- Research article
- Open Access
- Open Peer Review
Population-based SEER trend analysis of overall and cancer-specific survival in 5138 patients with gastrointestinal stromal tumor
© Güller et al. 2015
- Received: 16 December 2014
- Accepted: 14 July 2015
- Published: 30 July 2015
The objective of the present population-based analysis was to assess survival patterns in patients with resected and metastatic GIST.
Patients with histologically proven GIST were extracted from the Surveillance, Epidemiology and End Results (SEER) database from 1998 through 2011. Survival was determined applying Kaplan-Meier-estimates and multivariable Cox-regression analyses. The impact of size and mitotic count on survival was assessed with a generalized receiver-operating characteristic-analysis.
Overall, 5138 patients were included. Median age was 62 years (range: 18–101 years), 47.3 % were female, 68.8 % Caucasians. GIST location was in the stomach in 58.7 % and small bowel in 31.2 %. Lymph node and distant metastases were found in 5.1 and 18.0 %, respectively. For non-metastatic GIST, three-year overall survival increased from 68.5 % (95 % CI: 58.8–79.8 %) in 1998 to 88.6 % (95 % CI: 85.3–92.0 %) in 2008, cancer-specific survival from 75.3 % (95 % CI: 66.1–85.9 %) in 1998 to 92.2 % (95 % CI: 89.4–95.1 %) in 2008. For metastatic GIST, three-year overall survival increased from 15.0 % (95 % CI: 5.3–42.6 %) in 1998 to 54.7 % (95 % CI: 44.4–67.3 %) in 2008, cancer-specific survival from 15.0 % (95 % CI: 5.3–42.6 %) in 1998 to 61.9 % (95 % CI: 51.4–74.5 %) in 2008 (all PTrend < 0.05).
This is the first SEER trend analysis assessing outcomes in a large cohort of GIST patients over a 11-year time period. The analysis provides compelling evidence of a statistically significant and clinically relevant increase in overall and cancer-specific survival from 1998 to 2008, both for resected as well as metastatic GIST.
- Gastrointestinal stromal tumors (GIST)
- Surveillance, Epidemiology and End Results (SEER) database
- Trend analysis
- Gastric GIST
Gastrointestinal stromal tumors (GIST) are the most frequent mesenchymal malignancies of the gastro-intestinal tract. The origin of GIST is the cell of Cajal, which is the pace-maker cell located between the circular and longitudinal muscle layer along the gastro-intestinal tract and is responsible for the gastro-intestinal motility. GIST occur most frequently in the stomach and small bowel, other locations such as esophagus, colon, rectum and extravisceral locations are rare.
For many decades surgery was the only efficient treatment modality for GIST. However, despite complete resection, the high recurrence rate remained an unsettling problem. The use of chemotherapy or radiation was proven to be largely ineffective . However, over the past 15 years substantial improvements were made in the understanding of the pathogenesis and treatment of GIST. Around the change of millennium physicians began to understand that GIST are a result of a KIT or PDGFR mutation and more importantly, that the resulting mutated KIT or PDGF receptor could be blocked by the tyrosine kinase inhibitor imatinib. This targeted agent, which previously had a tremendous success in treating chronic myeloid leukemia by blocking the ABL-kinase of the BCR-ABL fusion protein, was now also applied in this solid tumor entity. Imatinib was first used in a female patient with a metastatic GIST, who was unsuccessfully treated with different chemotherapies . After 4 weeks of imatinib treatment, a phenomenal response was seen on PET scan. Since then, many studies including several randomized trials have been performed using imatinib in non-metastatic [3, 4] and metastatic GIST [5, 6].
However, it remains unknown whether improvements in understanding and management of GIST patients have resulted in relevant patient benefits on a population-based level. Therefore, the primary objective of the present analysis was to assess whether overall and cancer-specific survival of GIST patients have improved over a 11-year time period.
The recent ASCII text data-version of the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute in the United States, covering approximately 28 % of cancer cases in the United States, was the source of present population-based analysis . SEER data were collected and reported using data items and codes as documented by the North American Association of Central Cancer Registries (NAACCR) . Primary cancer site and histology were coded according to criteria in the third edition of the International Classification of Diseases for Oncology (ICD-O-3) .
Statistical analyses were performed using the R statistical software (www.r-project.org). A two-sided p-value < 0.05 was considered statistically significant. Continuous data are expressed as median and interquartile range (IQR). After descriptive analysis, survival was assessed by Kaplan-Meier analysis. Overall and cancer-specific survival were the designated endpoints. For analysis of overall survival, the time from diagnosis until the end of the follow-up was used together with the information whether a patient died or not. For cancer-specific survival, cancer-associated deaths were counted for the estimation of the cancer-specific survival whereas other deaths unrelated to GIST were censored. The censoring was based on the coding of these endpoints in the SEER database (alive, cancer-associated death, other death). P-values were computed using Cox-regression and likelihood-ratio-tests. To assess the association between GIST size and survival, locally weighted scatterplot smoothing (LOWESS)-Regression was performed . To analyze the predictive value of the continuous variables size and mitotic rate for survival, a generalized receiver-operating characteristic (ROC)-methodology for survival analysis was applied . Sensitivity and 1-specificity for prediction of one-year survival were simultaneously plotted as ROC-curves and the area under the curve (AUC) was estimated. Mitotic count was systematically recorded after 2009, therefore only one year survival rates were computable. For each distinct value of mitotic count and size, the pairs of ‘true positives’ (number of patients for whom death was predicted and who died) and ‘false positives’ (number of patients for whom death was predicted and who survived) are displayed . These pairs form the receiver-operating characteristic (ROC)-curve. The area under the curve (AUC) of a perfect predictor would have an AUC of 1 and the ROC-curve would have an ROC plot along the left side and the top of the graph. For prediction due to chance, the AUC is 0.5 and the ROC-curves are on the diagonal line (“chance diagonal”) . The statistically optimal cut-off value was estimated by maximizing the Youden index (computed as Sensitivity + Specificity-1). Multivariable survival analyses were done using Cox regression analyses. The proportional hazard assumption was tested by scaled Schoenfeld residuals and by inspection of the hazard ratio (HR) plots . For trend analysis, Spearman’s rho was applied. Extrapolation of survival rates was based on the covariate vector for the year of diagnosis modeled as a factorial variable in Cox regression.
This study was based on public use de-identified data from the SEER database and did not involve interaction with human subjects or use personal identifying information. The study did not require informed consent from the SEER registered cases and the authors obtained Limited-Use Data Agreements from SEER.
(N = 5138)
3018 (58.7 %)
1603 (31.2 %)
517 (10.1 %)
29 (0.6 %)
139 (2.7 %)
172 (3.3 %)
3 (0.1 %)
174 (3.4 %)
1280 (24.9 %)
5 cm–9.9 cm
1678 (32.7 %)
1471 (28.6 %)
709 (13.8 %)
7.0 cm [4.5 to 11.8 cm]
4071 (79.2 %)
264 (5.1 %)
803 (15.6 %)
<2 per 50 HPF
397 (7.7 %)
2–5 per 50 HPF
171 (3.3 %)
>5 per 50 HPF
159 (3.1 %)
4411 (85.9 %)
Surgery of primary
No surgery of primary tumor
865 (16.8 %)
Surgery of primary tumor
4263 (83.0 %)
10 (0.2 %)
4211 (82.0 %)
927 (18.0 %)
−M1, no surgery of metastasis
−763 (14.8 %)
−M1, surgery of metastasis
−139 (2.7 %)
−M1, surgery of metastasis
−25 (0.5 %)
1998 to 2002
1120 (21.8 %)
2003 to 2005
1195 (23.3 %)
2006 to 2008
1227 (23.9 %)
2009 to 2011
1596 (31.1 %)
2709 (52.7 %)
2429 (47.3 %)
1060 (20.6 %)
1805 (35.1 %)
1682 (32.7 %)
591 (11.5 %)
3536 (68.8 %)
920 (17.9 %)
682 (13.3 %)
3008 (58.5 %)
832 (16.2 %)
1298 (25.3 %)
Cause of death
3545 (69.0 %)
Dead from cancer
1080 (21.0 %)
Dead not from cancer
513 (10.0 %)
37.0 [14.0 to 74.0]
Univariable survival analysis
Tumor size and mitotic count
Multivariable survival analysis
Univariable and multivariable analysis of overall and cancer-specific survival
Cox regression, full model b
Cox regression, full model b
HR (95 % CI)
HR (95 % CI)
HR (95 % CI)
HR (95 % CI)
5 cm–9.9 cm
Surgery of the
No surgery primary
1998 to 2002
2003 to 2005
2006 to 2008
2009 to 2011
This is the first population-based trend analysis of GIST patients over an 11-year time period. The present study provides compelling evidence of a statistically significant and clinically relevant overall and cancer-specific survival increase from 1998 to 2008, both in non-metastatic GIST as well as metastatic GIST. In addition to the well-known poor prognostic factors such as larger tumor size, nodal or distant metastases, and older age, we found that earlier time point of diagnosis, male gender, and single marital status are associated with worse overall and cancer-specific survival.
The present trend analysis was based on over 5000 GIST patients from the SEER registry. In this real-world analysis overall 3-year overall survival increased from 15 % in 1998 to 55 % in 2008 in metastatic GIST and from 68 to 89 % in patients with non-metastatic GIST. There are several reasons for this substantial improvement. First, a large increase in overall and cancer-specific survival was observed during the first 4 years of our analysis (1998–2001). This was prior to the FDA approval of imatinib. One explanation is that very low risk GIST may have been misclassified as leiomyoma and hence were not included into our analysis prior to the GIST consensus meeting of 2001 [14, 15]. Perez and colleagues showed a significant increase in reported GIST incidence from 1992 to 2002 based on SEER data, which is almost certainly related to reclassification of various tumors (e. g. leiomyoma) as GIST.  The inclusion of these tumors may have falsely increased the incidence and survival of GIST patients . In the early years of our SEER analysis, the pivotal role of CD117 immunostaining was not systematically performed as previously pointed out by Tran and colleagues . Hence, the incidence of GIST patients reported in SEER may be lower compared to studies, for which CD 117 staining was mandatory. Another explanation of the survival increase seen in the metastatic and non-metastatic group in the present analysis is stage migration. Indeed, PET scanning became a popular tool in the evaluation of GIST patients in the early and mid-2000’s, potentially leading to stage migration (Will Rogers phenomenon). Another explanation of the improved outcomes seen in the present investigation may the introduction of imatinib and other tyrosine kinase inhibitors in GIST treatment. There is no doubt that the advent of imatinib in treating GIST represents an important step forward in cancer care as this targeted therapy—already very successful in patients with chronic myeloid leukemia—was now being applied for the first time to a solid gastrointestinal cancer. Over the past decade, several randomized controlled trials investigating imatinib were performed demonstrating improved outcomes in patients with completely resected [3, 4] and metastatic GIST [5, 6]. While there are currently no other drugs than imatinib being used in non-metastatic GIST, several tyrosine kinase inhibitors have been associated with increased overall survival in patients with metastatic GIST. In addition to imatinib, which is used as a first line treatment, sunitinib  and regorafenib  have been evaluated in phase III randomized trials and resulted in an overall (sunitinib) and progression-free survival benefit (regorafenib) in second and third line treatment. Unfortunately, the use of tyrosine kinase inhibitors is not coded in the SEER database and hence an association between use of these systemic treatments and improved outcomes remains speculative.
Therefore, with more efficacious treatment options in advanced GIST patients, it is expected that overall and cancer-specific survival will continue to increase in the coming years as also shown in a data extrapolation in the present study (Fig. 5). In the adjuvant setting, the outcomes will most likely improve as well. In 2012, the German/Scandinavian study by Joensuu and colleagues provided compelling evidence that high-risk GIST patients have a better progression-free and overall survival with three years of adjuvant imatinib compared to only one year . It is well known and also clearly seen in the German/Scandinavian trial that most recurrences occur within the first 12–24 months after stopping imatinib. Currently large randomized studies are undertaken to prove the hypothesis that 5 years of adjuvant imatinib treatment is superior to three years in the high-risk GIST subset. Selected patients with high-risk features (e. g. gastric GIST with very high mitotic count or non-gastric GIST with high mitotic count) may even benefit from life-long adjuvant imatinib treatment. However, this remains to be proven in well-designed and well-conducted trials as well as large cohort studies.
Both size and mitotic rate—the two best-known risk factors for recurrence—were evaluated in receiver operating curves in the present study. We identified a cut-off value of 8 cm and a mitotic rate of 5 per 50 high power fields (HPF) to be most predictive for cancer-specific survival. While the 5 mitosis per 50 HPF is a largely used cut-off value to risk stratify GISTs , a size cut-off value for worse prognosis set at 5 cm may be overly pessimistic (Fig. 4). Indeed, in an investigation by Woodall et al., which analysed GIST tumours based on SEER data from 1974 through 2004, a size cut-off of 7 cm was identified as an independent poor prognostic factor .
Moreover, in both univariate and multivariable analyses, a GIST size above 10 cm was associated with worse cancer-specific and overall survival while patients with GIST size between 5–10 cm had similar outcomes compared to those with a size of 5 cm and below. There is no doubt that a risk categorization of continuous biological variables such as size and mitotic rate is problematic. In this regard, prognostic contour maps as described by Joensuu et al. are helpful in assessing the risk of recurrence in GIST patients .
In the present analysis, patients with small bowel GIST had no worse overall and cancer-specific survival compared to patients with gastric GIST. This is opposed to other studies . It is unclear why such a discrepancy occurs, however, may be due to different time periods in which the patients were enrolled in our study compared to the one by Gold and colleagues .
We would like to acknowledge the limitations of this study. The main drawback of this analysis is the lack of information on tyrosine kinase inhibitors used, data that cannot be ascertained in the SEER registry. Similarly, information about comorbidities, performance status, and information on site and number of metastases are not available in the SEER database. In addition, there is a relevant number of missing values for certain parameters e. g. mitotic rate, which was only systematically collected in the SEER database starting 2010. Despite these limitations, the present study has a variety of strengths. First, the population-based nature of the registry mirrors the real-world outcomes for GIST patients and is associated with a high degree of generalizability. It is key to evaluate to which extend advances in often highly selected patients in randomized controlled trials have translated into the overall patient population. Second, our study reports overall and cancer-specific survival data on a 11-years time period with extrapolation to a 14-years period. Third, the large sample size is associated with a high degree of power.
In conclusion, larger tumor size, location other than stomach or small bowel, nodal or distant metastases, older age, earlier time point of diagnosis, male gender and single marital status are associated with significantly worse overall and cancer-specific survival. There has been a substantial increase in overall and cancer-specific survival from 1998 to 2008. It is anticipated that the current availability of different tyrosine kinase inhibitors in the advanced setting and better selection of high-risk patients benefitting from long-term adjuvant imatinib will continue to lead to a further improvement in patient outcomes.
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