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Christine Shaffer’s Legacy for benefitting other patients

Author: Michael D. Shaffer, Christine Shaffer's husband
Email: mdshaffer@hotmail.com

This story is about my wife Christine’s Pancreatic cancer journey and it is provided to help other patients understand the shortfalls of chemotherapy and the dire need for a clinically effective alternative for metastatic pancreatic cancer.

Christine was diagnosed with pancreatic cancer on 4 January 2017. She lost her battle to this horrible disease on 14 September 2019, 33 months after her diagnosis and exactly 38 years to the day after we first met.

She had been having lower back pain during the Christmas holidays with our family. Her primary care doctor diagnosed it as a urinary tract infection (UTI) and prescribed antibiotics. I actually thought it was kidney stones since we live in Florida where many outdoor active people develop them. But a couple of weeks later she began experiencing similar symptoms again—the pain was now affecting her abdomen along with lower back pain continuing. While I went to play a round of golf, she went to get rechecked and found out that she did not have a UTI. A CT scan revealed a mass on her pancreas. After a meeting with an oncologist and having an endoscopy done it was confirmed that she had a 2.7 x 2.8 cm tumor near the tail of her pancreas. There were no visible metastases and no spread to the lymph nodes so we were optimistic that resection surgery could save her. What we did not yet understand is that by the time a primary tumor is discovered on CT, there are nearly always undetectable micro-metastases circulating in the vascular and lymphatic systems.

We went to Moffitt Cancer Center in Tampa, Florida, and selected a surgeon who was highly experienced in this very complex and lengthy surgery. The pancreas is buried deep inside the body, near major blood vessels such as the Superior Mesenteric Artery (SMA) which can easily serve as a super highway on-ramp to spread pancreatic cancer cells to distant sites.

The Moffitt Tumor Board determined that the tumor was borderline resectable and established a plan for neoadjuvant chemotherapy, state of the art radiation, and then if the tumor became far enough away from the SMA, resection surgery. The chemo (FOLFIRINOX) was brutal. She had four cycles (three doses per cycle), which were very debilitating. She could not eat or drink . . . even drinking water was difficult. She lost 40 pounds and had to go the ER five times by ambulance because she passed out from dehydration. But she persevered and made it through.

I have a graduate degree in biomedical engineering and I resolved to be the best patient advocate anyone could be. I read scientific research papers night and day looking for everything I could find about her cancer and how to best treat it. For example, I found that at Mass General in Boston they were doing research using Losartan (a blood pressure drug) during FOLFIRINOX chemo to down regulate the TGF-Beta signalling. By using Losartan to enhance permeation of the chemo into tumor micro-environment, Christine's tumor size decreased by 55 percent, an exceptional response.

The next step was Stereotactic Body Radiation Treatment (SBRT). After SBRT the tumor shrunk to 25 percent of its original size and what remained was necrotic tissue. The tumor had initially been very close to abutting the SMA. After both chemo and radiation there was now a fat R0 plane between the tumor and the SMA, her CA-19 tumor marker was near zero; and just before the 4th of July holiday, it was a “go” for a distal resection surgery.

Two-thirds of her pancreas was resected, leaving the head intact and thus she would not be a diabetic. The surgery was as successful as could be hoped for. A vascular surgeon was on stand-by but was not needed. Her spleen had to be removed, as the splenic artery had been occluded by the tumor (her gallbladder had been removed 40 years earlier). There were no signs of any local invasion and the pathology report showed no lymph node invasion. After the surgery, typically sixteen doses of Gemzar are given to mop-up potential metastases that are too small to detect on CT, but she was only able to tolerate three doses before she had to say enough is enough due to the development of neuropathy and constant bone pain. Her CA-19 tumor marker continued to be near zero and enough of the pancreas body was left that she didn’t even need digestive enzymes such as Creon.

She was all clear for her first few three-month CT scans and CA 19-9 tumor marker checks. But in August 2018 she hit a bump in the road. All along, I and her medical team had been worried about what were considered at the time of the surgery to be Indeterminate Pulmonary Nodules (IPN) of about 1 MM in size. This is right at the detection limit of CT technology. The problem was that they were way too small to biopsy, many people have them, and they are usually benign. Of course the odds of them being malignant go up when the patient has had cancer. However, the fact that the FOLFIRINOX cocktail shrunk the dense stroma protected primary tumor while the neoadjuvant chemotherapy and adjuvant Gemzar had no effect on these seemingly more vulnerable IPNs, seemed to suggest that these were not malignant metastatic pancreatic cancer. Since the CA 19-9 before and after surgery was well within normal range, we had adopted a cautious wait and see approach on these IPNs.

However in August 2018, with CT finally detecting some growth in these subcentimeter nodules, and her CA-19-9 spiking to 486 IU/ml from being in the normal range (under 37 IU/ml) just three months before, we knew we needed to take action, but what action? The cancer was now restaged as Stage IV metastatic PDAC which was probably the scariest diagnosis we had ever heard.

Although the nodules were still not growing rapidly, I began to investigate whether the subcentimeter Pulmonary Nodules (PN) could be safely resected in-vivo instead of systemically with chemotherapy which had already demonstrated questionable efficacy (probably because they weren't fast growing) and debilitating side effects in her biology. I researched a procedure called Photodynamic Therapy (PDT) that had been developed at Roswell Park Cancer Institute some 50 years ago. When combined with Electromagnetic Navigation Bronchoscopy (ENB) and newly developed sensitizing agents, subcentimeter PNs could theoretically be safely imploded through multiple outpatient procedures. PDT under ENB guidance had been successfully demonstrated to navigate the bronchial tree, getting close to the pleura in clinical settings in parts of Asia but its conceptual use in the narrower passageways of the lungs where these PNs were located, had not been adopted in the United States. There was only one clinical trial ongoing at the University of Florida (UF). We applied to the clinical trial at UF but she was turned down because her number of subcentimeter PNs exceeded the trial admittance criteria. We then contacted a leading Interventional Pulmonologist but he declined to try the procedure because he felt a systemic treatment should be tried first. Our counter argument of “this could help buy more time or we could just keep repeating the procedure as needed” did not convince him and he recommended more chemotherapy, just as all the oncologists had done.

Unable to surgically resect the subcentimeter PNs, I began an exhaustive search of systemic drugs in the university and biotech research labs and those that had entered clinical trials. This led to the creation of a detailed survey of over 50 experimental drugs for metastatic PDAC. They generally fit into two broad categories which were combinations of chemotherapy and immunotherapy, and metabolic drugs. However none were showing much promise to move the needle substantially except the entirely unique FL118 molecule being developed at Roswell Park Cancer Institute, a leader in precision medicine. I had long felt that with all the different mutations inherent in cancer, that a one size fits all approach would be inadequate and that a gene-based precision or personalized medicine approach was needed. I read all the FL118 scientific papers and began to converse daily with the FL118 chief research scientist, Dr. Fengzhi Li.

After much back and forth to help me understand the Mechanism of Action (MOA), testing, analysis and safety we traveled to Buffalo in November 2018 to have a biopsy on the PNs. Two lung wedge resections successfully yielded enough tumor tissue that organoids could be created, insertion into SCID (nude) mice, and for Foundation One to conduct a global molecular profile of the tumor.

The first result received was the molecular profile. Unfortunately it portrayed the worst possible scenario where there was a low Tumor Mutational Burden (thus checkpoint inhibitors were not an option) and no actionable mutations present e.g. NTRK Fusion, BRCA or High Microsatellite Instability (MSI). In addition her p53 gene was null, meaning the “guardian of the human genome” no longer was able to control or stop the cancer from freely mutating. However the organoid test gave us hope because when FL118 was applied, her tumor tissue was determined to be highly sensitive to FL118 and the cancer was quickly eliminated at well below calculated Maximum Tolerated Dose (MTD). We then aggressively pursued attaining this experimental drug through the FDA Individual Expanded Access protocol often known as Compassionate Use, but FL118 was still in the lab and did not possess an Investigational New Drug (IND) permit. We were subsequently told that no physician in the country would go before their Institutional Review Board (IRB) unless the drug possessed its IND. Her oncologist who was in private practice would even lose his malpractice insurance if he administered a drug that did not have an FDA New Drug Authorization (NDA) or if it was being used off label. An attempt to ask the FDA to waive the IRB review process for Compassionate Use was denied.

By January 2019, the cancer had now spread to Christine’s liver and peritoneum and the CA-19 tumor marker had skyrocketed to over 35,000 IU/ml. At first I thought this was secondary spread from the PNs, but I subsequently hypothesized that no, this was not due to the slow growing PNs but new metastases with probably entirely different mutations and molecular profile. Without any other options and the past side effect experience of FOLFIRINOX still fresh in our memory, we began the other FDA recommended first line treatment of Gemzar and Abraxane. It seemed to be effective as the CA-19 fell to 4,000 IU/ml after two cycles (4 biweekly doses.) However the adverse events were unrelenting with constant diarrhea, nausea, and vomiting leading to severe weight loss that we were soon to find out was indicative of what is called cancer cachexia. Cancer cachexia or wasting syndrome is not well understood, it has no approved FDA treatment, and it is indicative of a poor prognosis for cancer patients.

To make treatment going forward even more challenging there was now mild enteritis and colitis showing up on CT and we thought this might be due to a bacterial infection. Her medical oncologist prescribed two tough antibiotics Flagyl and Cipro, however they just made the diarrhea worse and did nothing to resolve the inflammation as it was probably not due to a bacterial infection but further spread of the cancer. By April 2019, Christine had lost an additional 50 lbs and had become so weak and emaciated that she could not continue on chemotherapy and needed time to get her blood chemistry back to normal. So every two weeks her blood chemistry would be evaluated and found unable to continue due to one factor or another being out of range. We even checked into blood transfusions but those were denied.

By June 2019 and without any treatment her CA-19 had now gone up to a shocking 85,000 IU/ml and her only chance to stop the cancer would be starting chemotherapy again which was initiated as first Gemzar and then adding back in Abraxane due to the need to get more aggressive. While Gemzar by itself was less toxic, the addition of Abraxane was not. After just one more cycle of Gemzar/Abraxane (two doses) both good and bad happened. The good was that the cancer was responding as her CA-19 had reduced from 85,000 back to 35,000 IU/ml where it was in January. But the bad was that a Deep Vein Thrombosis (DVT) occurred in her right leg while ascites was accumulating in her adbdomen. A CT was requested which showed that the ascites was most likely due to a left Portal Vein Thrombosis (PVT). These thromboses could have been due to Abraxane or the past use of Megace that had been used to counter the cancer cachexia. Despite immediate use of Xarelto to give the body time to resolve the thromboses without risking a pulmonary embolism or stroke, the ascites continued building up in her abdomen and repeated paracentesis procedures only provided short term relief from the abdominal pain. These complications combined with the cancer cachexia where she literally was nothing but skin and bones left her so debilitated that she had become bedridden and soon had to go into hospice where no further treatment is a condition of admittance.

I tell this story to illustrate that patients desperately need a better solution to metastatic PDAC than decades old DNA cleavage chemotherapy that is incapable of discriminating between fast growing normal and cancerous cells. Patient reaction to chemotherapy is like a bell shaped curve. Most patients are somewhere in the middle of the curve and have some side effects which won’t kill them. But some patients are on one side of the curve and have very limited side effects while others like Christine, are on the other side of the curve where chemotherapy can end up being worse than the cancer. As I write this only a few weeks after her passing, I still assess that FL118 is the ONLY drug currently in the labs or clinical trial that has a chance to save many patients from the collateral damage that chemotherapy caused Christine. As such I have written an executive summary style paper on FL118 so that other patients and their advocates can get a better understanding of the drug and why it is so novel (FL118 Executive Summary).

Christine suffered immensely in 2019 as she wasted away to nothing and she was in a lot of pain as the end drew near. Yet she always smiled and said she was doing alright, and she never wavered from her deep Catholic faith in Jesus as her lord and savior. Dr. Li attended the short notice funeral mass as did about 100 of her friends and family. Another funeral mass will be held in Erie Pennsylvania in August 2020 for the many who did not have enough notice to attend.

Christine (always the optimist) with the Stage IV metastatic PDAC diagnosis, just before chemo was started again in January 2019-

Christine Shaffer 10 April 1951 - 14 September 2019. She loved God, people and living life. She is already missed by everyone who knew her. I was blessed that she chose me to marry and that I got to share in her life for 38 years. Her only regret was that she would not see her three year old grandson Theo (who she called Theodorable) grow up.

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