Irinotecan/Gemcitabine Plus Radiation Tested in Locally Advanced Pancreatic Cancer

WINSTON-SALEM, North Carolina—Preliminary data from a phase II trial of induction irinotecan (Camptosar)/gemcitabine (Gemzar) followed by twice-weekly gemcitabine and radiation in patients with locally advanced pancreatic cancer show partial responses in 2 of 7 evaluable patients. There were no local progressions, and median time to progression of 6 months, according to A. William Blackstock, MD. Dr. Blackstock is assistant professor at Wake Forest University, Winston-Salem, North Carolina, and at the University of North Carolina at Chapel Hill.

"Today pancreatic cancer is essentially a lethal diagnosis," Dr. Blackstock said. "With current approaches to chemoradiation for locally advanced pancreatic cancer, the median survival of about 10 to 12 months is about the best you can achieve. Until we develop more effective systemic regimens, improving local tumor control is not likely to make a significant difference." The phase II trial follows previous work showing single-agent activity for gemcitabine and improved activity for gemcitabine plus radiation.

"A number of preclinical and clinical studies have suggested that a twice-weekly dosing of gemcitabine with radiation is a better way to sensitize than a weekly dosing schedule. In some phase I work, we determined that a gemcitabine dose of 40 mg twice a week given with radiation was feasible. We pursued this in Cancer and Leukemia Group B (CALGB) trial 89805. This study is now closed after accruing 43 patients. While the median survival for performance status 0 patients was 13.5 months, overall survival was 9.0 months; only 4 patients had local failure as the initial site of failure. While I don’t think these data are impressive, there was some inference that we improved local control," Dr. Blackstock said.

Complementary Toxicity

The investigators added irinotecan to gemcitabine induction therapy because the two drugs have complementary toxicity profiles, different mechanisms of cytotoxicity, and overlapping antitumor activity in pancreatic cancer. Preclinical studies also suggested synergy at concentrations of gemcitabine above 0.1 µM and irinotecan above 3.2 µM.

Patients on the ongoing phase II trial are treated with irinotecan 100 mg/m² and gemcitabine 1,000 mg/m² on days 1 and 8. This is followed by twice-weekly gemcitabine at 40 mg/m² and radiation at 50.4 Gy. "We are using very standard radiation doses and fractionation," Dr. Blackstock said.

The trial is enrolling patients with histologically or cytologically confirmed nonmetastatic pancreatic cancer who have a life expectancy greater than 6 months. Dr. Blackstock said that patients with regional (peripancreatic) lymph node involvement are eligible. Study endpoints are time to progression, local-regional control, and overall survival. The investigators will also measure CA-19 responses and assess the predominant site of failure.

"We don’t have much in terms of data yet, but I can tell you that the 8 patients we have accrued range in age from 59 to 87 years. Two patients developed grade 3 diarrhea, but otherwise the patients treated thus far have tolerated the induction regimen very well and completed treatment," Dr. Blackstock said.

"We have seen partial responses in 2 of the first 7 patients, with no patient progressing locally, but we are very early in the trial," he added. Median time to progression is 6 months, but with only 8 patients, I’m not certain what that means yet. We can conclude that toxicities seem to be acceptable. We certainly can’t comment on activity, but we have opened this trial up to additional research groups and we hope to complete accrual in a timely manner.