Faculty Bibliography

PURPOSE/OBJECTIVE:The epidermal growth factor (EGF) receptor is frequently overexpressed in epithelial tumors. C225 is a human-to-murine chimeric monoclonal antibody that binds to the receptor and inhibits growth of cancer cells expressing the receptor. We evaluated the pharmacokinetics and toxicity of C225 in patients with advanced tumors overexpressing EGF receptors. PATIENTS AND METHODS/METHODS:We treated 52 patients in three successive phase I clinical trials of C225 as a single dose (n = 13), weekly multiple dose (n = 17), and weekly multiple dose with cisplatin (n = 22). C225 dose levels were 5, 20, 50, and 100 mg/m(2). In the study combining C225 with cisplatin, limited to patients with either head and neck or non-small-cell lung cancer, C225 was further escalated to 200 and 400 mg/m(2). Cisplatin was given at a dose of 60 mg/m(2) once every 4 weeks, and treatment was continued for up to 12 weeks if no disease progression occurred. RESULTS:C225 displayed nonlinear pharmacokinetics, with antibody doses in the range of 200 to 400 mg/m(2) being associated with complete saturation of systemic clearance. C225 clearance did not change with repeated administration or with coadministration of cisplatin. Antibodies against C225 were detected in only one patient, and C225-associated toxicity was minimal. Patients experiencing disease stabilization were seen in all studies. In the study combining C225 and cisplatin, nine (69%) of 13 patients treated with antibody doses >/= 50 mg/m(2) completed 12 weeks of therapy, and two partial responses were observed. CONCLUSION/CONCLUSIONS:C225 has dose-dependent pharmacokinetics, and doses that achieve saturation of systemic clearance are well tolerated. C225 given in combination with cisplatin has biologic activity at pharmacologically relevant doses.

BACKGROUND: The fifth edition of the American Joint Committee on Cancer staging manual defines new rules for classifying nasopharyngeal carcinoma. The authors tested the value of this new system by applying these rules retrospectively to their previously treated patients and comparing the results with those obtained using the fourth edition of the AJCC staging manual or the Ho staging system. METHODS: Information from 107 patients who had biopsy-proven squamous cell carcinoma of the nasopharynx that was treated in a constant fashion with definitive-intent radiation therapy alone at one institution provided the data base for this analysis. The extent of disease of each patient was staged according to the rules of 1) the fourth edition of the AJCC staging manual, 2) the Ho staging system, and 3) the fifth edition of the AJCC staging manual. RESULTS: The new system appears to be better than the two previous systems. It separated patients into cohorts of more equal size than did either of the other systems. It also correlated with outcome for the study population more appropriately than did the fourth edition of the AJCC staging manual or the Ho staging system. CONCLUSIONS: The fifth edition of the AJCC staging manual appears to be an improvement over the previous AJCC or Ho staging systems for the staging of nasopharyngeal carcinoma

PURPOSE: The purpose of this report was to compare the dose distribution at a field edge defined with divergent alloy blocks to the distribution obtained with a multileaf collimator (MLC). The comparison is made for simple block replacement situations. METHODS AND MATERIALS: A tertiary multileaf collimator mounted on a linear accelerator operating at 6 MV was compared to divergent alloy blocks positioned at the level of the blocking tray. The leaves of the MLC were positioned to give maximum stepping (leaf displacement equals leaf width), and the blocking produced the same field shape. Three different treatment plans were compared: single field, opposed fields, and a four-field 'box.' Dose distributions were determined using radiographic film scanned with a laser densitometer with a 0.45-mm spot size. One experiment was repeated using radiochromic film with reduced energy dependence. Dose distributions were examined on the isocenter plane, and on planes displaced by 1.0 and 2.5 cm. The effect of daily setup variations was also studied by comparing a single fraction treatment with a fractionated treatment consisting of 15 fields slightly displaced relative to each other. The magnitude of these displacements was determined using available literature on treatment reproducibility. RESULTS: For a single field plan, maximum stepping of an MLC-defined edge produces an obvious undulating dose pattern compared to an alloy block edge. At the isocenter plane, this pattern is unchanged when parallel opposed fields are used. However, blurring occurs for both MLC and block edges when planes displaced from the isocenter are examined. The gradient for the block edge is 8%/mm for opposed fields and a plane 2.5 cm from the isocenter, compared to 15%/mm for the isocenter plane. Adding two additional fields does not change the dose pattern in the isocenter plane, but does reduce the gradient across the steepest portion of the penumbra to 8%/mm, and shifts the isodose line with the most pronounced stepping to higher values (from 50 to 80%). Introducing daily setup variations results in a reduction of the sharp dose gradient along the sides of a single field, and around the periphery of the beam at the isocenter plane of opposed fields. Smaller changes are found for edges already blurred by other factors. Radiochromic film was generally noisier than radiographic film, but comparison of the two films did not show a significant difference, indicating that the energy dependence of the radiographic film was not a problem. CONCLUSIONS: The obvious dose stepping seen on a portal image of a single field with MLC shaping is shown to be partially erased by the addition of other fields, and for planes away from the isocenter. However, the effects of daily setup variations must be included to more effectively blur dose stepping along the external envelope of a single field or near the isocenter plane of opposed fields. This result conflicts with attempts to improve immobilization

OBJECTIVE: To test the hypothesis that interleukin-8 (IL-8) is produced by human head and neck squamous cell carcinomas (HNSCCAs) and may therefore be a possible mediator for lymphocyte recruitment and neovascularization by these tumors. METHODS: Nine fresh samples of HNSCCA were analyzed for expression of IL-8 antigen using radioimmunoassay and immunohistochemical staining techniques. Also, four short-term primary cultures of HNSCCA and two continuous HNSCCA cell lines were then analyzed for production of IL-8 expression under both baseline conditions and following stimulation with other cytokines. RESULTS: The IL-8 antigen was detected in all fresh tumor homogenates by radioimmunoassay (5.58 to 331.69 ng of IL-8 per gram of tissue), and immunohistochemical results localized staining predominantly within the tumor cells. Primary cultures of HNSCCA and continuous HNSCCA cell lines produced only low levels of IL-8 (0.04 to 4.49 ng of IL-8 per 10(6) cells) under baseline (unstimulated) conditions. Stimulation of both primary cultures and cell lines with interleukin-1 and tumor necrosis factor induced significant increases in IL-8 antigen, while other cytokines failed to induce a significant increase. CONCLUSIONS: This study demonstrates that IL-8 antigen is expressed by HNSCCA in vivo, and that cultured HNSCCA in vitro can be stimulated to express IL-8 antigen by both interleukin-1 and tumor necrosis factor. Local production of IL-8 by HNSCCA cells, and its regulation by other cytokines, may be important in both the lymphocyte recruitment and tumor neovascularization seen in HNSCCA, and may thus ultimately affect the natural history of the disease.