A Study Of Gastrointestinal Stromal Tumors: Clinical Features, Prognostic Factors, Mutational Analysis And Clinical Management

[Objective] (1) To investigate the clinical features, prognostic factorsand the status of c-kit and PDGFRA mutations in the gastrointestinalstromal tumors (GIST) in china. (2) To evaluate the efficacy and safetyof imatinib (Gleevec^TM) in the adjuvant therapy or in the management ofmetastatic/unresectable GIST[Method] (l)The clinic and pathological data of a series of patients withgastrointestinal stromal tumors in 1998-2006 yrs were analyzedretrospectively. (2) 141 cases were evaluated for the presence of c-kitand PDGFRA mutations, exon 9, 11, 13, 17 of c-kit and exon 12, 18 of PDGFRAwere analyzed by PCR amplification and direct sequencing. The clinicalfeatures, prognostic factors, mutational status and their relationshipswere analyzed with statistical tools in this study. (3) Among total 73GISTs proved pathologically, 18 cases of them was managed as adjuvanttherapy and 55 cases was palliative. All the GIST received oral imatinib(Gleevec^TM) at the dose of 400-800mg/d.[Result] (1) The 1 year , 3 years and 5 years overal survival (OS) of the109 gastrointestinal stromal tumors treated in our hospital in1998-2004yrs was 87．6%, 56．1%, 45．7%. In this series, The 1 year , 3 yearsand 5 years overall survival was 94．1%, 79．2%, 69．3% for gastric stromaltumor and 81．8%, 33．5%, 26．8% for small intestinal stromal tumor . Tumorsize, Mitotic rate , primary tumor organ , grade of malignant potentialand radical surgical excision or not were analyzed respectively and thedifference was statistical significance (P<0．5) ; there were no significant differences between the groups of gender, age, immunohistochemistryexpression and multi-organ resection or not. COX regress analysisindicated that grade of malignant potential(P=0．004) and radicalsurgical excision or not(P=0．000) is the independent prognostic factors.(2) Generally, c-kit mutations were identified in 76．6% (108/141) in allour 141 GISTs: 70．2% ( 99/141) involving exon 11, 5．7% ( 8/141 ) involvingexon 9, 0．7% ( 1 /141 ) involving exon 13 and no mutation detected in exon17．The gene mutations were mostly heterogeneous. The c-kit exon 11mutational format included deletion ( 65．7%), point mutation(24．2%) andinsert duplications(10．1%). The mutations clustered in the classic "hotspot" at the 5' end of the exon mostly heterogeneous and the second "hotspot" were internal tandem duplications(ITD) at the 3' end of the exon.PDGFRA mutations were totally identified in 12．1 % (4/33) ofno-ckit-mutation GISTs and 40 % (4/10) of CDH7-negative GISTs: allinvolving exon 18 with the mutations D842V. With the analysis betweenclinical features and mutation status, we found the significantdifference of gene mutation rate in the different primary tumor organs (x²= 7．229, p=0．027; x²=7．000, p=0．03) . The overall mutation rate in theGIST originated from colorectum or extra-gastrointestinal tract was lowerthan that from stomach and small intestinal and the difference issignificant(x2=6．728, p=0．009; x2=4．059, p=0．044) . The ckit exonllmutation rate in the gastric stromal tumors is higher than that in theother sites and the difference is significant(x2=5．713, p=0．017; x2=4．341, p=0．037) . The mutation rates , whatever overall mutation rateor ckit exonll mutation rate, were no significant differences between thegroups of age, gender, tumor size, mitotic rate, grade of malignantpotential and liver metastasis or not. (3) 18 of total 73 GISTs weremanaged as adjuvant therapy with oral imatinib (Gleevec^TM) at the doseof 400mg/d, therapeutic time ranged 4-13 months(median time7months) , time of follow up ranged 4-27 months (median time 8 months), norelapse occured and all of 18 cases was disease-free. 55 cases wasadvanced GISTs and received oral imatinib (Gleevec^TM) at the dose of400-800mg/d palliatively and median therapeutic time is 8．5months.2 of55 cases (3．6 %) achieved complete response (CR), 20 cases (36．4 % )had partial response (PR), 25 cases had stable disease (SD), 5 cases (9．l%)hadprogression disease (PD) and 3 cases were unable to evaluate because ofno measured tumor. The total clinical effective rate(CR+PR+SD) is 85．5%. 6 cases experienced disease progression after PR/SD and 1 of themre-achieved stable disease with increasing the dose to 800mg/d. 22 caseshad been followed up more than one years and the 1 years survival was 93．8% in the palliative group. According to the NCI-CTC 2．0 standard, themain toxicity we observed included gradeâ… -â…¡edema 47．9%; nausea andvomiting 31．5%; leukopenia 27．4%; liver dysfunction 11．0%; kidneydysfunction 2．7%; fatigue 16．4% ;alimentary tract hemorrhage 1．4% ;skinrash 1．4%。[Conclusion] Fletcher's classification was rational,scientific,simple and feasible to predict the behaviors of GIST. Radical surgicalexcision was the best therapy to the primary gastrointestinal stromaltumor. Most GIST had the ckit or PDGFRA gene mutation. There wassignificant difference between gene mutation rate and primary tumor organ.Imatinib was effective and safe to metastatic/unresectable GIST and itstoxicity was acceptable. For the high risk GIST, imatinib may be used asadjuvant therapy after radical operation.