STAGE IV Pancreatic cancer: Cisplatin plus Gemcitabine, A Good Option After FOLFIRINOX?
From, the blog of Dr. Robert A. Nagourney, MD
STAGE IV PANCREATIC CANCER: A GOOD OPTION AFTER FOLFIRINOX?
In early April of 2022, I was asked to cross-cover for a colleague. One of his patients was a 40-year-old Hispanic female who had been transferred from UCSD after presenting several weeks earlier with widely metastatic pancreatic cancer and near complete replacement of her liver. She had undergone a very thorough evaluation and with the diagnosis established she began the standard-of-care combination FOLFIRINOX.
The patient was desperately ill, jaundiced, with extremely elevated tumor markers and rapidly re-accumulating ascites fluid. When we met I felt deeply concerned that despite her young age and a cycle of treatment already completed, she would not survive.
I conducted not one, but two, paracenteses removing almost three liters a week apart.
During my brief time covering the patient, I felt she was not responding to FOLFIRINOX but hesitated to change the regimen on someone else’s patient mid-stream as she was just completing her second dose.
For those of you familiar with pancreatic adenocarcinoma there are two principal treatments: FOLFIRINOX and Gemcitabine plus Abraxane. These treatments are mechanistically different as one, FOLFIRINOX relies upon the DNA damage associated with the Oxaliplatin while the other, Gemcitabine plus Abraxane targets cellular mitosis, the process by which cancer cells divide.
Upon my colleague’s return, I recommended that he change her treatment from FOLFIRINOX to a combination that I had originally developed in my laboratory years earlier, the Cisplatin plus Gemcitabine doublet.
This was where the story took an interesting turn.
As the patient had already failed a platinum-based regimen (FOLFIRINOX) virtually all physicians would immediately move to the taxane-based, Abraxane plus Gemcitabine.
This reflects the widely held belief by oncologists that the mechanisms of action (DNA damage vs mitosis inhibition) are different enough to render them “non-cross resistant”. On the other hand, it is widely believed that you “Cannot go back to the well” with a platinum-based treatment as it cannot work in a “platinum-resistant” patient.
But in this patient’s case, I felt confident that Cisplatin plus Gemcitabine would work and she began her first cycle in mid-May. By this time, she was desperately ill with a CA 19-9 tumor marker that had climbed to 21,348 (normal under 35) .
She remained hospitalized for rapidly re-accumulating ascites and required blood transfusions, hydration, and pain control as her husband maintained a vigil at the bedside.
With one dose of my recommended treatment, the May 21st CA 19-9 fell to 16,000 and then on June 17th to 6,500, and by July 29th, 1422, while the CEA fell from 2665 to 7.7.
I was largely unaware of all this until today, when during my clinic, I was introduced to a healthy-appearing young woman, there for routine blood work. This was the very same young woman upon whom I had conducted two urgent paracenteses several months earlier. Instead of requiring hospitalization or transport by her husband, she had driven herself to the clinic looking for all the world, the picture of health.
I marveled at her well-being and asked my nurse if this was indeed the same young woman. Yes, she explained the response had been nothing short of miraculous.
What is striking about this case is that the patient had already received very appropriate care at UCSD. FOLFIRINOX is the most widely used combination in this setting. It is just that in her case FOLFIRINOX was not the right treatment for her.
For the vast majority of cancer specialists, following FOLFIRINOX, a platinum-based regimen there would be almost no expectation that Cisplatin plus Gemcitabine; a different platinum-based regimen would possibly work: None! Except, that in this particular patient’s case it worked extremely well.
Any self-respecting academic would review this case and say “Yes, but wouldn’t the Gemcitabine plus Abraxane have worked as well?” My response to this all-too-common line of reasoning is very simple.
First: Abraxane plus Gemcitabine can be quite toxic, much more so than dose-adjusted Cisplatin plus Gemcitabine. Second: Abraxane based regimens are mechanistically very different and didn’t appear active for this patient consistent with our published analysis showing very low synergy (<20%) for Abraxane plus Gemcitabine (Nagourney, RA in Deoxynucleosides in Analogs in Cancer Therapy). Third: We cannot waste the time of dying patients. Time is not their friend. Finally: “Nothing Succeeds Like Success”.
This 40-year-old woman is alive and well despite almost insurmountable odds a few months earlier. All patients deserve the best possible outcome and our assay-guided individualized therapy offers just that.