The incidence of pancreatic cancer in the United States is increasing at an alarming rate. With 57,600 new diagnoses and 47,050 deaths in 2020, pancreatic cancer is one of the most lethal forms of human malignancy.
Only 10% of patients survive 5 years.
The management of this cancer is very dependent upon the extent of disease.
Early-stage cancers are treated with surgery while more advanced cancers are treated with radiation and chemotherapy. With so many patients confronting the need for chemotherapy, choosing the right drug combination can literally be a matter of life and death.
Statistics That Do Not Inspire
But this is where patients suddenly find themselves adrift.
Their well-intentioned medical oncologists start spouting statistics on response rates (31% vs 23%) and survival (11.5 vs 8.5 months) that leave the average patient bewildered and depressed. Like the 1932 Irving Berlin lyric “Say it isn’t so” patients suddenly confront the very real likelihood that they will not be here one year hence.
The Common Drug Solutions for Pancreatic Cancer
To address this disease, several drug combinations have been developed.
Since its original description in 2011, the combination known as FOLFIRINOX (Conroy, NEJM, 2011) has become the standard of care followed by nab-paclitaxel plus gemcitabine (Abraxane/Gemcitabine) first reported in 2013 (Von Hoff, et al., NEJM, 2013).
However, the long-held belief that FOLFIRINOX was superior to Abraxane/Gemcitabine has not been fully supported as several recent trials have shown relative parity between these two different drug regimens.
One study, from Korea showed equivalent survival (Cho, World J. of Gastro. Oncol., 2020) and a second from MD Anderson came to a similar conclusion (Perri, et al., JAMA Surgery, 2020). Interestingly, the MD Anderson study found response rates (measureable benefit) in the pre-operative setting to be a disappointing 13% for FOLFIRINOX and 9% for Abraxane/Gemcitabine, none of which were complete responses, only partial.
For patients confronting the question "what is the right treatment for me?" an honest medical oncologist would have to say "we don't know."
How Do These Drugs Work?
When we examine these therapies more closely, we realize that they have very different mechanisms of action. FOLFIRINOX beats up the DNA like a buzz saw while Abraxane/Gemcitabine gums up the cell’s ability to pull themselves apart during the process of cell division known as mitosis (think tiny rubber bands tugging at the cell’s nucleus).
When we look at these treatments through this lens, we can then ask the rather obvious question: Is it not likely that some cancers are better candidates for buzz saws while others are more sensitive to “rubber-band” inhibitors?
The answer is a resounding yes!
Looking for the Right Custom Solution
In my laboratory we have studied hundreds of pancreatic cancer patients. What we find is that patients are quite unique.
While one patient is resistant to every drug, the next patient is sensitive to many. One patient may be a slam dunk for the DNA buzz saw while the next needs the rubber band effect of Abraxane, and never the twain shall meet.
More importantly, FOLFIRINOX and Abraxane plus Gemcitabine are not the only choices.
One combination known as GTX remains an active regimen with less severe side effects. Another combination, Cisplatin plus Gemcitabine, has re-emerged as a treatment for patients with certain DNA damage repair deficiencies like BRCA-2. All of these and others can be examined in the laboratory before patients start therapy as we previously reported (Nagourney RA et al Proc ASCO, 2015)
Genetic Sequencing Has Not Helped So Far
What drives these different degrees of drug sensitivity is still largely unknown but the answers have certainly not been predicted by next generation DNA sequencing (NGS) that has become so popular at the major centers.
Most pancreatic cancer patients (> 90%) carry mutations in the genes k-RAS and p16, over one half have abnormalities in the gene TP53 and another 25% have abnormalities in SMAD4 yet every single patient is offered FOLFIRINOX. What?
It is like Henry Ford who once said “Any customer can have a car painted any color they want so long as it is black”.
Recent Cases That Were Made More Difficult
All of this came painfully to mind when I was asked to assist a nice gentleman with newly diagnosed pancreatic cancer. Following a biopsy, the patient underwent a surgical procedure known as laparoscopy that identified disease throughout the abdominal cavity (stage IV) and he was then offered…. You got it! FOLFIRINOX!
As so often happens, the patient and his wife failed to ask the hard questions upfront like “Am I going to respond?”, “How toxic is this treatment?” and the most uncomfortable of all “Isn’t there a better way to find out what I should take before I begin?” That last one is the kicker because the answer is yes, but the doctors won’t tell you that.
That patient is now meeting with a second surgeon to see if a second biopsy can be conducted. All of this would have been entirely unnecessary if his first doctor had submitted a sample for tissue culture to make some of these extremely difficult, life and death decisions, frankly, less difficult.
A very similar recent experience with a lovely young woman with advanced gastric cancer led to the same dilemma. She had already undergone laparoscopy and would require a second procedure.
The patient and her husband were desperate for my help and argued vociferously for the second biopsy but the question is why did we not get a portion of tumor the first time?
The answer is that no one thinks of it until it is too late.
Cancer institutePatients Need to Take Charge of Their Treatment
That is why patients need to be informed of all their options before they embark on what, for some of them, could be the last journey of their life.
People don’t go to the airport and tell the airline steward that they want to go somewhere…and then let the steward choose their destination. People don’t go to a restaurant and ask the waiter to give them something to eat, leaving the choice up to the waiter.
But when it comes to selecting pancreatic cancer treatments that can mean the difference between living or dying, patients fold their hand and take what they are offered whether it is likely to work or not.
Cancer of the pancreas remains one of the most lethal forms of cancer. Progress in this disease has been slow. Even incremental improvements in outcome should be applauded.
Most importantly, patients should be given the opportunity to make smart decisions for themselves.
As always, I appreciate your thoughts and comments.
Dr. Robert Nagourney, has been internationally recognized as a pioneer in cancer research and personalized cancer treatment for over 20 years. He is a TEDx speaker, author of the book Outliving Cancer, a practicing oncologist and triple board certified in Internal Medicine, Medical Oncology and Hematology helping cancer patients from around the world at his Nagourney Cancer Institute in Long Beach, California. For more info go to NagourneyCancerInstitute.com