5-FU AS EFFECTIVE AS GEMCITABINE FOR PANCREATIC CANCER IN ADJUVANT SETTING?

June 10, 2009 (Orlando, Florida) — Don't dismiss the value of 5-fluorouracil (5-FU) in the treatment of pancreatic cancer, say experts.
In the adjuvant setting, 5-FU provided overall survival — about 23 months — similar to that of gemcitabine (Gemzar), according to the results of a new randomized trial presented here at the American Society of Clinical Oncology (ASCO) 45th Annual Meeting.

"It's a fantastic result," said lead author John P. Neoptolemos, MD, adding that of the 1088 resected patients, 35% had positive resection margins and 72% had metastases to the lymph nodes.

"Keep in mind that, in the past, many of these patients would have died within 12 months," said Dr. Neoptolemos, who is head of the Division of Surgery and Oncology at the University of Liverpool in the United Kingdom. He addressed reporters at a meeting press conference

The study was an affirmation of the effectiveness of 5-FU, said Dr. Neoptolemos.

"Gemzar arrived in 1996 and changed the treatment landscape for advanced pancreatic cancer. It acquired a mythical status," Dr. Neoptolemos told Medscape Oncology, suggesting that the reputation of 5-FU suffered as a consequence, in the United States at least.

"It's been previously thought by [American] clinicians that 5-FU might not be as effective," Dr. Neoptolemos continued. Gemcitabine combined with radiation has been the treatment of choice in the United States; however, 5-FU remains the preferred treatment in many parts of the world, including Europe, he said

The new study addressed an information gap in pancreatic cancer, suggested Jennifer Obel, MD, who moderated the press conference. "We've never had a large study comparing these 2 therapies," she told Medscape Oncology. Dr. Obel is a gastrointestinal oncologist at the NorthShore University HealthSystem in Evanston, Illinois. She also is a member of the ASCO Communications Committee.

Dr. Obel also suggested that 5-FU might be even better, at least in terms of adverse events, than the study reported.

"This study shows that 5-FU, even when given in an outdated fashion, which is more toxic, is equivalent to gemcitabine. Perhaps 5-FU in an updated fashion — namely, oral capecitabine — will be even more effective. It will certainly be less toxic," she told Medscape Oncology.

Combination Chemotherapy Now Makes Sense

The new study, known as the European Study Group for Pancreatic Cancer-3 trial (ESPAC-3), is the largest adjuvant trial ever conducted in pancreatic cancer, said Dr. Neoptolemos

The results should "harmonize treatment worldwide," he said, explaining that they "open up the opportunity to give both drugs at the same time" because the drugs work equally well and have different mechanisms of action.

Dr. Neoptolemos also offered clinicians worldwide some advice. "The [United States] should drop chemoradiation, which is very expensive and lacks good evidence, and adopt 5-FU, and the Europeans should adopt gemcitabine," he said.

In addition to being a cheerleader for gemcitabine–5-FU combination therapy, Dr. Neoptolemos is also part of a new clinical trial (ESPAC-4) that aims to find out if it's effective.

"It's exciting that there's a potential for combination therapy," said Dr. Obel. Oral capecitabine (Xeloda) is the form of 5-FU being used in ESPAC-4, she added.

There is a great need to improve chemotherapy in this setting, Dr. Obel continued. "The main problem with the treatment of early-stage pancreatic cancer is that there is only a 20% cure rate at 5 years postsurgery," she said, even though more than 200 drugs have been tested in pancreatic cancer.

Gemcitabine Has Better Safety Profile in Current Study

For clinicians who want to choose either 5-FU or gemcitabine, the new data show that gemcitabine is likely to be the preferred adjuvant therapy because of a better safety profile, said Dr. Neoptolemos.

In the study, patients who received 5-FU reported more toxicities than those treated with gemcitabine, including grade 3/4 toxicity stomatitis (10% vs 0%, respectively), diarrhea (13% vs 2%), and treatment-related hospitalizations (10% vs 3.5%).

All patients taking part in the 16-country phase 3 study had either an R0 or R1 resection for pancreatic ductal adenocarcinoma and were randomized (stratified for resection margin status and country) within 8 weeks of surgery to receive either 5-FUl/folinic acid (FA) or gemcitabine.

The 5FU/FA regimen consisted of an IV bolus injection of FA 20 mg/m², followed by an IV bolus injection of 5-FU 425 mg/m² given on days 1 to 5 every 28 days. The gemcitabine regimen consisted of an IV infusion of gemcitabine 1000 mg/m² on days 1, 8, and 15 every 4 weeks for 6 months.

Dr. Neoptolemos is a consultant to Pfizer and has received research funding from Pharmexa, Oxford Biomedica, and Cytimmune. Dr. Obel is a consultant to Onyx.

American Society of Clinical Oncology (ASCO) 45th Annual Meeting: Abstract LBA4505. Presented May 31, 2009.