Although therapeutic strategies have advanced for many common gastrointestinal cancers, significant progress in the treatment of pancreatic cancer remains elusive. The eagerly anticipated results of randomized trials that evaluated gemcitabine-based combination regimens have proven to be disappointing, researchers report in a review paper that discusses the use of systemic therapy in advanced pancreatic cancer. Whereas 2 recent trials have demonstrated a modest survival benefit with combination therapy, some consider the improvement to be too small to justify the risk of toxicity or added cost.
The article appears in the July issue of the Annals of Oncology.
"Not many trials have been promising, unfortunately, as this is a difficult disease," said coauthor John R. Zalcberg, MD, PhD, professor and director of the division of haematology and medical oncology at the Peter MacCallum Cancer Institute, in Melbourne, Australia. "The new biologics have really not, at this point, been as hopeful as we would have liked or expected."
One disappointment has been the negative results from trials combining bevacizumab (Avastin, Roche) and gemcitabine (Gemzar, Eli Lilly), especially because an early-phase study showed a survival benefit. "We were hoping that it would be the opening of a new treatment era for pancreatic cancer, but unfortunately, that hasn't happened," Dr. Zalcberg told Medscape Oncology.
Pancreatic cancer is the eighth most common cause of cancer death; even with treatment, less than 5% of patients survive 5 years. This disease presents a number of challenges that the clinician has to consider and that make effective therapy so difficult, the authors point out. It is frequently diagnosed at a late stage, often after it has metastasized, and disease-related symptoms, including pain and cachexia, negatively affect performance status and limit the safe delivery of treatment.
The disease is highly resistant to chemotherapy, and systemic treatments produce only modest benefits. Only about 10% to 15% of patients have tumors that can be surgically resected; even then, the risk for recurrence is high. However, it is possible that adjuvant therapy will improve outcomes in this population as new strategies are developed.
Adjuvant and Combination Therapy with Gemcitabine
Gemcitabine has become the standard treatment for advanced pancreatic cancer. Even though it is superior to other agents, its use as a single agent confers only a small benefit. A large number of trials have attempted to examine the value of adding gemcitabine to other treatment protocols, with varying success.
"We are making progress with adjuvant therapy, and we do know that adjuvant therapy does improve outcomes, compared with no therapy," said Dr. Zalcberg. "Adjuvant chemotherapy is the standard of care."
The final results of the CONKO-001 (Charité Onkologie Clinical Studies in GI Cancer) study, which were presented at the American Society of Clinical Oncology (ASCO) 44th Annual Meeting, showed that in the adjuvant setting, gemcitabine is more effective than observation alone. Among patients who had undergone complete resection for pancreatic cancer, median progression-free survival was 13.4 months in the gemcitabine group and 6.9 months in the control group.
"Treatment with gemcitabine greatly improved disease-free survival…and doubled overall survival," said investigator Helmut Oettle, MD, PhD, Charité School of Medicine, Campus Virchow-Klinikum, in Berlin, Germany, during a press conference. "It should be the standard of care for adjuvant treatment of pancreatic cancer."
The CONKO-001 researchers pointed out that numerous randomized trials of gemcitabine-based combination treatment did not show better outcomes than gemcitabine monotherapy. However, 2 recent trials have reported a modest improvement in survival with a combination regimen; the United Kingdom National Cancer Research Institute (UK NCRI) GEMCAP trial; and the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) PA.3 trial.
The GEMCAP trial, which combined gemcitabine with capecitabine, was the first study to suggest that combination chemotherapy might be more beneficial than gemcitabine monotherapy in the treatment of advanced pancreatic cancer. Patients in the gemcitabine-plus-capecitabine group had a median overall survival of 7.4 months, compared with 6.0 months for gemcitabine alone, and had a 7% absolute improvement in 1-year survival (26% vs 19%). The improvement in outcome was small, but Dr. Zalcberg pointed out that another trial with a similar drug combination did not show the same effect. Although there was a trend toward a benefit in favor of gemcitabine plus capecitabine over gemcitabine alone, it was not statistically significant; it is possible that the study was underpowered.
"Even though there has been at least 1 positive study, it has not yet been published," explained Dr. Zalcberg, referring to the GEMCAP study. "Until we see the full data, we can't be sure about the extent of the benefit. For now, gemcitabine will probably remain the standard."
Biologic Agents
As with other areas of oncology, research in pancreatic cancer has begun to focus on novel targeted agents that antagonize the pathways that support the development, survival, and progression of cancer cells. Pancreatic cancer has particular biologic characteristics that suggest that this class of agents will eventually prove to be useful, the authors write.
The epidermal growth-factor receptor (EGFR) and vascular endothelial growth-factor (VEGF) pathways are believed to be relevant in the biology of pancreatic tumors. Results of the PA.3 trial demonstrated that blocking the EGFR pathway with the tyrosine kinase inhibitor erlotinib, used in combination with gemcitabine, improved survival. The difference in median overall survival between patients in the erlotinib-plus-gemcitabine group and those in the gemcitabine-plus-placebo group was small (6.24 months vs 5.91 months). However, the overall reduction in risk for death and improvement in 1-year survival with combination therapy were more pronounced (23% vs 17%, respectively).
Despite initial promise, targeting VEGF has not been successful, the authors note; other biologic agents that have been evaluated in pancreatic cancer, including the farnesyltransferase inhibitor tipifarnib and the matrix metalloproteinase inhibitor marimastat, have also shown disappointing results.
Increasing Role for Radiotherapy?
Although the efficacy of radiotherapy has never been conclusively proven with large randomized trials, it is a commonly used and widely accepted mode of treatment for patients with unresectable locally advanced disease. Radiotherapy in this setting is frequently administered with concurrent fluoropyrimidine therapy (as a radiosensitizer) , in addition to systemic palliative chemotherapy.
Some randomized trials have shown a benefit with multimodal therapy, including a study presented at ASCO in June 2008, which showed that gemcitabine plus radiotherapy was associated with a small survival benefit over gemcitabine alone among patients with localized unresectable pancreatic cancer. Although the survival benefit associated with the addition of radiation therapy to the regimen was modest, lead investigator Patrick J. Loehrer, MD, from Indiana University School of Medicine, in Indianapolis, felt that the difference was significant.
"At a minimum, I believe that this is a provocative trial that is worthy of further investigation," he said during the presentation
Two recent systematic reviews did not find a benefit for chemoradiotherapy over chemotherapy alone, although many of the studies included in the analyses had a number of limitations.
"We are increasingly becoming more sophisticated about exploring the role of radiation in patients with unresectable advanced disease," said Dr. Zalcberg. "The issue of whether we should even be doing adjuvant radiotherapy is currently being studied. The French Intergroup Study is currently exploring the role of definitive radiotherapy with chemotherapy."
Future Trends
The impact of the results of the GEMCAP and PA.3 trials on standard practice is unclear, the authors note, and it is likely that single-agent gemcitabine will continue to be used as standard treatment in many centers worldwide, at least for now.
"Now more than ever is the time for collaboration between clinicians, scientists, the pharmaceutical industry, and regulators to ensure that innovative drug combinations can be explored preclinically and clinically without having to traverse minefields of contracts between the competing priorities of multiple pharmaceutical and biotechnology companies," they write. "Such an initiative needs to be led by regulators and the major funding agencies if this type of long-term collaboration is to be fostered in the interests of future patients."
Dr. Zalcberg has received research support and/or honoraria and/or travel support from Roche, Sanofi-Aventis, Amgen, Pfizer, MerckSerono, and BMS. Coauthor Yu Jo Chua has received honoraria from Roche, Sanofi-Aventis, Pfizer, and Amgen.
Reviewed by Ramaz Mitaishvili, MD
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