Interpreting research: dilemmas facing patients and physicians. Recently, GIST discussion groups have debated the value of the LRG study that examined dosage levels and survival rates. It is important for us to have this debate in the patient community; yet it is equally necessary to spur debate among scientists and physicians. But we should be clear about what exactly we are debating. No current study, neither the MetaGIST Project study nor the LRG study, can offer definitive answers on the correct dosage levels of Gleevec, but both do provide information that can help us ask the right questions. Informing patients and empowering them to question and challenge the orthodoxy of the medical community is precisely what the LRG is all about. Many GIST patients would not be alive today were it not for the shared willingness of the GIST community to question their healthcare providers when their needs were not being adequately heard or met.
The LRG study never purported to prescribe the appropriate dosage for every individual with GIST. Rather, it examined the relationship between dosage level and survival rates among a specific subgroup of patients: 169 metastatic GIST patients who had demonstrated initial tumor shrinkage in response to Gleevec therapy and remained progression free for at least one year (See Figure 1). However, what distinguishes the LRG study from the MetaGIST Project study is that the data collected and analyzed for the LRG study represents actual dosage (as opposed to starting dosage) taken by these 169 patients. By focusing on the actual dosage the LRG study was able to show overall survival and higher doses. These results point to some significant weaknesses in the MetaGIST Project study; weaknesses that are reflected in the current, rather inflexible treatment guidelines. The LRG study’s results represent a major challenge to the medical and research community to re-examine the data of earlier clinical studies as well as the treatment consensus which derives from them. It may not always be comfortable to look at new ways of interpreting things but doing so may save someone’s life.
What do we know about Research?
Let’s continue the dialogue we began when we presented our data on the relationship between Gleevec dosage levels and survival, and re-examine what we know and what we don’t know.
- The LRG study demonstrates a strong correlation between dosage levels and progression, and between progression and death. In fact, the LRG study shows that the single most important factor in long-term survival for metastatic patients is staving off progression. In the study, which included 169 metastatic patients who had shrinkage and who were stable on Gleevec for at least one year, 81 percent of the patients who had progressed by 2004 died by 2007, compared to only 11 percent of the group that remained stable in 2004.
- For some patients, a lower dosage of Gleevec is enough to maintain stability but at the current time we have no conclusive way of predicting which patients fall into this category and which will progress.
- The reliability of LRG’s patientderived data has been demonstrated by the following:
• Results of the LRG dosage study replicate those of the MetaGIST Project study when using starting dose.
• Patients self-reporting progression had a mortality rate approximately eight times higher than those selfreporting stability, verifying that patients can accurately report progression (See Figure 2).
There is no one dosage study that answers all of our questions. While we could choose to wait for more definitive data, there are no studies that will soon address the issues brought up by the LRG dosage study or the recent blood level study presented by Dr. George Demetri at the Gastrointestinal American Society of Clinical Oncology meeting. In his study, Dr. Demetri found that a higher concentration of Gleevec in the blood correlates with better clinical outcomes and a longer time to progression, demonstrating the need for ongoing monitoring of patients’ blood levels.
We do not have a simple answer about what constitutes an adequate Gleevec dosage level for every patient. Physicians and patients are making decisions based upon the existing state of medical knowledge, imperfect as it is. More authoritative interpretations of newly collected data available five years from now will be of little help to those who develop resistance and progression now.
What are the weaknesses of the MetaGIST Project Study?
• The most serious concern was the exclusive use of starting (intent to treat) dosage levels. The MetaGIST Project study considered only these starting doses, and ignored the actual dose taken by patients if it changed. The fact is that of the patients originally assigned to the higher 800mg dose, 62 percent could not tolerate that dosage and were dropped to a lower dose. However, these patients were included in the 800 mg group analysis.
• No 600mg arm was included in the study. The only two doses examined were 400mg and 800mg.
• There was no dose escalation strategy employed to get patients to a higher dose. As a result, the study was not able to determine the impact of increasing doses. Had it included such a strategy, the MetaGIST Project study might have established much earlier what is now known. Namely, that side effects ease over time and that patients are more able to tolerate higher doses after first adjusting to lower doses.
What are the weaknesses of the LRG study?
• The LRG study sample was nonrandom and was relatively small compared to clinical trials.
• The LRG patients who submitted data for the study may not be representative of the entire population of GIST patients.
• The use of patient-reported data and subjective progression criteria may have introduced a bias into the progressionfree data; however, neither would affect overall survival data.
What does this mean for patients?
The data gathered in the LRG study clearly suggest that the MetaGIST Project study results do not justify an overly rigid insistence on a dosage level of 400mg. This is supported by research demonstrating that all patients do not metabolize drugs at the same rate, and that absorption rates may change over time. We need to optimize dosages for GIST patients through individualized treatment plans that take the following four key factors into consideration:
Over the last few years, the LRG has frequently found itself ahead of the curve when tracking information and trends. This was the case with our initial data on response rates to Gleevec and with our side effects survey. We find ourselves in this situation again with the LRG dosage study. We recognize it as our obligation to share what the study results tell us about how to best survive this disease.
The Empowered Patient’s Responsibility
One of the consequences of becoming empowered patients is that we enter into the world of medicine and science where there are sometimes more questions than there are answers. In addition to the burden of dealing with a life-threatening illness, many of us have taken on the additional responsibility of educating ourselves, supporting each other and ultimately making life-changing medical decisions. We have a responsibility to ourselves, to our loved ones and to our fellow GISTers to do our homework, to ask questions, to read the studies and to stay abreast of the latest scientific developments and medical breakthroughs. As informed patients, we often find ourselves in unchartered territory with respect to the medical community, sitting in the unfamiliar seat of making critical treatment decisions that may go against physician recommendations. Likewise, physicians may be uncomfortable allowing their patients to call the shots and choosing treatment options that are not part of the current medical consensus.
Ultimately, what makes data reliable or unreliable is an understanding of what they are based upon and whether they can stand up to rigorous and unbiased methodological and statistical scrutiny. No data and no study should be considered “untouchable”; but neither should they be ruled out in advance. We would hope that the patients, caregivers and physicians reading the LRG dosage study would find it more than just a “good read” and would have the objectivity and the wisdom to decide for themselves what this data means and what actions to take.