Review of Safety Data for Adenovirus 5 as a Delivery Vector for Intratumoral Cancer Gene Therapy.

With efficient transduction across most cell types and larger packaging capacity, Adenovirus 5 (Ad5) makes an attractive choice as a viral vector. However, a reported past mortality and known immunogenicity cast doubt on the safety of its use. An online database search was performed for all clinical trials administering intratumoral injection of gene therapy packaged in Ad5, being conducted in the United States, and using the Common Terminology Criteria for Adverse Events (CTCAE). Studies with unclear adverse events (AE) were excluded. The primary outcome collected was grade ≥3 (AE). Analyses were performed using Fisher's exact test. Thirty-nine prospective clinical trials across a variety of cancers were identified: 14 studies of therapeutic Ad5 alone, 12 with chemotherapy, 16 with radiation, and 11 with surgery. There were 3 mortalities out of 756 patients (0.4%), which were most likely unrelated to Ad5: 1 due to hypoxic encephalopathy, 1 due to splenic vein thrombus, and 1 due to disease progression. In trials that reported total AE (grades 1-5), there were 284 (10.3%) grade ≥3 AE out of 2,745 total AE in 477 patients. The overall life-threatening (grade 4) AE rate was 1.4% (34/2,425 AE in 428 patients). Overall, the most frequent grade ≥3 AE were lymphopenia (20.6% in 14 trials, 209 patients), dyspnea (8.7% in 11 trials, 208 patients), and neutropenia (8.6% in 12 trials, 174 patients). The most frequent grade 4 AE were neutropenia (4.6%), lymphopenia (3.3%), and leukopenia (3.1% in 13 trials, 192 patients). Our analyses demonstrated relative overall safety of Ad5 and warrant re-evaluation for the use of Ad5 as a delivery vector for gene therapy products.

A cost analysis of sorafenib for desmoid tumors.

INTRODUCTION: A recent randomized trial demonstrated that sorafenib improved progression free survival (PFS) in patients with desmoid tumors despite many patients experiencing stable disease or spontaneous regression without treatment. Utilizing these trial data, we performed a cost analysis of sorafenib efficacy through two years of treatment. METHODS: Current Medicare Part D rates for sorafenib were utilized (dose 400 mg/day, cost $309/day). Annual costs per progression and objective response were calculated. Radiologic progression and response were defined using RECIST criteria. Patients with disease progression were separately analyzed in two groups: both clinical and radiologic (CAR), and radiologic alone. RESULTS: 84 previously randomized patients were analyzed (placebo: 35, sorafenib: 49). At one year, sorafenib was associated with a 43% absolute risk reduction (ARR) of CAR progression and number-needed-to-treat (NNT) of 2.3 patients/year, costing $259,406. At two years, ARR was 48% and NNT of 2.1 patients/year, costing $473,697. When evaluating only patients with RECIST defined radiologic progression, sorafenib patients experienced ARR of 13.9% with NNT 7.2 and estimated costs of $812,052 at one year. Two-year ARR was 17.5% with NNT 5.7 and estimated costs $1,285,052. Sorafenib patients experienced improved RECIST partial response rates at 1 and 2 years of 14.7% and 14.3%, with NNT 6.8 and 6.9, and costs of $766,938 and $1,556,433; respectively. CONCLUSION: For the treatment of desmoid tumors, Sorafenib led to improved PFS, but at a significant cost per patient. Favorable RECIST outcomes were less likely and costlier. Patients should be informed of possible benefits of treatment versus potential financial burden.