, with no cardiac event reported [70]. Different schedules and doses have been investigated in an effort to improve tolerability while maintaining antitumor efficacy [28, 35, 36, 71]. Several studies have shown that a more acceptable toxicity profile, in terms of decreased rates of hand-foot syndrome and stomatitis/mucositis, can be obtained with a PLD dose of 40mg/m2 every 28 days compared to the traditional dose of 50mg/m2, with comparable response rates and outcomes [26, 32, 33]. According to the studies published, the optimal dose intensity appears to range from 10mg/m2 to 12.5mg/m2 per week (given at doses of 40–50mg/m2 every 4 weeks) when used as a single-agent
selleck compound therapy. The results obtained with a single-agent PLD Inhibitors,research,lifescience,medical in the subgroup Inhibitors,research,lifescience,medical of platinum-resistant patients were the basis for the development of PLD/platinum (cis-, carbo-, oxaliplatin)
combinations. The trials that evaluated the combination regimen of cisplatin or carboplatin with PLD showed an overall response rate ranging from 46 to 68% according to the platinum-free interval. In the Rapoport trial, the overall response rates were about 65% in a population Inhibitors,research,lifescience,medical including platinum-sensitive (81%) and partially sensitive patients (52.6%) [38]. Cisplatin combination regimen (PLD at 50mg/mq dosage, plus cisplatin at 60mg/mq d.1 q 28 days) was also developed showing a moderate tolerability profile (10% grade 2 neurotoxicity, 18% grade 3/4 anemia, 41% neutropenia, and 9% hand-foot syndrome) [34]. Due to these results, the PLD/carboplatin combination was considered more manageable due to the lower neurotoxicity [37–39, 72–74]. In two phase I-II trials PLD has been associated with carboplatin AUC 5-6 in sensitive or partially sensitive (>50%) ovarian or other gynecological cancer patients.In both studies, data of ORR Inhibitors,research,lifescience,medical (62 and 68%, resp.), PFS
(9.2 and 11.6 months), and median overall survival (OS 23.4 and 32 months) substantially overlap [37, 39]. Based on toxicity results, the authors recommended a PLD dose of 40mg/m2 when given in combination with carboplatin AUC 5, both drugs Inhibitors,research,lifescience,medical administered on a 4-week schedule in epithelial ovarian or endometrial carcinoma. Gemcitabine is another drug studied in combination with PLD. In several trials (PLD 30mg/m2-gemcitabine 1000mg/m2 days 1–8 every 21 days) this combination has been associated with overall response rates of about 30–35% in the overall population (21–25% in platinum-resistant and 50–53% in platinum-sensitive diseases), with an acceptable toxicity profile. Myelosuppression Anacetrapib was the most common toxicity and was found in 35% of patients [41, 42]. Combinations of PLD with oxaliplatin (OXA) have been also reported, with response rates that appear in the range of those reported with PLD/carboplatin. In these trials a very acceptable rate of stomatitis/mucositis and hand-foot syndrome has been shown, likely due to the use of the PLD at the dosage of 30mg/m2, every 21 or 28 days. Nicoletto et al.