ABSTRACT
Cyclooxygenase-2 (COX-2) overexpression is associated with a poor prognosis in non-small-cell lung cancer (NSCLC) and may promote resistance to epidermal growth factor receptor inhibitors. This randomized phase 2 trial evaluated apricoxib, a novel COX-2 inhibitor, in combination with erlotinib in biomarker-selected patients. Patients with stage IIIB/IV NSCLC previously treated with platinum-based chemotherapy were randomized (2:1) to 400 mg/day apricoxib plus 150 mg/day erlotinib (AP/E) or placebo plus erlotinib (P/E) in 21-day cycles until disease progression or unacceptable toxicity. The primary endpoint was time to progression (TTP). A decrease of 50% or more from baseline urinary prostaglandin E2 metabolite after a 5-day, open-label, run-in period was used to select eligible patients. One hundred twenty patients (median age 64 years) were randomized (78 to AP/E and 42 to P/E). Overall median TTP was 1.8 months in the AP/E group and 2.1 months in the P/E group, with a 12% objective response rate in both groups (intent-to-treat analysis). A subgroup analysis in patients aged 65 years or younger demonstrated a statistically significant TTP benefit for AP/E (hazard ratio 0.5 [95% confidence interval: not applicable-0.9]; p=0.018) and overall survival advantage at minimum 1-year follow-up (median 12.2 versus 4.0 months; hazard ratio=0.5; p=0.021). The most common adverse events were rash, diarrhea, fatigue, and nausea. Toxicity contributed to early discontinuations in patients aged more than 65 years treated with AP/E. This is the first randomized placebo-controlled study of a COX-2 inhibitor in NSCLC to use a prospective patient-selection strategy. Although AP/E seemed to improve TTP and overall survival in a subset of patients aged 65 years or younger, the primary endpoint of the trial was not met.
Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Neoplasm Recurrence, Local/drug therapy , Prostaglandins/urine , Pyrroles/therapeutic use , Quinazolines/therapeutic use , Sulfonamides/therapeutic use , Adenocarcinoma/drug therapy , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Adenocarcinoma/urine , Adenocarcinoma, Bronchiolo-Alveolar/drug therapy , Adenocarcinoma, Bronchiolo-Alveolar/mortality , Adenocarcinoma, Bronchiolo-Alveolar/pathology , Adenocarcinoma, Bronchiolo-Alveolar/urine , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols , Biomarkers, Tumor/urine , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/urine , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/urine , Cyclooxygenase 2 Inhibitors/therapeutic use , Disease Progression , Double-Blind Method , Erlotinib Hydrochloride , Female , Follow-Up Studies , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Lung Neoplasms/urine , Male , Middle Aged , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/urine , Neoplasm Staging , Prognosis , Prospective Studies , Protein Kinase Inhibitors/therapeutic use , Survival RateABSTRACT
A bronchioloalveolar carcinoma of lung associated with hyperamylasemia occurring in a 40-year-old woman is described. Another 13 cases of such a tumor from the English literature are reviewed. A majority of the lung tumors associated with hyperamylasemia were adenocarcinomas. When the amylase isoenzymes were determined, the amylase appeared to be salivary-gland type (S-type). Electron microscopic studies had revealed membrane-bound electron-dense granules within the tumor cells.
