Progression/progress

Progress, from the Latin progressus, can be defined as "a movement toward a goal or to a further or higher stage." The word generally has positive connotations. If we hear that progress is being made in the fight against cancer, for instance, we regard this as a good thing.

A synonym for progress is progression.

Many people, myself most definitely included, associate the word "progression" with cancer, and in that context, progression, unlike progress, is a decidedly negative term.

(Note: this interesting relationship between the words progress and progression was put into my mind by a widow friend I've been having some very interesting discussions with. It's good to have people like that to talk to, other people who really "get it.")

Earlier today, I saw in my Twitter feed an article from the Journal of Clinical Oncology with an amazing result that brought me to the verge of tears.

The title of the article is Three-Year Follow-Up of an Alectinib Phase I/II Study in ALK-Positive Non–Small-Cell Lung Cancer: AF-001JP. You can see the whole thing yourself at that link if you feel up to wading through dense scientific prose. Here, I'll provide an explanation and summary of the key findings and how they relate to my dearly departed wife.

Alectinib is something I'm very familiar with. It's a drug that Cara took for about six months, from late 2013 to mid 2014, as part of a clinical trial. The article is also about a clinical trial of alectinib, but a different one from that in which Cara was enrolled.

Alectinib is an inhibitor of the ALK protein; a rearrangement of the gene encoding that protein is what drove the growth of Cara's lung cancer (hence, "ALK-positive.") The first FDA-approved ALK inhibitor drug was called crizotinib. That was the first drug Cara received after being diagnosed. As I wrote in a previous blog entry, "Being a scientist, I had naturally looked up research articles about crizotinib, and had seen that, in the clinical trial, the median progression-free survival [and there's that word - progression] was about 8 months longer with crizotinib than with traditional chemotherapy. This meant that the typical outcome for someone taking crizotinib was that they would gain about 8 months in which their disease would be under control, but ultimately they would still die of lung cancer."

For Cara, progression on crizotinib occurred after only two months. Bad luck, much worse than average. Why? We'll never know. But after crizotinib stopped working, and after Cara underwent a surgery that brought her back from near death's door by draining a massive accumulation of fluid from around her heart, and after her condition stabilized, she started a clinical trial for alectinib, a newer ALK inhibitor drug. The title of that clinical trial was An open-label, non-randomized, multicenter phase I/II trial of RO5424802 given orally to non-small cell lung cancer patients who have ALK mutation and failed crizotinib treatment. As you can see from the title, it was a trial specifically for people who had already taken crizotinib and for whom crizotinib had stopped working.

I've just looked up the results of that trial for the first time on the ClinicalTrials.gov website. The median progression-free survival is listed as 7.5 months. So again, Cara did worse than the average patient, but not to as great an extent.

To summarize, the typical outcome for someone who was diagnosed with ALK-positive lung cancer, put on crizotinib until it failed, and then put on alectinib until it failed, would be that within a year and a half, both drugs would have stopped working, and then it would be time to move on to still other treatments. Until ultimately (in most cases) all treatments fail and death occurs.

That's still significant progress from the previous status quo. I remember well, after being told that it looked like Cara had lung cancer, sitting there in the hospital's surgery waiting area and looking up lung cancer survival statistics on my laptop, and reading that the median life expectancy for someone diagnosed with stage IV lung cancer was only 8 months. Cara lasted 20 months. If not for the heroic work of research scientists in discovering the ALK driver mutation and developing treatments targeting it, that probably would have been less than 8.

But now, given all that background information, let's return to the article that so shook me today. The study in that article was of alectinib as a first-line ALK inhibitor - that is, the patients had not previously received crizotinib or any other ALK inhibitor. And here's the thing - cancer that has evolved to become resistant to crizotinib, even if it's not yet resistant to alectinib, could very well be closer to developing that resistance. So the median progression-free survival in the study of alectinib for ALK-inhibitor-naive patients?

At the three-year followup point, it had not yet been reached.

62% of the patients had not had disease progression after three years. 78% of patients were still alive after three years.

Cara was diagnosed three years and seven months ago. The two-year anniversary of her death is fast approaching.

There are other advantages to alectinib. Unlike crizotinib, it can cross the blood-brain barrier and treat brain metastases. Cara, like many lung cancer patients, developed metastases in her brain, and had to undergo radiation therapy for them. (Fortunately, they never grew large enough to significantly affect her quality of life - although the steroids she took to reduce swelling while undergoing the radiation therapy had some nasty side effects. I remember being woken by her crying in pain from horrible cramping in her calves.) As well, although the specific side effects of specific drugs vary from patient to patient, in Cara's case (and I know she wasn't alone in this) alectinib had by far the least adverse side effects of any of the treatments she received. Alectinib was so effective (until a small spot of disease on her liver evolved to become resistant to it) and its side effects so minimal that for a little while it seemed Cara was almost back to her normal self!

I write all this in the hopes that it will be educational, that people will gain a little bit better understanding of what goes into the fight against cancer, both from the patient perspective and the research scientist perspective. I also write in the hopes of persuading. Cancer research is so important. Great progress has been made in our efforts to control disease progression, but we have a long, long way to go.

What can you do, today, to help?

I'll suggest two things.

One: help promote lung cancer awareness and research funding. One way to do this is to sign up for and/or donate to Team Cara in the Breathe Deep Cleveland event that Cara helped found before she passed away. I've written before about the shocking statistics for lung cancer research: it only gets about 1/15 the federal research funding per patient death as breast cancer research. This needs to change.

Two (and sadly, this is probably far more important right now): speak out in any way you can against Trump's proposed budget and its massive cuts to the NIH. Call your elected officials, write letters to the editor, tell your friends. Use personal examples. This article that just came out is one perfect example of the importance of funding medical research. If such research was better funded, the critical discoveries might have been made sooner, and Cara might still be alive. Conversely, if more cuts are made, a lot of potentially life-saving studies will be shut down. Let's not let that happen.