We all agree that pancreatic cancer patients need more effective treatments. Towards that goal, much research time, money and effort go into the new treatment pipeline where only a tiny fraction will emerge with approval for pancreatic cancer, up to a decade later. I’ve advocated that today’s patients need something sooner. We need to figure out how to make treatments we have right now, more effective. In this post, I present one such example.
In a recent phase 1 clinical trial known as NCT01674556, researchers in Norway have found promising results by combining gemcitabine and ultrasound on ten pancreatic cancer patients who were stage 3 and 4. Using gemcitabine, commercially available ultrasound equipment, and SonoVue®, a sonogram contrast agent with microbubbles, they raised the median overall survival in these patients with pancreatic cancer from 8.9 to 17.6 months (p=0.011). The patients tolerated many more treatments (13.8 ± 5.6 cycles versus 8.3 ± 6.0 cycles (p=0.008, unpaired t-test). And 5 of 10 of the patients saw their pancreatic tumor size decrease.
Patients were intravenously given gemcitabine for 30 minutes (a standard pancreatic cancer treatment duration). A 31.5 minute sonogram treatment followed where patients received periodic doses (every 3.5 minutes) of sonogram contrast agent while an ultrasound probe targeted the tumor.
The same research group published an earlier set of results using gemcitabine, microbubbles, and ultrasound with similar results on five patients with pancreatic cancer.
We must remain aware that these are phase 1 results on ten Norwegian patients. The comparison group was a set of 63 similar patients with pancreatic cancer treated with gemcitabine prior to the trial. If we are to get full-on excited about this, it needs to be tested head-to-head against gemcitabine by itself using patients randomly selected to each treatment.
What’s going on here?
Gemcitabine must get inside the tumor cell in order to disrupt cell division. It enters by diffusion through the cell membrane. Higher concentrations of gemcitabine outside the cells diffuse inside to equalize the concentrations levels. Gemcitabine passes through the cell membrane to get inside, which takes some effort (energy). Because there’s a barrier to overcome, the transfer of gemcitabine from outside to inside the cell is slowed. The result is that gemcitabine penetration into the cell is not complete. Likely a lot of gemcitabine will be cleared out before it can work against the tumor.
An interesting fact about the cell membrane (see Khan Academy biology videos) is that it is not fixed and taut like the surface of a balloon. The cell membrane is like a sheet of fluid made of molecules that shift around. In fact, cell surface proteins and receptors float around the membrane sheet like ships on the sea. Certain molecules can diffuse through the membrane with rates determined by size and charge.
Given these two ideas, how can they facilitate gemcitabine’s diffusion through the cell membrane? Previous research had already shown that ultrasound can destabilize the fluid-like cell membrane to allow molecules to penetrate it more easily in a process called sonoporation. If we follow an infusion of gemcitabine with ultrasound waves directed at the tumor and we can increase the tumor cell’s uptake of chemotherapy. Another attractive aspect of this is that the increased uptake is where the ultrasound waves are directed – at the pancreatic tumor site.
This technique may have achieved increased activation of chemotherapy at the physical intersection of two treatments. Chemotherapy and the sonogram microbubbles, which are body-wide agents, and ultrasound waves which can be directed at the pancreatic cancer tumor. This is not unlike how multiple directed beams of radiation are used to maximize the effect at the tumor. Could a similar technique be used to activate a treatment only at the tumor site?
I look forward to their next steps, with a larger trial and different type treatments. Researchers in Beijing have already started their own ultrasound clinical trial for pancreatic cancer using Gemcitabine & Cisplatin (NCT02233205).
More than a year ago (10/22/15), the U.S. Food and Drug Administration approved a modified form of the FOLFIRINOX regimen as a second line treatment for patients with metastatic pancreatic cancer whose gemcitabine-based therapy had failed. We reported this development Here.
The modified FDA-approved regimen was different from the “standard” FOLFIRINOX for pancreatic cancer in that the oxaliplatin element was dropped, and the irinotecan was substituted with a liposomal irinotecan known as Onivyde (by Merrimack Pharmaceuticals, and known earlier as MM-398 and PEP02). The concept underlying this modification was aimed at seeing if similar or improved efficacy could be achieved in the treatment of advanced pancreatic cancer with a lessening of the tough side-effects of the multi-drug chemotherapy regimen.
The data related to this approval was primarily gleaned from the so-called NAPOLI-1 clinical trial for pancreatic cancer which was essentially fully available in November 2015, but was finally more widely available in the February 6, 2016 issue of the journal Lancet. The primary authors and researchers were world-wide in scope, and the pancreatic cancer research entities included TGen, Merrimack Pharmaceuticals, and Washington University among many others. The results were promising, and as promised.
Most of the subsequent recent research related to this or related drug regimens for pancreatic cancer have been either heavily oriented to reviews of the NAPOLI-1 results, or a further explication of the properties and effects of liposomal irinotecan, Onivyde. Please note Here, Here, and Here.
One interesting more stand-alone study was done by Ohio State University, Emory University and Israeli researchers as published in the April, 2016 issue of the British Journal Medical Oncology. They compared the Onivyde modified FOLFIRINOX regimen (sans oxaliplatin) with 5-fluorouracil/leucovorin “alone” in the treatment of metastatic pancreatic cancer in a forty pancreatic cancer patient cohort who had previously failed one line of gemcitabine therapy. The median progression free survival of the modified regimen was 2.59 months, and the median overall survival duration was noted as 4.75 months.
The authors concluded that the Onivyde modified FOLFIRINOX treatment regimen in the context of heavily pre-treated advanced pancreatic cancer patients appeared to confer survival advantage with reasonably tolerable side-effects.
Thus, the confirmation of the possible advantages of modified FOLFIRINOX, including liposomal irinotecan, as second line after gemcitabine failure in the treatment of advanced pancreatic cancer as was suggested by the NAPOLI-1 study continues to appear promising. Further research, confirmation and creativity eagerly awaited !
Dale O’Brien, MD
At one point several years back, we at Pancreatica looked at the number of studies in pancreatic cancer that dealt with early detection versus those aimed at treatment. We found that less than 3% were aimed at the detection of pancreatic cancer. This rate has since increased, but when interesting studies related to the early detection of pancreatic adenocarcinoma are published, we try to highlight them.
Thus, we note with interest the work of researchers from the United kingdom and Spain which include a number of those well known to the pancreatic cancer literature including John Neoptolemos and Nick Lemoine who published a paper in the August 2015 edition of Clinical Cancer Research (the official journal of the American Association for Cancer Research) that presented an intriguing method aimed at the early detection of pancreatic cancer. The authors developed an inexpensive three-protein panel array of biomarkers which appears to identify early stage pancreatic adenocarcinoma via a non-invasive urine test.
After preliminary work, in-depth proteomic urine analysis was performed on 18 individuals (nine women and nine men), six each with adenocarcinoma of the pancreas, chronic pancreatitis, and healthy volunteers. Approximately 1,500 proteins were identified. The protein array in men and women was not identical, and only 481 were found to be common to both. From this group, three proteins were selected on careful examination as expressing discrimination for pancreatic cancer. Two of these, REG1A and TFF1, had already been shown to be associated with adenocarcinoma of the pancreas; LYVE1 had not.
On subsequent testing, this three-panel urine protein array demonstrated a sensitivity for the diagnosis of adenocarcinoma of the pancreas of greater than 75%, and a specificity of greater than 85%. The panel showed increased concentration of the biomarker in early stage pancreatic cancer, as well as late stage. It discriminated between pancreatic cancer and chronic pancreatitis. In stage I-II pancreatic adenocarcinoma, the 3-panel biomarker showed a higher AUC of 0.97 (95% CI, 0.94-0.99) than that of serum CA19.9. And though adding the serum 19.9 results to the urine panel increased the AUC to 99%, it did not improve upon the diagnostic identification by the 3-protein urine panel of early stage pancreatic cancer patients as compared with that of the urine in healthy controls.
The authors conclude that this three-protein urine panel is a tool that can detect stage I and II pancreatic cancer with over 90% accuracy.
This research is an impressive study which deserves further confirmation, explication and possibly practical application. We applaud the ingenuity and care of the authors of this impressive and grounded systematic investigation.
Dale O’Brien, MD