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Primary GIST: Risk stratification

DR LOVE: Dr Trent, how do these two cases fit into the spectrum of primary GIST?

DR TRENT: These are both common presentations for primary GIST. With an 11-cm GIST and a high mitotic rate, the risk of that patient developing metastases in her lifetime after surgery alone is probably more than 50 percent, which is the rationale for starting the adjuvant and neoadjuvant studies.

On the other hand, in the case of a small tumor (three centimeters) with a low mitotic rate, particularly a gastric tumor, the chance of that tumor recurring in the patient’s lifetime is significantly less. I suspect it is less than 20 percent, and it may be less than 10 percent.

DR LOVE: Doctors are accustomed to using Adjuvant! Online in breast and colon cancer. Do we have similar algorithms for GIST?

DR TRENT: Tables are available that estimate the risk of disease progression based on tumor site, size and mitotic rate, but they have originated from different data sets, and people interpret them in different ways (Miettinen 2006; [1.1]). Therefore, no widely accepted risk model exists.

Epidemiology of GIST

DR LOVE: Dr Demetri, would you discuss the evolution of GIST as a diagnosis?

DR DEMETRI: GIST was essentially unrecognized before 1999 to 2000. It was hiding in other diagnostic “bins.” Most cases were being called sarcomas, sometimes leiomyosarcomas.

At least one third of GISTs, which are epithelioid, were being incorrectly categorized as epithelioid, poorly differentiated carcinomas. We have seen patients with GISTs who initially were told they had ovarian, gastric or prostate cancer, depending on where in their body the tumor arose.

Before 2000, people thought fewer than 500 cases of GIST occurred per year. Population studies have now shown that more than 5,000 cases of GIST occur in the US alone.

Many people believe there are probably more like 15,000 cases if you include the micro-GISTs that are increasingly seen on endoscopy.

Primary GIST: Clinical trials of adjuvant imatinib

DR LOVE: Dr Eisenberg, can you review the current status of adjuvant therapy for GIST?

DR EISENBERG: Both of the ACOSOG adjuvant imatinib trials have now been completed, but they have short-term follow-up.

ACOSOG-Z9000 was a Phase II trial, which enrolled patients with the highest-risk disease (ie, tumors 10 centimeters or larger or evidence of tumor rupture during surgery).

Those patients were treated with adjuvant imatinib at 400 milligrams per day for one year (DeMatteo 2008; [1.2]).

ACOSOG-Z9001, which started at almost the same time, was a Phase III trial for patients with intermediate-risk disease (ie, tumors three centimeters or larger).

None of these patients were selected by mitotic rate because the general feeling was that this was rather subjective and couldn’t be reproduced in a large, multi-institutional trial (DeMatteo 2007).

ACOSOG-Z9001 was subject to an independent interim analysis, which yielded a positive effect in terms of relapse-free survival for the group of patients treated with imatinib.

When you break those numbers out, you see that the group with the highest-risk tumors benefited the most. The statistical evidence that imatinib helped the patients who had 3- to 6-cm tumors was much less impressive (DeMatteo 2007; [1.3]).

Remember that these patients received imatinib for only one year. After a year, recurrences in the treated group were on a slope that was similar to the one for the untreated group (DeMatteo 2007).

It’s probably reasonable to expect that (1) one year of imatinib is not enough for those patients at particularly high risk of recurrence and (2) one would obtain about a six-month progression-free survival benefit by receiving one year of imatinib.

Several ongoing trials in Europe are evaluating imatinib at different doses and intervals. EORTC-62024 is evaluating survival, which will probably take a long time and many patients to do. So we’re still trying to solve this question.

My guess is that imatinib will probably be effective in preventing recurrences in patients with high-risk disease. I believe patients will have to receive it for a long time, perhaps until their cancer recurs.

Primary GIST: Clinical use of adjuvant imatinib

DR LOVE: Dr Demetri, in a clinical setting, what is a rational approach to adjuvant therapy for patients with primary GIST?

DR DEMETRI: A global argument exists about the value of a benefit in recurrence-free survival without a documented benefit in overall survival, which leads to dramatic differences even among experts.

In Europe, the consensus guidelines say, “We don’t think patients should receive adjuvant therapy as a standard.”

In the US, however, we are much more confident that the strength of the randomized study is sufficient to justify using adjuvant imatinib for at least one year for appropriately selected patients with high-risk disease.

What is an appropriately selected patient with high-risk disease? The curves are dramatically different for the patients whose tumors are greater than 10 centimeters.

They relapse relatively quickly if they receive no adjuvant therapy, and they relapse more slowly if they receive one year of imatinib, but they still relapse (DeMatteo 2007; [1.3]).

So the question is, are we committing these patients to potentially lifelong therapy to keep their disease at bay?

If a young person has a 30-cm tumor, it may not be an unreasonable tradeoff. Those are unusual situations, though.

Part of the challenge for any practicing oncologist — community or academically based — is trying to help patients and families deal with the issue of the relative risk and benefit of imatinib.

Individuals make different choices. It is a matter of whether someone is saying, “I am comfortable with the concept that if my disease recurs three years from now, I will take imatinib. You have data indicating that I have a 90 percent chance of benefit.”

Other people are less willing to do that, and they’re much more willing to take an adjuvant approach to try to prevent recurrences.

DR LOVE: Dr Trent, what is the available evidence that earlier treatment is better?

DR TRENT: In most solid tumors, metastatic disease is not curable, so we try to avoid catching it late. I am an early adopter of the adjuvant data. These results have been presented only in abstract form, and they have not been peer reviewed or published.

However, the adjuvant data with imatinib for primary GIST are good. So I tend to maintain a low threshold for treating patients who have primary GIST with adjuvant imatinib.

On the other side of the coin are some arguments that treating with imatinib early may be selecting for resistance, so when a recurrence does develop, it is imatinib resistant and is much more difficult to treat.

Arguments exist for and against that view, but I don’t let it deter me from treating a patient who I believe will benefit from adjuvant therapy.

DR EISENBERG: We have to remember also that in most of these adjuvant studies, stratification of risk will be important because, historically, some of these patients will be cured with surgery alone and won’t need the drug. So that information will be extremely important.