Smokers are three to four times more
likely than nonsmokers to develop pancreatic cancer.

Surviving Pancreatic Cancer -- Full-Length Doctor's Interview

Ivanhoe Broadcast News Transcript with
Kenneth Chang, M.D., Gastroenterologist,
H.H. Chao Comprehensive Digestive Disease Center, University of California, Irvine,
TOPIC: Soothing Back Pain

What’s the incidence of pancreatic cancer?

Dr. Chang: The pancreatic cancer incidence is 28,000 to 30,000 cases per year, and it’s the fourth leading cause of cancer death in the United States.

When pancreatic cancer is diagnosed, what is the prognosis?

Dr. Chang: The prognosis is terrible. This cancer has the worst prognosis of any solid tumor. The mortality rate per year is almost the same as the incidence rate. So, 28,000 diagnosed per year and 28,000, close to 28,000, die per year.

Why do you think that is? Is it not detected until the later stages, or is it just such a hard cancer to treat?

Dr. Chang: Pancreatic cancer often, by the time patients have symptoms that present, it already is an advanced case. Even when it’s detected at a small size, because of the surrounding vasculature, the pancreas is very well vascularized, so the cancer has a chance to spread and metastasize to the bloodstream even early on.

Before the symptoms appear, is there a screening test to detect it earlier, before symptoms could ever appear?

Dr. Chang: There is a small number of the population that is at risk, and they would be people with family members with pancreatic cancer, especially if they had more than one first-degree relative. There are screening tests available -- one of the most powerful diagnostic ultrasounds, endoscopic ultrasound. However, that’s considered a minimally invasive procedure, and so you cannot apply that to the general population. There is no sensitive and specific, easy blood test, serum marker, that can screen for pancreatic cancer at this time. So, for the most part, we wait for symptoms, unless we can identify a family of pancreatic cancer. Then we can start screening early.

What are currently the standard treatments?

Dr. Chang: Standard treatment includes surgery, chemotherapy and radiation therapy. If the cancer is very, very small, very localized, less than two centimeters, then surgery is the mainstay of therapy. The surgery is quite extensive. The operation that’s performed is called a Whipple resection, and in that resection, half of the pancreas, portions of the duodenum, gall balder and bile duct are all removed and everything is put together. So, surgery is the mainstay, and surgery represents the only chance for cure, although even with surgery, the chance for cure is very small. Surgery offers the only chance for cure. In very early, localized disease, surgery at best can offer a 25 percent to 30 percent cure rate, even in very small, limited tumors. The other therapies that are available include chemotherapy and radiation therapy. Chemotherapy and radiation therapy are usually reserved for palliative treatment -- patients who are not thought to be curable -- but therapy is offered to hopefully extend life and increase the quality of life.

Is there an average survival after you’re diagnosed?

Dr. Chang: The median survival in patients with advanced pancreatic cancer is somewhere in the range of three months to six months, if they don’t receive any treatment. With palliative treatment -- chemotherapy, radiation therapy -- that may extend that to perhaps six months, nine months, but usually within the year, most patients don’t survive.

So the intent of chemo and the radiation isn’t necessarily to stabilize the disease and shrink the tumor?

Dr. Chang: The hope of chemotherapy and radiation therapy is palliative, meaning try to shrink the tumor, keep it from spreading, try to keep it at bay, and try to extend life as long as possible. But we don’t usually talk about cure with chemotherapy and radiation therapy.

When is surgery is not an option for these patients?

Dr. Chang: Surgery is not an option when the tumor is large, when it has metastasized to lymph nodes, especially lymph nodes that are away from the tumor, when the tumor has extended into vital blood vessels near the tumor, as well as if it has metastasized to the liver or somewhere more distant.

What is this new drug you’re studying?

Dr. Chang: This new treatment modality that we’re studying is very new, cutting edge and very exciting. It’s a new paradigm in cancer treatment. What it involves is a product called TNFerade, which is a tumor necrosis factor that is delivered by a virus into the cancer. The background of this is that our immune cells produce TNF, which is a cytokine protein that has anti-tumor properties. It kills cancer cells, but in small quantities. It’s produced in small quantities by our immune cells. So, the concept is that if we took the TNF and injected large quantities into the patient, the toxicity would be overwhelming. The challenge is to produce TNF inside the cancer cell and only in the cancer cells and not in the normal cells. What has been designed then for this therapy is to take the human TNF alpha gene and place that gene into a virus. The virus is also especially engineered not to replicate and cause viral illness. So, the virus is a vehicle to deliver the gene. That has been delivered to the tumor through yet another breakthrough in terms of a medical technology with endoscopic ultrasound. Endoscopic ultrasound is a scope that goes into the body, into the stomach, just like a routine endoscopy, but it allows us to see through the stomach into the tumor and we can then place a needle through the endoscope and deliver the virus directly into the tumor working from within the stomach and GI tract. Once we deliver the virus into the tumor, we deliver four times 10 to the ninth to four times 10 to the 11th viral particles. These viruses then spread among the cancer cells and attach to the cancer cells. Once it attaches, the TNF from the virus, the TNF gene from the virus is actually injected into the cancer cells and that’s what viruses do very well.

Once the TNF gene is injected into the cancer cell, the virus itself does not replicate and dies off. So, it’s done its kamikaze mission, and it’s delivered the TNF. When the TNF is in the cancer cell, it will start to replicate and produce TNF. The TNF will then destroy the cancer cell.

Now, this therapy also works in synergy with chemotherapy and radiation therapy, so it’s actually a combined synergistic modality. So, what happens is that the patient receives chemotherapy and this is the standard 5FU chemotherapy, which has anti-tumor effect as well as causes the tumor to be more radiation sensitive. Then the patient receives radiation, and the radiation has anti-tumor effect. The radiation also has a special effect on the TNF gene. It causes the TNF gene to replicate much faster, so it steps on the gas pedal. So now the TNF is being produced in larger quantities. The TNF has anti-tumor properties, and it also is a radiation sensitizer, so you can see that three different modalities, all synergistically, each one makes the other more potent and more powerful, so you have a really strong combination in this combined therapy.

So it is used in combination with these others, but for a reason? That’s designed very much that way.

Dr. Chang: That’s right. It’s designed in combination with chemotherapy and radiation therapy to active in synergy, as opposed to just an add-on, ABC, off-the-menu type thing.

Now how does the TNF that you’ve injected react after it’s worked on cancer? Does it die off eventually?

Dr. Chang: The TNF, the gene for TNF is in the cancer cell and the cancer cell itself will produce TNF. Then the TNF will destroy the cancer cell. There may be some spillover once the cancer cell is destroyed, but the half-life of TNF is rather short, and the chance of it spreading throughout the body is very small. During the trial, we measured the serum blood level of TNF, and it’s not detectable in most patients.

Is it a one-time injection?

Dr. Chang: No. There are multiple injections. It’s once a week for five weeks.

How is that procedure done?

Dr. Chang: The procedure is an outpatient procedure. It usually takes usually less than an hour. It’s done under conscious sedation, so the patient is given some medications. They’re sleepy; they don’t remember the procedure, but they’re conscious. It’s not under general anesthesia. Usually, after about 30 minutes to an hour of recovery, the patient can go home. The procedure is called an endoscopic ultrasound, and once the patient is comfortably sedated, we insert the endoscope through the mouth and down into the stomach. From there, we use the ultrasound to image the pancreas and locate the tumor. Once we locate the tumor and we’ve got it in good position, then we advance a very fine needle into the tumor and we can see all that on our screen. We can then very precisely inject the TNFerade directly into the tumor. Part of the study is looking at EUS as the delivery system for the TNF and part of the study is looking at more traditional CT scan to deliver the therapy. When the study is completed, we’ll be comparing EUS delivery vs. CAT scan delivery.

What have the early results shown?

Dr. Chang: It’s a phase I/II, and the preliminary data was presented at ASCO this past June and they had 17 at that time, 17 evaluable patients that enrolled, of which 11 patients had enough time to have follow-up in terms of looking at response rate. Out of those, we had four partial responders, two minor responders and five stable diseases. The results showed that of the 11 patients that were followed long enough to have response to treatment evaluated, we had four patients that had partial response, two patients with minor response and five patients with stable disease, which means the tumor did not progress during the time the patient was evaluated. To achieve a partial response, the tumor needs to have shrunk at least 50 percent from the original volume, so four patients achieved that.

Tell me that about the four patients that you had at UCI.

Dr. Chang: Here at UCI, we have enrolled to date four patients in this trial. Our first patient was a success story. He came to us with a very advanced pancreatic cancer that was not felt to be surgically resectable, so he enrolled in the trial and we started the weekly injections. Each week, we had the opportunity not only to inject the TNFerade into the tumor, but we could also measure the tumor and see dynamically each week the tumor shrinking and shrinking and getting smaller and smaller. After the five-week therapy, the tumor shrunk about 65 percent from its original size. That was such a dramatic response that we re-evaluated the patient and felt that at that point he was a surgical candidate, and he went to surgery. At the time of surgery the tumor was removed, and we took careful search and biopsied throughout the area where the tumor used to be to make sure that there’s no residual cancer, and it was all negative. The specimen itself was then sent to pathology. The pathologist sliced up the tumor into small splices and looked at all the splices under a microscope, and he called me immediately saying, ‘We find no cancer cells remaining in the tumor.’ So, the patient had what we call a pathologic, complete response, which is essentially unheard of in pancreatic cancer. After the surgery he has done very, very well. He enrolled in the study back in January and we are now eight or nine months down the road. He should have, by all statistics, been dead at this time, but he is alive, he is well, he is fully functioning.

And there’s still no sign of cancer? Is there a risk of a recurrence?

Dr. Chang: Up to this time, there have been no signs of any cancer recurrence. We’ve been following very closely based on imaging, ultrasound, by CAT scan. We’ve been following the CAT 19-9, which is a blood test, tumor marker. Initially, it was very, very high. After the treatment, it went to normal, and it has stayed at normal all this time. So, we are very excited. Obviously, we need to continue to follow before we can make any claims about the results, but up to this point, we are very enthusiastic about what we’re seeing.

What was it like for you to know patients with pancreatic cancer up until now having not very good success? What was that like to see his tumor shrink and then to get those pathological reports back?

Dr. Chang: It was an unbelievable feeling. I have seen many, many patients with pancreatic cancer as that is my clinical focus, and I’ve seen so many patients die and die very quickly. This is a very aggressive cancer, and so to see a pathologic complete response and to see the patient doing so well, the feeling, I can’t even put it into words. It’s so wonderful. Obviously, we have to contain our enthusiasm. We need to finish this study and look very carefully at the data, but for that one patient, I was so happy for him and for his family, it goes beyond words.

Are there any additional side effects?

Dr. Chang: What the clinical trial showed us is that the side effects of the gene therapy are very well tolerated. With 5FU chemotherapy, you have some side effects, although they are rather mild in the spectrum of chemotherapy. Radiation therapy, there can be some side effects as well -- nausea, loss of appetite. With the TNFerade itself, there’s the potential of having a cold or flu-like symptoms, although we’ve not seen that in our patients, so overall, this is considered very-tolerable treatment for pancreatic cancer. In the clinical trial, we did not reach what’s called the maximal-tolerated dose, which would stop us from going on to higher doses. We actually went to the third-highest dose without significant toxicity.

What are the implications of this drug in pancreatic cancer?

Dr. Chang: The implications of this drug are that we have a new paradigm for treating pancreatic cancer, as well as other cancers, that this represents a potential to truly advance our ability to treat and potentially cure cancers as lethal as pancreatic cancer.

Is it under study for other cancers?

Dr. Chang: Currently there is another protocol that is a multicenter trial regarding to yet another very lethal cancer, which is esophageal cancer. The study is now ongoing in esophageal cancer. Other solid tumors will follow suit as well, I’m sure.

Is the pancreatic cancer study ongoing?

Dr. Chang: The data of the phase I and II study have been evaluated, and it looks very promising. We are continuing this study to a randomized phase in which patients will be randomized now to receive conventional chemotherapy, radiation therapy, vs. the TNFerade treatment.

Has the other enrollment started?

Dr. Chang: No. We will probably start late in the fall.

This article was reported by Ivanhoe.com, who offers Medical Alerts by e-mail every day of the week. To subscribe, go to: http://www.ivanhoe.com/newsalert/.

END OF INTERVIEW

 

If you would like more information, please contact:

H. H. Chao Comprehensive
Digestive Disease Center
(888) 717-4463
http://www.ucihealth.com/cddc

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