The incidence of second primary malignancies after gastrointestinal stromal tumor before and after the introduction of imatinib mesylate

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Imatinib mesylate was FDA-approved in 2002 for the treatment of unresectable and metastatic GISTs and has become the standard of care. Its use has resulted in greatly increased survival rates for patients with GIST. The increased survival in patients with GIST raises concerns about long term effects of therapy, particularly the development of second primary malignancies (SPMs), which has been reported with imatinib treatment of chronic myeloid leukemia. In addition, the diagnosis of GIST itself may pose a risk for the development of SPMs. The purpose of this study was to examine the incidence of SPMs after GIST, particularly before (pre-imatinib era: 1992-2001) and after (imatinib era: 2002-2009), and factors related to the occurrence of SPMs. Data from the NCI’s Surveillance Epidemiology and End Results (SEER) 1992-2009 program was utilized. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for these were calculated using SEER*Stat 8.0.1. Observed incidences were then compared between pre-imatinib and imatinib eras using Fisher’s exact test. The relationship between the presence of SPMs and each of the variables was examined using logistic regression. There were significantly more patients in the imatinib era alive after follow-up (n=533, 63.99%) than in the pre-imatinib era (n=130, 22.41%, P<0.001). Overall, the rate of SPMs after GIST in the imatinib era was 7.07%, compared with the rate of 1.15% that occurred in the pre-imatinib era (P=0.030). This difference was mainly accounted for by a higher incidence of colon adenocarcinoma in the imatinib era (P=0.023). Renal cell carcinoma also accounted for this difference. In contrast, the rate of melanoma of the skin was significantly lower in the imatinib era compared with the pre-imatinib era (P=0.030). In the pre-imatinib era for melanoma, the SIR was 17.64 (95% CI: 3.64-51.57). Patients with SPMs were significantly older at diagnosis (mean =64.18, SD =12.95) than patients without SPMs (mean =60.63, SD =15.27, P=0.024). Marital status was significantly related to the presence of SPMs (78.26% vs. 65.62%, P=0.0154) with those patients with SPMs more likely to be married compared to those without SPMs. This relationship is most likely due to increased survival. Of note, patients with SPMs had greater number of months of survival (mean =70.83, SD =51.54) than those without SPMs (mean =39.33, SD =37.30, P<0.0001). The findings in our study demonstrate that patients after GIST are at increased risk of developing SPMs and that this risk is increased following the introduction of imatinib in 2002. The increased incidence of SPMs in the era of imatinib could be explained by the increased survival of patients with metastatic GIST and therefore more time to develop SPMs, however, further studies are needed to investigate this mechanism.