Preoperative taxane-based chemotherapy and celecoxib for carcinoma of the esophagus and gastroesophageal junction: results of a phase 2 trial.

PURPOSE: The primary objective of this study was to determine the rate of pathological response after preoperative celecoxib and concurrent taxane-based chemotherapy in patients with cancer of the esophagus and gastroesophageal junction. METHODS: Thirty-nine patients were enrolled in this single-arm, phase II clinical trial. Patients were administered daily celecoxib in combination with two to three cycles of carboplatin and paclitaxel with preoperative intent. Levels of cyclooxygenase (COX)-2 expression in resected tumors were analyzed by immunohistochemistry and correlated with clinical outcome measures. Postoperatively, patients were administered daily celecoxib for 1 year or until documented tumor recurrence. RESULTS: All patients received two to three cycles of chemotherapy plus celecoxib 800 mg/d. Toxicities were as expected. A major clinical response (complete response + partial response) was noted in 22 patients (56%); six patients (15%) had a complete clinical response. Thirty-seven patients underwent esophagectomy. Five patients had a major pathological response (12.8%). Four-year overall and disease-free survivals were 40.9% and 30.3%, respectively. Patients with tumors expressing COX-2 demonstrated a higher likelihood of a major clinical response response (62% versus 50%) and an improved overall survival, compared with patients with COX-2-negative tumors. CONCLUSIONS: Preoperative celecoxib with concurrent chemotherapy demonstrated sufficient effect on pathologic response to warrant further study. Patients with tumors expressing COX-2 demonstrated trends toward improved response to preoperative therapy and improved overall survival compared with nonexpressors.

TNM stage is the most important determinant of survival in metachronous lung cancer.

BACKGROUND: Distinguishing a metachronous lung cancer from a metastatic or recurrent lesion in patients with a prior history of non-small cell lung cancer is a challenging task. Previous studies have suggested histologic type and disease-free interval as criteria for diagnosing metachronous lung cancer. These factors may not be as relevant now that current imaging allows for earlier detection of tumors and with the rising incidence of adenocarcinoma. The purpose of this study was to reexamine the factors that determine outcomes in patients with a second primary lung cancer. METHODS: A retrospective review of a prospective lung cancer database was performed to identify patients with metachronous lung cancer. Metachronous lung cancer was defined as any non-small cell lung cancer occurring after a prior resection regardless of disease-free interval or histologic type. The Kaplan-Meier method was used for survival analysis. The Mantel-Cox method was used to compare overall survival. Cox regression was used for multivariate analysis. RESULTS: Fifty-eight patients had metachronous lung cancer. Overall survival at 5 years was 66% (stage IA, 74%; IB, 59%; all other stages, 0%; p = 0.01). Seventy-two percent (42 of 58 patients) had similar histologic type. There was no difference in overall survival based on similar versus different histologic type (65% versus 73%; p = 0.77). Median disease-free interval was 42 months (range, 8 to 312 months). Disease-free interval was not a significant predictor of overall survival (p = 0.24). The extent of resection included wedge (36%, 21 of 58 patients), segmentectomy (24%, 14 of 58 patients), and lobectomy (40%, 23 of 58 patients), with no difference in overall survival (58% versus 60% versus 75%, respectively; p = 0.32). CONCLUSIONS: These data suggest that early tumor stage is the only significant determinant of survival after surgical treatment of metachronous lung cancer. Neither histologic type nor disease-free interval was of prognostic value. Limited resections may be adequate treatment.

NAD+-dependent 15-hydroxyprostaglandin dehydrogenase regulates levels of bioactive lipids in non-small cell lung cancer.

Elevated levels of procarcinogenic prostaglandins (PG) are found in a variety of human malignancies including non-small cell lung cancer (NSCLC). Overexpression of cyclooxygenase-2 and microsomal prostaglandin synthase 1 occurs in tumors and contributes to increased PG synthesis. NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the key enzyme responsible for metabolic inactivation of PGs, is down-regulated in various malignancies. The main objective of this study was to elucidate the effect of loss of 15-PGDH on levels of bioactive lipids in NSCLC. We found that levels of cyclooxygenase-2 and microsomal prostaglandin synthase 1 were commonly increased whereas the amount of 15-PGDH was frequently decreased in NSCLC compared with adjacent normal lung. Reduced expression of 15-PGDH occurred in tumor cells and was paralleled by decreased 15-PGDH activity in tumors. Amounts of PGE1, PGE2, and PGF(2alpha), known substrates of 15-PGDH, were markedly increased whereas levels of 13,14-dihydro-15-keto-PGE2, a catabolic product of PGE2, were markedly reduced in NSCLC compared with normal lung. Complementary in vitro and in vivo experiments were done to determine whether these changes in PG levels were a consequence of down-regulation of 15-PGDH in NSCLC. Similar to NSCLC, amounts of PGE1, PGE2, and PGF(2alpha) were markedly increased whereas levels of 13,14-dihydro-15-keto-PGE2 were decreased in the lungs of 15-PGDH knockout mice compared with wild-type mice or when 15-PGDH was silenced in A549 lung cancer cells. Collectively, these data indicate that 15-PGDH is commonly down-regulated in NSCLC, an effect that contributes to the accumulation of multiple bioactive lipids in NSCLC.