Our Cancer Journey, Part 4: Lessons from the science

March 19, 2020

Let me start our post today with some numbers, and some explanation of numbers.

First the numbers:

  • The median life expectancy of a person diagnosed with Stage IVa metastasized colon cancer is 2 ½ years. I am now more than 3 years out from my diagnosis.
  • I have had cancer most likely for somewhat more than 10% of my life
  • Marion and I have lived, loved, and sometimes cried through a bit more than 5% of my life knowing that I have cancer
  • I have now three CT scans in a row the report for each of which says, “no evidence of metastatic disease.”

We’re not sure why I am alive. A person diagnosed with the same cancer, same stage, and same month as I was passed away almost a year ago. Another such person is now receiving only palliative care. Cancer is indiscriminate, and life is fickle. There are many factors that helped keep me alive, to be sure:

  • My wife. Marion took on as her full-time job making me healthy. I did things to take care of myself that I would never have done without her.
  • The doctors, nurses, and staff of the Simon Cancer Center and IU Health. When we got to the Simon Cancer Center, their message was simple: we think we may be able to cure you; if not we can provide a good quality of life for many years; and we will always be honest with you. The Simon Cancer Center is a place where everyone acts like they always expect good outcomes.
  • My family. My family was right there with me every step of the way, supporting me emotionally and in practical ways to numerous to count.
  • My colleagues near and far. The depth and kindness of the professional communities in which I work has always been clear to me; needing to be on the receiving end this much was new for me. Learning to receive was an important but difficult lesson, one not yet completely learned.
  • Everyone who supported me, near and far, including readers of my earlier blog on Caringbridge.org. I remain overwhelmed by the support I have received.
  • My new teachers in life, including those who helped teach me about mindfulness, Qi Gong, and First Nations spirituality.
  • Whatever power it is in the universe we call God.

Perhaps some of my own behavior moved the odds a bit, but I’ll put faith in everyone and everything else first. There were times when I was definitely not in control of my own behavior at all, anyway, thanks to pain and / or pain medications, so my own behavior can’t be the cause of my current good condition.

The biggest factor in me being alive today is the incredible rate of progress of research and development of new treatments for many sorts of cancers. Immunotherapy and the feasibility of sequencing a patient’s tumor genome are two major contributing factors. Science, the journal of the American Association for the Advancement of Science, identified immunotherapy as the “breakthrough of the year” in 2013 (see https://www.cancerresearch.org/blog/december-2013/cancer-immunotherapy-named-2013-breakthrough-of-the-year). 

At a very practical level, I am alive today for the following reasons:

  • The typical, by-the-book, “standard of care” approach to cancer did pretty darn well in keeping me alive and functioning for 1 ¾ years. The importance of this cannot be overstated. There is a reason that doctors treating cancer start off with the treatment recommended by the AMA guidelines for standard of care for cancer: this standard, which is updated regularly, represents the best general approach to any particular form of cancer based on the most recent established treatment options. 
  • A particularly important point is that while I was treated by the “standard of care” approach, I moved from a local general oncologist and local “very good” quality surgeons to the Simon Cancer Center, now recognized as one of just 51 comprehensive cancer care centers in the US. There I was treated by some of the best GI cancer oncologists in the US, and operated by surgeons who are among the best in the Midwest. Finesse in implementing the standard of care is an issue. And again: thanks go here to Marion. Without her insistence, I would have just been content to be treated by the local general oncologist, and it’s clear from what I have seen of his notes that he viewed treating me as management of quality of life of a dying cancer patient. That’s NOT the approach that was taken by the Simon Cancer Center.
  • Lucky timing. A new study for an immunotherapeutic approach to metastisized colon cancer began on March 18, 2018, just over a year after I was initially diagnosed. This study is very precise in its focus: to qualify, a patient has to have refractory (recurrent) metastasized colon cancer, three specific genetic alleles, and ‘moderate’ levels of mutation in the tumor genome. Luckily enough, I have all three of these characteristics.

The science of my treatment is, I think, pretty interesting. It also demonstrates how carefully targeted newly emerging cancer treatments are.

My tumor includes two specific genes that are overexpressed, and each when overexpressed “hides” the cancer cells from being detected by my immune system. At a cartoon level what happens is that when T-cells come along – the part of the immune system that identifies foreign and abnormal cells and marks them for destruction – the cancer cells say, “nothing to see here, move along, move along.” And the T-cells simply leave the cancer alone. This is the key to why my cancer kept coming back. One of the important recent understandings about cancer treatment is that successful curing of people depends on the immune system playing a key part. When a patient is cured of cancer, what happens is that some combination of surgery, radiation treatment, and chemo knock the cancer down… but it’s the immune system that finishes it off. In my case, chemo, radiation, and surgery knocked my cancer down to the point that nothing was detectable on a CT scan twice. But because my cancer cells “protected” themselves from my immune system, each time my doctors got me to the point of no signs of cancer visible in a CT scan, the remaining – and still very many – cancer cells in my body grew to the point of creating new tumors. This also helps explain how I went from a clean CT scan in at the end of 2011 to Stage IVa metastasized cancer when I was first diagnosed at the beginning of 2017. Whenever it was that my cancer started, it was able to grow without interference from my immune system. 

The experimental drug trial I am in involves three monoclonal antibodies: Nivolumab, Ipilimumab, and Panitumumab. Nivolumab and Ipilimumab each suppress one of the two genes that, when overexpressed, “hides” my cancer from my immune system. That lets a person’s immune system “see” the cancer cells and attack them. But these two drugs, which are already approved for treatment of metastasized colon cancer, have a success rate of about 25%. That’s a great success rate if you are a major league baseball player, and plenty good if you are one of the patients who is cured by virtue of being in that 25% of patients who can be successfully treated. The “trial” aspect of the treatment I am in is adding Panitumumab to treatment with Ipilimumab and Panitumumab. Panitumumab is already approved for treatment of some types of melanoma (a form of skin cancer). It blocks the action of something called Epithelial Growth Factor – a compound that in our body enables the proliferation of epithelial cells (https://www.cancerquest.org/patients/drug-reference/panitumumab). And recall for a moment that while we are a fairly complicated torus (https://en.wikipedia.org/wiki/Torus) and the lining of our gut is basically an epithelial cell. The three-drug combination I am on basically functions like this: the Panitumumab suppressed proliferation of the cancer cells enough that my immune system, enabled by Nivolumab and Ipilimumab, can kill cancer cells faster than they grow. Or in more cartoon-ish terms, the Panitumumab holds down the cancer while the Nivolumab and Ipilimumab enable my immune system to beat it up. 

Way cool. And it is this brand-new therapy that has me free of visible signs of cancer in my CT scans, also with normal levels of Cancer Embryonic Antigen (CEA – a measure of how your body is reacting to new cancer cells, and therefore a measure of how much cancer there is in your body). Without this brand new advance we would be playing a game of “let’s see how long chemo can keep Craig alive.” I am ever so grateful for the researchers who are inventing new therapies. I’m also a bit lucky: I have a relatively common cancer – one that is actually increasing in incidence. There is a lot of money for the pharmas in finding new cures for colon cancer – as opposed to some other very rare cancers or other rare and fatal diseases. This situation also shows how silly the statement “let’s find a cure for cancer” really is. The drug combination that is keeping me in such fine fiddle is prescribed now for people with recurrent cancer, three specific drug alleles, and a specific range of DNA mutation rates. Cancer is a category of diseases, and curing all – or even many – cancers will take hundreds or thousands of different approaches. But for now, Marion and I are glad that there is a treatment that seems to help me, while cognizant that many other people are not so lucky. Thanks to all cancer researchers and health care professionals treating people with cancer. You are keeping me, and many others, alive and enjoying life.

Our Cancer Journey – Part 3: 2018 continues, 2019, and on into 2020

Professionally I work in what is referred to in industry and academia as high performance computing – or more commonly supercomputing. This involves what is referred to as “parallel processing” – multiple different computer processors work on different part of one problem at the same time (in parallel).

From the moment we had news that something icky was growing back in my liver, we took a parallel processing approach to my cancer. At Marion’s insistence we looked into two additional sources of opinions. One source of opinion was Dana Farber Cancer Institute – affiliated with Harvard University, located in Boston, and like IU one of the best institutions in the world when it comes to gastrointestinal (GI) cancers. We trekked out to Boston and sat down with an oncologist who specialized in colon cancer, who looked through my records, chatted with me for a good while, and then said two things: 1) the treatment that Dana Farber would have given me was exactly what I had been getting at IU, with the possibility that the surgeons I ended up with in Boston might not have been as good as the surgeons who operated on me in Indianapolis; 2) the oncologist said something that helped ease my mind a lot – he said that this cancer had not progressed in a normal fashion and at a normal pace, and that I needed to stop beating myself up. With this information we went home back to Indiana.

But Marion and I had really already known deep in our hearts that my cancer had not progressed normally … and that caused us to have less confidence than we might otherwise have that the plan to just rip out a lot more liver might not work. While we were in that time period between finding out that my cancer had come back, and having my second liver surgery, we continued to investigate other options. One option that we became aware of was in Europe – specifically the clinic of Dr. Rolf Kleef (http://www.dr-kleef.at/en/) who does a combination of hyperthermia and immunotherapy. I wanted to pursue my treatment at the Simon Cancer Center following their guidance. But I also knew that there was a possibility that the US approaches to treatment would take us to a point where we would be playing a game of “let’s see how long chemo can keep Craig alive.” If we did get to that point I wanted to have options.  Treatment at Dr. Kleef’s clinic constituted an option. Given that Marion is a native speaker of German, and given my decent facility with German, treatment at Dr. Kleef’s clinic in Vienna was seemed a fairly accessible option. 

The 0th step in making treatment at Dr. Kleef’s clinic a practical option was getting an analysis of gene expression in my tumor – a type of analysis called EST (Expressed Sequence Tag). EST analysis indicates what DNA in the tumor genome is actually being expressed. Dr. Kleef’s lab required that such analysis be done in a lab in Dusseldorf. My doctors and medical team at the Simon Cancer Center were wonderful about this. As part of my second surgery, surgeon Dr. Michael House dropped a bit of my tumor in a test tube and one of his nurses put that tumor on dry ice and shipped it overnight to the lab in Dusseldorf. 

The results of the EST analysis of my tumor were interesting. In particular, this analysis showed that there were a couple of genes in my tumor that were overexpressed – and when overexpressed these genes “masked” my cancer cells from my immune system. At a cartoon level, it was as if the T-cells in my body – the cells that detect ‘foreign’ cells – would come around looking for cells to mark for death, my cancer cells would say to them ‘nothing to see here, move along, move along’ and the T cells would do just that. This was really interesting news. A genetic explanation for how fast my cancer seemed to be growing, and possibly genes that might be susceptible to immunotherapeutic intervention.

I took the EST analysis report sent to me by the lab in Dusseldorf to the doctors in the Precision Genomics group at the Simon Cancer Center. Their first reaction was to say, “we’ve never heard of this lab and we won’t work with RNA analyses anyway.” Their second reaction was to say, “Hey… there’s some interesting stuff in here.” Given the potential for something interesting to be found in my genome, we made arrangements to get a full DNA sequence of my tumor. This analysis was done – gratis – by a company called Nantomics, Inc. It took weeks for the results to come back. Marion and I were on edge the whole time. In fact, it took so long that Marion and I were on vacation by the time the results came in. And the results offered a ray of hope. A new study, with a new combination of three monoclonal antibodies, had just started at IU in March of 2018 … and if my cancer came back again, I qualified to get into the study.

One part of the “parallel processing” activities was pursuing the possibility of treatment in Dr. Kleef’s clinic, which then turned into the possibility of being entered into a research trial in the US for a novel form of immunotherapy.

The other strand of “parallel processing” was continuing to monitor my health. By early summer I was sure that my cancer was on its way back. One of the blood tests I have gotten regularly is an analysis of something called Cancer Embryonic Antigen. It’s a measure of how many antibodies my body was making against new (embryonic) cancer cells. A normal level is 2.5 nanograms per milliliter or less. CEA levels are not a particularly precise indicator for colon cancer, but they tend to be indicators in a general way. In the summer of 2018, I made a graph of my CEA numbers, all of which were in the normal range – less than 2.5 nanograms / mL. But they made a very nice straight line up. I was sure when I graphed them that the next sample was going to be out of the normal range. I then started asking (pestering?) my doctors about putting me on the experimental drugs in this new trial. As one of my doctors said, they couldn’t do that because they could not study the effectiveness of treatment against cancer until there was cancer to measure.

My CT scans on October 22nd of 2018 solved that problem. My cancer was back. This time I was not flustered. I expected it, as did Marion. We had a plan. Right away the research nurse working with this new study went to work to get me accepted into it. One week – to the day – after a bad CT scan I was receiving my first set of monoclonal antibodies. That’s really light speed, in terms of cancer treatment, and I remain thankful to this day for the work of the doctors, nurses, and staff at the Simon Cancer Center for getting me into this study so quickly.

The study protocol was fairly straightforward: three monoclonal antibodies, in sequence, on the first session of a 6-week cycle. Two drugs at the beginning of week three. Two drugs at the beginning of week 5. Two cycles – 12 weeks – and then a CT scan. Because the MABs (monoclonal antibodies) had to be given in sequence, my visits to the infusion center in Indianapolis could be pretty long. One top of that, one of the drugs I was taking tended to reduce my magnesium levels. I thus generally actually had four bags of stuff put into me on “three drug days” – each drug by itself, and then magnesium, and three bags of stuff put into me on “two drug days.” Another aspect of this whole schedule was that we would celebrate Christmas of 2018 and New Year’s Day of 2019 without knowing if the drugs were working or not. For most of the last many years I have written and sent out a little letter outlining the key and cool points of the past year, tucked away in the Christmas cards we sent. I did not do that in 2018. I could not bring myself to write to a bunch of people that maybe the drugs would work, maybe they would not and I would go from living with cancer to starting to die of cancer. But with now almost two full years of practice Marion and I both did a better job of compartmentalizing. I was alive, and it was Christmas time. We celebrated. We shared with family and friends. And we hoped. And now and then, alone and by ourselves, we cried.

And the closer we got to my next CT scan, the more scared we got. I doubt that the two of us together got as much as one hour of sleep in the two nights prior to January 21st – the date of my first CT scan after the start of immunotherapy. And because we just hate waiting, we always schedule our CT scans for first thing in the morning. This means getting up at 5 am to be at the hospital at 7 am for scans that start at 7:20 am. On the morning of January 21 2019 I informed the technician doing my CT scan that I was declaring 2019 to be “the year of good CT scans.” A stupid thing to do of course, but then again, I often do stupid things. 

One of the great things about being treated at the Simon Cancer Center is that it’s very quick from scan to report. I was done with my CT scans by 8 am. Then off to have blood drawn for blood tests. Then into a consulting room to await my oncologist and my fate. At about 9:15 that morning Dr. Loehrer and research nurse John Spittler walked into the room holding a piece of paper. Marion and I were on the edge of tears. Dr. Loehrer handed me the report and said “here. I want you to read this sentence right here.” I looked at it. Looked again. And then I blurted out, while crying, “significant interval decrease” in my tumors. The immunotherapy was working. Marion and I cried. Gushed. We all hugged. 

The rest of the year was similar. I got to a point where I enjoyed going to the Infusion Center. I know all of the nurses and techs by name. It was the place where good people did bad things to bad cells. It was where I went to get better. Yet each CT scan was preceded by anxiety. During the summer I did what I had done before. I made a graph of my test results. I came to the conclusion that my tumors might simply be gone by the time of my CT scans in fall or winter. September 30 arrived – CT scans just under one year after I started on immunotherapy. For once in my life I kept my predictions to myself. Like usual, my scans were set for 7:20 am. Like usual, I reminded the technician that I had declared 2019 to be the year of good CT scans. Unusually, as Marion and I were walking back to a consultation room, where we usually waited to meet with Dr. Loehrer, we heard him call out to us. “Hey Craig – want to look at your CT scans?” What do you say to this question? Yes, of course. Marion and I walked over, with trepidation. Dr. Loehrer said “o.k. here on the left-hand screen are your scans from a year ago. Here on the right are your scans from today. Look – see where this tumor was a year ago? Look on the right. Nothing there. That spot on your liver we were worried about last year? Look – gone.” The CT scan was clean. “No evidence of recurrent or new metastatic disease.” What that meant was not that cancer cells were gone completely, but rather that there were no clumps as large as about 2 mm (the lower range of what can be detected in the sort of CT scan in use at the Simon Cancer Center). We cried. We gushed.

We worried more. Interestingly enough for me the impact of being told I had a clear CT scan was to worry more. Before I simply expected to die. Now… the possibility of living for a good while was presented to me. I had something to lose again. Not until December 23rd of 2019 and a second clean CT scan did I begin to settle my emotions. And yes… we thought about having had a colonoscopy the day before Valentine’s day in 2017, and what that had done to that holiday. But we decided to go ahead with a CT scan on schedule on Dec 23rdof last year because … well, because without it we would have worried about the worst. This way, good or bad, we would celebrate Christmas without uncertainty. And it was indeed a wonderful Christmas.

So that’s where things stand. Two clean CT scans in a row. I feel great overall. I have a skin rash from one of the MABs, but I can life with that. And as I am (perhaps too) found of saying, your skin tone doesn’t stay good very long when you are dead. I am VERY much alive and living life with my wife and our family. I ran my first 5K trail race of 2020 last weekend. I didn’t do great, but I did better than expected based on how much I have been able to work out so far this year. I am looking forward to what I hope will be a good 2020. I am ever so grateful to the many doctors, nurses, and technicians who have gotten me this far. The median survival time for people who are diagnosed with stave IVa colon cancer is 2 ½ years. I’m well past that with no evidence of cancer visible on a CT scan. Pretty darn amazing. In my next post I’ll talk a bit more about the biological action of the treatment that has gotten rid of my tumors, talk a bit about what I have learned, and try to convey some information that will help you think about your own health.

And for the moment, Marion and I are doing everything we can to savor every minute we have together, with each other, with our family, with our friends. 

Our Cancer Journey – Part 2

March 9 2020

2018 – starting our second year with cancer

2018, our second calendar year of living with cancer, seemed to begin pretty well. As of 1 January 2018 I had learned to work my reconfigured insides pretty decently, after having had my ileostomy reversed in December of 2017. My odds of being o.k. in the long run seemed good. I was possessed of a truly irrational level of optimism about the future. And every day I walked past three of the most wonderful gifts I have ever received – a limestone carving from younger granddaughter Madeline that said “Opa Survivor,” a framed letter from elder granddaughter Katja, and a cardboard life-size cutout of Rocket Raccoon. I felt about as invincible as Rocket.

I began the year by registering my sweetie Marion Krefeldt and myself for the Indy Mini half marathon. We have run that race together for many years. I signed up for a season pass for the DINO (Do Indiana Offroad) trail race series – a series of trail races I have run since 2015. My goal for the year was to finish in the top 20 of the points race within that series. (One collects points on the basis of finishing place in the several races of that series). I purchased tickets for Marion and myself for Donizetti’s Lucia di Lammermoor at the Metropolitan Opera in April. Lucia di Lammermoor is Marion’s second favorite opera, behind La Boheme, which we had seen in 2017I made plans to attend the International Supercomputing Conference held in Frankfurt, Germany – a very important conference in my line of work, and a conference that I had missed only three times since the first time I attended in 1997. (One of which was 2017, when being treated for cancer made it impossible for me to travel). As a sign of my confidence I purchased absolutely killer tickets to a performance of Bellini’s opera Norma to be performed by the Frankfurt Opera. The Frankfurt Opera is one of the best opera companies in Germany, and Norma is another of Marion’s favorite operas. In other words: I began the year half in the belief that I was just going to be o.k., and half in hope that I was just going to be o.k.

Marion was more circumspect. In 2018 we both continued to see a psychiatrist and a therapist, and Marion refused to let go of her concerns about my health. But she did finally let me organize a celebration of her 60thbirthday. Her mandate was that I had to be cancer-free for 6 months before she would allow that celebration. This did matter in practice. Her actual birthday was early in December, and we had to wait till the 13th of February for a party – 6 months after a clean CT scan, and a year to the day after the colonoscopy that initially revealed my cancer. And we did it up big. Marion had previously expressed a desire for an e-bike. I worked for months to prepare for a celebration that included about 40 people and included crowd-sourcing her birthday present. I researched e-bikes and found out that one particular model of the Dutch brand (Gazelle) was widely recognized as the best e-bike in the world. There were no local dealers. I talked a bike dealership in Indianapolis to become a registered Gazelle dealer. A large number of friends and colleagues contributed to the purchase of Marion’s e-bike. In the end family and friends paid about half the price, and I paid the other half. And a bit of excess was donated to one of Marion’s favorite local not-for-profits – Women writing for (a) change (https://www.womenwritingbloomington.org). On the evening of the party, all of the guests hid in our garage with Marion’s bike and she was REALLY and very happily surprised. February 13 would prove to be the high point of the year. 

As the spring wore on, I continued to thing all would be well. I ran, prepared for the first DINO race of the spring, and generally tried to get on with my life. But Marion noticed little things. Skin rashes that did not go away quickly enough. The color of my skin was a tad blanched. And yet I worked toward my first CT scan of 2018 completely confident all would be well. That scan was set for 5 April. It was not o.k. There was a “hypodense” mass in my liver, right on the border of where my liver had previously been resectioned.  (“Resectioned” is cancer-doctor-speak for cut apart to remove cancerous tissue and then put back together as best possible with what was left). There was some back and forth about whether or not it was a tumor or an artifact of the scan, and whether it was cancerous or benign. All of this happened when I had been so stupid as to schedule a trip to New York to see Lucia di Lammermoor the weekend after my CT scan. I expected to celebrate good news. We went ahead anyway. It was hard. We both cried – gushed really – during the performance. But it was a wonderful performance. And this was a lesson: go ahead and live life even in the face of uncertainty and worry about mortality. We are all going to die. It’s just that a cancer diagnosis makes one think about it as a clear and present reality, not a far-off abstract concept. But Pretty Yendi in the role of Lucia in Marion’s favorite Donizetti opera: that was both concrete in the here and now and a celestial musical and emotional experience. 

The way to find out if what I had was an artifact or a malignant tumor was simple: a biopsy. That was scheduled for the next week. Like usual, my wife and my son were by my side. Interestingly enough the way to get a sample from the problematic spot was to knock me out, stick a probe into my stomach, and then poke through the stomach wall into my liver. Before the procedure, I told the MD doing the work that I expected the results to be bad. After I woke up from anesthesia the doctor walked in and said that we needed to wait for the final report but that the initial analysis of frozen samples looked bad. I looked at him and said “We both know that tissue that when the initial results look bad, the final results don’t come back o.k.”

My cancer was back. Marion cried. Our kids and grandkids cried. I was numb. I think. I am not sure I remember clearly. Part of me, I am sure, felt that somehow I deserved this. That this was my punishment for not being a good enough person, for not being careful enough with my health.

Surgery was scheduled. Dr. Michael House was once again to be the surgeon – he is one of the best liver surgeons in the Midwest. The surgical plan was simple, to the joint satisfaction of me, Marion, and our surgeon: be aggressive. Get rid of it. Take out enough liver that we were sure we had all of the cancer. On May 4 of 2018 I was wheeled into the operating room with four-ish lobes of liver, and was wheeled out of the operating room with two lobes of liver. As usual, the nurses and my wife got me up and around to walk at the end of the day on the 4th. I woke up on Saturday morning the 5th of May and could hear the start of the Indy Mini half marathon outside. It really pissed me off. I could hardly walk a lap around the floor of the hospital. I didn’t go to the International Supercomputing Conference in June, missing it for just the 4th time in my career since I started going in 1997. As a result, a friend got great tickets for Bellini’s Norma at the Frankfurt Opera … courtesy of me, my overconfidence, and my cancer.

On the 5th of May I was forced to think back to things I had said during the Good Friday service at my church just a bit more than a month earlier. In that service, a group of people had each focused on the last things Christ had said as he neared death. My assignment was to speak on the sentence “I thirst.” The end of what I had to say was as follows:

 I thirst. I thirst that my next checkup will be good.

I long for something that I know will not come. I long for surety about my future, and what we learn from Christ’s example and from our own experiences is that there is no surety to be had for us in this life other than the surety that it will end.  Tomorrow is promised to no one. 

What we are promised is that we will thirst and we will live this life in longing, and in the end we will die. 

So now I pray not for water, but for the strength to handle thirst.

My plans and hopes for 2018 were in shambles. Marion had done her best to moderate my hopes. I had been overconfident. Little did I know how much I would need the strength to handle thirst. The bad news for 2018 wasn’t over.