The big news in the world of Follicular Lymphoma this week is an article in JAMA Oncology describing results of a 15 year follow-up of FL patients who received R-CHOP (or CHOP + Radioimmunotherapy). The study suggests that 42% of the patients in the cohort have been cured of their FL. It's a big deal because it's really the first time anyone had seriously suggested that FL might be curable.
There's a lot going on in this study. It's worth looking into a little further.
The article is called "Treatment of Follicular Lymphoma With CHOP and Anti-CD20 Therapy: 15-Year Follow-Up of the SWOG S0016 Trial." The goal of this analysis was to see how many of the patients in the trial were cured after 15 years. They determined which patients were cured by a statistical method called "cure modeling," which provides an estimate of how many patients were cured.
I think that's important to note here. Part of the problem with determining whether someone is cured has been the nature of FL. With many other cancers (as I'm sure you are aware), if a patient is disease free after 5 years, they are often considered cured. That's harder with FL, since some patients will have the disease return after 6 years, or 10 years, or 15 years. So it's risky to say someone has been "cured" of their FL.
And it's why many FL experts use the term "functional cure" instead. Someone can be diagnosed at 65, get a Complete Response, and never need treatment again, and die of something unrelated at 85 years old. Were they "cured"? It's hard to say. But they lived a life as if they were cured -- it was a "functional cure."
So this study defined "cure" using statistical methods because it's really difficult to say whether or not someone was cured the way they could for patient with something like colon cancer.
I won't pretend to understand the statistical analysis of the cure modeling, but I will say that since the article was peer-reviewed, it would have been approved by other experts in statistics before it was published, so I don't have any doubts about the analysis.
The SWOG study itself involved 531 patients. They received either R-CHOP or CHOP-RIT between May 2001 and October 2008. I don't write about CHOP much these days, so a reminder: CHOP is a traditional chemotherapy made up of four components (Cyclophosphamide, Hydroxydaunorubicin/doxorubicin, Oncovin, and Prednisone). It's been around for a while, and it's still a very popular treatment. R-CHOP is CHOP combined with Rituxan (rituximab/mabthera). When R was added to CHOP about 30 years ago, it increased its effectiveness. It's pretty standard now to include R with CHOP. RIT, RadioImmunoTherapy, is a treatment like Zevalin. It's essentially something like Rituxan, which can find the CD20 protein on a Lymphoma cell, but with a tiny bit of radiation attached to it, so the radiation can be delivered directly to the cancer cell.
So of the 531 patients in the study, 267 received R-CHOP and 264 received CHOP-RIT. The 15 year Overall Survival rate was 70%, about the same for each of the two groups, though the RIT group had a better 15 year Progression Free Survival (the cancer didn't come back for 15 years for 47% of the CHOP-RIT patients, versus 34% of the R-CHOP patients).
The cure modeling estimated that 42% of the patients in the study had been cured. The highest cure rates were in patients with low FLIPI scores and normal β2 microglobulin levels, essentially the patients with the lowest risk. (You can read more about FLIPI levels here, but keep in mind that it doesn't say anything about you as an individual, even though it seems like it does.) This isn't a surprise, really -- we expect less aggressive version of FL to be less problematic and more successful with treatment.
One important finding of the study was that the rate of relapse declined over time. For the first 5 years after treatment, 6.8% of patients in the study relapsed. But between years 15 and 20, just 0.6% of patients relapsed. So the longer the patients went in the study without relapsing, the less likely it was that their disease would come back.
That's really important. Think back to the idea of "functional cure." It's hard to say someone is "cured" because the disease might come back after 10 or 15 years. But this study shows that it's much less likely to happen, so someone can be more confident after 15 years that the "functional cure" is an actual cure.
Te conclusion to all of this from the researchers is that maybe FL isn't incurable after all. The call this a "paradigm shift" -- a complete change in the way we think and thus the way we act. It could mean that doctors have very different conversations with patients, and that maybe R-CHOP is presented as a possibility for someone who might want a cure. It also has implications for future research.
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As I said, there's a lot happening here. This article was published about 4 days ago, and I've been waiting to hear what other FL experts have to say. So far, I haven't seen or heard much, but I think everyone is trying to take some time and digest it all. Paradigm shifts don't happen in 4 days -- they take years for everyone to break out of the way they have been thinking for so long (at least according to Thomas Kuhn).
And I absolutely understand that. We (meaning much of the Lymphoma community) get so locked in to the idea that "newer is better" -- that every new CAR-T or bispecific or inhibitor must be an improvement over chemotherapy -- that's it hard to see a study like this and not be skeptical. It's certainly my own reaction to it, and I immediately start with a long list of "Yes, but" statements. "Yes, but it's just a statistical estimate, not an actual look at the patients." Or "Yes, but 42% is hardly a cure for all of us." Or, "Yes, but it's still a fairly small number of patients in the study, compared to the thousands that are diagnosed every year."
Particularly for me as a patient who was diagnosed 18 years ago, and who has been told this is incurable for all of that time, it's pretty tough to suddenly think otherwise, and even tougher to think the cure might be from chemotherapy.
That's why I'm especially impressed with the statement from Dr. Jonathan Friedberg from the University of Rochester Wilmot Cancer Institute. He was one of the authors of the study, and he's the one who is talking about paradigm shift (see the story that came out of the Fred Hutch cancer center where he is quoted). He's a Lymphoma Rock Star, doing cutting edge research on FL, and he's willing to look at the data and say "Maybe it's chemotherapy after all."
The few comments from Lymphoma specialists that I have seen have been positive. It's clear that no one expects R-CHOP to suddenly replace bispecifics and CAR-T. But it could mean that conversations with patients are different. For some patients with low risk disease, and who are otherwise healthy and can tolerate the side effects, maybe R-CHOP is an option. CHOP contains an anthracycline, a type of drug that can be very effective but can also cause long-term heart issues. That kind of factor will need to be taken into consideration.
I saw one commentor who said this study will have an effect on future research in a couple of ways. First, long-term studies of FL treatments will be measured against this. It's really interesting that this come out just after a 15 year follow-up of R-Squared. It's a much smaller study -- only 79 patients. But could the same cure analysis be applied to it? Could it be applied to a larger study of 500+ patients? If it was, could we make a direct comparison between the two treatments? It will be hard to look at any long-term study of an FL treatment now and think "Yeah, but....does it have a better cure rate than 42%?"
Another way this might change research is that there might be a greater emphasis on second-line treatments. That emphasis already exists, in some ways -- most new treatments get approved for relapsed/refractory disease first, and then as first-line treatments. But this cut back on the number of treatments that do that second step and get approval as a first-line treatment. In other words, we could possible have something closer to an agreement on how newly diagnosed patients are treated, and that treatment could be traditional chemotherapy.
That's not to suggest that everyone will be getting chemo from now on. There are and will be lots of options out there, and more to come, for a long time. But I expect those conversations to happen.
I'm going to keep an eye open for more commentary about this. I expect some of the oncology websites to have videos of experts discussing this. I'm hoping for more debate-style videos, with multiple experts arguing for and against using R-CHOP. They would be more enlightening to me.
But I think the main take away for all of us should be the same thing. For at least some FL patients, a cure may be possible. For the first time, people seem willing to say so.
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