So That's What a Falling Shoe Sounds Like


(This is part 8 of a series. You can read the previous part hereNew to the series? Start here.)

We had a great morning at Dana-Farber Cancer Institute today. I had been anxious all week about this visit, and I had some kind of weird premonition that something would be awry. So after we made it to DFCI at 5:45am for a full morning of thee CTs, two MRIs, and a blood draw, and the preliminary report from Dr. Enormous Brain was, “Yes, I think it all looks good. Not sure what these little things are because the neuroradiologists haven’t read the scans yet, but the thoracic radiologist and I think that’s probably a blood vessel or something” we were both overjoyed! Relief! I could stop clinching.

We went to lunch at The Mission Bar and Grill and enjoyed a delicious cucumber martini (Heidi) and Diet Coke (me—because I was running on fumes at that point—did you catch the 5:45am arrival time, which required departing Connecticut at 3:30am?). Throw in the shrimp Cilantro Lime Shrimp Salad for Heidi and The Mission Burger for me, and we had one humdinger of a lunch. And the bartender was very friendly, too!

On a whim, Heidi checked to see if the final reads had come back for the MRIs, and indeed, they had. She started reading at the top. I jumped to the last chapter. “Oh, shit.” That’s all I could say.

“What? This?” she said, pointing at the Big Word Description at the top.

I pointed at the bottom line: “…are most likely metastatic tumors.” Tumors. Plural. My innards went wobbly, and Heidi and I both began to sob quietly on the barstools with each other. I’m sure that the bartender has seen that happen there before, and it happened again today.

So that’s what a falling shoe sounds like. Silence. Quiet muscle spasms racking our bodies as we silently and tearfully recognized that the day we had been dreading… the first of the many that we have been dreading… had actually come. Our first of the worst fears had been realized.

We were fortunate that we were at DFCI which, though it is an enormous cancer institute with thousands of specialists and caregivers and patients, had enough time to see us again. We called and left a message for Dr. Enormous Brain, who had clinic hours continuing into the afternoon, and his coordinator called us back to say, “Come on up. Wait and he’ll squeeze you in.” And so we did. And indeed he did, too. He came out to the waiting room, retrieved us, and said in a compassionate way, “Well. That is not what I was hoping for.”

Though he was squeezing us in, he carefully reviewed the notes from the radiologist with us, helped us understand that the tumors are 2mm in size (which is very small, and very early days yet), and described some of the possible treatment plans. In the intervening days (I am finishing this several weeks later following that visit) we have returned to DFCI to consult with Dr. Zapthetumor, the radiological oncologist (another enormous brain!) and he’s expanded our knowledge of what’s going on exponentially.

Essentially, there are four combinations of changing drugs and zapping tumors. They are: change drugs, zap tumors; change drugs, don’t zap tumors; don’t change drugs, zap tumors; don’t change drugs, don’t zap tumors. Add in wait/don’t wait, and there are really eight paths.

Let’s do a rundown on the possibilities, starting with drug changes.

First, should she change drugs? Well, really, is there a reason to? Her current drug is crizotinib. It is doing very well at controlling the tumors in her body. From the neck down, all’s currently in check. Crizotinib doesn’t cross the blood/brain barrier particularly well. That’s an amazingly hard-to-cross physical barrier between the bloodstream and the brain tissue. It really does a great job of keeping everything out of the brain that shouldn’t be there, and only admitting the good stuff to the brain. You know, oxygen, nutrients, and so forth. However, some drugs don’t make the cut particularly well, and crizotinib is one of them. There are several other drugs that do make the crossing well: lorlatinib, entrectonib and reprotrectonib, all newer drugs of the “…nib” type. They can cross that boundary and, in theory, can find these two tiny tumors in her brain and kill them with carefree abandon. So why not go ahead and switch to one of those?

There are four reasons not to switch:

1 - Each one comes with more side effects than the crizotinib, which she’s tolerating pretty well.

2 - Every new tyrosine kinase inhibitor (TKI) that she starts means that she can’t go back to one that she’s already been on, so it’s forward motion only, so that’s the downside. Weight gain, neuropathy (tingling and numbness in fingers and toes, for example), and other unpleasant side effects can happen, but they’re not guaranteed, nor are they worse than death. So lorlatinib has a pretty good upside. If it works.

3 - We think that the more TKIs she’s been on, the less likely she’ll be accepted into a study for a drug which is entering clinical trials (we hope!) this fall. I am hypothesizing that the more confounding factors involved in her previous treatments, the less likely the statisticians will recommend her as a good candidate for the new drug’s trial.

4 - We don’t know how effective the new drug will be in general. Remember that none of these “nib” drugs were specifically designed for ROS1 fusions. Really?! Yep. They were all designed for ALK mutations and they happen to work against ROS1. There’s a risk, though pretty small, that the new drug won’t be as effective.

So, stick with crizotinib.

Second, there’s the question of what to do to the two 2mm tumors in her brain. They are very small: 2mm is a bit thicker than a penny, so they’re very, very small. (Note to Dr. Inthedark, the enormous brain who read those films: Thank you! for finding those minuscule spots!! Every doc we’ve met with who saw those spots says they were impressed that they were found in the first place! In fact, Dr. Zapthetumor said that they are at the hairy edge of being visible on an MRI—a 2mm spot is as small as can be detected!)

I’ll start with the punchline first: Dr. Zapthetumor said to wait and get another MRI six weeks after this one because there are several unknowns:

1 - Are these two spots real, and might they go away on their own? In answer to the first question, they are most likely real and not necessarily an artifact of, say, the angle at which Heidi’s head was placed in the MRI. Two of them appeared at the same time, which is too coincidental to ignore. And in answer to the second question, yes, they could. Crizotinib does have some effectivity on the other side of the blood/brain barrier, but that’s a low probability outcome. Could they just get absorbed somehow? Yes, that’s happened, too, according to others in the ROS1ders group. So a second MRI is necessary to see if they’re real and if they’re still there to treat.

2 - If these two spots are real, how fast are they growing? If they’re growing quickly, then intervention is necessary sooner than later. Again, since our goal is to preserve Heidi’s candidacy for the clinical trial this fall, we might want to delay until the study gets to say “Zap em!” or not. However, with larger size comes greater risk to surrounding tissue during SRS and greater the chance that neurological effects (when the tumor’s around 20mm or so, roughly the diameter of a penny) may be observed, so there’s a delicate balance here. Also, Dr. Zapthetumor said that the trials he’s known of have asked that SRS be performed before the trial. So we don’t know much more than that.

3 - Are there more of them? If so, how fast are they appearing? We only have two snapshots in time separated by six months, so we have no idea whether there are more, tinier tumor seeds lurking elsewhere in her brain. Beyond a certain number of lesions (fancy word for “tumors”), you don’t get to use SRS and have to look at whole-brain radiation.

Err… es-squeeze me? SRS? Whole brain radiation?! Like, Three-Mile Island?!

Yes. Well, sort of. So let’s take a moment to talk about radiation.

Every minute of every hour of every day, you and I are bombarded by radiation. It comes naturally from the sun, from our environment, from electrical devices and radio stations, and really there’s no way to avoid it. Most of that radiation, if not all, has absolutely no effect on us. But when a cell is exposed to a high enough dose of radiation, the cell is damaged beyond repair and it dies or mutates. (Of course, in the case of cancer, we hope to kill the cell, not have it mutate!) What is “enough”? Well, it’s a function of both time and intensity. Expose a cell to a low dose of radiation for a long enough time, and it’ll die. Expose a cell to a high dose of radiation for a short time, and it’ll die. Keep that time-dose exposure low enough, though, and not much happens.

The least-invasive and lowest-side-effect means of killing cancer cells in the brain is to do what is known as stereotactic radio surgery, or SRS. The procedure is entirely non-invasive and uses upwards of 200 very small beams of radiation to kill cancer cells. The procedure works because each of these 200 small beams isn’t strong enough to do much harm to the tissues it passes through. However, where all 200 of them intersect, there’s a lot of radiation and the cells in that intersection are killed. If you want to see how this works for yourself, next time you have a campfire, shine two flashlights through the smoke at each other. You’ll notice that the beams are brightest where the two of them intersect. That’s exactly what SRS does, except with 200 very low-power beams of radiation so that where they intersect, you get 200 times as much radiation.

I asked three questions about SRS which I hadn’t been able to find on the web.

First, what’s the resolution of SRS? It’s 1mm, which is amazing (to me, anyway), which means that that 2mm lesion can be zapped, and a minimal amount of tissue around the lesion will be touched.

Second, when a tumor is removed from the body, a “clean margin” is established around the tumor. The margin is determined by microscopic examination of the tissue to see that there are no cancer cells at the edge of the removed tissue. Since you can live without good chunks of each organ in your body, that’s OK below the neck. But in the brain, since all brain tissue is important, the minimum amount of tissue is zapped because you might zap something important, like Aunt Irma’s recipe for carrot cake, and that would be a tragedy. (Or walking. You know, nothing all that important.)

Third, what’s the upper limit to the number of lesions you can treat with SRS? Right now, that number seems to be about six. Why six? There’s a lot of computation that goes into making sure that the current treatment doesn’t intersect with any other ray from any other treatment. Why not? Well, same reason as before—the more radiation that a cell gets, the more damaged it becomes. However, at DFCI, they’re experimenting with a randomized group of patients where they think they can treat up to 20 lesions before damage becomes a problem.

Then what about whole-brain radiation? How do the cancer cells get zapped and not the good brain cells? Well… they all do, and nobody really knows enough yet. There are very likely to be long-term side-effects of whole-brain radiation. So we’d really, really, really like to avoid it.

There’s a lot that will go into the decision whether to use SRS or WBR and when, which led to another one of my questions, Is there a risk of leaving these tumors there? Will they spawn other tumors? The simple answer is, No, they won’t, but they might get bigger and require intervention anyway. Wait a minute… how’d they get there in the first place? What I didn’t know is that when you talk about a metastatic cancer, what you’re saying is that the cancer from one part of the body left that part of the body and is now found somewhere else. These things in Heidi’s brain are most likely not brain tumors, but likely are lung cancer cells growing in Heidi’s brain. Weird. What that means, though, is that they travelled north from her lymph nodes through the bloodstream until they got caught in the brain and started to grow there. (There’s a fancy word with the root of “hemo” which I can’t remember for this activity of wandering about via the bloodstream.)

And there you have it. Wandering cancer cells, zapping tumors, the blood brain barrier, and hope.

Speaking of hope, someone asked me how we cope with this. Heidi is an effervescent ray of sunshine and somehow “optimistic”s her way through things, and if there’s one thing that you apparently need as a cancer patient, it’s optimism. (Tell somebody about cancer, and without a scintilla of expertise, they’ll assert that you need to keep your spirits up and to be positive—whether it’s true or not.) Me? I bury myself in the research and look at all possible avenues, and as long as there’s an avenue, I’ve got hope. I can tell you that I don’t place all my hope in science and that I have a good deal of faith in God, too, because there are just too many variables of the cancer’s progression (or regression!) for any of us to have true control of what’s going on.

Only One has that kind of power.

Read Part 9 here.

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