Survival of gastrointestinal stromal tumor patients in the imatinib era: life raft group observational registry

Abstract

Background: Gastrointestinal stromal tumors (GIST), one of the most common mesenchymal tumors of the gastrointestinal tract, prior to routine immunohistochemical staining and the introduction of tyrosine kinase inhibitors, were often mistaken for neoplasms of smooth muscle origin such as leiomyomas, leiomyosarcomas or leiomyoblastomas. Since the advent of imatinib, GIST has been further delineated into adult- (KIT or PDGFRα mutations) and pediatric- (typified by wild-type GIST/succinate dehydrogenase deficiencies) types. Using varying gender ratios at age of diagnosis we sought to elucidate prognostic factors for each sub-type and their impact on overall survival.

Methods: This is a long-term retrospective analysis of a large observational study of an international open cohort of patients from a GIST research and patient advocacy's lifetime registry. Demographic and disease-specific data were voluntarily supplied by its members from May 2000-October 2010; the primary outcome was overall survival. Associations between survival and prognostic factors were evaluated by univariate Cox proportional hazard analyses, with backward selection at P < 0.05 used to identify independent factors.

Results: Inflections in gender ratios by age at diagnosis in years delineated two distinct groups: above and below age 35 at diagnosis. Closer analysis confirmed the above 35 age group as previously reported for adult-type GIST, typified by mixed primary tumor sites and gender, KIT or PDGFRα mutations, and shorter survival times. The pediatric group (< age 18 at diagnosis) was also as previously reported with predominantly stomach tumors, females, wild-type GIST or SDH mutations, and extended survival. "Young adults" however formed a third group aged 18-35 at diagnosis, and were a clear mix of these two previously reported distinct sub-types.

Conclusions: Pediatric- and adult-type GIST have been previously characterized in clinical settings and these observations confirm significant prognostic factors for each from a diverse real-world cohort. Additionally, these findings suggest that extra diligence be taken with "young adults" (aged 18-35 at diagnosis) as pediatric-type GIST may present well beyond adolescence, particularly as these distinct sub-types have different causes, and consequently respond differently to treatments.

Figure 1

Age at diagnosis by gender. Female gender is known to be associated with pediatric-type GIST. Using high female to male ratio as a surrogate marker for pediatric GIST, our data suggests that pediatric-type GIST occurs with decreasing frequency until about age 35 (at diagnosis). Also see Table 3.

Figure 2

Overall survival: males vs. females. Females displayed significantly longer overall survival than males. This appears to be influenced by the long survival times and greater number of females in those with pediatric-type GIST. A smaller, but significant survival advantage was still noted for females > 35 at diagnosis (see Discussion)

Figure 3

Patient and disease characteristics by age group at diagnosis. Patients diagnosed below the age of 18 had characteristics associated with pediatric-type GIST: female gender (panel A), predominantly stomach primaries (panel B), prolonged overall survival (panel C), and wild-type GISTor SDH mutations (panel D). Patients diagnosed over age 35 had characteristics associated with adult-type GIST: slight male preference (panel A), slight preference for stomach primary tumor location followed closely by small intestine primaries (panel B), shorter overall survival (panel C), and dominated by KIT mutations (panel D). The 18-35 at diagnosis age group had characteristics between those of pediatric-type and adult GIST. Tumor locations were provided as free text and are depicted as a relative percentage within each age-group (panel B). Some sites have been grouped post hoc including, multiple GI (stomach and esophagus, stomach and small intestine, small and large intestine), and "other" which includes all remaining reported primary tumor sites (table 2); the rest were as reported (esophagus, stomach, small intestine, colon or rectum/anus). This was an attempt to adhere to published groupings without changing the data as reported. Multi GI, colon, and rectum/anus in the > 35 group, and multi GI in the 18-35 group were ~3% (2.9-3.3%); the remaining unlabelled sites were all < 2% of age-group (0.8-1.6%).

Figure 4

Overall survival by disease stage. The effect of disease stage on overall survival for patients > 18 years at diagnosis is shown in panel A. Patients that had metastatic disease at the time of diagnosis did significantly worse than patients that presented with primary disease only (panel B). Patients that had a recurrence later still did relatively well, but predictably, not as well as patients without a recurrence (panel C).

Figure 5

Overall Survival by Genotype. When calculated from the time of diagnosis, patients with wild-type GIST/SDH deficiencies or KIT exon 11 mutations did better than other types. The long survival times for wild-type GIST/SDH deficiencies in this series may reflect a high percentage of pediatric-type GIST patients. The relatively short survival time noted for PDGFRα mutations should be interpreted with caution given the small numbers and short follow-up.