Environmental information disclosure programs seek to motivate firms to reduce their environmental impact. A variety of environmental impacts are reported in these programs and often this information is aggregated into a composite environmental index (CEI) for easier communication. The challenge is to create a meaningful index that allows environmental performance to be compared over time and space without ambiguity. In this paper, we argue that it is important to develop a cardinally meaningful and standardized CEI and use a nonparametric frontier approach to constructing such an index. This approach has the advantage to handle issues associated with data irregularity and the mixed measurability of underlying variables. We apply this approach to constructing a CEI for evaluating the environmental performance of manufacturing facilities in different industrial sectors in Los Angeles based on data from the toxic release inventory. We show how the CEI can be used to improve facility-level environmental performance. A sensitivity analysis is conducted with respect to the uncertainty in data accuracy, which demonstrates the robustness of the nonparametric frontier approach in constructing meaningful environmental indices.

Objective

Src family kinase (SFK) activation circumvents epidermal growth factor receptor (EGFR) targeting in head and neck squamous cell carcinoma (HNSCC); dual SFK-EGFR targeting could overcome cetuximab resistance.

Patients and methods

We conducted a Simon two-stage, phase II trial of the SFK inhibitor, dasatinib, and cetuximab in biomarker-unselected patients with cetuximab-resistant, recurrent/metastatic HNSCC. Pre- and post-treatment serum levels of interleukin-6 (IL6) were measured by ELISA. HNSCC cell lines were assessed for viability and effects of IL6 modulation following dasatinib-cetuximab treatment.

Results

In the first stage, 13 patients were evaluable for response: 7 had progressive and 6 had stable disease (SD). Enrollment was halted for futility, and biomarker analysis initiated. Low serum IL6 levels were associated with SD (raw p=0.028, adjusted p=0.14) and improved overall survival (p=0.010). The IL6 classifier was validated in a separate trial of the same combination, but was unable to segregate survival risk in a clinical trial of cetuximab and bevacizumab suggesting serum IL6 may be specific for the dasatinib-cetuximab combination. Enhanced in vitro HNSCC cell death was observed with dasatinib-cetuximab versus single agent treatment; addition of IL6-containing media abrogated this effect.

Conclusion

Clinical benefit and overall survival from the dasatinib-cetuximab combination were improved among patients with low serum IL6. Preclinical studies support IL6 as a modifier of dasatinib-cetuximab response. In the setting of clinical cetuximab resistance, serum IL6 is a candidate predictive marker specific for combined dasatinib-cetuximab. The trial was modified and redesigned as a biomarker-enriched Phase II study enrolling patients with undetectable IL6.