Prospective randomized trial of high-dose cisplatin and fluorouracil infusion with or without sodium diethyldithiocarbamate in recurrent and/or metastatic squamous cell carcinoma of the head and neck.

Abstract

Previous studies have indicated that sodium diethyldithiocarbamate (DDTC) can reduce cisplatin's (CP) toxic effects without altering the antitumor activity. DDTC has also been shown to have immunostimulative properties. Sixty patients with objectively measurable recurrent and/or metastatic squamous cell carcinoma (SCC) of the head and neck were randomized to receive either (A) CP at 120 mg/m2 over one hour on day 1, plus fluorouracil (5-FU) at 1,000 mg/m2 over 24 hours as a continuous infusion on days 1 through 5, or (B) CP/5-FU as in A, plus DDTC at 600 mg/m2 over 30 minutes administered intravenously (IV) exactly 30 minutes after CP infusion. Group B also received DDTC at 200 mg/m2 administered IV over 30 minutes on days 8 and 15. Each cycle was repeated at 3-week intervals. Objective responses were achieved in 41% of the CP/5-FU group and in 29% of the CP/5-FU with DDTC group (P = .26). Median survival was 9 months in group A and 10 months in group B. CP-related toxicity between the groups was equivalent with respect to nausea and vomiting, renal impairment, neurotoxicity, ototoxicity, and hematologic toxicity. The pharmacokinetics of reactive platinum species in plasma ultrafiltrate and urine samples obtained from both groups were comparable. The immune status of 48 patients was evaluated before and after completion of therapy. There were no significant differences in mean pretreatment and posttreatment values within or between groups A or B, except for absolute pretreatment OKT4 values (P = .02). We conclude that (1) the present dose and infusion schedule of DDTC did not significantly reduce CP-mediated toxic effects, (2) DDTC did not alter the disposition of ultrafilterable platinum species, (3) DDTC did not affect immune responses, and (4) the addition of DDTC improved neither the clinical response nor the survival of patients with recurrent SCC of the head and neck.

Cytoprotection in the treatment of pediatric cancer: Review of current strategies in adults and their application to children

“…Although results of an early historically controlled study appeared promising [82], those findings were not corroborated in patients receiving cisplatin and 5-FU simultaneously [83] or in a follow-up, placebo-controlled study of patients treated with cisplatin and cyclophosphamide or cisplatin and etoposide [57]. At this stage, DDTC does not appear to be a viable option for the prevention of nephrotoxicity or neurotoxicity in either adults or children.…”

Cytotoxicity of diethyldithiocarbamate in human versus rodent cell lines

“…Interestingly, DDTC and disulfiram cause substantial cell killing at concentrations which are extremely low from a clinical perspective. For example, DDTC has been investigated in man as an adjunctive therapy to modulate the toxicity of cisplatin chemotherapy [5]. Relatively low DDTC doses up to 600 mg/m 2 have been used in this setting [5].…”

“…Cd, Ni [1]), in the vulcanization of rubber, in aversion therapy for alcohol addiction as well as in other applications [1][2][3]. In the oncology setting there has been clinical interest in the complex and possibly useful "immune restorative" effects of diethyldithiocarbamate ("DDTC") and its oxidized form, disulfiram [4,5]. Because of its high affinity chelation of certain metallic ions (e.g.…”

“…Because of its high affinity chelation of certain metallic ions (e.g. Zn, Cu, Ni) and inactivation of certain metalloenzymes [3], DDTC is also being actively investigated as an adjunctive oncologic therapy to reduce the normal tissue toxicities of cisplatin chemotherapy [5,6] or to enhance the efficacy of cyclophosphamide [7,8], bleomycin [9], and ionizing irradiation [10].…”

Phase I and pharmacokinetic study of the novel chemoprotector BNP7787 in combination with cisplatin and attempt to eliminate the hydration schedule

“…The mechanism of action of sulphur-containing nucleophiles that have been tested to prevent cisplatin-induced nephrotoxicity is based on inactivation of highly reactive monohydrated platinum species at the site of organ damage, that is, the kidney. Several modulating agents to prevent nephrotoxicity, such as thiosulphate (Leeuwenkamp et al, 1991), diethyldithiocarbamate (Gandara et al, 1995;Paredes et al, 1988), glutathione (Smyth et al, 1997), amifostine (Kemp et al, 1996;Hartmann et al, 2000) and mesna (Leeuwenkamp et al, 1991;Hausheer et al, 1998;Boven et al, 2002), have been investigated. Strong chemical reactivity of thiosulphate, diethyldithiocarbamate and mesna with cisplatin preclude their clinical usefulness (Verschraagen et al, 2003b).…”