Since Nico was in the hospital, we have been very cautiously increasing his medications. We go to clinic every two weeks to check blood counts, liver enzymes and the metabolites of 6MP (the staple medication of maintenance chemotherapy). We went to clinic yesterday, and Nico’s favorite volunteer, Daniel, had returned after a long break. Nico transformed from angry and bitter to completely charming in about two seconds. Daniel stayed with Nico for hours. Daniel will never know what a positive influence he has had in Nico’s life. His time is invaluable to us – it is the difference between a traumatic experience in a scary place and a fun time with someone who cares for you.
I am going to backtrack, and this might be a technical post. So if you just want an update on life in general – we are fine, chugging along and doing our best. Nico continues to have chronic pain, but he has graduated from physical therapy because he has resumed a normal gross motor trajectory. Great news!
There was a glitch, as I mentioned before, in Nico’s chemo dosages. In maintenance therapy, two of the main staples are a daily medication called 6MP and a weekly medication called Methotrexate (MTX). These two medications are titrated based on blood work, specifically ANC (neutrophil count) and liver enzymes. Both 6MP and MTX can cause liver inflammation, and this manifests as elevated liver enzymes in blood work. When Nico’s liver enzymes started to climb, we checked 6MP metabolites to determine whether Nico was metabolizing 6MP into the desired anti-leukemic (“good”) metabolite or the liver-toxic-with-no-therapeutic-benefit (“bad”) metabolite. Testing metabolite levels is not commonly done. It depends on your doctor and your hospital. It might even be controversial in some ways. The protocol allows for liver enzymes to reach 40 times the upper limit of normal before considering a chemo hold. So, Nico’s elevated liver enzymes would not concern some doctors because his enzymes were never anywhere near that high. The argument is that bone marrow suppression alone, not metabolite levels, is correlated to treatment success. Whether metabolites really matter, especially if ANC is suppressed, is unknown. Some doctors argue that metabolite levels only matter when the liver is so obviously inflamed as to create a host of secondary problems itself. But there is a caveat. ANC is used to determine proper suppression specifically because if the ANC is too low, a life-threatening infection becomes a very real jeopardy. More children in treatment die from infection than from cancer. So the treatment calls for bone marrow suppression, but only within a range that allows an individual some reserve to fight off potential infections. ANC, however, is not always the best indicator of suppression.
The problem is that Nico’s bone marrow preferentially makes neutrophils. He maintains a higher ANC even when all other counts indicate that his marrow is suppressed. He is frequently not in the desired range for ANC, and based on the protocol his chemo dosages should be increased. Increased dosages means increased risk of liver toxicity. The other problem is that Nico’s 6MP metabolites fluctuate. The oncologists like to see the metabolites in a certain range. But generally, they look at the ratio of good versus bad metabolites, and this ratio does not usually change over time (in theory). This is not true in Nico’s case - his ratio has fluctuated wildly. We have tried to ferret out the lynchpin, or even if there is a lynchpin, but it is all a guess. Jeff and I postulated to our doctors that the timing of 6MP administration affects Nico’s metabolite levels. Nico’s 6MP metabolites were always in the desired range when we administered 6MP in the morning. But (and this is a big but) that was also the period of time in which his ANC was way too high. Circadian rhythm effects drug metabolism generally, and this has been studied specifically with 6MP. There is a very slight advantage for most kids if 6MP is given in the evening (but Nico has never been “most kids” during treatment). Nico has big problems with low blood sugar when we give 6MP in the evening. But we switched Nico back to evening administration specifically because we were worried this was contributing to his high ANC. We want any advantage that we can get. We were desperate to get his ANC down, and although it is finally coming down now, his metabolites are terrible again. Yesterday, his ANC was 1780, just barely over the desired range of 500-1500. Two weeks ago, his ANC was over 4,000, so this is a positive direction. We should know his metabolite levels in the next few days, but based on his liver enzymes, they are not good. So what is more important in this situation – ANC or metabolites? No one knows for sure.
As stated, 6MP and MTX are titrated to blood counts and are periodically adjusted to height and weight (usually at the beginning of each new 3-month cycle). These dose adjustments are reported as percentages. A child on the standard prescribed dose is said to be at “100% dosing.” Some kids only take 25% of a dose because that is all that is needed to suppress the child’s ANC into the desired range. Some kids require 200% of a dose to get the same amount of suppression. This is because every individual metabolizes medications differently. So this was the other glitch in our treatment course. Apparently, Nico’s doses were not titrated to height or weight for several months. This did not ultimately change the dose that we administered, but it did change the way his dose was reported to Jeff and me. We thought that Nico was taking 175% of both 6MP and MTX and still not getting adequate marrow suppression. In reality, based on his growth, he was just slightly over 100% of MTX and 125% of 6MP. That sounds like a completely different scenario to a parent. In the first scenario we believed that chemo was no longer working, and frankly, we were beyond worried. We essentially stalked our primary oncologist for a private meeting specifically to discuss these doses and that was when all this was uncovered. The next problem occurred when the above situation was “remedied” by applying the higher percentages to the updated height and weight. So basically, Nico’s doses of 6MP and MTX were both increased by 30%. And then he caught enterovirus. That was my last update. We spent a week in the hospital. Nico required a lot of intervention and was very sick. Between the higher doses of chemo and the viral exposure, he had no reserve left.
For the record, I do feel that I bear some responsibility for what happened. I double-check everything. But when I originally asked about when height and weight were calculated into the formula, I was told that during maintenance adjustments are made based on counts alone. The source of this information was not our primary oncologist, and I accepted this answer until Nico’s counts and doses started to look wonky. Then I kicked myself for failing to continue to calculate doses myself. Should patients have to do this? No. But this is the reality, and I knew this reality from working in healthcare for years. From diagnosis, I have always told our oncologists that I want to see the exact orders so that I can double-check. I should not have stopped questioning.
So since then, we have been gradually increasing the medications back to the pre-enterovirus dose. We have done this slowly. We also check blood counts and metabolites every two weeks. The question that has been posed is whether we need to add an additional medication that would shunt 6MP metabolism into the desired pathway. This would mean that after 3 years in a clinical trial, we would be pulled out of our current protocol. Nico’s data would no longer count towards the study’s ultimate conclusion. The additional medication is experimental. It is not a new medication, actually it is medication commonly used for gout, but it is not yet indicated for shunting 6MP metabolism. We would be part of a new study, only being done at a few hospitals, that is looking specifically at the medication’s use for this purpose. Adding this medication would mean adding another drug with a whole new set of side effects. And all of this would happen during the last 4 months of a 3.5-year treatment period. It seems a little late in the ballgame. It would also mean that Nico has to get weekly blood draws. The doctors added that Nico could “just” get an arm stick at a laboratory near our home so that we would not have to travel to the hospital every week. The suggestion that weekly lab draws from his arm (rather than his port) had an upside indicated a real lack of understanding of our situation. Asking a 5-year old to submit to weekly lab draws in some two-bit, drop-in lab after enduring over 3 years of traumatic, sometimes brutal, treatment is too much. If we enroll in this, we will have to figure something else out.
Obviously this is weighing on our minds. We are not making any decisions right now. Nico’s doctors want to see his metabolite levels after a couple of weeks of chemo at his pre-enterovirus dose before we decide what to do next. Jeff and I are wondering if we should just switch him back to morning administration. We do not want to make too many changes at once, and again be left wondering what caused what. But we should have the latest set of metabolite levels within a few days. If they are high (as suspected based on Nico’s liver enzymes and abdominal pain), I think we will explore that option. Nico’s doctors are skeptical that timing of 6MP administration will make any significant difference, but Jeff and I are both convinced that timing could shift metabolism. If you look at Nico’s labs, the trend seems obvious. But then we run the risk that we just exchange one problem for another - shifting metabolites but then potentially running the course of treatment with a high ANC. This is all a roll-of-the-dice, and it is scary. Some kids just stay in the desired range through treatment, and do not have to titrate doses very often, if at all. That just has not been our experience.
What does this mean? We do not know. Our oncologists say that Nico has been closely monitored, which is true. And his doses have been appropriate, which is true based on the protocol. The oncologists also state that although Nico has been a tricky patient, his bone marrow has generally been very well suppressed. The doctors insist that they still expect the best possible outcome. As parents you wonder if this is just a pat-reassurance because there really are no guarantees. There are so many aspects of care that have no clear answers. We just do the best we can with what we know and hope for both personal success and that our experience aids others in the future.