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On the basis of the demonstrated single-agent activity of cisplatin in patients with advanced cervical cancer and the observation of in vitro synergism between this agent and decitabine, a new DNA hypomethylating agent, we designed a phase II trial in which the combined use of the two agents are used as first-line therapy in patients with recurrent and/or metastatic disease. Eligible patients were those with histopathologically proven diagnosis of squamous cell carcinoma of the cervix, which was not considered suitable for curative surgery and/or irradiation, having measurable disease, leukocyte counts more than or equal to 4,000/μl, thrombocyte counts more than or equal to 100,000/μl, serum creatinine more than or equal to 1.5 mg/dl, and normal liver function tests. Initial dose of cisplatin was 40 mg/m2, whereas decitabine was 50 mg/m2for 3 consecutive days every 21 days. Because of toxicity, the dose of cisplatin was reduced to 30 mg/m2. Twenty-five patients were included in the study; 24 of them were eligible for the evaluation of toxicity, whereas 21 of them were eligible for the evaluation of tumor responses. Nineteen (79.2%) patients had received prior radiotherapy. A total of 75 cycles of chemotherapy were administered to the patients, with a median of 3 cycles (range: 1–8) per patient. The most frequently observed side effect was neutropenia, which was National Cancer Institute- Common Toxicity Criteria grades III and IV in 68.0% of cases. One patient died of complications caused by drug-related neutropenic sepsis. The most common nonhematologic grades III and IV toxicities were nausea and vomiting, which occurred in 17.3% and 9.3% of the cycles, respectively. Of a total of 21 patients evaluable for tumor response, 8 (38.1%) achieved a partial response, whereas stable disease was documented in 5 cases (23.8%). Median progression-free interval (PFI) was 16 weeks, and median survival was 19 weeks (95% CI 7.9–31.2). Objective responses were more frequent in patients with metastatic lesions in nonirradiated sites. Cisplatin- decitabine combination was moderately active in patients with advanced squamous cell carcinoma of the cervix, mainly in patients presenting with metastatic disease at previously nonirradiated sites. However, this regimen produced significant hematologic toxicity. Further studies with this combination including a larger patient population, preferably with the concomitant administration of hematopoietic growth factors, are warranted.