Liposomal cisplatin combined with paclitaxel versus cisplatin and paclitaxel in non-small-cell lung cancer: a randomized phase III multicenter trial

Abstract

Background: Liposomal cisplatin is a new formulation developed to reduce the systemic toxicity of cisplatin while simultaneously improving the targeting of the drug to the primary tumor and to metastases by increasing circulation time in the body fluids and tissues. The primary objectives were to determine nephrotoxicity, gastrointestinal side-effects, peripheral neuropathy and hematological toxicity and secondary objectives were to determine the response rate, time to tumor progression (TTP) and survival.Patients and methods: Two hundred and thirty-six chemotherapy-naive patients with inoperable non-small-cell lung cancer were randomly allocated to receive either 200 mg/m2 of liposomal cisplatin and 135 mg/m2 paclitaxel (arm A) or 75 mg/m2 cisplatin and 135 mg/m2 paclitaxel (arm B), once every 2 weeks on an outpatient basis. Two hundred and twenty-nine patients were assessable for toxicity, response rate and survival. Nine treatment cycles were planned.Results: Arm A patients showed statistically significant lower nephrotoxicity, grade 3 and 4 leucopenia, grade 2 and 3 neuropathy, nausea, vomiting and fatigue. There was no significant difference in median and overall survival and TTP between the two arms; median survival was 9 and 10 months in arms A and B, respectively, and TTP was 6.5 and 6 months in arms A and B, respectively.Conclusions: Liposomal cisplatin in combination with paclitaxel has been shown to be much less toxic than the original cisplatin combined with paclitaxel. Nephrotoxicity in particular was negligible after liposomal cisplatin administration. TTP and survival were similar in both treatment arms.

Formulation and physiologic factors affecting the pharmacology of carrier-mediated anticancer agents

“…In a Phase II study of patients receiving lipoplatin every 21 days at doses of 120 mg/m 2 (n = 47) or cisplatin doses of 100 mg/m 2 (n = 41) combined with gemcitabine 1000 mg/m 2 , no patients showed signs of nephrotoxicity before and after treatment [94]. Additionally, a Phase III study of patients (n = 229) randomized to paclitaxel 135 mg/m 2 and lipoplatin 200 mg/m 2 or cisplatin 75 mg/ m 2 every 2 weeks demonstrated significantly lower toxicities, including nephrotoxicity, leukopenia, nausea/vomiting and asthenia in the lipoplatin treatment arm versus the cisplatin arm (p £ 0.001, 0.017, 0.042, 0.019, respectively), while demonstrating equivalent overall survival [95]. The lower toxicity associated with lipoplatin may be related to relatively low release of cisplatin from the lipoplatin formulation which would reduce toxicity but also hinder antitumor response that has been problematic with other liposomal and CMA formulations of Pt analogues [5].…”

Preclinical Activity of the Liposomal Cisplatin Lipoplatin in Ovarian Cancer

“…1A, bottom). A2780 cells were more sensitive to carboplatin than A2780cis that showed the highest IC 50 together with OVCAR5 and TOV21G cells.…”

“…In conclusion, replacing cisplatin with lipoplatin in aggressive cisplatin-resistant patients with ovarian cancer would add the advantage of lower toxicities as already shown in randomized phase II and III studies in NSCLC (48)(49)(50). Adding the advantage of reducing the metastatic potential and the putative ovarian CSCs, and its synergistic activity with Abraxane and doxorubicin, lipoplatin in combination with Abraxane or doxorubicin should be compared with cisplatin þ Abraxane/doxorubicin in a randomized clinical study against ovarian cancer.…”

Lipoplatin Treatment in Lung and Breast Cancer

“…Also in this experience, Lipoplatin arm showed a lower nephrotoxicity, myelotoxicity, and neurophaty [12, 14]. No difference was observed in median overall survival or TTP but patients with adenocarcinoma or undifferentiated NSCLC treated with lipoplatin had a better response rate (49.5% versus 42.5%) and median survival (10 against 8 months).…”