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PURPOSE: Cisplatin-induced hearing loss is a common side effect in patients treated with cisplatin-based chemoradiation (CRT) for head and neck squamous cell carcinoma. The extent of hearing loss after concurrent CRT was compared between triweekly (3 × 100 mg/m2) and weekly (7 × 40 mg/m2) cisplatin CRT. METHOD: This retrospective cohort study was conducted in the Antoni van Leeuwenhoek Hospital and included 129 patients with cisplatin-based CRT for head and neck cancer (72 treated in the triweekly and 57 in the weekly regimen). Baseline and follow-up pure tone audiometry was conducted to assess hearing loss. Clinically relevant hearing loss was defined as a decline upon treatment of ≥ 10 decibel at a pure tone average 1-2-4 kHz and/or 8-10-12.5 kHz. RESULTS: The incidence of clinically relevant cisplatin CRT induced hearing loss was 42% in the triweekly versus 19% in the weekly group (p < 0.01). The mean threshold shift at a pure tone average (PTA) 1-2-4 kHz was 9.0 decibel in the triweekly compared to 4.3 decibel in the weekly CRT group (p < 0.01). At PTA 8-10-12.5 kHz, the incidence of clinically relevant hearing loss was 75% in the triweekly compared to 74% in the weekly CRT group (p = 0.87). The mean threshold shift at PTA 8-10-12.5 kHz was 20.2 decibel versus 15.6 decibel, respectively (p = 0.07). CONCLUSION: Cisplatin-dose reduction to a weekly cisplatin CRT regimen for head and neck cancer may reduce the incidence of clinically relevant hearing loss at frequencies vital for speech perception.
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Background: Adoptive cell therapy with peripheral blood T cells expressing transgenic T-cell receptors (TCRs) is an innovative therapeutic approach for solid malignancies. We investigated the safety and feasibility of adoptive transfer of autologous T cells expressing melanoma antigen recognized by T cells 1 (MART-1)-specific TCR, cultured to have less differentiated phenotypes, in patients with metastatic melanoma. Materials and methods: In this phase I/IIa trial, peripheral blood T cells from HLA-A2∗02:01-positive patients with unresectable stage IIIC/IV melanoma expressing MART-1 were selected and stimulated with anti-CD3/CD28 beads, transduced with a modified MART-1(26-35)-specific 1D3 TCR (1D3HMCys) and expanded in interleukin (IL)-7 and IL-15. Patients received a single infusion of transgenic T cells in a dose-escalating manner. Feasibility, safety and objective response rate were assessed. Results: Twelve pretreated metastatic cutaneous (n = 7) and uveal (n = 5) melanoma patients were included. Patient 1 received 4.6 × 109 1D3HMCys T cells and experienced grade 5 toxicity after 9 days. Subsequent patients received 5.0 × 107 [n = 3; cohort (c) 2], 2.5 × 108 (n = 2; c3) and 1.0 × 108 (n = 6; c4) 1D3HMCys T cells. The study was prematurely terminated because of dose-dependent toxicity, concerning skin (10/12), eyes (3/12), ears (4/12) and cytokine release syndrome (5/12), with 7 patients experiencing grade 3-5 toxicity. Partial responses were seen in 2/11 (18%) assessable patients and persistence of 1D3HMCys T cells corresponded to infused cell dose. Conclusions: Production of TCR-modified cells as described leads to highly potent T cells. Partial responses were seen in 18% of patients with dose-dependent 'on-target, off-tumor' toxicity and a maximum tolerated dose of 1.0 × 108 cells.