Statistical controversies in clinical research: building the bridge to phase II-efficacy estimation in dose-expansion cohorts.

BACKGROUND: Regulatory agencies and others have expressed concern about the uncritical use of dose expansion cohorts (DECs) in phase I oncology trials. Nonetheless, by several metrics-prevalence, size, and number-their popularity is increasing. Although early efficacy estimation in defined populations is a common primary endpoint of DECs, the types of designs best equipped to identify efficacy signals have not been established. METHODS: We conducted a simulation study of six phase I design templates with multiple DECs: three dose-assignment/adjustment mechanisms multiplied by two analytic approaches for estimating efficacy after the trial is complete. We also investigated the effect of sample size and interim futility analysis on trial performance. Identifying populations in which the treatment is efficacious (true positives) and weeding out inefficacious treatment/populations (true negatives) are competing goals in these trials. Thus, we estimated true and false positive rates for each design. RESULTS: Adaptively updating the MTD during the DEC improved true positive rates by 8-43% compared with fixing the dose during the DEC phase while maintaining false positive rates. Inclusion of an interim futility analysis decreased the number of patients treated under inefficacious DECs without hurting performance. CONCLUSION: A substantial gain in efficiency is obtainable using a design template that statistically models toxicity and efficacy against dose level during expansion. Design choices for dose expansion should be motivated by and based upon expected performance. Similar to the common practice in single-arm phase II trials, cohort sample sizes should be justified with respect to their primary aim and include interim analyses to allow for early stopping.

CT perfusion can predict overexpression of CXCL8 (interleukin-8) in head and neck squamous cell carcinoma.

BACKGROUND AND PURPOSE: Increased angiogenesis in head and neck squamous cell carcinoma correlates to more aggressive tumors with increased morbidity. Because both elevated blood flow and high serum CXCL8 levels are correlated with increased angiogenesis, our objective was to see if elevated blood flow measured with CT perfusion correlated with CXCL8 levels, thereby helping to identify candidates for targeted therapies that inhibit the Bcl-2 proangiogenic pathway associated with CXCL8. MATERIALS AND METHODS: Seven patients with locally recurrent or metastatic head and neck squamous cell carcinoma were enrolled in the trial. These patients underwent CT perfusion and the following parameters were measured: blood volume, blood flow, capillary permeability, and MTT; relative values were calculated by dividing by normal-appearing muscle. Serum was drawn for CXCL8 enzyme-linked immunosorbent assay analysis in these patients. RESULTS: There was a significant positive correlation between the CXCL8 levels and relative blood flow (r = 0.94; P = .01). No correlation was found between CXCL8 and relative blood volume, relative capillary permeability, or relative MTT. CONCLUSIONS: Relative blood flow may be useful as a surrogate marker for elevated CXCL8 in patients with head and neck squamous cell cancer. Patients with elevated relative blood flow may benefit from treatment targeting the Bcl-2 proangiogenic pathways.