In a sense, the pancreatic cancer research underlying this blog posting is a bookend to the one that we discussed here in the Pancreatica Blog about a month ago. Then, researchers had incorporated the Ki-67 cell proliferation marker into a standard Tumor-Node-Metastasis system (American Joint Committee on Cancer – AJCC) to see if the novel schema improved concurrence between staging and survival duration prediction in pancreatic adenocarcinoma – the most common form of pancreatic cancer. It did.
In the present study, the researchers also tried to discern a relationship between a standard TNM system (European Neuroendocrine Tumor Society – ENETS) and the grade of cell proliferation as represented by Ki-67 level, but now in neuroendocrine tumors.
Ki-67 is an antigen, also known as MKI67 that appears to be essential for cell proliferation in humans. It is integral to ribosomal RNA transcription, and is encoded by the human gene MKI167. Its name is derived by the city of its discovery (researchers in Kiel, Germany), and the number of the lab dish on which it was found. As evolved, the referent labeling index represents that portion of sample cells which are Ki-67 positive. At its most basic level, the Ki-67 index IS a measure of cell proliferation. This index number appears to be correlated with the clinical history in a number of tumor types. The higher the index, the more aggressive the clinical course of the cancer.
Frilling and colleagues from the Imperial College London UK published the results of their work in the area of TNM staging and Ki-67 marker levels in neuroendocrine tumors on February 4, 2014 in the World Journal of Surgery, a publication of the International Society of Surgery. In this retrospective study, the researchers reviewed the records and laboratory results of 161 patients with neuroendocrine tumors of the GI-pancreatic organ system seen at the Imperial College Healthcare Trust between the years 2010 and 2012. The patients were divided into three Ki-67 level cell differentiation categories according to ENETS recommendations: G1 (low to intermediate grade cell differentiation), G2 (well to moderate grade cell differentiation), and G3 (moderate to poor cell differentiation).
The researchers found that in patients with neuroendocrine tumors, the more advanced the stage the higher the Ki-67 index levels. This finding was tempered by the observation that the organ of origin also was strongly correlated with Ki-67 levels.
The findings of this study move our understanding forward. One point to note is that in the United States’ SEERS cancer registry data show about 27% of patients with neuroendocrine tumors as having distal metastases, whereas the European registry databases typically show this figure at 44% to 73%. Whether this staging difference represents a different natural history, a difference in staging criteria, or a difference in diagnosis, remains to be seen.
Nevertheless, this is an interesting finding that appears to further integrate our understanding of TNM staging and cell dynamics, as we try to better integrate staging with prognosis in neuroendocrine tumors.
Dale O’Brien, MD
The findings of the European Study Group for Pancreatic Cancer (ESPAC-1) clinical trial and championed by surgeon John Neoptolemos of Liverpool University more than a decade ago challenged the assumption that chemotherapy combined with radiation was a superior regimen after pancreatic cancer (ductal adenocarcinoma of the pancreas) surgery. The chemotherapy alone arm of this trial (using bolus 5-fluorouracil with folinic acid) showed improved survival advantage over the multi-modal (chemoradiation) arm post-surgery for cancer of the pancreas.
But subsequently, aspects of the clinical trial including the conclusions of ESPAC-1 have in turn been challenged. And the debate including dueling non-dispositive research findings back and forth has continued to rage. We have covered this matter HERE and HERE.
Now comes an interesting study by Lipscomb and colleagues from the Department of Surgery at Emory University as published in the October 2013 issue of the Annals of Surgical Oncology. These researchers surveyed and queried the U.S. National Cancer Data Base in terms of overall survival, reviewing the results of more than eleven thousand patients who had received pancreatic cancer surgery over a four year period (1998 – 2002). They developed propensity scores to help produce matched samples for those patients receiving adjuvant chemotherapy versus chemoradiation versus no adjuvant therapy.
The authors found that adjuvant chemoradiation offered the longest duration survival advantage (overall survival) over chemotherapy and no-adjuvant-therapy with a hazard ratio of 0.70 (95% CI of 0.61 – 8.0).
This study is pretty strong tea – and should serve as ammunition in the adjuvant therapy wars. It is possible, as earlier research has hinted, that certain variables may mitigate toward one approach or another. In the meantime, we expect that the debate to carry on for now.
Nevertheless, this clever research work by the Emory University group is powerful dispassionate evidence for the possible superiority of chemoradiation for the adjuvant treatment of pancreatic cancer.
Dale O’Brien, MD
One of our favorite physician pancreatic cancer researchers, Daniel Von Hoff, has been honored by induction into the Joshua Lederberg Society on February 13, 2014 primarily for his work in shepherding the development of Abraxane (nab-paclitaxel) in combination with gemcitabine for the treatment of advanced cancer of the pancreas (ductal adenocarcinoma of the pancreas). This award is presented by Celgene (which the late Dr. Lederberg, a Noble laureate, helped found) on the criteria of researchers whose work has changed the practice of medicine. Celgene produces Abraxane which is now approved for the treatment of pancreatic cancer.
Daniel Von Hoff is certainly one of the world’s foremost experts on pancreatic cancer. Presently, he is the Physician in Chief and Director of Translational Research at the Translational Genomics Research Institute (TGEN) in Phoenix. He is also the Chief Scientific Officer for US Oncology, and a Clinical Professor of Medicine at the University of Arizona.
Interestingly, in the mid-1990s Dr. Von Hoff led a team in key early clinical studies on the drug-agent gemcitabine for the treatment of advanced pancreatic cancer. The U.S. Food and Drug Administration (“FDA”) approved gemcitabine for the treatment of pancreatic cancer in 1996.
In the case of the more recent Abraxane plus gemcitabine work, Dr. Von Hoff functioned as the lead of an international consortium of 151 academic and community centers in eleven nations in Europe, including the United States and Australia. The study was called the Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT), eventually evaluating the outcomes of 861 patients with advanced pancreatic cancer.
The results of the research from this Phase III clinical trial were published in the October 31, 2013 issue of the New England Journal of Medicine. Essentially, the combination regimen of gemcitabine and Abraxane demonstrated an improved survival benefit for patients with advanced pancreatic cancer over that of treatment with gemcitabine alone. The Pancreatica Blog has followed the results of this work Here, Here and Here. The combination of Abraxane plus gemcitabine for metastatic pancreatic cancer was approved by the FDA in September 2013. In December, the European Commission followed suit.
Dr. Von Hoff took his undergraduate degree at Carroll College in Montana, and his MD from the Columbia University College of Physicians and Surgeons in New York. He took residency at UCSF and completed a Fellowship in oncology at the U.S. National Cancer Institute.
Dr. Von Hoff is currently serving on the U.S. National Cancer Advisory Board. He is a past president of the American Association for Cancer Research (AACR). And he has served on the ASCO Board of Directors. He has received numerous awards in medicine. Dr. Von Hoff has to his credit the publication of two medical books, more than 135 book chapters and more than one thousand scientific papers.
Dale O’Brien, MD
Dr. Daniel Von Hoff