Monday, November 21, 2016

ASH: A New Way to Think about Watching and Waiting

I'm fascinated by studies that ask whether or not Watching and Waiting is worth it for Follicular Lymphoma patients, even though they drive me crazy. It seems like these studies go back and forth with one another -- one will provide some evidence that Watching and Waiting is a better choice than being treated right away, and then a few months later, another study will say the opposite.

I don't think there is any right answer, but I keep reading them anyway, mostly because I want someone to tell me I was right to hold off on treatment for two years.

(Really, I don't need anyone to tell me I was right. I'm coming up on my 9 year diagnosiversary, and I'm still here. That's about as right as it gets. But I'd still like that decision to backed up by science, if that's possible.)

Since there doesn't seem to be any right answer to this question, I was pretty thrilled to see an ASH proposal that asked a different question: is there a better way to measure whether or not Watching and Waiting is an effective strategy?

The session is called "Intervention Versus Observation: What Is the Appropriate Endpoint? Assessment of Endpoints in Patients with Advanced Stage Follicular Lymphoma Who Are Initially Observed." Most research that compares the two options (watching and waiting vs. treating right away) by comparing Progression Free Survival or Time to First Next Treatment, these researchers suggest a better way to measure is Time to 2nd Treatment (TT2T).

Here's the logic: Imagine a trial that involves half of patients watching and waiting, and then measuring how long it takes to get to their first treatment. The other half involves patients getting Rituxan, and then measures how long it takes for them to get to their next treatment. Those two times are compared to see which approach works better.

But this is an unfair comparison. One group is measured by how long it takes to receive their first treatment, and the other is measured by how long it takes to receive their second treatment. What if we looked at that first (W & W) group and measured how long it took them to get to a second treatment?

More importantly, could TT2T be a replacement for measuring Overall Survival? In other words, studies that use that first treatment as a way of measuring success might be stopping their measurement too early. The big question with FL treatments is always "Dies this treatment improve Overall Survival (OS)?" Does TT2T give us a better idea (since it is measured over a longer period) of how well W & W might contribute to Overall Survival?

The answer, they say, is Yes. In a study of 264 FL patients, with a median follow up of almost 11 years, they found that the Time to First Treatment was 43.5 months -- just under 4 years. But the median Time to 2nd Treatment (TT2T) was 151.8 months -- almost 13 years. Median Overall Survival was not reached, so it will be more than 13 years. So the TT2T would seem to be a better measure of Overall Survival when comparing W & W with initial treatment.

The researchers think there needs to be more research before TT2T can be a replacement for OS, and I think there's some value on figuring out whether it can be (Overall Survival measures death by any cause at all, from cancer to heart attack to getting hit by a bus, while TT2T focuses only on how whether the lymphoma has progressed enough that treatment is necessary).

I like the statistics presented, too: 8 or 9 years is a long time between the first and second treatment, and it roughly follows the path that I seem to be on (2 years until first treatment, and almost seven years since and I still haven't needed a second one yet). My first treatment came exactly two years to the day from my diagnosis -- shouldn't that put me in that high risk group that needs treatment within 24 months? But my (not yet needed) second treatment puts me a very different group, one that has a slower-growing for of FL, and seemingly lower risk.

Mostly, I like that this gives us a different way to think about Watching and Waiting, and whether it is worth recommending as a strategy. In the end, that's an individual choice, one that involves an emotional assessment, and not just a scientific one. But it's ncie to have something else to add to the conversation.

I still feel like I made the right choice -- for me.

Before I go, a note about terminology: The researchers use the term "Observation" instead of"Watching and Waiting." I had someone comment a while ago suggesting we stop using the "and waiting" part of that, and just call it "Watching" -- essentially the same thing as "Observation" -- because the "waiting" part brings on unnecessary stress. I use the "W & W" term mostly because it's the term I've been using for almost 9 years, and switching might be confusing to some people. I also think the "and waiting" is kind of unavoidable. We don't just watch -- we expect something to happen. I certainly did. So I respect the idea of going by a different term for a very good reason, but I'm sticking with W & W. It's a more accurate reflection of own experience.


Anonymous said...

What kinda treatments were these patients using to go 8-9 years? I thought most treatments had a Median PFS of about 3 or 4 years back then.

Terrilyn McCormick said...

Similar to the above question, I read a study you just shared on R and R-squared that showed the TT2T to be somewhere short of 3 years for the rituxin arm. So I guess we can assume the 8-9 year TT2T in this one is because people are getting stronger treatment say RCHOP as their first line? I like to read all the studies and find them helpful in thinking about future treatments but also find them maddening in the methods and results which often seem all over the place. It also maybe because I'm looking for the study that shows a woman diagnosed at age 43, treated with rituxin mono-therapy at diagnosis went on to live for 50 more years and never had another treatment :)

Christina Stijnen said...

Dear Bob

When you speak about 24 months being the timegap between treatments. How do you count these 24 months. I had 6 RCVP sessions, from August till December 2015, followed by 12 sessions of mabthera or rituximab (ending November 2017). So what is considered to be the end of my treatment: December 2015 or November 2017?
Thanks in advance for your answer and for your forever hopeful blog.



Anonymous said...

Bob, I truly feel you are the exception. I have ran across many, many, many patients. All have had at least 1 treatment. I know of none that had just R and went as long as you have. You will be fine.

I do know of many who had just 1 treatment, but it was Chemo-R. I did know of one pt who went 10 years in W&W with no treatment and then transformed and took R-CHOP. She is fine. Question for her was, if treated sooner would she have transformed? Again, many new options today involving immunotherapy and many more to come soon. Studies seem useless in a way if you try to apply results from a study using R-Chemo vs the new treatments available today. It is like saying computer programs wrote in 2001 typically take 2 years to build, use up 50% of the computer, and run slow. Not so today. What is on your iPhone would not fit on PCs 10 years ago. If Onc's had the options available to them in 2001, decisions and results would be totally different. So in a way, a lot of these studies are almost like the subject of History in school. This is the way it was, but not the way it will be. I would rather focus on what IS and what IS to come. Median OS is also History. Good to see it is high, and has gone higher, but it basically means the trend is it will be even Higher and as you say not really used anymore since it is likely 80% of the pts pass of something else. TT2T can be used, but again, different treatments are available, so the playing field is not the same. If I wanted to buy a car 10 years ago and had only $1,000, I would wait. But if I had $100,000...I would not have waited.

Anonymous said...

I know of a pt who took R-CHOP and relapsed 2 or 3 years later and took RR and is still in remission 6+ years later. Another had many treatments and then an SCT and took RR and his onc said it is likely he will not need treatment again. AND, RR can be used again as a treatment unlike R-Chemo where PFS is likely less if you use the same R-Chemo for 2nd treatment. My onc said immunotherapies can be used again for re-treatment. Thing is, by the time the next treatment comes around, an even better immunotherapy will be available.

CAR-T sounds great. My question is what the options if you do relapse after a CAR-T infusion? Take another? That sounds good to me. Diabetics take shots everyday. HBP folks pop pills everyday. Taking and infusion every few years would not be such an inconvenience with the likely hood that eventually it will knock it out for good.

Anonymous said...

Hi Bob,

If I recall correctly you like I were diagnosed at Stage 1, which makes us somewhat different from the 85% of follicular lymphoma patients who are not diagnosed until stage 3 to 4. I am in my 6th year of watch and wait and have had no treatment so far.

I have tried to research the average time on watch and wait for follicular lymphoma patients diagnosed at stage 1 to 2 and the only study I have come across comes from Stanford, which shows from a retrospective case study of their untreated watch and wait stage 1 to 2 patients over many years, that at 7 to 8 years the majority of patients had still to commence any treatment. This compares to an average time of 3 years for advanced stage 3 to 4 patients.

Personally I am glad I have had all these years of non-treatment and therefore relative normality, as even treatments like rituximab are not without potential serious risk.


Lymphomaniac said...

Wow! So many comments to respond to!
I guess the big question in all of this is, how did they get to such a long (12 years) TT2T? The abstract doesn't specify which treatments the patients received, except that half received Rituxan as their first treatment, and 69 received immunochemotherapy (Rituxin plus chemo, probably CHOP, CVP, or Bendamustine, though it doesn't say).

I think there are a few things happening here. One is that some patients probably did have a treatment that often results in long remissions: CHOP, or Bendamustine, or maybe even a transplant. It's possible that the full presentation at ASH will give those details, but we don't know that from what we have. Another possibility is that some patients went a long time before they even had their first treatment, so the TT2T was long overall, but not the time between treatments wasn't as long (for example, some patients might have gone 4 or 5 years before their first treatment, and then another 5 or 6 before their second). Remember we're dealing with medians here: those numbers mean half of the patients had shorter times, and half had longer times. Not all of them followed the same pattern of treatments and time between them. All were advanced stage (3 or 4), so no stage 1 or 2's here. (I was stage 3 at diagnosis, by the way, not stage 1.)

As far as the question about how 24 months is measured, that measurement is always determined by the researchers before the trial begins. Usually it's from the time of diagnosis (with the complication that the patient possibly had FL for years before it was diagnosed, but they have to agree on some starting point). In this case, they measured EFS 12 from the date of the last round of treatment (sorry -- I said 24, not 12 -- my mistake).

There's a lot going on in this study, and I think it kind of reaffirms the value of measuring Time to Second Treatment. If the FL is fairly slow-growing, as it is for many patients (and often not the patients who are in trials, since they don't need treatment as often), the remissions are longer than the ones we often read about.