NEW YORK CITY—Although results are preliminary, a Phase II trial reported encouraging overall and one-year survival rates using the combination of docetaxel (Taxotere), cisplatin, and irinotecan (TPC) in patients with advanced esophageal and gastric cancer.
Patients with esophageal cancer and cancer at the gastroesophageal junction fared better in terms of response and toxicity than those with gastric cancer, a difference that has also been shown in other trials.
“Results of this trial are as good as any study that has been presented or published in advanced esophageal and gastric cancer,” Peter C. Enzinger, MD, Clinical Director of the Gastrointestinal Cancer Center at Dana-Farber Cancer Institute, said in his presentation here at the Chemotherapy Foundation Symposium.
“The combination of TPC deserves further study, including in combination with molecular targeted agents.”
Separate studies showed that the combination of irinotecan/cisplatin achieved good results in advanced esophageal and gastric cancer, respectively, with a median survival ranging between five and 15 months.
Dr. Enzinger and his colleagues added weekly docetaxel to the irinotecan/cisplatin combination, based on a 20% response rate achieved with the taxane in advanced gastric cancer.
“The taxanes are thought to have the highest single-agent response rate in gastric cancer,” he said.
A Phase I trial showed good tolerability with TPC given on Days 1 and 8 of a 21-day cycle, with more toxicity observed in patients with gastric cancer than in those with other solid tumors.
The final results of the Phase II study presented at the Symposium were based on a study population of 49 patients with measurable metastatic, previously untreated esophageal and gastric cancer.
Patients received a weekly infusion of docetaxel over 30 minutes, followed by cisplatin over 30 minutes, followed by irinotecan over 30 minutes.
The first 18 patients were treated with docetaxel at 30 mg/m2, cisplatin at 25 mg/m2, and irinotecan at 65 mg/m2. Grade III and IV toxicity related to irinotecan was unacceptable, with 56% of patients experiencing diarrhea, 22% neutropenia, 11% emesis, and 11% fatigue.
A treatment delay was needed in 72% of patients due to toxicity, and half of the patients required at least one dose reduction.
The dose of irinotecan was reduced to 50 mg/m2 in the next 31 patients, and toxicity was reduced. Treatment delays were needed in 59%, and two thirds of patients did not require any dose reduction, Dr. Enzinger said.
“With lower doses of irinotecan, neutropenia occurred in 14%, diarrhea in 14%, and fatigue in 7%. In context with other studies, this is dramatically less neutropenia.”
TPC with lower-dose irinotecan resulted in little emesis, less fatigue compared with other treatments, and no mucositis, he added.
The overall response rate (including complete and partial responses) was 60%. Overall response was higher (69%) in those with esophageal cancer or cancer of the gastroesophageal junction.
The median progression-free survival was 8.4 months. “This is the best progression-free survival I've seen to date,” Dr. Enzinger observed.
Median overall survival was 12.5 months (range of 9.7 to 16 months), and the one-year overall survival rate was 64%.
In terms of survival by type of cancer, the one-year survival rate was 59% in those with esophageal cancer and 47% in those with gastric cancer. Previous studies of cisplatin/irinotecan showed a median survival time of 14.6 months in patients with esophageal cancer and nine months in gastric cancer.
“At the 50 mg/m2 dose of irinotecan, TPC was well tolerated compared with other regimens, less toxic, and demonstrated impressive overall survival rates,” Dr. Enzinger concluded.
Asked for a comment, David Ilson, MD, PhD, a GI cancer specialist at Memorial Sloan-Kettering Cancer Center, said, “This Phase II study is encouraging, with reasonable tolerance and respectable anti-tumor activity. However, as with any single-institution Phase II study, caution is always warranted.”
Dr. Ilson noted that over two thirds of patients had significant treatment delays, which may argue for further treatment dose reductions.
“Taxotere is active as a single-agent in esophageal/gastric cancer, and there are other Phase III data suggesting that the addition of Taxotere to a two-drug combination of 5-FU/cisplatin may improve the response rate, time to progression, and overall survival compared with the two-drug regimen alone,” he said.
Further study is warranted, including the potential addition of targeted agents, he said.
“I always question whether a three-drug combination is better than a two-drug combination. Ultimately there needs to be a trial comparing a two-drug versus a three-drug regimen—i.e., irinotecan/platinum versus Taxotere/irinotecan/platinum.”