Irinotecan-Containing Chemotherapy Regimens Active in Pancreatic Cancer and Ovarian Cancer

NEW ORLEANS—Treatments combining irinotecan (Camptosar) with other drugs are active and well-tolerated in patients with advanced and metastatic pancreatic and ovarian cancer, according to two reports presented at the 36th annual meeting of the American Society of Clinical Oncology.

Pancreatic Cancer

Based on phase II results, patient accrual has begun at 75 institutions for a phase III trial of irinotecan and gemcitabine (Gem-zar) as first-line therapy of advanced and metastatic pancreatic cancer, said Caio Max S. Rocha Lima, MD, assistant professor of medicine, Medical University of South Carolina, Charleston.

In Dr. Rocha Lima’s phase II study, irinotecan and gemcitabine were administered on days 1 and 8 for 3 weeks to 45 patients with locally advanced and metastatic pancreatic cancer, three of whom had had prior radiation therapy.

Of these, nine (20%) showed a tumor response, and 13 (32.5%) had a reduction of 50% in CA 19-9, a tumor marker that is elevated in a majority of patients with pancreatic cancer. Median survival was 6 months, with a range of 9 to 12.2 months.

The researchers reported that “toxicity was modest.” Only 4.2% experienced significant vomiting, while 6.7% experienced serious diarrhea. Grade 3-4 neutropenia was reported in 15.5% of patients. As many as 6.7% experienced thrombocytopenia.

Dr. Rocha Lima agreed that the combination is spurring hopes for new treatment approaches in pancreatic cancer, which “tends to be aggressive and is associated with very short survival.”

“Before gemcitabine, there was very little evidence that any therapy could have an impact on the quality of life or survival of patients with this disease,” he told ONI. “In a randomized pivotal trial where gemcitabine was compared to 5-FU, gemcitabine resulted in a ninefold improvement in clinical benefit.”

This pivotal trial led to FDA approval of gemcitabine in the therapy of pancreatic cancer. “Trying to build on that is one of the approaches one might take to improve outcome in the disease,” he said.

Ovarian Cancer

Toru Sugiyama, MD, PhD, department of obstetrics and gynecology, Kurume University, Kurume, Japan, combined irinotecan with cisplatin (Platinol) as first-line therapy for advanced epithelial ovarian cancer in 26 patients.

Irinotecan was administered intravenously on days 1, 8, and 15, with cisplatin on day 1. Cycles were repeated every 28 days for at least two cycles.

Median overall survival was 38 months, with a range of 4.1 to 60 or more months, Dr. Sugiyama reported. The team was able to record an objective response in 19 of 25 evaluable patients. Two of these patients experienced complete response, defined as complete disappearance of all known disease for 4 weeks. Seventeen experienced a partial response, defined as a reduction of greater than 50% in the sum of the length-width products of all indicator lesions.

Two patients experienced stable disease, two had progressive disease, and in two, image-guided evaluation of response “was judged to be unfeasible at the time of independent extramural review,” Dr. Sugiyama said.

Progressive disease was defined as an increase of greater than 25% in the sum of the products of all indicator lesions, the reappearance of any lesion that had disappeared, or appearance of any new lesion. Stable disease was defined as any situation that did not qualify as response or progression.

Toxicity

“The major toxic effects were leukopenia, neutropenia, and diarrhea,” Dr. Sugiyama said. Grade 3-4 leukopenia, neutropenia. and diarrhea occurred in 17 patients (68%), 20 patients (83%), and five patients (20%), respectively.

The neutropenia was quickly ameliorated with the administration of G-CSF (Neupogen) or by omitting irinotecan on day 8 or 15, Dr. Sugiyama said, with no resulting delay in the next chemotherapy cycle. Diarrhea and vomiting also improved with treatment.

Dr. Sugiyama said that irinotecan may have applications in clear-cell carcinoma, which has a more aggressively malignant course than adenocarcinoma of the ovary.

Pilot studies have suggested a combination of irinotecan and cisplatin may be effective in these patients. Dr. Sugiyama’s team is planning to start a phase III study comparing irinotecan plus cis-platin with paclitaxel (Taxol) plus carboplatin (Paraplatin) for this disease.

Encouraging Results

Mace Rothenberg, MD, associate professor of medicine, Vanderbilt University Medical Center, Nashville, called the results from Japan encouraging and reasonable enough to pursue phase III studies.

The response rate was within the range of what might be expected from other drug combinations used in ovarian cancer treatment, such as paclitaxel and cisplatin. However, he added, “it isn’t so far outside the realm of what we have achieved with other regimens that I would make it my standard of therapy. It’s important to be realistic,” Dr. Rothenberg said.

The strategy of giving irinotecan over weeks, with cisplatin dosage administered all at once on the first day of the cycle, was pioneered in Japan, Dr. Rothenberg commented. While some researchers elsewhere use this method, others believe it is better to divide the cisplatin dosage and give it with the irinotecan.

Dr. Rothenberg said research using irinotecan in pancreatic cancer is also encouraging, and that phase III testing is the logical next step. He noted that tumor response is “probably not a very good surrogate for survival in pancreatic cancer.”

In a phase III comparative study, it may not be necessary, he said, but in a phase II trial in which there is no control group, tumor response measurement provides an objective way to observe whether the drug in question is having any effect on the cancer.