What have we learned?

1. You must be your own advocate. Take responsibility for your own care.
2. Attitude and gratitude matters. A lot. That doesn’t mean pretend or deny the seriousness of your disease. There will be dark moments. Keep going. You and those you love are worth it.
3. Ask for help and support, whether you are a patient or a caregiver. You will need it.
4. Get genetic sequencing. Know your tumor!
5. Don’t wait for an appointment to get results. Insist on getting them when they become available.
6. Search for organizations dedicated to your cancer type. Non-profit organizations can help a lot here. You are only 1-2 degrees of separation from finding what you need, whether it be a trial, a doctor, an institution, or a drug. Keep asking until you find it.
   
7. Remember that the statistics you find are backward looking, representing the past and the averages in the fight against your cancer, NOT the future available to your individual needs and possibilities. And discoveries are happening faster.
8. The medical industry operates in many disconnected ways. This is not the fault of any individual participant. Drug companies are trying to find cures. They have to focus on that as their priority to find safe drugs. Hospitals must be busy to be affordable. They are full of doctors and nurses who care deeply.
9. All of this conspires to make it necessary that you take ownership of your treatment and disease. Others may not have the time to do as much as you can do. You must find caregivers with energy and belief to match your own.
10. You will need a quarterback and a team that you trust, a team that may save your life. Interview those doctors and institutions that you meet. Hire the people you believe in. Keep looking until you find them. They are out there. In the words of one of our favorite docs – ‘if you find yourself being told there is nothing else that can be done against your cancer, get up and go find another doctor.”

A pancreatic cancer journey to healing – one patient’s perspective

This is a story of learning and discovery, on a journey taken by Joanie and Scott Kriens, with a team of caring and committed professionals gathered to help us. Joanie, as the patient, and I, Scott, your storyteller, have learned a lot along the way, and we share our story with great hope that it may ease the journey for others, should cancer cross your path. It is accompanied by a paper attached which describes the clinical timelines, diagnoses, therapies, trials, and drugs brought to bear against the disease and its progression.

While the medical explanations are important, and the technologies, therapy, and research trials employed are instructive, they do not alone tell the whole story. There is the human side; the fears, the doubts, the discoveries, and the celebrations that also happened on the path to today, and beyond. This is that story.

In the summer of 2017, Joanie had a routine blood test which revealed a suspiciously elevated marker, CA-125, typically indicative of the possibility of cancer in the pelvic area. Our first response was that this must certainly be a mistake and a re-test would confirm same. After all, Joanie is perfectly healthy with no discomfort or otherwise cause for concern. However, the second test only confirmed the first, leading to an ultrasound to see what could be seen of the area and what the explanations might be. What we found was, we thought, the worst possible news – there was evidence of a mass, more than one, strongly suggesting cancer was indeed present in Joanie’s ovaries. After facing the reality of the prognosis and discussing options, the decision was made, based on the desire to once and for all eradicate the disease. Joanie was 57, had no need for ovaries, uterus, fallopian tubes, or anything else that could be removed to prevent the spread of disease. A radical hysterectomy followed, after which came a deep sigh of relief. We weren’t completely out of the woods, as there was still a need for prophylactic chemotherapy to be sure the disease would be put to rest. A port was placed in her body, with the expectation that regular access for intravenous delivery of chemotherapy would be required for 6+ months.

All of this was made bearable by the knowledge that the surgery was behind us, it was successful, and however difficult the chemo would be, it was all part of the recovery and subsequent return to normal life for the next several decades.

Except that is not what happened.

Upon returning to see the surgeon three weeks after the hysterectomy to have the obligatory follow up and review of the procedure, and to confirm that Joanie was indeed recovering nicely, we found out something very different. The biopsied tissue was tested in routine pathology following surgery, and the findings were ominous. The tumor tissue was mucinous, a quality not typically found in ovarian cancer, and indicative of a different point of origin for the cancer.

At this point, we were sent to another building to get on the calendar of a different doctor, to discover a different and potentially much more lethal disease. After walking numbly across the hospital campus in a fog of disbelief and making the appointments for the unknown, we found ourselves in the parking lot, unable to start the car, unable to even comprehend what had just happened. We expected to be well on the way to cure of a stage three ovarian cancer, and instead were told we were in a fight with a stage four pancreatic cancer diagnosis, with a far more deadly disease already at work elsewhere in Joanie’s body. What do we do now? How do we tell the kids? What do we even say? How do we say it? Who do we tell? Oh my god, what are we going to do? We each thought, though neither could say it out loud…Is she going to die? Am I going to die? Soon? Painfully? Oh my god.

We put the best face on it we could, told the kids what we knew, tried our best not to speculate, and mostly all failed to follow the advice given by the doctors at the time – whatever you do, don’t go looking for the answers on the Internet. Only Joanie was able to do this, as the rest of us, both overtly and covertly, looked and scared ourselves with all the statistics, and the 90%+ likely conclusion; yes, she is going to die, and the only question is whether this is going to happen in 6 or 12 or 18 months. A subsequent visit with the first GI oncologist at the hospital revealed only that there was a trial but unfortunately, we didn’t qualify, and there was no more they could recommend except start chemo and see how many months we would have before it stopped working.

That was too much to handle, and there was nothing to do with the prognosis, so we did what we could – put one foot in front of the other and started to find the treatment that was available. Fortunately, we were led from the outset, and to this day, by Dr Mike Nichols, who did his best to point out some facts that should have, but didn’t yet, comfort us. These statistics about pancreatic cancer are averages, usually representing very late-stage discovery of the disease. They are representative of patients with any number of other health deficiencies and advanced ages, and they were all historical, backwards looking findings. Our reality was different. Joanie was 57 years, in very good health, and with the best care in the world at her disposal, and the future includes many discoveries not found in the past. These words of comfort, while true, weren’t enough to overcome the initial shock of the statistics searching the net had presented us with, but they would come to be the very basis of the success Joanie would eventually realize.

The first thing we found is that the medical industry is horribly siloed, with pockets of progress being made in clinical treatment, research, and trial activities, none of which is connected in any comprehensive way. We found PANCAN (www.pancan.org), an excellent organization dedicated to its best effort to organize pancreatic cancer activity and help patients. We found Cancer Commons (www.cancercommons.org), and we met Willy Hoos, not himself a doctor but as helpful as anyone we would ever meet on our journey. Cancer Commons has a vision of putting the patient at the center of the journey, in contrast with the competing reality that the research and trials were for the benefit of the drug companies and the patients were only participants in that undertaking when they could comply with the drug trial protocols. This on the surface sounded wrong, but in fact the testing of drugs must isolate the conditions to be

sure the drugs developed are safe, and it is an unavoidable consequence that the priority of patient comes second.

In our case, the discovery of the first trial, treatment and institution came with a purely coincidental meeting with a friend whose ex-husband happened to be a doctor at Stanford. Upon her recommendation and introductory phone call, we contacted Stanford to discover that indeed a trial for which Joanie was qualified was underway and that we could join. There we met Dr. George Fisher, and a trial using the chemotherapy standard of care in conjunction with Indoximod, an IDO inhibitor that was being tested to see what improvement to outcomes it could bring to standard chemotherapy.

This involved use of the chemotherapy drugs Gemcitabine and Abraxane, or Gemabraxane, along with the trial drug, for the next year, and the results were positive. There were tumors in the pancreas, the liver, and the lungs, all of which responded to treatment and shrunk by 60- 80%. Along with this result found in regular images from CT scans, the marker CA 19-9 was falling from a high of 17,000 to less than 100, where normal was anything less than 35. This was indeed encouraging, until progress stalled, and the masses remained at their reduced levels, while the CA 19-9 began to climb, an indication that the tumor was active and growing, even though evidence was not yet visible on the images of the scans. An additional mass was discovered in the peritoneum, a new mass as large as those found initially in the pancreas a year earlier.

Something else would be needed. The treatment was no longer working.

Fortunately, at the onset of treatment, tissue from the tumors found in the ovaries was sent to Tempus clinic, where whole exome sequencing was done to see the precise genetic makeup of the tumor mass, the individual signature from the biology of Joanie’s disease. We cannot stress enough the importance of this step at the outset of discovery and treatment of cancer of any type. In Joanie’s case, this sequencing was done initially in 2017 when we began treatment, and then done again when the tumor in the peritoneal cavity was resected in 2018. Here again, another example of coming up against conventional medical thinking about cancer; some would say that there is no use resecting disease – removing it from the body when you find it – in the case of metastatic disease, where the cancer has spread elsewhere in the body. This was probably true in the past when there were few or no options to treat metastatic cancer. As the thinking once went, if it has already spread in the body, no sense in making the patient suffer surgeries. Instead focus on quality of life for the few remaining months or years that remain.

This is no longer true today, though that view has not been adopted everywhere. Fortunately for us, at Stanford they took on the challenge of removing what they could of the newfound disease, which was again sent out for genetic testing. Cancer doesn’t just take on a form at the outset and wait for you to attack it. It has the same quality that the rest of our body has – it adapts and fights to survive, and therefore when fighting it, it is very important to assume cancer will mutate, and therefore to keep tracking and monitoring its progression. Do not

assume that cancer will present you a static target. It will move and change to survive and you must track it, move with it in order to get ahead of it.

In our journey, with the removal of as much of the tumor as possible from the peritoneal cavity, and the results of both lab and genetic testing, we confirmed an earlier finding that became very important; Joanie’s tumor had high expression of HER-2, receptors found 25 years earlier in breast cancer which became the basis for development of the HER-2 drugs Herceptin and Perjeta. These drugs are FDA approved, originally developed by Genentech, and commercially available. However, they are only approved by insurance companies for use in treating breast cancer, where the occurrence of HER-2 is found in approximately 25% of cases. In pancreatic cancer only 1-2% of tumors exhibit this overexpression of HER-2.

This sent our team looking for trials where there were efforts to see if HER-2 breast cancer drugs might be effective on HER-2 positive tumors found elsewhere in the body. We found such a trial, called TAPUR, with an institution locally as one of the trial sponsors. So we switched care from Stanford to Sutter, the trial sponsor, and began a new regimen of treatment, with Herceptin and Perjeta administered intravenously every 3 weeks. This is also when we met Dr. Ari Baron, the oncologist Joanie still works with today, and a positive supportive force from that very first day. The Herceptin/Perjeta combination proved successful in stemming the advance of the CA 19-9 marker, reducing it again to less than 100. In addition, these results came without the body-wide toxicity of chemotherapy. Joanie’s hair grew back, her strength returned, and we felt that perhaps we were lucky enough to be out of the woods, at least for the foreseeable future.

This remained true for about 9 months, and then the markers began again to climb.

By this point, something had changed materially from the perspective we both had at the beginning of the journey, a change in attitude, confidence, and outlook. This did not have to be a fatal story. This disease and its prognosis were not a given. It was still true in most cases, but not all, and not ours.

What was instead becoming clearer was that attitude and belief matter. It matters in the outlook of the patient, and it matters in the approach and commitment of the team surrounding that patient. Joanie believed, and does today still believe, and so do her caregivers, that this disease can be managed into a chronic condition that one can live well with, and not be at its mercy. In her words, not to be just a survivor, but to be a thriver!

This belief proved to have real self-fulfilling power, and though no one attribute can be assigned to improvement, including medical treatment, with belief comes possibility, and without, I wouldn’t want to find out. What became clear, over and over again, was that gratitude and resilience were a large part of the treatment and outcome.

Joanie said many times, ‘I think of my chemo as nectar, and I’m grateful that it can help me heal’. Not the attitude one might be expected to bring to receiving a toxic drug that does

widespread harm to the body in its efforts to poison the offending cancer cells within. Joanie’s gratitude for her care professionals, her regular appreciation for their care for her, expressed with a box of candy, a loaf of fresh bread, a bag of tomatoes from her garden, or simply a kind word of thanks for all that was being done for her, matters to her. And it matters to the people she is grateful for. It makes a difference.

The other attitude that emerged was resilience, different than defiance, or refusal to acknowledge. Sometimes people take on the fight against cancer as if it were an alien force, an evil actor who should be engaged with in a fight-to-the-death mentality, a desperate struggle to survive. This expends a lot of energy when energy is perhaps the most valuable ingredient to healing. Instead, what Joanie brought to the reality of facing the disease was more a quiet determination, a grace under fire, a resolve with no wasted motion, no energy lost, but rather a laser focus to bring every ounce of healing energy to where it was needed most, to the growth in her body that was indeed part of her, and to tame it with her intention and commitment.

Back to the journey…the climbing 19-9 numbers once again indicated activity of the unwanted kind. The tumor was likely growing, and in doing so, could be spreading elsewhere as well.
The team again responded, this time with the approach of stereotactic radiation therapy, again an unconventional undertaking. Conventional thinking says there is no use employing radiation treatment to metastatic disease. Once it has metastasized radiation con only chase but never contain the progressing cancer. But we were fortunate to meet Dr. Joe Herman, a radiation oncologist who had other ideas. Joe and others in his field believe that with limited metastatic disease there is reason to radiate, with positive results. The basic theory is that radiation can stem the progression by frying the tumor tissue with very precisely applied beams of radiation, and that this reduction of the tumor tissue, in conjunction with other treatments, could again get the cancer under control. Joanie underwent radiation treatments aimed at the pancreas, the liver, and the lungs, with the effect of dramatically reducing or eliminating evidence of tumors in all areas.

Around the same time, two additional therapies were brought to the treatment strategies. One was the introduction of immunotherapy, the use of immune drugs to essentially interfere with the tumor’s use of specific cells in the body to hide itself from the immune system. Cancer is smart, and as we said earlier, it’s adaptable. If it were easily visible to our immune systems, it would be attacked and removed just as would any other foreign agents in our body. But while our bodies rely on our immune system to attack disease, we also must protect the vital body parts we need from those attacks. Thus, the immune system also relies on the presence of specific cells that protect our valuable body parts from attack. These cells are hijacked by the cancer to hide from attack, disguising itself as friendly so that it can continue to exist and to grow. So, state-of-the-art immunotherapy under development targets these cancer strategies, attempting to block cancer’s use of cloaking cells, and in so doing reveal the tumors so that the immune systems can do its job. In our case, this meant the use of ipilimumab and nivolumab to do exactly that. The clinical details of this, and all Joanie’s therapies and drugs, are covered in the attached medical narratives. What we could understand was that we needed to uncover the disease so the immune system could go to work.

In addition, there are vaccines under development to further assist in the strategy. In our case, this meant finding Washington University in St. Louis, and its work on neo-antigen vaccines developed from the genetic information describing the precise biology of the tumor found in Joanie’s body. These personalized precision approaches feel to us like the future of successful cancer treatments; find out what exactly is going on with the unique understanding that comes from genetic sequencing and then design a personalized vaccine to boost the immune system’s capacity to respond, in concept not unlike the vaccines for Covid-19 or the flu, or polio of the past.

To add this all up, in the March/April 2020 timeframe, there were three main elements of the approach that worked for Joanie, with the benefit of genetic sequencing to inform the approach with exact understanding of her individual DNA. First, radiate the tumor masses to reduce them as much as possible. Second, and simultaneously, the use of immunotherapy to disable the cloaking strategies the tumor is using to hide from the immune system. Third, supercharge the immune system with information specific to the cell types it needs to attack so that the immune system can build and deploy its armies of T-cells, the cells responsible for attacking foreign elements in our body and eradicating them to return us to health.

In October of the same year, 2020, when the aftereffects of the radiation appeared to have introduced an ulcer from the stomach lining being affected by the radiation treatment, Joanie was taking what are known as PPIs, basically antacids for dealing with discomfort of ulcers and excess stomach acid in the body. The (at the time) unfortunate side effect of this medicine was to elevate the creatinine in Joanie’s body to dangerous levels, introducing the risk of having to go on dialysis if there was kidney failure. This necessitated the immediate discontinuance of all these cancer medicines, and the PPIs, to allow the kidneys to return to normal function, which thankfully they did rather quickly. The silver lining in this was that it forced the discontinuance of all treatments, only to find that the CA-19-9 levels remained very low, (below 10 and well below normal levels), even with no treatments onboard. There have been three scans over the last 9-10 months, to July 2021 as of this writing, with no visible evidence of disease.

Once the kidney function returned to normal, we reintroduced the cancer vaccine monthly, and that remains the only treatment in use today. Without the elevation of creatinine levels in the kidney, we would have had the happy but perplexing problem of not knowing how to reduce the use of which drugs, as it was not possible to separate the effects of one drug approach from another, as all were deliberately employed simultaneously to have maximum benefit.

What we know today is that it is possible, at least in one case described here, to stare at the most dire of diagnosis, and find a path to a stable outcome, and the real possibility of the reduction of a potentially terminal cancer to a chronic condition to be managed for a long lifetime. We also have been at this long enough and learned by too many other examples, that it is dangerous to casually declare a cure. Victories are won daily, and vigilance is a must. Gratitude matters a lot. Attitude matters a lot. Caregivers who take their work seriously and bring energy and optimism to the treatment of tough disease, are so needed for the journey.

We have been fortunate to find many of these people in clinical care, research, specialty practices, and support, for all the treatments we have been fortunate to receive. Simple thank yous hardly say enough for the dedication and commitment we’ve found. These people are heroes.

What have we learned?

1. You must be your own advocate. Take responsibility for your own care.
2. Attitude and gratitude matters. A lot. That doesn’t mean pretend or deny the seriousness of your disease. There will be dark moments. Keep going. You and those you love are worth it.
3. Ask for help and support, whether you are a patient or a caregiver. You will need it.
4. Get genetic sequencing. Know your tumor!
5. When we found out that the suspected ovarian cancer was in fact pancreatic cancer in 2017, it was only after three weeks of waiting to be informed of test results that were actually available in 2-3 days. This taught us never to wait for the next appointment to get test results. This is a time of uncertainty and stress that does not have to be. Insist on results as soon as they become available, and make sure that they are posted to your medical file for your review. If you don’t have what you need when you want it, demand it. There will be somebody in the system who can help you. Find them. Don’t wait!
6. Search for organizations dedicated to your cancer type. Non-profit organizations can help a lot here. You are only 1-2 degrees of separation from finding what you need, whether it be a trial, a doctor, an institution, or a drug. Keep asking until you find it.
7. Remember that the statistics you find are backward looking, representing the past and the averages in the fight against your cancer, NOT the future available to your individual needs and possibilities. And discoveries are happening faster.
8. The medical industry operates in many disconnected ways. This is not the fault of any individual participant. Drug companies are trying to find cures. They have to focus on that as their priority to find safe drugs. Hospitals must be busy to be affordable. They are full of doctors and nurses who care deeply, or they would have never gone through the work to attain their professional ranks.
9. All of this conspires to make it necessary that you take ownership of your treatment and disease. Others may not have the time to do as much as you can do. You must find caregivers with energy and belief to match your own.
10. You will need a quarterback and a team that you trust, a team that may save your life. Interview those doctors and institutions that you meet. Hire the people you believe in. Keep looking until you find them. They are out there. Sometimes we can assume that because they’ve all been to medical school, or work at a famous institution, that somehow, all doctors will deliver the same care. Realize that these are human beings, and as in any profession, some are better and more inspired with their craft than others. And some are tired and not as able to bring the energy and optimism you need to take control of your cancer. In the words of one of our favorite docs – ‘if you find yourself being told there is nothing else that can be done against your cancer, get up and go find another doctor.”