GSTM1, GSTT1 and GSTP1 Ile105Val polymorphisms in outcomes of head and neck squamous cell carcinoma patients treated with cisplatin chemoradiation.

Cisplatin (CDDP) combined with radiotherapy (RT) is employed in head and neck squamous cell carcinoma (HNSCC) with variable toxicities and clinical response. Glutathione S-transferases (GSTs) participate in CDDP excretion from cells, and genes encoding GSTs, GSTM1, GSTT1and GSTP1, are polymorphic in humans. This prospective study aimed to evaluate the roles of GSTM1, GSTT1, and GSTP1 Ile105Val polymorphisms in outcomes of HNSCC patients treated with CDDP chemoradiation. Ninety patients were genotyped by multiplex PCR. Urinary CDDP measurements were performed by HPLC. Treatment side effects and response were analysed by conventional criteria. Patients with GSTT1 genes showed 7.23- and 5.37-fold higher likelihood of presenting vomiting and ototoxicity, lower glomerular filtration rate (GFR), and lower elimination of CDDP in urine relative to patients with deleted genes. Patients harbouring the GSTP1 IleVal or ValVal genotypes showed 4.28-fold higher likelihood of presenting grade 2 or 3 vomiting and lower GFR with treatment than those harbouring the IleIle genotype. In multivariate Cox analysis, patients with the GSTP1 105ValVal genotype had 3.87 more chance of presenting disease progression than those with the IleIle or IleVal genotype (p < 0.01). Our findings provide preliminary evidence that inherited abnormalities in CDDP metabolism, related to GSTT1 and GSTP1 Ile105Val polymorphisms, alter outcomes of HNSCC patients treated with CDDP and RT.

Can acetylcysteine ameliorate cisplatin-induced toxicities and oxidative stress without decreasing antitumor efficacy? A randomized, double-blind, placebo-controlled trial involving patients with head and neck cancer.

The protective antioxidant activity of acetylcysteine (NAC) against toxicity due to cisplatin has been reported in experimental models; however, its efficacy in patients has not been elucidated. The aim of this study was to investigate the possible protective effect of NAC on cisplatin-induced toxicity and the effect of NAC on clinical response and oxidative stress in patients treated for head and neck cancer. This was a randomized, double-blind, placebo-controlled trial conducted in patients receiving high-dose cisplatin chemotherapy concomitant to radiotherapy. Patients were randomly assigned to groups and received: (a) 600 mg NAC syrup, orally once daily at night for 7 consecutive days or (b) placebo, administered similarly to NAC. Nephro-, oto-, hepato-, myelo-, and gastrointestinal toxicities, clinical responses, and plasma and cellular markers of oxidative stress were evaluated. Fifty-seven patients were included (n = 28, NAC arm; and n = 29, placebo arm). A high prevalence of most types of toxicities was observed after cisplatin chemotherapy; however, the parameters were similar between the two groups. There was a predominance of partial response to treatment. In the cellular and plasmatic oxidative stress analyses, minor differences were observed. Overall, there was no statistically significant difference between the groups for all outcomes. These findings show that low-dose oral NAC does not protect patients with head and neck cancer from cisplatin-induced toxicities and oxidative stress. The antitumor efficacy of cisplatin was apparently not impaired by NAC.