Non-allergic nature of docetaxel-induced acute hypersensitivity reactions.

Based on observations of a discrepancy between 'hypersensitivity' reactions to docetaxel (DT) and the clinical features of allergic reactions, we explored the hypothesis that DT-induced acute hypersensitivity reactions (AHRs) have a non-allergic origin. Forty cancer patients receiving DT and 16 patients receiving other potentially allergenic chemotherapeutic agents were included in the study. All DT patients received standard pre- and post-medication. Before, during and after administration of the drugs, clinical symptoms and signs were recorded, and serial blood sampling was performed for the first 2 cycles for all patients or in all subsequent cycles in case of AHRs. Plasma histamine and serum tryptase, two established drug allergy markers, were measured. Seventy-five chemotherapy sessions were evaluable. Nine patients on DT, two on paclitaxel (PT) and one on pegylated doxorubicin experienced an AHR during the first course of chemotherapy. In all cases, heart rate remained stable or increased, while arterial pressure was unchanged or raised; no hypotension or bradycardia was noted. All episodes resolved with discontinuation of drug and did not reappear during a re-challenge with the same agent 30 min later. Tryptase levels were normal in all pre- and post-exposure samples (post-exposure: 11.32+/-35.63 microg/l, normal values <13.5 microg/l). In all but one AHR-free PT, pre- and post-exposure histamine concentrations remained normal (post-exposure: 2.86+/-11.88 nM, normal values <10 nM). No eosinophilia or basophilia was observed. We conclude that 'hypersensitivity' reactions to DT seem not to be histamine or tryptase mediated; thus, their allergenic nature should be questioned. The underlying mechanism may be related to other biological processes such as the release of vasoactive molecules or non-histamine/tryptase-mediated allergy. If the former is demonstrated by further study, the safety of DT administration will be confirmed, and the pre- and post-medication practice might be revisited.

Evidence for in vivo synergism between docetaxel and gemcitabine in patients with metastatic breast cancer.

BACKGROUND: The docetaxel and gemcitabine combination is active as salvage therapy in taxane-resistant/refractory patients with metastatic breast cancer (MBC). We conducted a phase II study to determine if this activity is due to an in vivo synergistic effect. PATIENTS AND METHODS: Women with measurable MBC, who were refractory or resistant to docetaxel monotherapy as first- or second-line treatment, were enrolled. Patients with progressive disease (PD) or stable disease (SD) after receiving at least four cycles of docetaxel received gemcitabine 900 mg/m(2) on days 1 and 8 plus docetaxel 100 mg/m(2 )on day 8, every 3 weeks. Granulocyte colony-stimulating factor could be used prophylactically in patients who experienced grade 3/4 neutropenia after the first cycle. RESULTS: Between January 1999 and March 2002, 173 courses of docetaxel and gemcitabine were administered to 50 patients. The median number of metastatic sites was two (range one to three). Forty-six percent of patients responded (three complete responses, 20 partial responses), whereas 28% had SD and 26% had PD. The median duration of response was 6.1 +/- 2.4 months. The median time to disease progression was 7.5 months (range 1-25) and the overall median survival was 15 months (range 3-57). Neutropenia was the only National Cancer Institute Common Toxicity Criteria grade 4 toxicity (in seven patients). Hematological grade 3 toxicities included neutropenia in 12 patients, thrombocytopenia in seven and anemia in one, while non-hematological toxicities were mild and manageable. CONCLUSIONS: The high overall response rate of the docetaxel plus gemcitabine combination after docetaxel failure in patients with MBC can be attributed to an in vivo synergism between the two drugs. These data warrant confirmation in a randomized study.