March 17, 2014: First chemotherapy.
Last time, I presented a real-life, personal medical mystery. Mom's chemotherapy was supposed to happen a certain way, but it didn't. So what happened, and why?
- Mom starts water-only fast for 48 hours before chemo.
- Geoff goes to Game Developers Conference (GDC) for 1 week.
- March 17: Mom starts first chemotherapy.
- Mary stays with Mom in hospital.
- Muriel and Ron come to town.
- Hospital staff puts PICC line into Mom.
- Inject/infuse sodium bicarbonate continuously until Mom's urine is pH > 7.9.
- Infuse methotrexate at a high dose (3 g/m^2, or 4.8 g in Mom's case) over 4 hours.
- Wait 24 hours, then infuse leucovorin.
- Infuse Rituxan.
- Keep fasting until 24 hours after chemo.
- Wait a couple days until chemo out of Mom's body. Mom goes home.
- Geoff returns from GDC.
Knowing something went wrong with Mom's chemo, you might read the above list and jump to conclusions about the cause. For example, why is Mom fasting for chemo, especially her first one (step 1)? Why is Geoff leaving town during that time, especially for a "game conference" (step 2)? If you knew a little more, you might question why we're giving Mom two drugs the first time (methotrexate and Rituxan) (steps 8 and 10)? Why are we changing Mom's pH (step 7)? Why are we starting with a "high dose" of chemo (step 8)? Why put in a PICC line (step 6)?
You can say, "Why is Mom fasting?" in two very different ways. You can ask it as a straightforward question, like when a child asks, "Why is the sky blue?" Or you can ask it as more of a judgment, like when Judge Judy asks, "Why did you leave your child with a stranger?" The problem with judgment-questions (which aren't really questions at all) is that your bias clouds your judgment. If you're actually wrong, or only half-right, you may be too biased to see it.
I emphasize this point because I see it so often, and it's not helpful and can be very harmful. For example, it can lead one to stop something good because of fear: a PICC line, Rituxan, and dare I say, fasting during chemotherapy. If you find yourself jumping to conclusions, take a step back and try to ask the question as a real question.
For Mom's first chemo, all the above are good questions but bad conclusions, because something else in that timeline was the real cause.
Photo break! Mom and our friend Jenny from Hope for Horses in Seattle. January 27, 2014. Full photo here.
The doctors had to figure the cause in real-time, but we'll use hindsight. Mom was supposed to be in the hospital for 4 days. Instead, she was there for 12. Here's the discharge diagnosis after Mom's chemo:
- Diffuse B-cell lymphoma with central nervous system involvement status post chemotherapy.
- Acute renal insufficiency secondary to methotrexate toxicity.
- Wegener's granulomatosis followed by Dr. Barger.
- Hypertension, started on metoprolol.
- Hyperglycemia likely secondary to steroid.
- Hypocalcemia.
What's that saying? 1) is Mom's cancer: PCNSL (Primary CNS Lymphoma). 2) says Mom's kidneys were poisoned, because of the methotrexate. 3) is a pre-existing autoimmune disease Mom's had for years. 4) is, well, hypertension. 5) says Mom has high blood-glucose levels (which can lead to diabetes), probably due to steroids she's on. 6) says Mom has too little calcium in her blood.
What happened is that Mom's chemo started more-or-less as planned. She fasted a little, the PICC line was put in, her pH was increased, methotrexate was given, then leucovorin, then Rituxan. However, Mom's kidneys started to fail. (Our kidneys remove toxins and waste from the body. If our kidneys fail, we need to be put on dialysis or we'll die.)
Why did Mom's kidneys fail? At first, some of the doctors thought it might be Tumor Lysis Syndrome (TLS). But Mom's oncologist, Dr. Quadro, now believes it was due to the methotrexate. However, it wasn't due to the *high dose* of methotrexate (3 g/m^2, or 4.8 g); it was due to the TIME (given over 4 h). For example, if the same dose were given over 24 hours, Mom's kidneys would've been fine.
That's a very important distinction. We needed a high dose of methotrexate to fight Mom's brain tumor. If one assumes the high dose was poisonous to Mom's kidneys, we could lower the dose, but that would lower the effectiveness of the treatment. A better solution is to maintain the high dose and increase the time over which that dose is given.
You might be wondering, how will increasing the time span affect the effectiveness? Think about that for awhile, and I'll answer at the end. (It's a good mental exercise, in case you ever know someone who has cancer.)
It's hard to be certain in medicine. Each patient is individual, and each body changes over time. So why do we think Mom was poisoned due to the time-span of the methotrexate? Why wasn't it the amount of methotrexate? Or the fasting? Because in later rounds of chemotherapy, Mom fasted even more and had even more methotrexate (but over 24 hours, not 4 hours) and everything was fine.
So, Mom almost died from her first round of chemotherapy. The methotrexate was too concentrated for her, and the methotrexate probably formed tiny crystals in her kidneys, damaging them. It would take a long time for those crystals to dissolve and for Mom's kidneys to heal. The fallout included:
- Mom's extended stay in the hospital (12 days instead of 4).
- They had to give Mom a special drug (glucarpidase) to treat the poisoning, and it cost tens of thousands of dollars.
- Mom had to wait almost 6 weeks before she recovered enough to get her next chemo (her chemo should've been every 2 weeks).
- For the next several chemos, we had to give less methotrexate than the doctor would have liked, because Mom was still recovering (and we weren't sure how much she could take). This meant less chemo attacking the cancer cells.
Not a great start to chemo.
To clarify, I'm not mad at the doctors for Mom's methotrexate poisoning. PCNSL has been treated with methotrexate at both 4 hours and 24 hours, so the doctors were following a standard. At the time, I didn't know anything about Mom's chemo and I didn't think about the time span, so we didn't object. And 4 hours is definitely less waiting for the patient. On the other hand, Mom is older than the average PCNSL patient. Also, she's had quite a few other medical issues, including Wegener's granulomatosis for over 20 years.
Everyone makes mistakes. That's how we grow. We grow, learn and keep going.
Back to a question: How will increasing the time span of a drug affect its effectiveness? In particular, giving 4.8 g of methotrexate over 24 hours instead of 4 hours? If a drug needs to reach a certain concentration in the body, then a shorter duration may be better. Perhaps that's the case for drugs to cross the blood-brain barrier (BBB), but I'm not sure. On the other hand, giving a drug over a longer period of time can be more effective. Why? Why isn't the same amount of drug the same effectiveness?
My understanding is that methotrexate works at certain stages of the "cell cycle." Also, a tumor is a mass of cells (think of a ball), so the methotrexate can kill only the outer layer of cells per cell cycle. The longer the drug duration, then the more times the drug can kill the outer layer of cells, let those cells be shed, kill the next outer layer of cells, and so on.
Regardless of the reasoning, here's some proof from a scientific article, "Methotrexate Cytotoxicity for L5178Y/Asn- Lymphoblasts: Relationship of Dose and Duration of Exposure to Tumor Cell Viability."
Feel free to spend time with the chart above. The horizontal axis is increasing amounts of methotrexate. The vertical axis (Viability) is how well the cells survived. As we're interested in killing cancer cells, lower values are better. The lines connect experiments done with the same drug duration (e.g., 3 h, 6 h, 18 h).
In that chart, compare the red and blue circles. The red circle is cells in 100 µM methotrexate for 3 h; about 10% survived. The blue circle is 0.1 µM methotrexate for 42 h; less than 1% survived. Imagine that: one can give 1000x less drug but still get *much better* results than before simply by waiting 14x as long.
Since we're looking at charts, I want to end this post by re-explaining a graph from last time. I'll try to be clearer.
First, this graph is showing something different from the chart way above, so cast that out of your mind. Here, the horizontal axis is how many days have passed. The vertical axis (% Survival) is how many mice survived in a given group. There are 3 groups: "Control," "Chemo-cocktail" and "Fasted/chemo-cocktail." All 3 groups had cancer. The Control group had no chemo. The Chemo-cocktail group had a cocktail of chemotherapies. The Fasted/chemo-cocktail group fasted before receiving the same chemo-cocktails as the previous group. The graph also has notations that fasting was done on Day 7 (for the group that fasted), and chemo was given to all groups around Day 9.
Each line on the graph follows one of the groups as it goes from 100% alive on Day 0 to x% alive after so many days. (That's why all three lines are always decreasing, never increasing.)
I've circled three points on the graph and will describe them below. If you can figure out which description fits each circled point, you'll have gained a good understanding of the graph.
- After ~27 Days, the entire Control group was dead.
- After ~45 Days, ~18% of the Chemo-cocktail group was still alive. Chemo was much better than doing nothing.
- After ~52 Days, ~50% of the Fasted/chemo-cocktail group was still alive. This was much better than doing only chemo!
Whew! Mom's first chemo was a trial, but we made it through. Don't worry; I hope to summarize subsequent chemos more quickly. =)
Next timeline:
- March 17, 2014: First chemotherapy.
- April 25: Second chemo.
- May 27: Third chemo.
- June 10: Fourth chemo.
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