Although the true origin of the Latin phase “Primum non nocere” (First, do no harm) is a little murky, the principle can be traced to at least Hippocrates (or one of his students) written in Ionic Greek 2,500 years ago, and as recently as likely ALL first year training in contemporary medical schools. How might this principle play out in pancreatic cancer, arguably the most aggressive of malignant tumors?
A recent study by Michael Wallace, MD, MPH and colleagues from the Mayo Clinic examined the records and outcomes of more than two thousand patients who received surgery for “locoregional” (roughly: locally advanced) pancreatic cancer via SEER [Surveillance, Epidemiology, and End Results] cancer patient data to evaluate the possible advantage or disadvantage of obtaining a fine needle biopsy through the bowel wall to reach the tissue of a suspected pancreatic tumor to aid in the diagnosis of pancreatic cancer. For the purposes of this study, pancreatic cancer was defined as an adenocarcinoma, mucinous cystadenocarcinoma, intraductal papillary mucinous carcinoma of the pancreas, malignant endocarcinoma, or malignant carcinoid tumor.
Wallace and colleagues published the results of their work in the July issue of the well-named journal Gut (one of the British Medical Journal publications).
The use of a fine needle aspiration per esophageal ultrasound (EUS-FNA) is fast, relatively easy to perform, relatively benign as procedures tend to go, and could spare many patients much more intrusive procedures on the way to diagnosis. However, there has been a sense in the oncology community that the use of a needle to obtain a possible malignant tissue specimen and pulling that tissue via needle through body walls, space and other tissue may well “seed” the needle track with pancreatic cancer and even, for example, the peritoneum with in effect ready-made malignant metastases. Thus, this would violate perhaps the cardinal rule in medicine – do no harm. Several cases of such pancreatic cancer needle track seeding are present in the medical literature, but each of these is of cancer either from the body or the tail of the pancreas. There have been no reported cases related to FNA of pancreatic cancer from the head of the pancreas. So, the results of this current study are timely and perhaps more interesting and resonant than may first appear.
2,034 patients were identified by the researchers from the SEER database who met the study criteria of logoregional pancreatic cancer. All of the patients were aged 66 years or older, as this was a U.S. Medicare cohort. 76% of the patients (1,536) were in the (non)EUS-FNA arm and 24% (498) were in the EUS-FNA arm. 90% of the patients had adenocarcinoma of the pancreas. During the average (mean) review period of twenty-one months, 76% (1167) of the patients in the (non)EUS-FNA arm, and 57% (285) in the EUS-FNA arm died.
At analysis, the researchers found that the use of EUS-FNA was somewhat mildly associated with overall survival (but not cancer-specific survival). More importantly, the study data appears to show that the EUS-FNA procedure can be safely utilized as a part of the diagnostic work-up and evaluation for pancreatic cancer.
This gives impetus toward the use of EUS-FNA as a possible less intrusive aid for the diagnosis or exclusion of pancreatic cancer. The study may not be definitive, but gives comfort for a current indication. In time, more direct studies will undoubtedly offer better understandings as to more indications and contraindications related to the utilization of this procedure.
Dale O’Brien, MD
Yesterday, European researchers and those from MD Anderson Cancer Center/ University of Texas in Houston published an article in the prestigious journal, Nature, which carries the possibility of being a game-changer in the earlier diagnosis and consequent treatment of pancreatic cancer (ductal adenocarcinoma of the pancreas). It is difficult to overstate the potential for significant positive effects of these findings in the treatment of pancreatic cancer should the fascinating results bear up under replication and scrutiny.
The results of the presented research identify a diagnostic marker for pancreatic cancer that exists as an exosome containing a specific protein/saccharide complex that is attached to the outside wall of its spherical structure as it courses its way through human fluids (including serum) in humans with pancreatic cancer. This proteoglycan marker is known as glypican-1, a cell surface heparan sulfate.
The presence of these “glypican-1 exosomes” in human serum demonstrated 100% sensitivity and 100% specificity as to the presence of pancreatic cancer in individuals. These remarkable findings were seen in late and early pancreatic cancer, and extended even to the putative precursor: intraductal papillary mucinous neoplasms (IPMNs).
Here at our Pancreatica blog we have been intrigued by “exosomes” in the interest of the earlier diagnosis of pancreatic cancer for a while [Here] and [Here]. Exosomes, first discovered in the 1980s, are round lipid structures containing intracellular bits of RNA, DNA, parts of cellular proteins, and other substances. In a process that is not fully understood (and which may not be uniform) exosomes appear to be formed by the pinching off or budding of a cell wall. The resultant small structure has a typical diameter of approximately 30 to 100 nanometers, and essentially “floats” through the fluids of the mammalian body. Exosomes are found essentially in all fluids including, for example, saliva. It has been thought that the function of exosomes may include extracellular communication, waste disposal, unknown immune response or interaction, and tumor invasion. An exosome appears to be able to transfer its contents from one cell to another, even at a distance.
The fifteen named authors of this study are researchers from medical institutions in Dresden, Germany; Porto, Portugal; Orviedo, Spain; Madrid, Spain; and Houston, Texas. The corresponding author is Raghu Kalluri, MD, PhD at the Department of Cancer Biology, Metastasis Research Center, University of Texas/ MD Anderson Cancer Center, Houston, Texas 77054, USA. The 29-page article was published on June 24, 2015 in the journal Nature.
The research was done with cell lines, mice, and in human subjects. Other findings of this work demonstrate that the level of the concentration of the glypican-1 exosomes is correlated with overall pancreatic cancer tumor burden, and with the survival duration of pre-operative and post-operative patients. Glypican-1 exosomes reliably demonstrate KRAS mutation (common in pancreatic cancer, and thought to be an oncogenic driver) in messenger-RNA found in the structures. Glypican-1 exosomes appear to be a more valid biomarker than CA 19-9 for the detection of pancreatic cancer. In genetically-engineered mice models, glypican-1 exosomes are detectable in serum before pancreatic cancer tumors show anatomically by MRI. If the findings hold, the increased specificity of the glypican-1 exosomes avoids the pitfalls of confusion with pancreatitis or other pancreatic disorders, as is now the case with a number of biomarkers including CA 19-9.
The researchers additionally found increased glypican-1 exosome levels (but not as definitive) in breast cancer. And they note that glypican-1 could serve as a pan-specific marker of cancer exosomes.
The pancreas related patients and healthy controls were all from Germany: the University Hospital of Heidelberg and the University Hospital of Dresden. These included 246 patients with pancreatic cancer (pancreatic ductal adenocarcinoma), 24 patients with pancreatitis, 8 patients with a benign serous cystadenoma, 5 patients with diagnosed IPMN, and 20 healthy controls. The University of Texas / MD Anderson Cancer Center contributed data from 32 women with breast cancer.
In passing, we note that heparan sulfate is a member of the glycosaminoglycan family of carbohydrates and is very closely related in structure to heparin, the anticoagulant in common use. Both consist of a variably sulfated repeating disaccharide unit.
These research findings are remarkable. If replicable and verified, they will be a major breakthrough for the early diagnosis of pancreatic cancer. This could lead to potentially curative surgery for a major portion of those found to have pancreatic cancer, which now is available only to about 15% of patients upon diagnosis. We eagerly await confirmation.
Dale O’Brien, MD
In a certain way, the initial treatment considerations for local and advanced pancreatic cancer (ductal adenocarcinoma of the pancreas) are not as complex as those of locally advanced pancreatic cancer. 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