Tumor Scrubbing Bubbles in Pancreatic Cancer

We all agree that pancreatic cancer (ductal adenocarcinoma of the pancreas) 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 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 has 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 a separate ultrasound clinical trial for pancreatic cancer using gemcitabine plus cisplatin.

David Dessert