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.
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Agreeing with previous statements by other GIST experts, Trent noted that RECIST (Response Evaluation Criteria In Solid Tumors) substantially underestimates, at least initially, the value of therapy with Gleevec for GIST. At M.D. Anderson, Trent uses modified RECIST (Choi criteria) for assessing response in GIST:
• Tumor size decrease of ≥ 10 percent OR tumor density decrease of ≥15 percent by CT scan
□ These were highly correlated with decrease in the standardized uptake value (SUV) by >70 percent to a value of <2.5 on PET scans in GIST patients.
Note: SUV=Standard Uptake Value. It is a measure of glucose uptake into the tumor. In the nearly 50 M.D. Anderson GIST patients, a decrease in tumor size of 10 percent or more OR a decrease in density of 15 percent or more was almost always accompanied by a decrease in glucose uptake during a PET scan. The glucose uptake was almost always decreased more than 70 percent on PET scan (to a SUV value of less than 2.5).
Dr. Trent noted that when the above guidelines are used, PET imaging is not generally needed. He still uses PET in some circumstances, but it’s pretty rare.
Another set of slides (Figure 4), presented by Trent, showed another shortcoming of RECIST and a potential diagnosis pitfall. The CT on the left is before treatment with Gleevec. If you look carefully you can see a faint outline of a tumor (Black Arrow). During treatment with Gleevec, this tumor becomes progressively darker and much more visible; in fact, a new tumor appears (Right Panel, Black Arrow). This is the case of an existing tumor that is not apparent before treatment with Gleevec and appears as it responds to Gleevec. This patient was referred to M.D. Anderson after a physician discontinued Gleevec due to progression, when in fact, the lesions were responding to Gleevec. A strict interpretation of RECIST would classify this as a new lesion and therefore progressive disease. Use of the Choi criteria will help prevent the misclassification of patients benefiting from Gleevec.
In the pretreatment CT (left panel), the tumors have the same density as surrounding tissue and do not show up or are very faint. During treatment with Gleevec, the tumors begin responding to treatment and lose density and become much more visible. This can incorrectly be interpreted as progressive disease and is another example of why management by GIST experts is important.
What treatment is there for KIT negative GIST?
GISTs that do not express the KIT protein account for about 5 percent of all GISTs. This type of GIST may still respond to Gleevec according to Dr. Trent, although, as a group, their overall survival is not as long as the KIT positive group of patients.
What is the role of genotyping in GIST?
Dr. Trent is frequently asked about the role of genotyping in GIST. He noted that “it doesn’t play a major role clinically now, but it may in the future. It does appear to play a predictive role, in that patients whose tumors have mutation in KIT exon 11 in general have a greater median PFS (progression-free survival) on Gleevec therapy compared to those with an exon 9 mutation or no mutation.” Trent noted that any individual patient could do better or worse than predicted by genotyping due to other reasons.
Trent noted that genotyping may play an interesting role in the future since patients with metastatic GIST who crossover from a lower to a higher dose Gleevec have an 8-fold better chance of getting benefit from the higher dose of Gleevec if they have a kit exon 9 mutation compared to exon 11 patients. Kit mutation analysis is available at M. D. Anderson Cancer Center.
What is the role of Gleevec for primary tumors?
Dr. Trent often has patients referred with a primary tumor and questions whether or not they should take Gleevec in the preoperative (neoadjuvant) or postoperative (adjuvant) setting. Trent noted that the role of Gleevec in these settings has not been defined by published studies . . . “but that there is compelling evidence to suggest that we need to do something more than just surgery in patients with primary GISTs.”
The rationale for neoadjuvant and adjuvant therapy comes from the historical data on GIST. Trent especially singled out a primary tumor size of over 10cm as a negative prognostic factor for recurrence and survival in the pre-Gleevec era. Historically (before Gleevec) these patients have had only about a 20 percent chance of surviving 6 years.
Dr. Trent talked briefly about several ongoing adjuvant trials: Z9000 and Z9001 and a possible future Z9002 study. Trent also noted the two ongoing combination neoadjuvant plus adjuvant studies: the RTOG S-0132 trial for patients with potentially resectable GIST and the M.D. Anderson neoadjuvant plus adjuvant trial, (ID03-0023) combining preoperative imatinib, surgical resection and postoperative imatinib for 2 years.
Dr. Trent noted that the decision to resect the GIST immediately or take Gleevec prior to resection of a GIST is a difficult one. Given the choice between preoperative Gleevec plus postoperative Gleevec or just postoperative Gleevec, many patients prefer to take the drug both preoperative and postoperatively. He noted that patients often prefer to start taking Gleevec as soon as possible and to know whether the drug is working. In the Z9001 adjuvant study, patients don’t know whether or not Gleevec is working because they have already had the tumor removed.
Is there therapy for Gleevecresistant GIST?
Dr. Trent noted that there are really three different types of progression that can be seen on a CT scan: limited progression, progression of a nodule and widespread progression.
Trent noted that patients with limited progression (including progression of a nodule) can be treated differently than patients with widespread progression as shown below:
Limited progression
• Hepatic artery embolization
□ Clinical benefit in about half of patients
Note: Hepatic artery embolization is an alternative palliative therapy for patients with tumors that cannot be resected. Embolization is performed by reducing the blood flow through the hepatic artery, which minimally affects healthy liver cells as they get their blood supply from the portal vein. Embolization may not be suitable for patients with liver diseases such as hepatitis or cirrhosis.
• Hepatic Radio-frequency Catheter Ablation
• Surgical Resection
• Radiation Therapy (special situations)
Widespread progression
• Increase Gleevec to 800 mg daily
• Sutent
• Clinical trial
□ These clinical trials take two different forms:
■ Agents that don’t put pressure on KIT signaling, such as perifosine or RAD001, are given in combination with Gleevec.
■ Agents that bind to KIT with a higher affinity OR inhibit multiple kinases, such as the addition of VEGFR such as dasatinib.
How long do I take Gleevec?
Dr. Trent noted that “. . . patients with metastatic GIST, for the most part, needed to be on Gleevec for life. We get an idea that this is the proper approach from a discontinuation study that was led by Dr. Blay in France.” Patients with metastatic GIST were treated for 12 months and the responders were then randomized to either continue Gleevec or discontinue Gleevec. The patients who discontinued Gleevec were found to progress almost immediately, so discontinuation of Gleevec in a patient that is responding or has stable disease with metastatic GIST is to be avoided. This also raises the question as to whether a kit inhibitor should ever be discontinued in GIST patients.
Is Gleevec cytotoxic or cytostatic?
Note: What are cytotoxic and cytostatic? Cyto=cell. Cytotoxic means toxic to the cell; in this context it means something (Gleevec) that kills the cell. Cytostatic means something that keeps the cell in a static condition; in this case, it means it prevents the cell from dividing (prevents the tumors from growing) but it does not kill the cells (or tumor).
“The answer, of course is, yes”, according to Trent. Trent showed pathology slides of a GIST patient before Gleevec and after one month of Gleevec. After Gleevec most of the tumor cells were dead, having ruptured and released the contents of the cell. This dead mixture formed the bulk of the tumor. A few viable tumor cells remained however and these cells may start growing again if Gleevec is stopped.
Are my children at risk for GIST?
Dr. Trent noted that while this is possible, it is rare with only about 17 recorded cases in the literature. Trent presented a family pedigree on one large family with this type of GIST (familial GIST) that he cares for in his practice.
Summary
Dr. Trent made a number of important points in his presentation:
1. Side effects are worse and treatment interruptions and dose reductions occur more often if you start Gleevec at higher doses, but patients that crossover to a higher dose after being on a standard dose of Gleevec for awhile do significantly better in these regards.
2. Tumors do not always shrink even when Gleevec is working. Tumor cells may die but protein debris may linger on and be viewed as areas of low density on CT scans.
3. Gleevec is a life-long treatment for patients with metastatic GIST.
4. Gleevec appears to benefit patients with KIT negative GIST.
5. Genotyping currently plays a predictive role and will probably become more important in the future. Kit mutation analysis is available at M.D. Anderson Cancer Center.
6. Dr. Trent told us of modified RECIST criteria that M.D. Anderson uses in clinical trials for GIST. GIST experts have previously acknowledged that the current RECIST are inadequate for GIST. This new modified RECIST from M.D. Anderson is the first specific proposal that we are aware of (choi criteria).
7. Dr. Trent gave recommendations about the management of Gleevecresistant GIST noting that patients with limited progression should be managed differently than patients with widespread progression.
8. GIST can run in families, but this is rare.
