NEW YORKMedian survival has pushed past 18 months in a trial of concurrent low-dose gemcitabine(Drug information on gemcitabine) (Gemzar) and radiation therapy in highly selected patients with stage III non-small-cell lung cancer (NSCLC), according to a report at the Chemotherapy Foundation Symposium XVIII.
"We still have patients coming along," said A. William Blackstock, MD, assistant professor of radiation oncology, Wake Forest University School of Medicine, Winston-Salem, North Carolina. The study began in 1998 and closed in 2000.
Designed as a phase I trial to define the optimal dose of gemcitabine as a radiosensitizer, the trial accrued 17 patients, 14 with stage IIIA disease and 3 with stage IIIB. Dr. Blackstock said he was "very careful with selection" of patients for the study. Eligibility requirements included performance status of 2 or better and adequate pulmonary function. The group’s mean age was 67 years.
"We did have a high response rate," Dr. Blackstock said. Determined by independent review, the rate for the 16 evaluable patients was 88%, with 2 complete responses and 12 partial responses. At a median follow-up of 11 months (range, 3 to 24 months), 12 patients remained alive.
A twice-weekly regimen of gemcitabine was used in the trial, Dr. Blackstock said, because laboratory studies at the University of Michigan and his own institution had shown that enhanced cell-killing radiosensitization extends only about 48 to 72 hours after the drug is administered.
Doses tested in the clinical trial ranged from 20 mg/m2 to 100 mg/m2 weekly, with half the total dose given at a time. Gemcitabine was given by infusion on Mondays and Thursdays of the 3-week cycle. The optimal weekly dose of gemcitabine proved to be 70 mg/m2.
Radiation was given in standard fractionated doses, 1.8 Gy/day over 5 days each week. "The total dose was 60 Gy, a little bit lower than I would have liked," Dr. Blackstock said, "but we were trying to be very cautious here." He noted that significant toxicity and some deaths had been seen in a previous European study that used full-dose gemcitabine with a total radiation therapy dose of 60 Gy.
Radiation was directed at the gross disease with margins, "although we did treat the mediastinum electively to 39.6 Gy," Dr. Blackstock said.
The most significant adverse effect was an atypical grade 4 esophagitis seen in two patients who received the maximum dose, 100 mg/m2/wk. The esophagitis, Dr. Blackstock stressed, was not like that usually seen with radiation therapy. It did not resolve spontaneously, and both patients had to be hospitalized for treatment. "We don’t typically have to hospitalize people for a week or two to get over esophagitis with just radiation alone," he noted.
Endoscopy revealed severe ulcerations in both patients. "They both have actually done well," Dr. Blackstock said, "and I have no evidence that they will develop strictures, which are a late radiation complication, but it’s a little early to say."
A multi-institutional phase II study of induction carboplatin(Drug information on carboplatin) (Paraplatin) and gemcitabine, followed by twice-weekly gemcitabine and radiation therapy is now being initiated in patients with NSCLC, Dr. Blackstock said. The radiation dose will be escalated to 66 Gy in the phase II trial.
Based on preclinical data suggesting synergy between gemcitabine and oxaliplatin(Drug information on oxaliplatin) (investigational), Dr. Blackstock is working with the National Cancer Institute to initiate a phase I/II trial of induction gemcitabine/oxaliplatin followed by twice-weekly gemcitabine and weekly oxaliplatin in patients with advanced NSCLC. "This is an effort to build upon the encouraging results observed in this phase I/II study," he said.