Optimizing therapy for GIST: A discussion

Novartis Oncology recently hosted a Web cast titled, “Optimizing Therapy in CML and GIST: Bringing Hope to Patients.” Dr. Jonathan C. Trent, assistant professor, Department of Sarcoma Medical Oncology, M.D. Anderson Cancer Center, gave the GIST presentation.

Trent noted that the sarcoma community enrolled large numbers of patients into clinical trials rapidly, since no effective therapy existed prior to Gleevec. Prior to Gleevec, objective response rates (OR) were around 5 percent. The Gleevec studies found OR rates that ranged from 48 percent to 71 percent.

The largest study was the European Organization for Research and Treatment of Cancer study which randomized patients into groups of 400 mg. or 800 mg. He noted that patients receiving 800 mg. had a four- month advantage in progression-free survival. In the U.S. study the difference in progression-free survival was also present.

The following are a few questions that patients frequently ask Trent:

How do I manage or prevent side effects?

The longer progression-free survival time noted in the EORTC study has a cost: increased side effects from the higher dose. The U.S./Canada phase III study found that the reasons for dose reductions were different for patients starting at 400 mg. versus those starting at 800 mg., as shown in Table 1.

Trent noted that not only did patients starting at 800 mg. of Gleevec have more frequent and worse side effects, but they also required dose reductions and dose interruptions much more frequently. In the EORTC study, patients starting at 800 mg. interrupted treatment 64 percent of the time and reduced their dose 60 percent of the time, compared to 40 percent and 16 percent, respectively, for patients starting at 400 mg. The side effects were mostly fatigue and edema, with few effects on blood counts.

Data from the U.S. phase III trial showed that patients starting at 800 mg. required a dose reduction 44 percent of the time. Only 10 percent of patients on 400 mg. needed to reduce their dose. For patients starting at 400 mg. and then crossing over to 800 mg. due to disease progression, only 16 percent required a dose reduction). According to Trent, “toxicity doesn’t markedly increase after a patient has been on 400 mg. for a while and then increases the dose to 800 mg. In patients whom require a higher dose of Gleevec, I slowly titrate to the target dose over several weeks or even months.”

How do I know if Gleevec is helping me?

The mindset of many oncologists is based on studies from the 1970s that resulted in the “WHO” (World Health Organization) criteria, that later evolved into RECIST (Response Evaluation Criteria In Solid Tumors). To qualify for a “partial response,” RECIST requires a 30 percent or greater decrease in the sum of the largest diameter of all measurable tumors and an absence of any new tumors. Trent noted that for GIST, the RECIST criteria is misleading at times and doesn’t make for the best design of clinical trials — at least when using drugs like Gleevec.

Trent gave examples of why RECIST is inadequate to measure response of GIST tumors to Gleevec. Figure 1, above, shows two CT scans. In the scan at left, a large GIST tumor is shown before treatment with Gleevec. The variation in gray is characteristic of a GIST. The lighter areas indicate viable (alive/capable of growing) tumor and the dark areas represent non-viable (dead) tumor. The scan at right shows the same tumor after eight weeks on Gleevec. The tumor now is a darker shade of gray. This uniform, dark color and density change are characteristic of GIST that is responding to Gleevec.

“We’ve found that tumor cells have been replaced by myxoid degeneration in this setting, despite the fact that the size of the tumor hasn’t markedly changed,” according to Trent, “solely monitoring the size of tumor in GIST patients treated with Gleevec can be misleading if one doesn’t consider the changes in radiodensity of the tumor.”

In Figure 2, at right, the CT scans on the top show a tumor increasing in size but the majority of the tumor is turning a dark uniform color.

This is evidence of Gleevec response with only a smaller rim of tumor on the right side which appears to still be viable. The PET scans on the bottom confirm the response to Gleevec.

“GISTs treated with Gleevec can stay the same size when a patient is receiving incredible benefit,” said Trent. “In fact in some instances, the tumor can actually increase in size. This type of increase in size can be due acutely to intratumoral hemorrhage, but it may also be due to increased osmotic pressures after tumor cells rupture within an encapsulated mass (many GISTs are confined by a very thin surrounding pseudo-capsule).

Another example of patients getting excellent benefit from Gleevec in spite of limited tumor size reduction can be seen from the graph of overall survival by best response (see the “Patient status …”article, Page 9 Figure 1). In this trial, patients with stable disease had survival rates that were very similar to patients achieving a “partial response.”

SUMMARY

Gleevec-related side effects improve significantly over time. It has been suggested that this may be due to drug levels that tend to fall over time in GIST patients. A European study found that Gleevec levels may fall by 40 percent during the first 12 months of treatment (see the January 2005 edition of this newsletter).

Trent noted that for patients needing a higher dose of Gleevec, he slowly raises the dose over a period of several weeks or even months. This approach is known as dose escalation or a “run-in” period. It has been advocated by some GIST specialists, especially some European specialists. Patients seem to be able to tolerate this approach much better than starting at 800 mg.

The second half of this article will be featured in our May 2006 newsletter.