A phase I trial and viral clearance study of reovirus (Reolysin) in children with relapsed or refractory extra-cranial solid tumors: a Children's Oncology Group Phase I Consortium report.

BACKGROUND: Reovirus is a naturally occurring human virus that is cytopathic to malignant cells possessing an activated Ras signaling pathway. We conducted a phase I trial of Reolysin, a manufactured, proprietary isolate of purified reovirus, in children with relapsed/refractory extracranial solid tumors to define the recommended phase 2 dose (RP2D), toxicities, and pharmacokinetic properties when administered as a single agent or in combination with cyclophosphamide. PROCEDURES: Reolysin was administered intravenously for 5 consecutive days, every 28 days. Using a 3 + 3 design, the following dose levels were evaluated: 3 × 10(8) Tissue Culture Inhibitory Dose 50% (TCID50 )/kg; 5 × 10(8) TCID50 /kg (maximum dose was 3 × 10(10) TCID50 ); and 5 × 10(8) TCID50 /kg plus oral cyclophosphamide (50 mg/m(2) /day × 21 days). RESULTS: Twenty-nine patients were enrolled; 28 were eligible and 24 were evaluable for toxicity and response. There were no hematologic dose-limiting toxicities. Grade 5 respiratory failure and a Grade 5 thromboembolic event were reported, both in the setting of progressive disease. The median time to clear the reovirus viremia was 6.5 days. Eight of 24 patients were viremic beyond the 5 days of therapy, all were negative by day 17. No patient had detectable viral RNA in saliva or stool. There were no objective responses. CONCLUSIONS: Reolysin at a dose of 5 × 10(8) TCID50 /kg daily for 5 days was well tolerated in children alone and in combination with oral cyclophosphamide. Virus was cleared rapidly from the serum and shedding in stool and saliva was not detectable.

Cost-effectiveness analysis of mammography and clinical breast examination strategies: a comparison with current guidelines.

PURPOSE: Breast cancer screening by mammography and clinical breast exam are commonly used for early tumor detection. Previous cost-effectiveness studies considered mammography alone or did not account for all relevant costs. In this study, we assessed the cost-effectiveness of screening schedules recommended by three major cancer organizations and compared them with alternative strategies. We considered costs of screening examinations, subsequent work-up, biopsy, and treatment interventions after diagnosis. METHODS: We used a microsimulation model to generate women's life histories, and assessed screening and treatment effects on survival. Using statistical models, we accounted for age-specific incidence, preclinical disease duration, and age-specific sensitivity and specificity for each screening modality. The outcomes of interest were quality-adjusted life years (QALY) saved and total costs with a 3% annual discount rate. Incremental cost-effectiveness ratios were used to compare strategies. Sensitivity analyses were done by varying some of the assumptions. RESULTS: Compared with guidelines from the National Cancer Institute and the U.S. Preventive Services Task Force, alternative strategies were more efficient. Mammography and clinical breast exam in alternating years from ages 40 to 79 years was a cost-effective alternative compared with the guidelines, costing $35,500 per QALY saved compared with no screening. The American Cancer Society guideline was the most effective and the most expensive, costing over $680,000 for an added QALY compared with the above alternative. CONCLUSION: Screening strategies with lower costs and benefits comparable with those currently recommended should be considered for implementation in practice and for future guidelines.

Risk-specific optimal cancer screening schedules: an application to breast cancer early detection.

The optimal schedules for breast cancer screening in terms of examination frequency and ages at examination are of practical interest. A decision-theoretic approach is explored to search for optimal cancer screening programs which should achieve maximum survival benefit while balancing the associated cost to the health care system. We propose a class of utility functions that account for costs associated with screening examinations and value of survival benefit under a non-stable disease model. We consider two different optimization criteria: optimize the number of screening examinations with equal screening intervals between exams but without a pre-fixed total cost; and optimize the ages at which screening should be given for a fixed total cost. We show that an optimal solution exists under each of the two frameworks. The proposed methods may consider women at different levels of risk for breast cancer so that the optimal screening strategies will be tailored according to a woman's risk of developing the disease. Results of a numerical study are presented and the proposed models are illustrated with various data inputs. We also use the data inputs from the Health Insurance Plan of New York (HIP) and Canadian National Breast Screening Study (CNBSS) to illustrate the proposed models and to compare the utility values between the optimal schedules and the actual schedules in the HIP and CNBSS trials. Here, the utility is defined as the difference in cure rates between cases found at screening examinations and cases found between screening examinations while accounting for the cost of examinations, under a given screening schedule.