Health-economic analysis: cost-effectiveness of scheduled maintenance treatment with infliximab for Crohn's disease--modelling outcomes in active luminal and fistulizing disease in adults.

BACKGROUND: Infliximab has been shown to be efficacious in moderate-to-severe Crohn's disease (CD). AIM: To evaluate the cost-effectiveness of scheduled maintenance treatment with infliximab in luminal and fistulizing CD patients. METHODS: Markov models were constructed to simulate the progression of adult CD patients with and without fistulae during treatment with infliximab (5 mg/kg). Transitions were estimated from published clinical trials of infliximab. Standard care, comprising immunomodulators and/or corticosteroids was used as a comparator. An average weight of 60 kg was used to estimate the dose of infliximab. The costs and outcomes were discounted at 3.5% over 5 years. The primary effectiveness measurement was quality-adjusted life years (QALYs) estimated using EQ-5D. One-way and probabilistic sensitivity analyses were performed by varying the infliximab efficacy estimates, costs and utilities. RESULTS: The incremental cost per QALY gained was pound 26,128 in luminal CD and pound 29,752 in fistulizing CD at 5 years. Results were robust and remained in the range of pound 23,752- pound 38,848 for luminal CD and pound 27,047- pound 44,206 for fistulizing CD. Patient body weight was the most important factor affecting cost-effectiveness. CONCLUSION: Eight-week scheduled maintenance treatment with infliximab is a cost-effective treatment for adult patients suffering from active luminal or fistulizing CD.

In vivo gene therapy for colon cancer using adenovirus-mediated, transfer of the fusion gene cytosine deaminase and uracil phosphoribosyltransferase.

Virus-directed enzyme prodrug therapy (VDEPT) utilising cytosine deaminase (CD) converts 5-fluorocytosine (5-FC) into the chemotherapy agent, 5-fluorouracil (5-FU), and has entered into a clinical trial for metastatic colon cancer. To improve this system, a replication-deficient adenovirus, containing a bifunctional fusion gene, CD:uracil phosphoribosyltransferase (UPRT), was constructed (AdCDUPRT). UPRT enhances the conversion of 5-FU into its active metabolites, which inhibit DNA and RNA synthesis. In vitro, AdCDUPRT infection of colon cancer cells resulted in a marked increase in sensitisation to 5-FU, compared with AdCD-infected or uninfected cells. The corollary is a approximately 100-fold and approximately 10 000-fold increase in sensitisation to 5-FC in AdCDUPRT-infected cells, compared to AdCD-infected and uninfected cells, respectively. There was a strong bystander effect in vitro, 70% of tumour cells were killed by 5-FC when only 10% of cells expressed CDUPRT. In vivo, athymic mice with colon cancer xenografts treated with intratumoral AdCDUPRT and intraperitoneal 5-FC, significantly reduced tumour growth rates compared with untreated controls (P = 0.02), whereas AdCD/5-FC treated mice did not. At higher AdCDUPRT virus doses, 5-FC and 5-FU were equally effective at delaying tumour growth compared with controls. In summary, VDEPT for colon cancer utilising AdCDUPRT is more effective than AdCD and the bifunctional CDUPRT gene enables the use of either 5-FC or 5-FU as prodrugs.

Virus-directed, enzyme prodrug therapy with nitroimidazole reductase: a phase I and pharmacokinetic study of its prodrug, CB1954.

CB1954 [5-(aziridin-1-yl)-2,4-dinitrobenzamide] is converted by the bacterial enzyme nitroimidazole reductase (NTR) into a potent cytotoxic bifunctional alkylating agent, which can be delivered to tumors in adenoviral vectors as virus-directed, enzyme prodrug therapy. This report summarizes a Phase I and pharmacokinetic study of the prodrug, CB1954. Thirty patients, ages 23-78 years (median 62 years), with predominantly gastrointestinal malignancies were treated. CB1954 was administered by i.v. injection every 3 weeks or i.p. followed by 3-weekly i.v. injections, toward a maximum of six cycles. The dose was escalated from 3 to 37.5 mg/m2. No significant toxicity was seen until 24 mg/m2 (recommended i.v. dose). Dose-limiting toxicities (DLT) were diarrhea and hepatic toxicity, seen at 37.5 mg/m2. DLT has not been observed at the current i.p. dose of 24 mg/m2. There was no alopecia, marrow suppression, or nephrotoxicity. Clearance data suggest hepatic metabolism, and <5% of CB1954 was renally excreted. There was a nonlinear relationship between i.v. dose and area under the curve (AUC). At the recommended i.v. dose of 24 mg/m2, the AUC was 5.8 microM/h. Intraperitoneal administration (24 mg/m2) achieved an AUC of 387 microM/h, giving a considerable regional advantage. In vitro, the AUC required to achieve the IC50 for CB1954, in NTR-expressing cancer cells, ranges from 10-50 microM/h. Thus, CB1954 is well tolerated at a dose of 24 mg/m2, and sufficient serum/peritoneal levels are achieved for an enzyme-prodrug approach to be feasible. We are now conducting a Phase I trial combining adenovirus-mediated NTR and i.v. CB1954 (24 mg/m2) in patients with primary and secondary liver tumors.

Gene therapy for colorectal cancer: therapeutic potential.

Colorectal cancer is a leading cause of cancer mortality in Western countries. Gene therapy has been proposed as a potential novel treatment modality for colorectal cancer, but it is still in an early stage of development. The preclinical data have been promising and numerous clinical trials are underway. This brief review aims to summarise the current status of clinical trials of different gene therapy strategies, including immune stimulation, mutant gene correction, prodrug activation and oncolytic virus therapy, for patients with colorectal cancer. Data from phase I trials have proven the safety of the reagents but have not yet demonstrated significant therapeutic benefit. In order to achieve this and extend the scope of the treatment, continuing efforts should be made to improve the antitumour potency, efficiency of gene delivery and accuracy of gene targeting.

Gene therapy strategies for colon cancer.

Colorectal cancer is the second most common cause of cancer mortality in Western countries. Gene therapy represents a novel approach to the treatment of colorectal cancer, and this review addresses the current strategies and ongoing clinical trials, including gene correction, immunomodulatory approaches and virus-directed enzyme-prodrug systems. Although the pre-clinical results for these strategies have been encouraging, clinical trials have not yet reflected these data. However, gene therapy for colorectal cancer is still in the early stages of development, and its potential, particularly in combination with conventional cancer therapies, warrants further investigation.