In a certain way, the initial treatment considerations for local and advanced pancreatic cancer are not as complex as those of locally advanced adenocarcinoma of the pancreas. Local cancer is typically treated with surgical resection – some version of the Whipple Procedure. And the treatment of advanced pancreatic cancer is generally some form of chemotherapy regimen. The “standard” for non-operable locally advanced pancreatic cancer has been chemoradiation. And an active area of inquiry has been the best treatment option for borderline resectable locally advanced pancreatic cancer, or perhaps unresectable locally advanced pancreatic cancer as based on vascular encasement or abutment by the tumor.
Now comes a study by Allendorf and his surgical colleagues from Columbia University in New York City that examines outcomes for over five hundred patients who received the pancreaticoduodenectomy (Whipple) surgery for locally advanced pancreatic cancer at Columbia from the years 1992 to 2011. The authors’ review of patient records treated at their institution initially found 643 patients with locally advanced disease who had appeared to fit surgical criteria. At surgery, only 506 of these patients were found by the operating surgeon to merit surgery. Published in the May 2014 edition of the World Journal of Surgery, the authors looked at survival duration in terms of neoadjuvant status as well as whether vascular resection was done.
The authors found that although neoadjuvant therapy appeared associated with an increase in operative mortality (7% vs. 3%), that more neoadjuvant pancreatic cancer patients underwent vascular resection, and that neoadjuvant therapy status significantly increased overall survival (as compared to no receipt of neoadjuvant treatment) at a p < 0.5 confidence level of 27.3months versus 19.7 months.
It tentatively appears that certain patients with apparently unresectable locally advanced pancreatic cancer – as determined by traditional criteria – may gain a potentially improved survival advantage if they respond to neoadjuvant therapy such that they then become candidates for pancreatic surgery, including vascular resection.
This is an interesting and fine study that on one hand further complicates the treatment landscape for locally advanced pancreatic cancer, but offers potential improved results for many.
Dale O’Brien, MD
Our non-profit organization has been honored as the beneficiary of an incredible effort made by eleven 8th graders on a mission to help support pancreatic cancer.
With the support of friends, family, teachers, coaches and neighbors they put on a 5K Fun Run Event. These extraordinary young members of the National Junior Honor Society at Harrison Middle School have shown astounding dedication to help a very serious cause. We sincerely thank them and their community for such a generous exhibition of human kindness.
We are very impressed by their social effort, humbled by this effort, and grateful to these young men and women – and to the efforts of their families and community. Thank you guys !
Dutch and primarily other European researchers are about to begin a human clinical trial involving a regimen of two relatively new targeted therapies (afatinib plus selumetinib) for the treatment of pancreatic cancer. Afatinib is known as Gilotrif in the U.S., and is produced by the family-owned global but German-headquartered Boehringer Ingelheim Pharmaceuticals firm. Selumetinib is produced by the AstraZeneca firm (AZ); it is currently in the Phase III SELECT-1 clinical trial in combination with docetaxel for the second-line treatment of KRAS positive non-small cell lung cancer. AZ is partnering with Roche Molecular Systems to develop a test marker to help identify those patients who are most likely to respond to selumetinib.
The lead institution for the upcoming clinical trial involving pancreatic cancer will be the Antoni van Leeuwenhoek Hospital in Amsterdam. The work is based on earlier study by Bernards, Sun and other researchers who laid the predicate for this research in a recently published medical article on March 17, 2014 in the journal Cell Reports about the effects of this combination regimen in overcoming Kras resistant lung and colon cancer. The coming human clinical trial will also include lung and colon cancer, as well as pancreatic cancer.
The mutated ras oncogene is found in approximately 90% of cases of pancreatic cancer (pancreatic adenocarcinoma), and generally in about 20 – 30% of human cancer. These cancers tend to be ones that are particularly difficult to treat – with a tendency to poor outcome. In fact, one of the four specific initiatives proposed by the recent Scientific Framework for Pancreatic Ductal Adenocarcinoma of the U.S. National Cancer Institute is: “Developing new treatment approaches [for pancreatic cancer] that interfere with RAS oncogene-dependent signaling pathways.”
The recent study by Bernards et al. on Kras mutant colon and lung cancer found that suppression of the tyrosine kinase receptor ERBB3 had the effect of sensitizing these tumor cells to MEK inhibitors. Afatinib is a tyrosine kinase receptor inhibitor that not only affects epidermal growth factor receptor (EGFR – as does erlotinib -Tarceva), but also acts in a wider manner in these regards. Afatinib received U.S. FDA approval on July 12, 2013 for the treatment of metastatic non-small cell lung cancer which has EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test. Selumetinib blocks the enzyme MAPK kinase (MEK) that is just “downstream” from the BRAF gene and which is also involved in the Kras gene signaling pathways.
In the recent published study, the authors found that the combination of these targeted therapies acted synergistically in promoting cell death in Kras resistant lung and colon cancer cells, AND in significantly reducing tumor growth (to about zero growth over the 4-week study period) in referent mice models. It is easy to see why the authors have now added pancreatic cancer to the study.
Thus, the researchers have presented biological plausibility of the regimen in mutated Kras tumors and have established a basis for possible preliminary efficacy in pre-clinical studies. And so the process of human testing begins. It will be of some interest to see if the efficacy holds in human subjects, and what the tolerability profile will reveal. And the effect specifically on pancreatic cancer. This is interesting and promising work.
Dale O’Brien, MD