Day 860: Update, Chemo, and Genetics

 Since my diagnosis, I’ve become an active member in several online cancer forums.  My stock advice to those suffering a recurrence is that you only need one treatment to work really well.  That advice always felt a bit hollow, because early in my journey it seemed every treatment worked really well for me, and I was living a mostly normal life.  2020 was a rough year for me, with difficult side effects and treatments that either didn’t work for long, or didn’t work at all.  If only I had taken my own advice.

Things seemed pretty grim when I started on a new (to me) treatment, folfiri, which is actually a decades old chemotherapy commonly used for colon cancer.  So far 2021 is turning out much better, with a CT scan showing fewer and smaller tumors, improving blood numbers (including that pesky chromogranin-A test which was the lone voice of dissent previously), and me feeling more optimistic than I have in quite some time.  And all it took was finding that one treatment that so far seems to be working really well.

I find it amusing because there’s commercials all over TV for the latest cancer drugs and how patients are living longer and better lives because of them.  While these drugs do produce miraculous results for a minority of patients, they are not without their own side effects.  I was on one of these drugs in 2020, and it gave me side effects and did nothing obvious to slow down my cancer.  I’ve heard similar stories from other patients, where it didn’t give them any meaningful remission from the cancer, but oh yeah, it did cause their own immune system to kill their thyroid gland.  Yes, plural, because it’s happened to at least two people.

So here I am, on some old chemo drug being used off label and getting the kind of results they promise in the TV commercials.  At least so far.  I’m no longer cocky enough to assume this will last for years, though it would be very good for me if it did, and that is certainly a possibility.  But the saying goes “make hay while the sun shines”, and the sun is coming out from behind the clouds for me now.

There are no plans to stop this chemo after a fixed number of cycles.  I’ll be receiving it as long as it’s working and my body is tolerating the side effects.  As suggested above this could go on for years.  It requires a mind shift.  I can no longer think in terms of simply surviving chemo and then starting to live life again when it’s over.  Now I have to learn to live life during chemo.  This includes everything from going for walks in the woods to paying bills and fixing broken appliances.  I’ve always been good at the walk in the woods bit, it’s the tasks that are more drudgery that are the challenge. I wasn’t good at keeping up with them before cancer.

Shifting to another topic, a ton of thanks go to my wife for all she’s done to support me through this whole ordeal.  When we were married, we took a vow to stick together “in sickness and in health”, but certainly my 20-something year old self never imagined “sickness” as recurrent metastatic neuroendocrine cancer during a pandemic.  As of today I’ve been fighting cancer for 860 days.  Just a few decades ago, I’d either be cured or dead by now.

Because of the pandemic, my wife can no longer keep me company in the infusion room.  She either takes a drive back home and then returns to pick me up, making for a very long day of driving, or waits in the parking lot for hours and hours coming inside only to use the bathroom. While she’s waiting alone in the car, I’m chatting with the nurses and other patients and it generally feels like a party atmosphere by pandemic standards.

To go off on an automotive tangent, our Toyota Prius is turning out to be an ideal car for such situations.  It’s a hybrid with automatic climate control.  Simply leave the car “on” and set the heat to 70 degrees or so, and the car will figure out when to run the engine and how fast to spin the blower fan to keep the interior comfy.  It’s stunningly efficient at doing this on a moderately cold day.  In the six hours it takes to drive to the oncology office, wait for my infusion, then drive home we averaged over 40 mpg including the time waiting in the parking lot.  That works out to a little over 2 gallons of gas burned over six hours and almost a hundred miles of driving.  Our next most efficient car would burn a little over 3 gallons just driving there and back without any idling for heat.

My wife has also been doing most of the chores around the house and preparing most meals (I usually get my own breakfast, as toasting bagels and pouring cereal are within my abilities), and the menu is constantly changing as I go on and off of chemo and the foods I tolerate are different with each chemo.  Things should get more predictable with the plan to stay on my current chemo indefinitely.  I think she’s quite pleased that pepperoni pizza is not only tolerated by my digestive system, but being a calorie dense food helps me maintain my weight, and in the warped world of cancer could be considered a health food.

In all honesty, the nurse practitioner told me to avoid salads unless I drench them in dressing.  It’s all about calorie density and maintaining my weight right now.  A body that’s losing weight doesn’t heal from chemo and recover blood counts as well.  Pizza, ice cream, chili with real beef.  It’s a poke in the eye to anybody who says they beat their cancer with a vegan diet.  Usually when pressed such people admit they had their single tumor surgically removed, and then declined chemo to mop up any microscopic bits that may or may not have have been in their bodies.

Finally, let’s talk about genetics, or more specifically the genetics of my cancer.  Last fall I had a biopsy which was genetically tested at Dana Farber.  I’ve since found out that this was an experimental test, so if you want to get the same one I couldn’t say what you should ask for.  In addition to showing mutated genes, it also showed which genes that had “copy number variants”.

A quick bit of biology: Humans have 23 pairs of chromosomes.  Chromosomes are made up of genes, and as a result genes usually come in pairs as well.  There are several hundred genes that can be associated with cancer, and many fall into one of two categories.  Promoter genes are genes that promote cell growth and division.  Suppressor genes oppose the promoter genes and stop cell growth.  These genes are analogous to the gas and brake pedals in a car (credit for that analogy goes to “The Emperor of All Maladies”)

The balance between promoter and suppressor genes is important. It’s what allows our bodies to grow as children, and then maintain a stable size as adults.  When there is injury, a period of increased growth is needed for repair, followed by only enough growth to replace cells that are lost due to various causes.

When you look at my genetic report, I have very few actual mutations.  It turns out that 98% of cancers have more mutations than mine.  What I do have is a lot of is those copy number variants, which means I have the wrong number of certain genes.  My amateur explanation for this is that there is something very wrong in my cancer’s ability to repair breaks in chromosomes, and in the process of fixing those breaks it either loses genes or inserts extra copies.  And the general trend is that my cancer has extra copies of promoter genes and fewer copies of suppressor genes.  In several cases suppressor genes are missing entirely.  My cancer has a very large gas pedal while the brakes are either broken or missing entirely.

This probably explains why my cancer grows so fast, and really doesn’t care a whit about what I eat.  If you think about terminal cancer patients, they have usually lost their appetite and are losing weight until they become skeletal, yet their cancer continues to increase in size.  Think about that the next time somebody proposes that you can starve cancer with diet.  It might work for some low grade cancers, but not widely spread metastatic cancers.  Yes, I really do have an issue with people peddling diet as a cure for all cancers.

Let’s talk about some specific genes.  PTEN is a frequently mutated gene in prostate cancer, affecting an estimated 70% of patients at diagnosis.  In my case, one copy of PTEN is mutated, and the other is missing entirely.  PTEN is a suppressor gene, and is also thought to be involved in making cells stick together.

Looking at other suppressor genes, I’ve lost both copies of ARID1B, RB1, and TP53.  TP53 is important and we’ll get back to that in a moment.  These are all genes that can stop cell growth and division, and they’re missing entirely from my cancer.

Cancer is a disease of damaged genetics.  My cancer cells no longer require any external signal to grow, they just grow because they have extra copies of growth genes and lost the genes that can stop growth.  Neuroendocrine is a small cell cancer, and the cells are small because they just keep dividing and don’t have any time to grow between divisions.

If it isn’t obvious, I’ve been spending time looking up genes in my genetic report online, and trying to form a mental model of how my cancer behaves as a result of these mutations.  It’s being an amateur geneticist at it’s worse, because my genetic report only says which genes are mutated or have copy number variants.  It doesn’t say which genes are active or inactive, and it ignores that it usually requires a sequence of genes to carry out a cellular process.  As an example, I have an extra copy of a gene associated with ovarian development.  That’s probably important in ovarian cancer, but most likely the gene is inactive in prostate cancer.

But when patterns emerge that match the behavior of my cancer, it’s a reasonable theory that there is some cause and effect.  For example, I’ve noticed I’ve lost several copies of genes that are involved in cellular adhesion, which is basically cells sticking to each other.  This is necessary for cells to form organs or tumors.  It’s not helpful to have liver cells breaking off and floating around the body, but that’s exactly what my cancer is doing.  Some cancer patients have a single tumor the size of a brick.  That isn’t how my cancer behaves.  Instead it forms many small to moderate sized tumors scattered throughout my body, and I see evidence for that in my cancer’s genetics.  It was probably that way from very early on, as my prostate cancer had invaded countless bones before reaching the left side of my prostate.

It’s somewhat unfortunate, because when cancer cells stick together and remain in one place, they become good targets for radiation and surgery.  My cancer is systemic, and generally can’t be treated with radiation and surgery because there’s countless tumors to be treated.  I’d either die from radiation poisoning, or end up as a jelly fish because most of my bones would be removed from my torso.

But let’s get back to that TP53 gene and chemo (http://www.bioinformatics.org/p53/introduction.html).  TP53 has a very specific function: after DNA has been duplicated, it stops the process of division until any errors in DNA duplication have been fixed.  My healthy cells presumably have both copies of TP53 intact.  When chemo damages the DNA of healthy cells, TP53 steps in and stops cellular division until the damage is repaired, or will kill the cell if damage cannot be repaired.  As a result, growth of healthy cells is slowed, but they repair themselves and proceed to make more healthy cells.

But this is not the case in my cancer cells.  The quality control department that is TP53 has been laid off.  Cellular division proceeds regardless of the state of DNA, and most DNA damage is likely to be fatal to the cell as genes for important cellular processes are changed to gibberish.  About 50% of cancers involve mutations or loss of TP53, and that puts the cancer cells at a disadvantage to healthy cells when treatment is intended to damage DNA (radiation and some chemotherapies).

And this is potentially why a decades old colon cancer treatment is so effective against my cancer.  It works in part by damaging DNA.  So does carboplatin, and that was effective as well.  A few decades ago, when a bunch of new chemotherapy drugs were in development, I could very well have been the guy you read about in the newspaper who was about to die from cancer, but then had a miraculous recovery due to the latest in cancer treatments.

All the hype today is in the fields of immunotherapies and precision medicines.  This is generally good but it does imply chemotherapy is outdated, difficult, and useless.  My experience is the exact opposite.  The shiny new drug didn’t work for me, but decades old chemos did.  More importantly, it’s working after my cancer grew back following platinum chemotherapy, which seems to be considered the best standard treatment for neuroendocrine cancer.  When that doesn’t work or stops working, there is not a long list of second line treatments proven to work.

What all existing cancer treatment have in common is that none of them work by fixing the genetic damage at the heart of cancer.  But what if you could do that?  Viruses work by injecting DNA or RNA into a cell, and turn that cell into a factory for making more viruses.  What if a virus could be engineered to inject the missing TP53 gene back into my cancer cells?

That’s exactly what scientists tried according to the link above.  This is what a real cure for cancer might look like.  Genes would be added to or removed from cancer cells to either stop the uncontrolled growth, or make the cancer more susceptible to existing treatments.  It’s a fascinating idea.  Unfortunately in the case of TP53, the virus worked great in a petri dish, it worked great when injected into mice, but as frequently happens it didn’t work so well in humans.  Follow the link above and scroll down to section 7 for more information.

One final thought on genetics: genetic changes are random, and not all of the changes work in the cancer’s favor.  I found it interesting that my cancer has 6 copies of the CEPBA gene which is thought to be a tumor suppressor.  Obviously it’s not stopping the cancer from growing but it is an interesting detail nonetheless.  Also, I’m missing one of two copies of the XPO1 gene, which is thought to be related to resistance to chemotherapy.  Assuming extra copies would make the cancer more resistant to chemo, this seems like a rookie mistake by my cancer.  It gives me hope that my current chemo may work for a long time to come.

So to sum up: boring old chemotherapy can work as well as if not better than the latest and greatest drugs.  It all depends on the specific genetics of the cancer.  Also, cancer is not a death sentence, and failure of standard treatments is also not a death sentence.  I’m on my third chemo for neuroendocrine cancer and seem to be tolerating it well.  We’ve also learned from past experience that my cancer will bounce right back if chemo is stopped so we’ll be doing something different and continuing chemo as long as possible.  I’ve heard a handful of stories of patients getting chemo beyond the standard number of doses, and it seems in every case they’ve done quite well.

So I’m quite optimistic I might be able to get years out of folfiri, and should it fail there’s other off-label treatments that can be tried, or there might be a clinical trial.  If I do get years there may be brand new drugs to try that aren’t available today, perhaps even an engineered virus that could inject TP53 genes back into my cancer.  The only thing I’m certain of is that my ability to predict the future has been awful.

Another Scanxiety Post

Here I go again, writing a blog post before a CT scan instead of after.  If I wrote this a few days from now I could talk about the results and what it means for my prognosis and treatment plan.  But no, instead you’ll get speculation about the results and scanxiety instead.

Why would I be anxious about a CT scan?  After all, I’ve already had six of them, and this will be number seven.  It should all be routine by now.  I’ll be drinking a ghastly mixture containing barium contrast tonight while everybody else is having a beer or some other adult beverage during the super bowl.

But let’s consider the results of those previous six CT scans.  Four have been outright bad news showing cancer that wasn’t there on the previous scan.  Only two have shown a reduction in disease, and exactly none have shown the much coveted “no evidence of disease”.

More problematic, as a result of those six CT scans, four directly led to the initiation of a new chemotherapy regimen, and a fifth led to a round of radiation.  That leaves exactly one scan where my oncologist judged the current treatment plan to be sufficient and didn’t make any changes.  To put it in more human terms, over 80% of my CT scans have turned my life upside down by changing plans.

That said, there’s reason to expect this will be the second scan that doesn’t upset the apple cart that is my life.  My blood tests are all showing improvement with one unreliable exception, and generally I’m feeling better and doing more each cycle.

It’s generally unfathomable that the cancer in my liver hasn’t shrunk, given the significant drop in my liver enzymes.  I asked the nurse practitioner about this, expecting a safe answer such as “in most cases yes, but there have been exceptions”.  However, her answer was much more definitive leaving the impression that it’s almost unheard of for the cancer to grow despite improving blood tests.

But… I still worry.  Effectively I have two active cancers: The original prostate cancer I was diagnosed with in October of 2018 and the neuroendocrine variety that was found in January 2020.  Treatments that work against one form of the cancer generally don’t affect the other cancer.  It’s quite possible the neuroendocrine cancer has found a new organ or lymph node to establish a new foothold in, or that my original prostate cancer is progressing in my bones.

Such a result means more appointments to discuss my options and adjust my treatment plan, and then of course, changing the treatment plan and figuring out what the new side effects are.  In almost all cases I can guarantee increased fatigue will be a factor.

Having a CT scan is sort of like applying to a college or going on a job interview.  There’s that time where you’re waiting for them to make a decision that will significantly affect the future course of your life.  A new job could mean moving to a new state and making new friends, or maybe you didn’t get the job and you’ll stay in your current house a while longer.  It’s not a time to make long range plans because you literally don’t know where you’ll be in a few months.

But enough about the CT scan, I’ve been living in interesting times.  The day before my current cycle began we travelled to our getaway in VT and found the furnace had stopped working.  It was incredibly lucky timing because it was some of the coldest weather of the year and the furnace had only quit the night before meaning that it didn’t get below freezing inside.  We were able to drain the plumbing and pour RV antifreeze in the traps to prevent damage.  We only briefly thought about making an emergency call to get the furnace repaired, but with my infusion the next day we didn’t have time to wait for a repairman to show up.

It was odd but it was actually an enjoyable day.  There was a crisis and instead of panicking we simply went about the process of draining the plumbing for the third year in a row.  In the two previous years, extended power outages had threatened freezing temperatures indoors so we’ve gotten quite good at winterizing the place on short notice.  It felt good to be able to rise to the occasion and be moving up and down the stairs and all around the place repeatedly.  My watch logged the most steps in a day since November.

To go off on a slight tangent, many cancer patients downsize their lives to simplify life and reduce stress.  I’ve gone the opposite way and doubled down on keeping our Vermont property as a regular part of our lives.  In a way we chose our getaway well.  It’s a modest one bedroom affair with simple plumbing.  By simple I mean 90 percent of the pipes are easily accessible in the basement, and there are no places where a pipe has a long run through a wall or ceiling and could cause significant damage if it ruptured.  It’s supplied by a well which we shut off when we’re not there so the amount of water that can come out of a damaged pipe is limited.

In other words, we don’t worry about frozen plumbing because the damage should be limited and easy to repair.  If I have any health hiring a plumber to deal with frozen pipes shouldn’t be an issue.  If I don’t have my health then nothing really matters.

On Monday it was off to the oncology office extra early to get my infusion before the latest nor’easter hit.  For those not familiar with nor’easters they are sort of like a winter hurricane.  The weather system spins off shore, picking up moisture from the ocean and dumping it as snow inland.  It’s called a nor’easter because the wind (which is usually significant) comes onshore from the northeast.  This was a modest one that gave us only about a foot of snow.

As I’ve mentioned before my current chemo includes a 46 hour take-home pump.  Tuesday I awoke to a foot of snow in the driveway, and a plan to force myself out to the garage to start the snow thrower, make a token pass or two up and down the driveway, then hand it over to my wife to clean up the rest.  As it turned out, I cleared the entire driveway, the walkways, and the paved parking spot on the side of the garage.  I was on my feet and moving for about 90 minutes total, with a several hour break in the middle for lunch.  All that with a pump dripping poison into my vein.

Wednesday was relatively boring and routine and only involved a trip back to the oncologist to have the 46 hour pump removed and my port flushed.  But I did drive myself and after the snow clearing of the previous day I was feeling quite tired.

Thursday was when my wife made an appointment to get the furnace fixed in Vermont.  I loaded myself up on drugs to manage side effects and jumped into the passenger seat while my wife drove.  My goal was to help get the wood stove started to keep us from freezing while the furnace was being repaired.  That goal somehow expanded to bringing some firewood up from the basement, restocking the basement from the outdoor wood shed, and of course shovelling the path to the wood shed.  This on a day when side effects usually hit me quite hard.

Since then I’ve been acting more like a cancer patient, sleeping 12 hours a night, taking naps during the day, and generally paying the price for my enthusiasm earlier in the week.  It was great that I was able to rise to the occasion on several occasions, but now I’m feeling the consequences of that while waiting for my scan tomorrow.  It’s not the best place to be emotionally but I certainly wasn’t worrying about my scan on Sunday, Tuesday, and Thursday.

And in all this time I still haven’t mentioned my left eye.  Shortly after restarting chemo in October, I started having flashing lights in my left eye that vaguely resembled a migraine aura.  I thought it interesting at the time but didn’t think much about it.  As time went by the flashing lights became more prominent and were followed by an odd pattern of blind spots and occasional eye pain.  This unfortunately coincided with my low point in December.

I was worried that chemo or cancer was permanently damaging my vision.  I’d have to see an eye doctor to find out for sure, but at the time I didn’t have the energy for my chemo appointments and also have an eye appointment.  I asked if one of my treatments should be delayed a week to give me a chance to get to an eye doctor, but we all agreed fighting the cancer was more important than my vision.  What good is eyesight if you’re dead?

After changing treatments as a result of a disastrous CT scan that showed my cancer was growing despite treatment, my energy started to improve and I eventually was able to get to the eye doctor.  The result?  Eye migraines, which he admitted was a horrible term.  They’re largely a result of stress, and there was no observable damage to the eye other than the ravages of being over 50 years old, which apparently includes an increase in floaters.

I still get these eye migraines whenever I first encounter bright light, such as going outdoors.  But now I know it’s just a weird thing my eye does involving lots of flashing lights, temporary blind spots, and then normal-ish vision after everything subsides a short time later.  It’s really annoying, and I’m convinced chemo is contributing to the problem, but it turns out I’m not actually going blind.  So in this case procrastinating on getting a symptom checked out mattered not one bit.

Which brings me back to today.  Despite my especially busy week and resulting high step count, I haven’t actually done any formal endurance exercise in an entire week.  Thus, I shall be forcing myself out the door shortly for a walk up and down my street before the latest snow storm starts.  Activity really helps drain any extra physical energy which otherwise would be put into being anxious about my scan.