Since the introduction of imatinib in clinical trials in 2000, and its subsequent FDA approval for KIT-positive GIST in Feb. 2002, survival of patients with advanced/metastatic GIST has been well characterized within controlled clinical settings. Survival of patients without advanced disease, or otherwise ineligible for trial enrollment has been less well characterized. This observational registry reports on the survival of GIST patients at a range of ages, locations, and disease statuses. Many of these patients participated in clinical trials, but most did not.
GISTs have been previously divided into two distinct sub-groups: adult, primarily displaying KIT or PDGFRα mutations [31
] and pediatric GIST typified by wild-type GIST or deficiencies in the succinate dehydrogenase complex [26
]. In our cohort of patients, 2.4% were diagnosed before the age of 18, 10.6% were diagnosed between the ages of 18-35, and 87.0% were diagnosed after the age of 35. The youngest group was dominated by characteristics previously ascribed to pediatric-type GIST: female (75%; Figure ), stomach primary tumors (93%; Figure ), extended survival times (median OS had not been reached; Figure ), and wild-type or SDH mutations (80% wild-type, 13% SDH mutations; Figure ). Patients in the oldest age-group had characteristics more closely associated with adult-type GIST: slight male predominance (54% male), mixed primary tumor locations (37% stomach), shorter overall survival (median OS = 11.0 years), and dominated by KIT mutations (83%). Patients diagnosed between the ages of 18-35 appeared to be a mixture of pediatric and adult types, with all four characteristics (gender distribution, primary tumor location, mutational status and overall survival), falling between those expected of these previously described GIST types (Figure ).
The median overall survival for all patients in the LRG registry was 11.7 years, (14.5 years for females and 10.3 years for males). Females predominated in pediatric-type GIST and survival is longer in pediatric-type GIST. This may partially explain the longer survival times of females when the entire range of ages at diagnosis was considered; however, females still retained a significant, albeit smaller, survival advantage even when only patients > 35 years old were considered (median OS = 11.0 years, females vs. 10.3 years males; P- value = 0.0006, HR = 1.517). Approximately 24% of LRG registry patients reported metastatic disease at time of diagnosis. This compares to 11% from a population-based study from the Rhône Alpes region of France [34
], 15% from a population-based study in Western Sweden [1
], 18% from a registry of patients from the United States [35
], and 30% from the GOLD reGISTry (Global) [36
]. Patients that initially presented with primary disease only, and later reported a recurrence, displayed a median overall survival > 11 years.
The 276 patients diagnosed over the age of 18, and reporting metastatic GIST at the time of diagnosis, represent the group of LRG registry patients that is easily defined, and expected to be most similar to those in the phase II and III metastatic GIST trials with respect to overall survival. The median overall survival for this sub-group within the cohort was 6.4 years from the time of diagnosis, reflective of the negative impact of metastatic disease at diagnosis upon overall survival. This is however, a longer overall survival time than typically reported for adult patients with metastatic disease, warranting further investigation. Recently it was reported that overall survival was better in the SWOG SO33 trial for centers that treated more than 15 patients versus those that treated 15 or fewer patients (median OS, 57 months vs 49 months)[37
]. An intriguing question is whether patients receiving treatment or consultations at specialty centers that see many more GIST patients have better long-term outcomes than patients receiving care only at community- based practices. Another possibility is that approval of sunitinib in 2006 and off-label treatments such as nilotinib and sorafenib, which are commonly used by members (especially from the United States) with advanced disease, might be impacting overall survival compared to early trial results for metastatic disease.
The rate of mutational testing within this registry was 26.7% (30.5% for living members). While this is lower than typical research studies, it is much higher than the 6% testing rate reported in the reGISTry database of 822 patients treated in the United States [34
]. The authors therein noted that the low mutational testing rate observed could be ascribed to the difference between actual clinical practice and guideline recommendations of the National Comprehensive Cancer Network (NCCN) and European Society of Medical Oncology (ESMO). They also noted that "Differences in response rates among reGISTry patients may also be attributed to differences in dosing patterns and treatment compliance in the 'real-world' versus clinical trial setting". The LRG registry represents a self- reported and international community, where mutational testing was carried out at a number of different centers. The level of testing can vary by center. For example, in the past, some centers tested for KIT mutations only, whereas testing for any SDH mutation is relatively rare; The only center within the United State of which we are aware that routinely screens for SDH mutations is the National Institutes of Health (NIH). The level of screening for SDHA mutations, which have only recently been reported, is unknown. As reliable immunohistochemical tools for detecting SDH deficiencies are identified, and become more wide-spread, we would expect the reported number of cases of both pediatric-type GIST and those with SDH mutations to increase.
Although imatinib appears to be less effective in pediatric- than adult-type GIST, relatively long survival times have been reported for patients with Carney's Triad and pediatric GIST [21
]. These longer reported survival times pre-date the imatinib era and seem to be related to the relative indolence of the disease rather than any impact of imatinib or other targeted therapies. The LRG registry data confirms these observations for patients diagnosed below the age of 18. The median overall survival for these patients has not been reached and is significantly higher than older patients. In contrast, patients diagnosed over the age of 35 have shorter survival times in spite of effective drug therapies. Wild-type GIST/SDH-deficient patients had longer survival times, possible reflecting a high percentage of pediatric-type GIST in this group.
In our cohort, the ratio of females to males varied by the age at diagnosis. In the group of patients diagnosed below the age of 18, 75% (21/28) were female. The ratio of females to males remained higher until approximately age 35 and then dropped precipitously, and inverted with a slight male predominance in patients diagnosed after age 35. Adult- and pediatric-type GIST have different causes and respond differently to treatments. Pediatric GIST appears to be less dependent on KIT or PDGFRα than adult GIST, and may be somewhat dependent on IGF-1R signaling [38
], as well as having deficiencies in the tumor suppressor activity of succinate dehydrogenase.
Since 2008, the National Institutes of Health, in collaboration with the Consortium for Pediatric and Wild-type GIST Research (CPGR), have been conducting biannual clinics for patients with wild-type and pediatric GIST. In addition to providing a resource for these patients, this group is collecting valuable data on these GIST subtypes. Given the rarity of pediatric GIST, it is important that patients and physicians are aware of this clinic. Our data suggests that, in addition to pediatric and adolescent patients, a significant portion of diagnosed "young adults" may also have the pediatric form of GIST. Pediatric-type GIST in adults was also recently reported by Rege and colleages in 16 patients (13 women, 3 men), with a median age at diagnosis of 31.5 years (range 19-56) [39
Mutation testing is important for GIST patients including those diagnosed below the age of 35. Patients with characteristics associated with pediatric-type GIST (female gender, wild-type or SDH mutations, stomach primary tumors and epitheloid histology), should be referred to the NIH Pediatric and Wild-type GIST Clinic whenever possible. Immunohistochemical staining can also aid in identifying pediatric-type GIST, with a SDHB-deficiencies being strongly correlated with pediatric-type GIST [26
]. All GIST patients diagnosed below the age of 18 should be referred to the clinic unless they have documented KIT or PDGFRα mutations. In addition, patients of any age with wild-type GIST may be eligible to participate in the clinic.
In this study we report on the survival of a large heterogeneous group of GIST patients of all ages that includes both metastatic and primary tumors. While patients in the LRG registry comprise a diverse group, there are differences when compared to the entire GIST population worldwide. LRG members are self-referred and participation is via the internet which could be prone to inclusion biases. For instance, younger patients are more likely to be internet-savvy than older patients, and patients in less developed countries may be excluded due to a lack of internet access, and other socioeconomic and language barriers. In addition, patients with advanced disease may be more motivated to participate than patients with less advanced disease. Being by and large self-referred, patients in the LRG registry may be more proactive, more likely to seek treatment at GIST referral centers, and more likely to register for, and potentially participate in, controlled clinical trials. In addition, a higher percentage of LRG patients have mutational testing (30.6% of living patients) compared to either those treated by academic centers (12%) or at community-based practices (1%) in the United States [35
Patient-reported primary tumor locations should be interpreted with caution. In some cases, primary tumors may be adjacent, or adhered to other organs making reporting of a single, unique site difficult. For example, a doctor may report that the (primary) tumor was attached to the stomach, small intestine and pancreas. In most cases, operative notes and similar reports were not reviewed and in some cases primary tumor location cannot be conclusively determined even when these documents have been made available.