Rituxan, Watching and Waiting, and Reading Carefully

I was preparing to write a post this morning about some new research on R-Squared (you'll get that soon) when I got an alert about a  new piece in the ASCO Post about Watching and Waiting. As someone who spent two years watching and waiting, I'm always very interested in research on this subject. What I found was very interesting, but what was more interesting were the lessons and reminders I got about reading carefully. 

The ASCO Post is kind of daily newsletter for oncologists, and they often include stories about research. One of today's stories is titled "Benefit Suggested for Early Treatment of Advanced-Stage, Very Low–Tumor Burden Follicular Lymphoma," which describes a presentation at ASH (which I somehow missed). A group of oncologists from Japan wanted to know if their Follicular Lymphoma patients who were able to watch and wait were better off getting treatment with Rituxan right away instead of watching and waiting.

As I said, this always intrigues me, since I watched and waited for two years and then had 6 rounds of Rituxan. It seems like every few years, some researcher takes on this question, and finds one or the other approach is better. And then a couple of years later, someone presents data that says the opposite. For what it's worth, I am happy with the choice I made, and I think it's ultimately a personal choice. What this kind of research leaves out --always -- is the emotional factor. No matter what the data says, some people won't like the idea of knowing they have cancer and not treating it. That has to be a factor, no matter what the numbers say.

But back to the study from Japan. The researchers from the study say they usually recommend immediate treatment instead of watching and waiting, and so designed a study to test if their recommendation was a good one.

They designed a phase III clinical trial called the FLORA trial (it's phase III because the safety and effectiveness were already determined long ago -- this isn't a new treatment, so phase I and II aren't necessary). They studied 292 patients with low–tumor burden Follicular Lymphoma and divided them into two groups. The first had very low tumor burden, meaning the largest mass was less than 5 cm, the patient had two or fewer nodal sites, and no effusion (no fluid collecting in tissues). The second group had intermediate tumor burden, meaning the largest mass was more than 5 cm but less than 7 cm, had three nodal sites, and no serious effusion. Half of the patients were immediately given Rituxan, and the other half watched and waited until tumors grew enough to be classified as intermediate. The end point for the study was Event-Free Survival, which they defined as progression to high tumor burden, initiation of chemotherapy and/or radiotherapy, transformation to a more aggressive lymphoma, or death.

The results were interesting. After a median follow-up of 2.5 years for all patients, the ESF was much better for the patients who had been given Rituxan immediately.The events that caused the patients to no longer be "event free" were mostly transformation and having to begin chemotherapy. Twice as many patients in the W & W group transformed as in the Rituxan group (18 versus 9). The Progression-Free Survival rates were similar (50.6% in W & W versus 49.6% in the Rituxan group) and so were Overall Survival rates (98.4% versus 97.3%).

The researchers conclude that the difference in EFS is enough to justify giving patients Rituxan immediately rather than having them watch and wait.

Here's where the ASCO Post article gets interesting.

The editors asked a Lymphoma expert to take a look at the study. Dr. Andrew D. Zelenetz, who is the Medical Director of Quality Informatics at Memorial Sloan Kettering, "expressed some concerns" about the study. Among them were two things that I noticed with my non-expert eye -- there was no difference in Progression Free Survival or Overall Survival. In other words, taking Rituxan immediately won't make you live longer than watching and waiting, and it won't make the time until you need treatment again any longer. Those things have always been the criticisms of watching and waiting research -- no matter what the researchers do,there is never an OS benefit to one or the other. Patients end up living just as long no matter which option they choose.

Dr. Zelenetz also points out some other problems with the study. Their definition of "Even-Free Survival" is non-standard. In other words, when other studies talk about EFS, they do in a different way than this study does, so it's hard to compare them. In this study, an "event" only counts of it results in the patient being given chemotherapy or radiation. So taking more rounds of Rituxan, for example, doesn't count as an "event," and if that happened, it would stretch out the EFS time a little more. According to Dr. Zelenetz, the study is set up so the Rituxan group will come out ahead.

That doesn't mean the researchers were being dishonest. But it does mean that it's hard to compare this study with others, because they aren't using the same ways of measuring the data.

So what are the lessons here -- for me, anyway?

First, it seems like there is still no answer to the question "Is it better to treat immediately rather than watch and wait?" And that doesn't surprise me. I've been following that debate for 15 years, and here hasn't been anything new about Rituxan or about watching and waiting in that time, so it seems likely that any difference is just statistical.

Second, it's a reminder that Peer Review is essential with cancer research. A presentation at ASH or ASCO is not peer reviewed. That is, it's a presentation of data that hasn't been checked out first by other experts. When I write about ASH or ASCO, I always try to remind you (and myself) "this is a phase II trial, so it's still early in the process," or something like that. What Dr. Zelenetz has done here is what peer review is supposed to do -- ask questions, point out problems, make suggestions for improvement. If the researchers had tried to publish this in a medical journal, peer reviewers (others Lymphoma experts) would have pointed out those problems, and if the researchers couldn't fix them or explain them, the article wouldn't get published. ASH and ASCO presentations about new treatments are always exciting, but they also need the reminders that they have lots of time before they end up available to patients, and less than 10% of cancer treatments that start the clinical trial process actually end up getting approved.

Finally, for me, this is an excellent reminder to read carefully. I always read with hope. I want new treatments, exciting developments, and something to look forward to. But it's also very easy to be sucked in by a headline that's trying to catch a reader's attention. We all need hope -- it gets me out of bed in the morning. But we don't need false hope. And sometimes that means reading with a careful, critical eye, and deflating that hopeful balloon a little bit. 

I'll get back to work on that R-squared post. Look for it soon.