The standard of care for patients with metastatic colorectal cancer is the combination of irinotecan, 5-fluorouracil and leucovorin (IFL). However, IFL induces significant toxicities, including severe diarrhea and myelosuppression.

Research to date has suggested that inhibition of cyclooxygenase-2 (COX-2) can augment chemotherapy and might reduce the diarrhea associated with IFL.

Celecoxib, one of the non-steroidal anti-inflammatory drugs selective for COX-2, is approved in the United States for treatment of arthritis and familial adenomatous polyposis (FAP). Investigators have safely combined celecoxib with chemotherapeutic agents in phase I trials. In addition, animal studies suggest celecoxib might decrease the diarrhea experienced by patients receiving IFL.

Based on this information, investigators launched a 25-patient phase II trial of celecoxib plus the IFL regimen in advanced colorectal cancer. Patients started a 2-week trial period of celecoxib alone. Those who successfully completed 14 days received the standard IFL regimen until disease progression or the development of severe toxicity.

The celecoxib dose is 400 mg twice daily, the same dose clinicians use for FAP. The IFL follows the Saltz regimen of chemotherapy weekly for 4 weeks every 7 weeks. The primary endpoint of the study was overall response rate.

For the 22 patients who could be evaluated for toxicity, 18% had abnormal electrolytes. Neutropenia occurred in 27% although documented infection was extremely rare. Severe diarrhea or nausea occurred in 23%. Thrombotic events occurred in 3 patients.

In the intent-to-treat analysis, 24% of patients had a partial response, while 43% had stable disease for at least 7 weeks. Progression occurred in 14%, while 19% exited the study due to adverse events or withdrawal of consent.

Patients received a median of 2 cycles of treatment (range 1 to 9 cycles). The median duration of response is 6 mo, median progression free survival 6.8 months, and median survival 10.7 months.

Dr. Blanke said that this trial and another phase II study (reported at ASCO by the Hoosier Oncology Group) found rates of grade 3 or greater neutropenia. These rates were approximately half those expected from chemotherapy alone.

Investigators hope this trial might serve as a pilot for randomized studies testing the combination of chemotherapy and COX-2 inhibitors for treating adjuvant or advanced disease.

However, many questions remain. For example, investigators do not know the dose necessary to achieve reduced neutropenia. There will be more information on the true benefits of celecoxib plus chemotherapy when investigators report further results of this phase II trial and future randomized phase III trials.

(abstract #505)