Gefitinib and EGFR Gene Copy Number Aberrations in Esophageal Cancer.

Purpose The Cancer Esophagus Gefitinib trial demonstrated improved progression-free survival with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib relative to placebo in patients with advanced esophageal cancer who had disease progression after chemotherapy. Rapid and durable responses were observed in a minority of patients. We hypothesized that genetic aberration of the EGFR pathway would identify patients benefitting from gefitinib. Methods A prespecified, blinded molecular analysis of Cancer Esophagus Gefitinib trial tumors was conducted to compare efficacy of gefitinib with that of placebo according to EGFR copy number gain (CNG) and EGFR, KRAS, BRAF, and PIK3CA mutation status. EGFR CNG was determined by fluorescent in situ hybridization (FISH) using prespecified criteria and EGFR FISH-positive status was defined as high polysomy or amplification. Results Biomarker data were available for 340 patients. In EGFR FISH-positive tumors (20.2%), overall survival was improved with gefitinib compared with placebo (hazard ratio [HR] for death, 0.59; 95% CI, 0.35 to 1.00; P = .05). In EGFR FISH-negative tumors, there was no difference in overall survival with gefitinib compared with placebo (HR for death, 0.90; 95% CI, 0.69 to 1.18; P = .46). Patients with EGFR amplification (7.2%) gained greatest benefit from gefitinib (HR for death, 0.21; 95% CI, 0.07 to 0.64; P = .006). There was no difference in overall survival for gefitinib versus placebo for patients with EGFR, KRAS, BRAF, and PIK3CA mutations, or for any mutation versus none. Conclusion EGFR CNG assessed by FISH appears to identify a subgroup of patients with esophageal cancer who may benefit from gefitinib as a second-line treatment. Results of this study suggest that anti-EGFR therapies should be investigated in prospective clinical trials in different settings in EGFR FISH-positive and, in particular, EGFR-amplified esophageal cancer.

Obesity is not associated with increased myelosuppression in patients receiving chemotherapy for breast cancer.

Audits of adjuvant chemotherapy for breast cancer have revealed that obese patients receive a lower relative dose intensity (RDI). However, interpretation of these studies is complicated by the variable use of cytokine growth factors, empiric dose capping and first cycle dose reductions. We have analysed the impact of obesity on RDI in a cohort of 662 patients that is not confounded by these factors. Patients were classified as overweight or obese on the basis of a body mass index (BMI)>or=25 kg/m2. The mean RDI in patients with BMI>or=25 kg/m2 was actually significantly greater than in those with BMI<25 kg/m2 (p=0.03). Overweight patients were less likely to experience cycle delays due to prolonged myelosuppression (p<0.001), particularly towards the end of the treatment course. We conclude that drug doses need not be reduced on the basis of obesity. Overall obese patients are in fact less likely to suffer haematological toxicity.

Radiation pneumonitis following treatment of non-small-cell lung cancer with continuous hyperfractionated accelerated radiotherapy (CHART).

PURPOSE: To determine whether partial volume lung irradiation influences the risk of developing acute radiation pneumonitis after the treatment of non-small-cell lung cancer with continuous hyperfractionated accelerated radiotherapy (CHART). METHODS AND MATERIALS: We conducted an analysis of 32 patients treated with CHART at the Gloucestershire Oncology Center. Twelve patients were treated using conventional two-dimensional treatment techniques and received elective nodal irradiation (ENI). Their treatment plans were subsequently recapitulated using a three-dimensional treatment planning system. Twenty patients were planned using this system from the outset. For these patients, elective nodal irradiation was omitted. Dose-volume histograms (DVH) were constructed and several parameters analyzed for their ability to predict for the development of pneumonitis. RESULTS: Univariate analysis revealed that the percentage lung volume receiving more than 20 Gy (V20) and the mean lung dose are of predictive value for the development of pneumonitis after CHART. There is a strong correlation between these two parameters. Importantly, partial volume lung irradiation using CHART appears to be better tolerated than conventionally fractionated radiotherapy. The omission of ENI considerably reduces V20. Using a commonly employed 3-beam technique it was also noted that the shape of the planning target volume (PTV) in the transverse plane (expressed as an elliptical index) affects the conformity of the V20 isodose to the PTV. This influences the scope for dose escalation with irregularly shaped tumors. CONCLUSIONS: In relation to acute radiation pneumonitis, CHART appears to have a superior therapeutic index than conventionally fractionated radiotherapy. V20 and mean lung dose are useful factors for predicting the risk of this complication. The use of these parameters will aid the selection of optimal treatment plans and provides a basis for future dose escalation studies.