theoretically intriguing but to our knowledge this concept still lacks clinical evidence.We considered the reports of tolerability of disulfiram in range 250 to 500 mg daily.A possible reason why we failed in translating the laboratory results to the clinic may be inadequate bioavailability in the target tissue. We do not know the tissue concentrations reached in the present study, but 400 mg daily (allowing 200 mg in case of toxicity) could be considered sufficient given the signal in a study using 40 mg 3 times daily in patients with lung cancer.Considering the difficulties in translating the promising preclinical work to clinical benefit, future work needs to focus on novel application methods or treatment synergies, and some novel strategies have recently been published.