Efficacy of Sunitinib in Turkish Patients with Gastrointestinal Stromal Tumors: Retrospective Multicenter Experience

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1 NEW FRONTIERS IN CLINICAL AND EXPERIMENTAL RESEARCH Efficacy of Sunitinib in Turkish Patients with Gastrointestinal Stromal Tumors: Retrospective Multicenter Experience Umut Kefeli 1, Suleyman Buyukberber 2, Murat Akyol 3, Ramazan Yildiz 1, Muhammed Ali Kaplan 4, Aydin Ciltas 2, Alper Sevinc 5, Halit Karaca 6, Mesut Seker 1, Nuriye Ozdemir 7, Ahmet Alacacıoglu 3, Ugur Coskun 2, Abdurrahman Isikdogan 4, Faysal Dane 8, Mahmut Gumus 1, Metin Ozkan 6, Ali Suner 5, Mustafa Oktay Tarhan 3, Mustafa Benekli 2 for Anatolian Society of Medical Oncology (ASMO) 647 Οriginal Paper Department of Medical Oncology, 1 Dr. Lutfi Kirdar Kartal Education and Research Hospital, Istanbul, Turkey 2 Gazi University Faculty of Medicine, Ankara, Turkey 3 Izmir Katip Celebi University Ataturk Education and Research Hospital, Izmir, Turkey 4 Dicle University Faculty of Medicine, Diyarbakir, Turkey 5 Gaziantep University Faculty of Medicine, Gaziantep, Turkey 6 Erciyes University Faculty of Medicine, Kayseri, Turkey 7 Ankara Numune Education and Research Hospital, Ankara, Turkey 8 Marmara University Faculty of Medicine, Istanbul, Turkey Corresponding author: Mesut Seker and Ahmet Alacaioglu, Department of Medical Oncology, Dr.Lutfi Kirdar Kartal Education and Training Hospital, Istanbul, Turkey; Tel.: , Fax: ; ukefeli@yahoo.com ABSTRACT Background/Aims: Sunitinib is a multi-targeted thyrosine kinase receptor inhibitor used in patients with advanced gastrointestinal stromal tumours (GISTs). We evaluated the efficacy and tolerability of sunitinib therapy in Turkish patients with GISTs. Methodology: Between January 2001 and April 2012, 57 patients who had progressive disease or experienced unacceptable toxicity during imatinib treatment from multiple centers were investigated retrospectively. Results: Thirty-three patients were male and 24 were female. The median age was 55 years (range; years). Thirty-eight of the patients received imatinib for longer than 12 months, 13 patients received for 6-12 months, and 6 patients received for less than 6 months. The clinical benefit of sunitinib was 73.7%. Treatment-related adverse events were reported in 78% of the patients. Adverse events were generally mild to moderate in intensity. The median progression free survival (PFS) and overall survival (OS) of the patients that received sunitinib were 10.8 months and 23.9 months, respectively. The time of imatinib usage and response to sunitinib were independent prognostic factors for PFS and OS. Also, tumor size was an independent prognostic factor for PFS. Conclusions: Sunitinib is an effective treatment in Turkish patients with GISTs, with a clinical benefit of 73.7% and shows an acceptable tolerability. Key Words: GISTs; Sunitinib; Imatinib intolerance. Hepato-Gastroenterology 2013; 60:00-00 doi /hge12692 H.G.E. Update Medical Publishing S.A., Athens INTRODUCTION Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract and are highly resistant to conventional chemotherapy (1). In the medical literature, GISTs have been confused with true smooth muscle neoplasms because of their similar appearance by light microscopy. In the past 10 years or so, immunohistochemical staining for the tyrosine kinase, c-kit (also known as CD117), has shown the presence of this receptor in approximately 95% of GISTs, thereby enabling differentiation from other mesenchymal spindle-cell neoplasms (2). C-kit is a transmembrane receptor that is activated by binding of the KIT ligand - a stem cell factor. About 85-90% of GISTs are associated with gain-of-function KIT gene mutations that lead to constitutive activation of KIT kinase activity. A much smaller proportion (5%) are associated with analogous gain-of-function mutations in PDGFRA, the gene encoding platelet derived growth factor receptor α (PDGFRα); less than10% contain no identified receptor tyrosine kinase mutations (3-5). Experience gained from epidemiological studies and active GIST therapeutic trials suggests that the annual incidence of GISTs in the United States is at least 4000 to 6000 new cases (roughly 7 to 20 cases per million population) per year (6). Surgical resection remains the mainstay therapy for GISTs, but recurrence is common. The 5-year survival rates for GIST after complete resection range from 40% to 65% (7-11). Imatinib mesylate selectively inhibits certain protein tyrosine kinases: intracellular ABL kinase, chimeric BCR-ABL fusion oncoprotein of chronic myeloid leukemia, the transmembrane receptor KIT, and platelet-derived growth factor receptors (PDG-FR) (12-15). Imatinib mesylate induced a sustained objective response in more than 50% of patients with advanced GISTs in the West and the other countries (16-18). However, the response to imatinib therapy is time-

2 648 Hepato-Gastroenterology 60 (2013) Kefeli U, Buyukberber S, Akyol M, et al. TABLE 1. Patient characteristics. Characteristics n Age Median (range) 55 (16-84) Gender Men 33 (57.9%) Women 24 (42.1%) Tumor site Stomach 15 (26.3%) Small intestine 26 (45.6%) Colon 4 (7.0%) Other sites 12 (21.1%) Histopathology Spindle cell type 33 (57.9%) Epitheloid 3 (5.3%) Mixed type 10 (17.5%) Unknown 11 (19.3%) CD117 positivity CD117 (+), CD34(+) 40 (70.2%) CD117 (+), CD34(-) 16 (28.1%) PDGFR alpha 1 (1.7%) Site of metastases Liver 32(56.1%) Peritoneum 4 (7.0%) Lymph nodes 1 (1.8%) Lung 1 (1.8%) Others 3 (5.3%) FIGURE 1. Univariate analysis between the response to sunitinib treatment and overall survival. CR: Complete Response; PR: Partial Response; SD: Stable Disease; PD: Progressive Disease. limited and secondary resistance to imatinib therapy (after initial stabilization or response) develops in the majority of patients (19). Sunitinib malate is an oral multitargeted receptor tyrosine kinase inhibitor that has shown antiangiogenic and antitumor activities in several in vitro and in vivo tumor models (7,20-25). These effects were associated with the blockade of receptor tyrosine kinase signalling by KIT, PDGFRs, all three isoforms of the vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, VEGFR-3), Fms-like tyrosine kinase-3 receptor (FLT3), and the receptor encoded by the ret proto-oncogene (RET) (7,20-25). Sunitinib showed effective activity for patients with GISTs after imatinib failure or intolerance and induced a sustained clinical benefit in advanced GISTs (7,18). Therefore, the aim of this study was to report sunitinib treatment results in the Turkish GISTs patients. METHODOLOGY Patients and study design Two-hundred and fifty patients with GIST from ten institutions in Turkey were retrospectively evaluated. All cases of surgically or endoscopically resected GISTs, investigated by the pathology departments of the participating institutions (between January 2001 and April 2012), were reviewed. Of these, 57 patients who had progressive disease or experienced unacceptable toxicity during imatinib treatment were chosen for evaluation according to the Response Evaluation Criteria in Solid Tumors (RECIST) (26). Follow-up data were obtained from clinical records and histopathology reports. The GISTs were defined as primary spindle cell, epithelioid cell and mixed neoplasms of the tubular GI tract with the over-expression of CD117, with or without CD34 expression, according to well-established criteria for GIST diagnosis (27,28). Mitoses were counted in 50 high-power fields. Tumor size was recorded as the largest diameter in any dimension of the primary tumor and was classified as <2cm, 2-5cm, 5 to 10cm, or >10cm. The malignant potential of the GISTs was classified according to the risk categories proposed by Fletcher et al. (28). Patient, tumor and treatment variables were recorded. Patient data included age, gender and presentation status. All patients with any metastatic disease were considered to have a metastatic presentation, regardless of whether they had received prior therapy or whether they had also had local recurrence. All tumors were regarded as being histologically malignant. The margins of the resected specimens were analyzed for the presence of microscopic disease. Resections were classified as incomplete when the tumor was unresectable on exploration or when gross residual disease was present after resection. Complete resection was considered as the excision of all gross disease with negative microscopic margins. Resection of metastases was performed in selected patients in whom the primary tumor was controlled. Statistical analysis All data were analyzed using SPSS 17.0 (SPSS Inc., Chicago, IL, USA) software. The clinicopathological factors of patients were compared using the chi-squared and Fisher s exact tests. Actuarial survival was determined by Kaplan-Meier analysis. Tumor response rates were evaluated as complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) according to the RECIST criteria (26). Progression free survival (PFS) was defined as no progression after sunitinib use. Overall survival (OS) was defined as survival after administration of sunitinib and death was the endpoint of the study. The relationships between patient, tumor, and treatment characteristics with outcome were tested by univariate analysis using a log-rank test. Multivariate analysis was

3 Sunitinib for Turkish patients with GISTs Hepato-Gastroenterology 60 (2013) 649 TABLE 2. Tumor characteristics of the 57 patients with gastrointestinal stromal tumors using sunitinib treatment. Variables Number of patients (%) Tumor size <2cm 2 (3.5%) 2-5cm 6 (10.5%) >5cm 12 (21.1%) >10cm 37 (64.9%) Mitosis 5/50 HPF 17 (29.8%) >6-10/50 HPF 12 (21.1%) >10/50 HPF 22 (38.6%) Undetermined 6 (10.5%) Fletcher risk categories Very low risk 0 (0%) Low risk 3 (5.3%) Intermediate risk 4 (7.0%) High risk 50 (87.7%) FIGURE 2. Univariate analysis between the time of imatinib usage and overall survival. performed using the Cox proportional hazards model, and the only variables that were deemed statistically significant were included in the final Cox model. Multivariate p values were used to characterize the independence of these factors. The 95% confidence interval (CI) was used to quantify the relationship between survival time and each independent factor. All p values were twosided in the tests and p values less than 0.05 were considered to be statistically significant. RESULTS Clinical features Between January 2001 and April 2012, a total of 250 patients with GISTs were evaluated and a total of 57 who had failure of treatment with imatinib were included. Of these, 33 (57.9%) were male and 24 (42.1%) were female. The median age was 55 years (range; years) and the peak age was between 40 and 60. Seventy percent of the GIST patients were diagnosed as clinically symptomatic. The most common presenting symptoms were abdominal pain and non-specific symptoms due to an abdominal mass (54.3%). The tumors most commonly originated in the stomach (26.3%) and the small intestine (45.6%). Histologically, the majority of tumors were predominantly spindle-shaped (57.9%) and occasionally epitheloid (5.3%) in morphology, or a mixed type (17.5%). Positivity for CD117 was found in 98.2% of the tumors while 70.2% of them were CD34 positive. The diagnosis was made with platelet-derived growth factor receptor alpha (PDGFRA) mutation positivity in only one CD117-negative case. Forty-one patients (71.9%) presented with metastasis at diagnosis; 32 of the metastases sites were the liver (56.1%), 4 were in the peritoneum (7.0%), 1 each in the lymph nodes and the lung (1.8%), and 3 were in other sites (5.3%) (Table 1). The majority of the tumors were larger than 10cm (64.9%). Based on the size of the primary tumor, localization and the mitotic index, 3 (5.3%) patients were classified as low-risk, 4 (7.0%) as intermediate-risk and 50 (87.7%) as high-risk according to the NIH risk classification. There were no patients in the very-low-risk group (Table 2). Treatment outcomes Sunitinib (25-50mg/d) was given to 57 patients and all were followed after administration of sunitinib at regular intervals until death or until April Thirtyseven (64.9%) patients received 400mg/day imatinib, and 20 patients (35.1%) with progressive disease were administered mg/day imatinib as second-line treatment. Three patients (5.2%) were classified as intolerant to imatinib, while the remaining patients had progressive disease during imatinib treatment. Thirtyeight (66.7%) patients received imatinib for longer than 12 months, 13 (22.8%) patients received for 6-12 months and 6 (10.5%) patients for less than six months. Three (5.3%) patients achieved complete response while using sunitinib. Seventeen (29.8%) patients achieved PR, 21 (36.8%) patients achieved SD and 15 (26.3%) patients showed PD at the time of analysis according to RECIST. Overall, the clinical benefit of sunitinib was 73.7% as determined by the sum of CR, PR and SD. Treatment-related adverse events were reported in 78% of patients. Adverse events were generally mild to moderate in intensity and managed by dose reduction, dose interruption or standard supportive medical treatments. Hypothyroidism occurred in only one patient and only one patient discontinued sunitinib because of adverse events. The most common adverse events of any grade were anemia (48%) and fatigue (31%). The most common grade III side-effect was hand-foot syndrome (19%). At the median follow-up of 15.6 months (range; months), the median OS and PFS of the patients that received sunitinib were 23.9 months (95%CI: ) and 10.8 months (95%CI: ),

4 650 Hepato-Gastroenterology 60 (2013) Kefeli U, Buyukberber S, Akyol M, et al. TABLE 3. The univariate analysis between clinicopathological characteristics of the patient group, and OS and PFS. Variables PFS OS median 95%CI p median 95%CI p (months) (months) Age 0,621 0,956 <50 years 9.56 ( ) ( ) >50 years ( ) ( ) Gender 0,558 0,47 Men ( ) ( ) Women ( ) ( ) Tumor site 0,67 0,158 Stomach ( ) ( ) Small intestine ( ) ( ) Colon 7.92 ( ) ( ) Other sites ( ) ( ) Histopathology Spindle cell type ( ) ( ) Epitheloid 8.31 ( ) 9.56 ( ) Mixed type 9.19 ( ) (NA)* Tumor size 0,45 0,009 <2cm 9.19 (NA)* No event occurred 2-5cm ( ) ( ) >5cm 7.45 ( ) ( ) >10cm ( ) ( ) Mitosis 0,981 0,441 5/50 HPF ( ) ( ) >6-10/50 HPF ( ) ( ) >10/50 HPF ( ) ( ) Fletcher risk categories 0,397 0,959 Low risk 4.60 ( ) 4.60 (NA)* Intermediate risk 8.31 ( ) ( ) High risk ( ) ( ) Imatinib dosage mg ( ) ( ) mg ( ) ( ) The time of imatinib usage <6 months 2.38 ( ) 2.38 ( ) 6-12 months 8.50 ( ) ( ) > 12 months ( ) ( ) Response to sunitinib CR (NA)* (NA)* PR ( ) ( ) SD ( ) ( ) PD 6.54 ( ) 8.50 ( ) *Not available.

5 Sunitinib for Turkish patients with GISTs Hepato-Gastroenterology 60 (2013) 651 respectively. In univariate analysis, there were significant relationships between the time of imatinib usage (p<0.03), tumour size (p<0.01), response to sunitinib (p<0.05) and OS (Figures 1-3). There were also significant relationships between the time of imatinib usage (p<0.02), tumor size (p<0.05), histological type (p<0.05), response to sunitinib (p<0.01) and PFS. There were no associations between age, gender, mitotic count, risk category of tumor, imatinib dose, imatinib intolerance or failure, and PFS and OS (p>0.05). In multivariate analysis, there were significant associations between the time of imatinib usage (p<0.01), response to sunitinib (p<0.03) and OS. There were significant associations between the time of imatinib usage (p<0.01), tumour size (p<0.02), response to sunitinib (p<0.01) and PFS (Tables 3 and 4). DISCUSSION Approximately 50% of GIST patients eventually develop progression in 24 months after imatinib treatment and emerge as a challenge (29). Patients with advanced GIST who progress on or are intolerant to first-line imatinib therapy usually start second-line sunitinib malate therapy. A placebo-controlled phase III trial demonstrated significant improvement in time to progression in patients treated with sunitinib compared to those treated with placebo, as well as PFS and OS (7). Therefore, sunitinib was approved by the U.S. F.D.A as second-line therapy for patients with advanced GIST (30). In our study, sunitinib had a median OS of 23.9 and PFS of 10.8 months. Thus, this study confirms the improvement effect of sunitinib in patients with advanced GIST who experience imatinib failure or intolerance. Three patients enrolled into the study were classified as intolerant to imatinib, while the remaining patients faced with progression during imatinib treatment. In our study, the time of imatinib usage, tumour size and response to sunitinib significantly affected PFS and OS. Demetri et al. found no association between the time of imatinib treatment and survival (7). In our study, majority of the patients treated with sunitinib used imatinib for longer than 12 months. Of these, those who used imatinib for longer had improved OS and PFS than those who used it for a shorter time. There was no relationship between the dose of imatinib and OS and PFS (p>0.05). Also, there were no associations between imatinib intolerance, failure and OS and PFS (p>0.05). The current risk-group stratification according to Fletcher et al. (28) and another, recently suggested, GIST risk-group stratification system, takes the tumor site into account as well as tumor size and mitotic rate, dividing GISTs into probably benign, uncertain or low malignancy potential, and probably malignant (31). In our study, the majority of patients were classified as high-risk (84.2%) according to the NIH risk classification. This result is much higher than that reported by previous studies (32,33). Tumor size greater than 10cm had increased PFS but not OS compared to smaller tumors in the current study in contrast to these studies (32,33). There were no relationship between mitotic count, risk category and PFS and OS. These differences may be explained by the progressive nature of the GISTs in patients receiving sunitinib treatment and should be evaluated with further studies. In our study, the clinical benefit of sunitinib treatment was 73.7%. The majority (36.8%) of the patients achieved SD while 3 (5.3%) of the patients achieved TABLE 4. The multivariate analysis between clinopathological characteristics of the patient group and OS and PFS. Variables PFS OS Hazard Ratio 95%CI p Hazard Ratio 95%CI p Tumor size NS * Time of imatinib usage Response to sunitinib *Not significant. FIGURE 3. Univariate analysis between the tumor size and overall survival. complete response, and 17 (29.8%) of the patients achieved PR. This CR rate is higher than the CR rate in the US S0033 study which reported as 3% for 751 GIST patients (34). Chen et al. found this incidence rate as 8.7% in patients receiving sunitinib (18). Depending on the response rates achieved in our study and these studies, sunitinib-treatment can be accepted as clinically beneficial but the limited experience on response rates while using sunitinib treatment should be further evaluated with larger prospective series. Rutkowski et al. found that tumor genotype (kinase mutation) significantly affected PFS and OS (35). They found that patients with KIT exon 9 mutation or with wild-type genotype responded to sunitinib well in contrast to imatinib. However, Chen et al. found no association between KIT exon mutations and PFS and OS during sunitinib treatment (18). As a limitation to our study we could not determine the kinase mutations in our patients. In Turkey, it is not routine practice to determine kinase mutations. Kinase mutations might explain the differences in the longevity of the OS and response rates in our study if evaluated. Therefore, analysis of these mutations should strongly be done in further studies. Sunitinib treatment is associated with several adverse effects. Fatigue and hematological toxicity were the most common side-effects. They are generally mild and can be managed by dose modulation (36,37). The toxicity profile reported in our study is similar to

6 652 Hepato-Gastroenterology 60 (2013) Kefeli U, Buyukberber S, Akyol M, et al. that observed in other studies except hypothyroidism (7,18,36-37). The incidence of hypothyroidism was low and easily treated with thyroid replacement therapy. No serious treatment related hypertension was observed with sunitinib. There was only one treatment discontinuation and the patient was treated with another TKI. In summary, sunitinib is an active and effective agent with a reasonable side-effect profile in the treatment of Turkish patients with gastrointestinal stromal tumours that have progressed on or become intolerant of imatinib therapy. Many advanced Turkish GIST patients benefit from sunitinib with an overall survival of approximately two years. We found that the time of imatinib usage and response to sunitinib significantly were independent prognostic factors for PFS and OS. Future prospective studies of sunitinib in GIST should investigate these factors to correlate this clinical benefit. 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