Gleevec and Relapse Statistics

by George Demetri, MD, Dana Farber Cancer Institute

Much has been written in the lay press about the longer-term outcomes of advanced metastatic GIST patients with Gleevec, and some of it has confused the public. In particular, Judy Foreman, a nationally-syndicated health care columnist, recently wrote a column which touched on this very complex issue. Her column included a comment which was printed as follows:

"I have been saved by the bell," Gordanier wrote in his journal. "It looks like Gleevec will allow me to struggle on with a good possibility of a successful outcome, if you define success (as I do) as being able to live and work without pain and to enjoy each day as it comes and for what it brings." But 18 months later, by December, 2002, Gleevec had stopped working, as it does in about 75 percent of people after two years.

I have gotten many calls and inquiries about this issue of "75%...after two years," and I thought the most efficient and effective way to answer this might be to share with you a note to clarify my thoughts on this. I have been in touch with Ms. Foreman, who is exceptionally ethical and wishes to be sure that her work is as accurate as possible, and I have her permission to share with you what I wrote to her in response to her inquiries:

This figure is not really wrong, just a bit oversimplified due to the space constraints of a short health column for a newspaper. I would love to see this clarified, but that may be the subject for an entirely new piece. A correction, per se, would have to explain the complexities of the disease and its management, as well as how Gleevec is making us re-examine all of the older "conventional" rules by which oncologists have judged when a given anticancer drug is or is not "working".

The key to understanding this to recognize the answer depends upon the question. In less enigmatic talk, let me simply say that this point is more complicated than it seems. Please allow me to explain why:

Typically, cancer specialists have used a chemotherapy drug for a while, and then eventually resistance develops against that drug and the drug is stopped. This is not too dissimilar to the way we think of using antibiotics to fight infections. If bacteria are resistant to a given antibiotic "X", then it makes sense when treating a resistant infection to change to another Antibiotic "Y".

However, GIST is more complicated!!!! That has not been an easy concept to grasp, and yet it has enormous impact on the care of thousands of GIST patients.

There are several reasons for making this so:

Doctors have traditionally judged tumors to "progress" on therapy (which is usually considered the same as "failing therapy) when they expand by a certain amount of size. In the traditional rulebooks, a tumor that increases in area by 10 cm2 is judged to have "progressed". However, in our first international GIST study, we had many patients with huge tumors, often measuring 200 or even 300 cm2 in area. If a 200 cm2 tumor bulk increased on CT scan to 211 cm2, that was "counted" by our study as a tumor that "progressed" in the database. However, those of us caring for these patients knew that the patient was benefiting and the drug was not necessarily stopped (since the difference between 211 cm2 vs. 200 cm2 is only 11 cm2, and 11/200 is only about a 5% difference, which is within the range of variability of a CT scan!). Also, some GIST tumors were noted to have some fluid retention within them, but were not necessarily growing. We knew this because in our research we also used PET scanning extensively, so we could tell quite accurately when tumors were thrown into a metabolic "coma" by the Gleevec. This is but one small technical detail why the statistics on "disease progression on Gleevec" should not necessarily be considered exactly the same as "clinical failure of Gleevec".

We consider "disease progression" to be a VERY different thing from "clinical failure of Gleevec". But that is not easy to convey to people, not the lay public, nor even to other medical or surgical oncology specialists. It is very important to know that after more than 3 years of treating metastatic GIST patients with Gleevec, it is true and accurate to say that about 75% of those patients will have had some evidence of "disease progression." BUT THIS CANNOT BE OVERSIMPLIFIED TO MEAN THAT THE DRUG HAS FAILED THOSE PATIENTS COMPLETELY!!! (I am not shouting - just adding those caps for emphasis).

It is critical to see how these GIST patients can be managed by continuing the Gleevec, while doing something else to control the site of the disease progression.

In practical terms, this means that a patient may have developed a small site of disease re-activation (these areas even look quite characteristic on CT or PET) while continuing to take Gleevec. We typically see if that area can be taken out by an expert surgeon, or possibly "ablated" with a technique known as image-guided radiofrequency ablation. If we can do that, it appears to be much better for the patient, who then continues Gleevec to control all the other disease in the body that is still sensitive to the Gleevec. If one were to stop the Gleevec too soon, we have seen other sites of disease reactivate, which cannot be a good thing for the patient. Better to maintain as much control as possible, even if some limited disease progression has been noted.

So, in summary, I am not sure how best to communicate the subtleties of this to the general public or even to their physicians. We are working hard to get our research findings published and presented in the most accessible way possible, and I would value your insights and skill in communicating this as clearly and accurately as possible. A new set of updated data has just been collected from our study, and we will be doing all the relevant analyses to prove these points as part of these next-level analyses.

There are many other reasons too, why "disease progression" per se should not equate in the minds of physicians with "failure of Gleevec" (and should not lead to discontinuation of Gleevec dosing as a knee-jerk reaction). First, our patients in the initial research clinical trial had typically very very large bulky disease. We do not know how that relates to patients who start Gleevec with smaller burdens of disease (now that physicians are screening patients for GIST recurrences, we hopefully will catch these earlier before the recurrent tumors grow to massive, less manageable sizes). We believe, and we have some data to back this up, that GIST patients with smaller tumors may have longer disease control on Gleevec without disease progression than those who have huge, bulky tumors. That makes sense, really, too, from the standpoint of common sense.

There are many other things we have learned about this disease as well that are making us re-examine all sorts of "conventional wisdom" in oncology that was derived from the study of chemotherapy in the 1970's! However, this is a capsule summary of the situation at this time.

I hope this helps to explain some of the complexities and the controversies. There is no doubt but that it is accurate to say that the current clinical trial data indicates that some sort of disease progression will likely occur in about 75% of patients with metastatic, bulky GIST after about 3 years of therapy on Gleevec. However, it is important to recognize that such patients still have hope to continue living good quality lives with disease control if their care team implements a multidisciplinary care plan which might include surgery or other modality to control what may be only a tiny area of resistant GIST while the rest of the bulky tumor burden remains controlled by continuing the Gleevec. We have seen PET scans as an incredibly useful tool to get at this issue, and that is but one reason why we have formally filed paperwork with the government (the CMS) requesting that they formally approve CMS coverage of PET scanning for patients with GIST to help us evaluate the disease with the most appropriate and medically useful technology.

It is also important to recognize that the situation with Gleevec in treating metastatic GIST is somewhat different than treating CML: for advanced CML (in so-called blast phase), Gleevec usually only works for less than half a year! When viewed in that way, the control of metastatic GIST is already far superior to the control of advanced CML. However, for early stage CML, control of disease with Gleevec may go on for a lot longer than 3 years. We are only now beginning to see longer-term results with some of the patients with smaller amounts of GIST disease, and that looks as positive in some of them. Additionally, the results of the newer, ongoing studies using Gleevec in much earlier stages of GIST, will still be some years away. In general, though, I think it is fair to say that Gleevec continues to be an extraordinarily active agent against GIST, and not to become overly negative about the data. Nonetheless, more research is definitely needed to continue our insights into how and why GIST cells may eventually become resistant to this powerful drug, and to develop other newer drugs to complement the action of Gleevec. As you know, much of that research is already quite active and is already translating into other clinically relevant strategies for patients.

Thanks again for allowing me to clarify these important and complex points.

Best regards,
George

George D. Demetri, MD
Center for Sarcoma and Bone Oncology
Dana-Farber Cancer Institute and Harvard Medical School
SW 530, 44 Binney Street, Boston, Massachusetts 02115

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