Pancreatic cancer is one of the most difficult cancers to treat and challenging to diagnose. It is rare that a patient will be diagnosed early. Symptoms tend to be vague and unfortunately are not usually identified until the disease has already advanced. To date, the five-year survival rate for pancreatic cancer is one of the lowest, approximately 10%.
Gulam Manji, MD, PhD, is a leading expert in pancreatic cancer and a physician-scientist devoted to conducting translational research with the overall goal to develop new treatments for cancer. Much has been spent on finding better treatments for pancreatic cancer and investigating novel combination therapies that are more effective with less adverse effects. As director of medical oncology and translational research for the Pancreas Center at Columbia University Irving Medical Center and a member of the Tumor Biology and Microenvironment research program at the Herbert Irving Comprehensive Cancer Center, Dr. Manji discusses exciting key advances in the field and what the future holds for treatment and research.
Why is pancreatic cancer so difficult to diagnose and treat? What are the main challenges?
Unlike colon cancer where there is colonoscopy for screening, there is no screening test for pancreas cancer. Many times the symptoms are vague. The median age of diagnosis is in the mid-60s, and the initial symptoms are upper stomach or back pain, which are non-specific symptoms that don’t initially make you think of pancreas cancer. These symptoms linger and when the pain worsens with other alarming signs such as weight loss or jaundice, further tests identify the underlying pancreas cancer. Since stomach and back pain are common, many patients appropriately do not undergo CT scans to identify the cause initially. Unfortunately by the time of diagnosis, for nearly 50% of patients the cancer is already advanced, and is inoperable.
The other challenge is, believe it or not, that it’s a rare disease. It’s a blessing that many physicians don’t see it often enough but on the other hand, because it’s rare, the diagnosis at times is actually missed.
What have been some of the key treatment advances?
New combination chemotherapies have truly improved survival for patients with this disease. A chemotherapy doublet and triplet are now standard treatments for patients. FOLFIRINOX, the triplet therapy, is reserved for patients who are strong and are likely to tolerate the therapy. However, gemcitabine and nab-paclitaxel, the doublet therapy is also effective. Both treatments have extended survival in this disease and are used extensively. FOLFIRINOX has improved survival not only in the metastatic setting, but also for those who undergo an operation to remove the cancer. The rationale for giving chemotherapy after surgical operation that has removed the primary cancer is to treat micro-metastatic disease or potentially residual disease, meaning any small amount of disease that is lingering and cannot be seen. This strategy has really impacted the five-year survival rates. That's where things are exciting.
There are now many combination clinical trials. Immunotherapy has changed the treatment landscape for many different types of cancer but unfortunately in pancreas cancer, it hasn’t really proven effective for a majority of patients. But now understanding the tumor microenvironment, or the neighborhood of the tumor, and identifying signals that do not allow immunotherapy to work and specifically targeting those signals in combination with chemotherapy and immunotherapy is starting to show some activity. These glimmers of hope are from early stage clinical trials with limited number of patients, so we have to be cautiously optimistic. But the number of patients whose tumors are shrinking in some early stage studies makes me hopeful for what’s ahead.
Tell us about the clinical trials for pancreatic cancer.
There are many promising clinical trials currently underway internationally, including some at Columbia University. Based on prior results from other groups in genetically engineered mice which are designed to get pancreas cancer, we conducted a large study testing chemotherapy, immunotherapy, and testing a drug which is thought to allow immune cells to enter in the tumor. This combination in mice resulted in an extension of survival and based on this study, an immunotherapy and chemotherapy combination clinical trial was just activated in patients with metastatic pancreas cancer.
We have also just activated another clinical trial based on research from Drs. Andrea Califano and Ken Olive, called Hippocrates. This clinical trial is based on sophisticated tests which are performed on individual patient’s tumor and matches them to new drugs which are predicted to control the patient’s cancer. This exciting personalized clinical trial may identify new medications which were previously not tested in this disease. Whether this trial will result in matching patients to drugs, and whether the drugs will benefit patients, remains to be determined but holds promise.
There are multiple additional clinical trials which are ongoing, with a sophisticated design aimed at targeting pancreas cancer specifically. The only way we can make headway in this disease is for most, if not all, patients to make every effort to enroll onto a pancreas cancer-specific clinical trial because the current treatments are just not good enough. If we keep on doing the same thing over and over again, and hope for a different outcome, we're not really going to make progress.
What should patients know about clinical trials?
Our clinical trials are designed such that no patients receive placebo and use drugs which have a strong rationale or data in the lab which increase the chances of identifying an effective therapy. Most of the clinical trials we have in the first line setting utilize chemotherapy, which has proven benefit. We are combining additional agents to effective chemotherapy to add to their activity.
Some of our clinical trials also include biopsies prior to starting treatment and while on treatment which are investigated in the laboratory to ensure that the changes which we expect truly occur. We need to ensure that the intended drug effects are truly occurring in the patient’s tumor so that we can accurately interpret the results of the clinical trial and design better treatments in the future. Otherwise, we may give up on a promising pathway or idea, assuming that that target is negated when it may be very different in the patient's tumor.
What does the future hold for pancreatic cancer?
Pancreas cancer is challenge but we continue to learn more about the disease every day – in the laboratory and from new clinical trials. The challenge of treating a rare disease is being countered by awareness in this disease which is resulting in patients seeking out clinical trials. Likewise, there is a push to tackle this disease head-on both in the laboratory and the clinic to better understand the fundamental mechanism which make this disease so aggressive and to target these mechanisms for improved treatments. One such breakthrough changed how we treat pancreas cancer in patients who contain a mutation in BRCA1 or BRCA2, and I am hopeful that many such discoveries will result in personalized therapies which will change outcomes.