Treatment rationale and study design for a phase III, double-blind, placebo-controlled study of maintenance pemetrexed plus best supportive care versus best supportive care immediately following induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer.

BACKGROUND: To improve the efficacy of first-line therapy for advanced non-small cell lung cancer (NSCLC), additional maintenance chemotherapy may be given after initial induction chemotherapy in patients who did not progress during the initial treatment, rather than waiting for disease progression to administer second-line treatment. Maintenance therapy may consist of an agent that either was or was not present in the induction regimen. The antifolate pemetrexed is efficacious in combination with cisplatin for first-line treatment of advanced NSCLC and has shown efficacy as a maintenance agent in studies in which it was not included in the induction regimen. We designed a phase III study to determine if pemetrexed maintenance therapy improves progression-free survival (PFS) and overall survival (OS) after cisplatin/pemetrexed induction therapy in patients with advanced nonsquamous NSCLC. Furthermore, since evidence suggests expression levels of thymidylate synthase, the primary target of pemetrexed, may be associated with responsiveness to pemetrexed, translational research will address whether thymidylate synthase expression correlates with efficacy outcomes of pemetrexed. METHODS/DESIGN: Approximately 900 patients will receive four cycles of induction chemotherapy consisting of pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) on day 1 of a 21-day cycle. Patients with an Eastern Cooperative Oncology Group performance status of 0 or 1 who have not progressed during induction therapy will randomly receive (in a 2:1 ratio) one of two double-blind maintenance regimens: pemetrexed (500 mg/m2 on day 1 of a 21-day cycle) plus best supportive care (BSC) or placebo plus BSC. The primary objective is to compare PFS between treatment arms. Secondary objectives include a fully powered analysis of OS, objective tumor response rate, patient-reported outcomes, resource utilization, and toxicity. Tumor specimens for translational research will be obtained from consenting patients before induction treatment, with a second biopsy performed in eligible patients following the induction phase. DISCUSSION: Although using a drug as maintenance therapy that was not used in the induction regimen exposes patients to an agent with a different mechanism of action, evidence suggests that continued use of an agent present in the induction regimen as maintenance therapy enables the identification of patients most likely to benefit from maintenance treatment.

5-Fluorouracil-loaded poly(ε-caprolactone) nanoparticles combined with phage E gene therapy as a new strategy against colon cancer

This work aimed to develop a new therapeutic approach to increase the efficacy of 5-fluorouracil (5-FU) in the treatment of advanced or recurrent colon cancer. 5-FU-loaded biodegradable poly(ε-caprolactone) nanoparticles (PCL NPs) were combined with the cytotoxic suicide gene E (combined therapy). The SW480 human cancer cell line was used to assay the combined therapeutic strategy. This cell line was established from a primary adenocarcinoma of the colon and is characterized by an intrinsically high resistance to apoptosis that correlates with its resistance to 5-FU. 5-FU was absorbed into the matrix of the PCL NPs during synthesis using the interfacial polymer disposition method. The antitumor activity of gene E from the phage ϕX174 was tested by generating a stable clone (SW480/12/E). In addition, the localization of E protein and its activity in mitochondria were analyzed. We found that the incorporation of 5-FU into PCL NPs (which show no cytotoxicity alone), significantly improved the drug's anticancer activity, reducing the proliferation rate of colon cancer cells by up to 40-fold when compared with the nonincorporated drug alone. Furthermore, E gene expression sensitized colon cancer cells to the cytotoxic action of the 5-FU-based nanomedicine. Our findings demonstrate that despite the inherent resistance of SW480 to apoptosis, E gene activity is mediated by an apoptotic phenomenon that includes modulation of caspase-9 and caspase-3 expression and intense mitochondrial damage. Finally, a strongly synergistic antiproliferative effect was observed in colon cancer cells when E gene expression was combined with the activity of the 5-FU-loaded PCL NPs, thereby indicating the potential therapeutic value of the combined therapy.