About 10% of those diagnosed with pancreatic cancer (ductal adenocarcinoma of the pancreas) are found to have a reasonably strong pancreatic cancer family history or that of another genetic complex or syndrome which tends to include pancreatic cancer. Consequently, many family members often ask us or their medical teams what their risks are, and what measures might be taken to try and find pancreatic cancer earlier. There is no easy answer to this question as of yet. Various institutions have empirically begun to institute pancreatic cancer screening programs, often in conjunction with an attendant institution-based tumor registry. But, though research in these areas is proceeding (and pancreatic cancer tumor registries are growing in number) there is not yet a definitive answer regarding such surveillance.
We note then with interest the results of Swedish researchers including Professor Matthias Löhr from the Karolinska Institute / Karolinska University Hospital in Stockholm who published work in the June 15, 2015 edition of the JAMA Surgery journal (formerly, Archives of Surgery) in which the results of a prospective observational study using an MRI-based protocol for screening such family members were presented.
For a three year period beginning January 2010, relatives of patients with pancreatic cancer in their institution were evaluated by MRI and by looking for genetic mutations that are commonly found in pancreatic cancer. A total of 40 patients (family members) were enrolled in the study. The mean period for follow-up was 12.9 months. The number of relatives identified as possessing the common genetic mutations was 15, ranging stepwise from 5 related to one patient, down to one for another. The MRIs demonstrated 14 patients with intraductal papillary mucinous neoplasia (IPMN), and two patients with pancreatic adenocarcinoma. One additional patient was shown to have both a pancreatic cancer adenocarcinoma and an IPMN. Five patients required surgery. The additional 35 individuals remain in the surveillance program.
The researchers conclude that this MRI-based surveillance protocol appears to be working reasonably well. They acknowledge the limitations of interpretation due to the short duration of the study, but are continuing the program and the assessment of the program.
This study seems to us, given current tools, to be a reasonable early effort at establishing possible procedures and a baseline for following family members at high-risk for pancreatic cancer.
Dale O’Brien, MD
On the 22nd of October, 2015, the U.S. Food and Drug Administration approved a new combination therapy that includes the drug Onivyde for patients with metastatic pancreatic cancer (ductal adenocarcinoma of the pancreas) who had earlier been treated until progression of disease while on gemcitabine or a gemcitabine-based regimen. Onivyde is liposomal irinotecan, a topoisomerase I inhibitor (was called CPT-11, and originally derived from the plant extract camptothecin). This liposomal version was earlier known as MM-398 (and still earlier as PEP02). The combination that was approved is similar to the FOLFIRINOX regimen for pancreatic cancer, but without oxaliplatin – the 4th drug.
The liposome portion of the Onivyde refers to a fatty-like or “lipid” substance that covers the drug molecule generally creating a spherical shape. The underlying rationale typical for placing a drug-agent in a liposomal structure is to slow down absorption or to better target the drug to increase its duration or efficacy, and/or to reduce side-effects. The firm that owns Onivyde is Merrimac Pharmaceuticals of Cambridge, Massachusetts. They had or have Onivyde under study for the treatment a number of cancers including as the first line for advanced pancreatic cancer, breast cancer, pediatric sarcoma, brain cancer, and pediatric solid tumors.
This now approved FDA combination includes three drugs: Onivyde, with 5-FU and leucovorin. The full FOLFIRINOX regimen includes four drugs: irinotecan (standard version), 5-FU, leucovorin, and oxaliplatin. FOLFIRINOX has been in frequent use as first line therapy in advanced pancreatic cancer beginning from the May 12, 2011 study published in the New England Journal of Medicine (NEJM) that demonstrated an overall survival of those with metastatic pancreatic cancer in the FOLFIRINOX treatment arm of 11.1 months compared with 6.8 months in the gemcitabine treatment arm.
Since that time, the Pancreatica Blog has also been interested in a number of studies that have looked at so-called “modified FOLFIRINOX regimens.” For example, one combination that entirely avoided the use of irinotecan. Another, substituted the drug-agent S-1 for 5-FU. Still another study modified the dosages of the agents such that the side-effects might be reduced while still aiming to maintain the efficacy for combating pancreatic cancer.
The most recent previous published article on Onivyde for advanced pancreatic cancer that we have been able to find (anywhere) is a Phase II study published on August 20, 2013 in the British Journal of Cancer by authors including a member of our Science Board, Professor Margaret Tempero. This study was commented on at the time here in the Pancreatica Blog. Onivyde had earlier received orphan drug status with the FDA for pancreatic cancer and was eligible for a Priority (expedited) Review.
It appears that the much of data used by the FDA in determining its decision came from the NAPOLI 1 Phase III randomized open-label clinical trial that was begun on December 14, 2011 (estimated time of completion was June, 2015) for those with pancreatic cancer (417 patients; 79 study locations worldwide) who had become refractory to gemcitabine regimens. The three arms of this clinical trial included one for the use of Onivyde infusion alone, one for 5-FU and leucovorin, and one with Onivyde together with 5-FU and leucovorin. The metastatic pancreatic cancer patients who received the full three-drug combination had a median survival duration of 6.1 months, compared to 4.1 months with just 5-FU and leucovorin. There was not an advantage of Onivyde alone over 5-FU and leucovorin.
The two most common very serious side-effects of the Onivyde regimen resulting in what will be a boxed package warning are severe leucopenia (low white cell count) and diarrhea.
Until now, there has been no generally agreed upon official second line treatment for pancreatic cancer. This three-drug Onivyde regimen, as approved by the FDA, will be the first (of a sort). But there are some points that should be made. The results need to be verified. The liposomal form of irinotecan (Onivyde) may well be superior to the standard form of irinotecan in combination, but this will require more study to fully determine. The Onivyde regimen will need to be compared to the standard FOLFIRINOX regimen (and other modified FOLFIRINOX regimens) in the treatment of pancreatic cancer in those for whom gemcitabine regimens have allowed disease progression. And it should be noted that the survival advantage of the Onivyde regimen over that of 5-FU and leucovorin was somewhat small.
With these caveats, one might say that this FDA approval likely represents a modest step forward in the treatment of advanced pancreatic cancer in those for whom gemcitabine regimens have failed. And certainly this work establishes a new waypoint by which to compare further research on the range of options for the second line treatment of pancreatic cancer.
Dale O’Brien, MD
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