We are certainly used to the idea that things change, hopefully in a positive way, over time. The Talmud tells us that gold had 25 times the worth of silver in its time (400 CE), and now gold is about 75-80 times the value of silver. Certainly changes in medicine have also occurred in the recognition and definition of new diseases and the development of treatments over time as well.
We like to herald the multiple successes, and there are many that have occurred in various areas of cancer management. But the poster child for poor outcomes and minor or negligible advances has been for pancreatic cancer. While to some degree some improvement has occurred for those patients diagnosed while still resectable, those who are diagnosed with metastatic disease or who become metastatic have little to hope for.
For many cancer sites, a similar futile situation has often been extant in the past and then some new discovery or breakthrough occurs and the situation totally brightens. The discovery of the utility of the chemotherapy drug irinotecan for colorectal cancer in 1997 was one such turnaround. The revolution in immunotherapy and its profound impact on advanced melanoma has likewise completely revolutionized that disease in a similar fashion and later had a similar effect on non-small cell lung cancer as well.
Pancreatic cancer still awaits its epiphany. What makes pancreatic cancer doubly disheartening is that we in the field thought that its revolution had occurred in 1997. An article published that year in the Journal of Clinical Oncology described a study that randomized 126 patients with advanced pancreatic cancer to either gemcitabine (Gemzar) or 5-fluorouracil (5FU), the prior standard of care drug. The median overall survival was 5.6 months for the gemcitabine group versus 4.4 months for 5FU, with 18% alive at one year for the gemcitabine group versus 2% for the 5FU group. This may seem like a trivial difference, but it was the first drug to show a clear-cut statistically significant benefit and it was hoped that with other drugs added on, it could be built into more meaningful gains.
Alas, we stand here now about 25-30 years later and the promise of this “breakthrough” has not truly been realized. Dozens, indeed close to 200 trials have been conducted with various combinations of chemotherapeutic agents to try to find regimens superior to gemcitabine alone. At present, the standard best regimens for advanced pancreatic cancer are FOLFIRINOX and gemcitabine/nabpaclitaxel.
FOLFIRINOX is a complex combination regimen of FOLinic acid, 5FU, IRInotecan, and OXaliplatin. Given the drugs that are included in the regimen, its administration is somewhat complicated from a logistical point of view, and it also has a moderately severe constellation of adverse effects. A randomized trial published in the New England Journal of Medicine in 2011 described a study in which 342 patients were randomized to either FOLFIRINOX or gemcitabine. The median overall survival was 11.1 months in the FOLFIRINOX group versus 6.8 months for gemcitabine. While this showed a definite improvement for FOLFIRINOX over gemcitabine, it is currently the best option there is, but it is obviously not a home run.
The other treatment that has shown improvement is gemcitabine combined with nabpaclitaxel. A study published in the New England Journal of Medicine in 2013 showed that if gemcitabine was combined with nabpaclitaxel, the combination resulted in an overall patient survival of 8.5 months as compared to 6.7 months for gemcitabine alone.
The bottom line is that, even with the best available treatments, the outcomes are likely to be poor. There are obviously mechanisms of drug resistance that allow the pancreatic tumor cells to resist and survive systemic therapy. The tumors are generally encased in a thick fibrous stroma which inhibits the development of vascularization, and thereby reduces the oxygen and nutritional supply to the tumor. In such an environment there is a shift in how glycolysis takes place and thus the Warburg effect comes into play for the tumor cells and favors their survival.
We are talking about the usual routine pancreatic cancer. There are subgroups for whom certain specific treatments may be more successful. These include Ashkenazic Jews who are BRCA positive with pancreatic cancer for which certain chemotherapy drugs may be more efficacious. (Pancreatic cancer is one of the malignancies for which BRCA-positive individuals are at significantly enhanced risk.) Also, patients with MSI-high tumors may be more responsive to immunotherapy drugs.
Alfred I. Neugut, MD, PhD, is a medical oncologist and cancer epidemiologist at Columbia University Irving Medical Center/New York Presbyterian and Mailman School of Public Health in New York. Email: [email protected].
This article is for educational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment, and does not constitute medical or other professional advice. Always seek the advice of your qualified health provider with any questions you may have regarding a medical condition or treatment.
