Effect of Disulfiram and Copper Plus Chemotherapy vs Chemotherapy Alone on Survival in Patients With Recurrent Glioblastoma A Randomized Clinical Trial

KatjaWerlenius,MD;SaraKinhult,MD,PhD;ToraSkeidsvollSolheim,MD,PhD;HenrietteMagelssen,MD,PhD;DavidLöfgren,MD;MunilaMudaisi,MD;SofiaHylin,MD; Jiri Bartek Jr, MD, PhD; Michael Strandéus, MD; Magnus Lindskog, MD, PhD; Havyan Bahroz Rashid; Louise Carstam, MD; Sasha Gulati, MD, PhD; Ole Solheim, MD, PhD; JiriBartek,MD,PhD;ØyvindSalvesen,MSc,PhD;AsgeirStoreJakola,MD,PhD

JAMA Netw Open. 2023;6(3):e234149. doi:10.1001/jamanetworkopen.2023.4149

Key Points

Question  Does the addition of disulfiram and copper to chemotherapy improve survival for patients with recurrent glioblastoma?

Findings  In this randomized clinical trial of 88 patients with recurrent glioblastoma, the addition of disulfiram and copper to alkylating chemotherapy did not significantly improve survival at 6 months, as compared with alkylating chemotherapy only. Significantly more patients receiving disulfiram had adverse events of grade 3 or higher (34% vs 11%) and serious adverse events (41% vs 16%).

Meaning  These findings suggest that the addition of disulfiram and copper to alkylating chemotherapy should not be recommended for patients with recurrent glioblastoma.

Abstract

Importance  Disulfiram has demonstrated broad antitumoral effect in several preclinical studies. One of the proposed indications is for the treatment of glioblastoma.

Objective  To evaluate the efficacy and safety of disulfiram and copper as add-on to alkylating chemotherapy in patients with recurrent glioblastoma.

Design, Setting, and Participants  This was a multicenter, open-label, randomized phase II/III clinical trial with parallel group design. Patients were recruited at 7 study sites in Sweden and 2 sites in Norway between January 2017 and November 2020. Eligible patients were 18 years or older, had a first recurrence of glioblastoma, and indication for treatment with alkylating chemotherapy. Patients were followed up until death or a maximum of 24 months. The date of final follow-up was January 15, 2021. Data analysis was performed from February to September 2022.

Interventions  Patients were randomized 1:1 to receive either standard-of-care (SOC) alkylating chemotherapy alone, or SOC with the addition of disulfiram (400 mg daily) and copper (2.5 mg daily).

Main Outcomes and Measures  The primary end point was survival at 6 months. Secondary end points included overall survival, progression-free survival, adverse events, and patient-reported quality of life.

Results  Among the 88 patients randomized to either SOC (n = 45) or SOC plus disulfiram and copper (n = 43), 63 (72%) were male; the mean (SD) age was 55.4 (11.5) years. There was no significant difference between the study groups (SOC vs SOC plus disulfiram and copper) in 6 months survival (62% [26 of 42] vs 44% [19 of 43]; P = .10). Median overall survival was 8.2 months (95% CI, 5.4-10.2 months) with SOC and 5.5 months (95% CI, 3.9-9.3 months) with SOC plus disulfiram and copper, and median progression-free survival was 2.6 months (95% CI, 2.4-4.6 months) vs 2.3 months (95% CI, 1.7-2.6 months), respectively. More patients in the SOC plus disulfiram and copper group had adverse events grade 3 or higher (34% [14 of 41] vs 11% [5 of 44]; P = .02) and serious adverse events (41% [17 of 41] vs 16% [7 of 44]; P = .02), and 10 patients (24%) discontinued disulfiram treatment because of adverse effects.

Conclusions and Relevance  This randomized clinical trial found that among patients with recurrent glioblastoma, the addition of disulfiram and copper to chemotherapy, compared with chemotherapy alone, resulted in significantly increased toxic effects, but no significant difference in survival. These findings suggest that disulfiram and copper is without benefit in patients with recurrent glioblastoma.

Trial Registration  ClinicalTrials.gov Identifier: NCT02678975; EUDRACT Identifier: 2016-000167-16

요 약

중요성

Disulfiram은 여러 전임상 연구에서 광범위한 항종양 효과를 보였기에 그 중 하나로 교모세포종 치료가 제안됨.

목적

재발성 교모세포종 환자에서 알킬화 화학요법에 대한 보조제로서 disulfiram과 구리의 효능과 안전성을 평가

연구 설계, 환경 및 참가자

• 스웨덴의 7개 연구소와 노르웨이의 2개 연구소에서 2017년 1월부터 2020년 11월까지 진행된 다기관, 공개, 무작위 위약 대조 2/3상 임상 시험

• 대상자 : 18세 이상의 첫 번째 재발 교모세포종 환자로, 알킬화 화학요법 치료가 적합한 환자

중재

• 표준 치료(standard-of-care, SOC)군 : 알킬화 화학요법 단독

• 디설피람 및 구리군 : 표준 치료(SOC) + disulfiram(400mg daily)과 구리(2.5mg daily) 추가 투여 (경구 투여)

• 1:1로 무작위 배정

주요 결과 및 측정 지표

• 주요 결과 : 6개월 생존율

• 부차적 결과 : 전체 생존율(OS), 무진행 생존율(PFS), 환자 보고(patient-reporterd) 삶의 질 등

결과

• 총 88명의 환자 무작위 배정 :  표준 치료군 (n=45), 디설피람 및 구리군 (n=43)

• 평균 연령 55.4세, 남성 환자 72%(63명)

• 6개월 생존율 :  표준 치료 그룹 62%(26명 중 42명), 디설피람 및 구리군 : 44%(19명 중 43명)로 유의한 차이가 없음(P=0.10).

• 전체 생존기간(OS) : 표준 치료 그룹 8.2개월(95% CI, 5.4-10.2개월), 디설피람 및 구리군 5.5개월(95% CI, 3.9-9.3개월)으로 더 짧음

• 중앙 무진행 생존 기간(PFS) : 표준 치료 그룹 2.6개월(95% CI, 2.4-4.6개월)과 디설피람 및 구리군 2.3개월(95% CI, 1.7-2.6개월)

• 디설피람 및 구리군 에서 3등급 이상의 부작용이 더 많이 발생 (34% vs 11%; P=0.02), 심각한 부작용도 더 높게 나타남(41% vs 16%; P=0.02).

결론 및 의미

• 재발성 교모세포종 환자에서 화학요법에 disulfiram과 구리를 추가하는 것이 생존율에 유의한 향상을 가져오지 않았으며, 오히려 부작용을 증가시켰음.

• 재발성 교모세포종 환자에서 disulfiram과 구리의 추가가 이점을 제공하지 않음을 시사함.