Imatinib Escalation Or Sunitinib Treatment After First-Line Imatinib in Metastatic Gastrointestinal Stromal Tumor Patients

ANTICANCER RESEARCH 34: 5029-5036 (2014)

Imatinib Escalation or Sunitinib Treatment After First-line Imatinib in Metastatic Gastrointestinal Stromal Tumor Patients

CHIH-CHIEH HSU1, CHIAO-EN WU2, JEN-SHI CHEN2, JENG-HWEI TSENG3, KUN-CHUN CHIANG4, YU-YIN LIU1, CHUN-YI TSAI1, CHI-TUNG CHENG1, TSUNG-WEN CHEN1, YI-YIN JAN1, TA-SEN YEH1, YEN-YANG CHEN5 and CHUN-NAN YEH1

1Gastrointestinal Stromal Tumor Team, Department of Surgery, Chang Gung Memorial Hospital, Linkou, Taiwan, R.O.C.; 2Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou, Taiwan, R.O.C.; 3Department of Radiology, Chang Gung Memorial Hospital, Linkou, Taiwan, R.O.C.; 4Department of Surgery, Chang Gung Memorial Hospital, Keelung, Taiwan, R.O.C.; 5Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Kaohsiung, Taiwan, R.O.C.

Abstract. Aim: Imatinib mesylate (IM) is effective in p=0.161) compared to the IM-escalation group. Patients in metastatic gastrointestinal stromal tumor (GIST) patients; both groups with responses and stable disease (SD), and IM however, disease progression eventually occurs due to IM escalation patients who underwent surgery and who had KIT resistance or intolerance. Treatment options include IM exon 9 mutations, had favorable PFS. The most common non- escalation or a direct shift to sunitinib, but comparison of these hematological adverse events were edema in the IM escalation strategies is required. Patients and Methods: This study group and hand-foot syndrome and hypertension in the included 91 out of 214 metastatic GIST patients treated with sunitinib group. Conclusion: Comparable results were achieved IM, who experienced progression or intolerance between by IM escalation and sunitinib treatment. Physicians should August 2001 and December 2012 at the Chang Gung consider kinase mutations and specific adverse effects when Memorial Hospital. Treatment efficacy and safety profiles were choosing between these treatments. retrospectively compared between groups of patients who either received escalated IM or were directly switched to sunitinib. Gastrointestinal stromal tumors (GISTs) are the most Results: There were no significant differences in age, gender, common mesenchymal neoplasms of the gastrointestinal second-line treatment causes or gene mutations in the IM tract. In Taiwan, the annual incidence rate of GISTs is 13.74 escalation group (N=63) versus the sunitinib group (N=28). cases per 1 million people (1). Before 2001, there was no The 2 groups had similar progression-free survival (PFS, effective systemic treatment for GISTs (2). The discovery p=0.316) and overall survival (OS, p=0.599). Patients without that constitutively activated KIT and platelet-derived growth primary KIT exon 9 mutations and who treated with sunitinib factor receptor-alpha (PDGFRA) signaling were associated had significantly better PFS (14.3 vs. 6.2 months, p=0.037) with GIST oncogenesis provided justification for testing and a trend toward better OS (not reached vs. 16.4 months, small-molecule tyrosine kinase inhibitors in this tumor type (3). In malignant cells, imatinib mesylate (IM) was found to selectively inhibit not only the intracellular Abelson (ABL) Correspondence to: Yen-Yang Chen, MD, Division of Hematology- kinase and the chronic myeloid leukemia chimeric Oncology, Department of Internal Medicine, Chang Gung Memorial breakpoint cluster region (BCR)-ABL fusion oncoprotein Hospital, Kaohsiung Medical Center, Taiwan. Tel: +886 77317123, (4), but also KIT and PDGFR (5-7). IM treatment has led to Fax: +886 77322402, e-mail: [email protected] or Chun-Nan promising clinical results in advanced GIST patients (8-10). Yeh, MD, Department of Surgery, Chang Gung Memorial Hospital, In our previous study, IM significantly impacted the survival Chang Gung Memorial University, 5 Fu-Hsing Street, Kwei-Shan of 171 Taiwanese patients with advanced GISTs; the median Taoyuan, Taiwan. Tel: +886 33281200, Fax: +886 33285818, e-mail: [email protected] progression-free survival (PFS) and overall survival (OS) of patients with metastatic GISTs were 37.6 and 71.0 months, Key Words: Gastrointestinal stromal tumor, imatinib mesylate, respectively (11). Although IM demonstrates substantial second-line therapy, sunitinib. efficacy in most patients with metastatic GISTs, disease

0250-7005/2014 $2.00+.40 5029 ANTICANCER RESEARCH 34: 5029-5036 (2014) progression eventually occurs due to IM resistance. This escalation group, N=63) or a direct switch to sunitinib administration poses a treatment challenge. Several studies have identified (sunitinib group, N=28). National health insurance in Taiwan paid the major mechanisms underlying acquired IM resistance in for these treatments. To assess tumor response, standard computed tomography (CT) was performed every 3 to 6 months, according to GIST patients. These include mutations in the KIT or the judgment of the physician. Responses were assessed based on PDGFRA kinase domains, KIT or PDGFRA gene the RECIST criteria (20). PFS was defined as the period of time amplification and activation of alternative kinases (12). from administration of escalated IM or sunitinib to documented Based on the results of a phase III study, the standard-of- progression. OS was defined as the period of time from care for GIST patients who experience disease progression administration of escalated IM or sunitinib to death from any cause. or intolerance to IM treatment is to switch to sunitinib The last follow-up was in March 2013. Surgical excision could be treatment (13). Our previous study also supported this performed at our hospital in selected patients with controlled or limited progressive disease (PD). Toxic effects were recorded in strategy in patients who experienced disease progression accordance with the National Cancer Institute Common Toxicity after IM treatment (14). IM escalation (15) is an alternative Criteria for Adverse Events, version 3. The local institutional review option that is supported by the analyses of a subset of board of CGMH approved this study and written informed consent patients in two phase III studies (16, 17). However, the for drug administration and analysis of tumor-associated genetic MetaGIST study demonstrated that high-dose IM had only a alterations was obtained from each patient. small PFS benefit in patients with KIT exon 9 mutations (18). The partial response (PR) and stable disease (SD) rates Analysis of KIT and PDGFRA mutations. Analysis of KIT and PDGFRA mutations was performed in 46 of 63 patients in the IM amongst a group of 133 GIST patients in the European escalation group and 21 of 28 patients in the sunitinib group. Organization for Research and Treatment of Cancer Sections were prepared from formalin-fixed, paraffin-embedded, (EORTC) 62005 trial were 2% and 27%, respectively, after pre-treated specimens that were trimmed to increase the proportion dose escalation to 800 mg/day. The median PFS of these of tumor cells. Polymerase chain reaction (PCR) amplification of patients was 81 days (16). Another trial, S0033, reported that genomic DNA was performed for KIT and PDGFRA and the a group of 77 GIST patients had a PR rate of 7% and a SD amplified products were analyzed for mutations as previously rate of 32% after dose escalation to 800 mg/day. The median described (21). PFS time for these 77 patients was 4 months (17). Statistical analysis. All data are presented as percentages or means Therefore, treatment options include IM escalation or with standard deviations. Numerical data were compared using switching to sunitinib administration, possibly combined independent two-sample t-tests. Pearson’s chi-square test and with a local ablative therapy such as surgery (19), Fisher’s exact test were used for the analysis of nominal variables. radiofrequency ablation, radiotherapy or trans-arterial Time-to-event analyses were performed using the Kaplan-Meier embolization. However, no studies have compared the method. The following potential prognostic variables were effectiveness and safety of IM dose escalation versus directly investigated for their impact on long-term outcomes: mutational status (including exons 9 and 11), response (complete response switching to sunitinib. Therefore, the present study (CR)+ PR), clinical benefit (CR+PR+SD) and surgery. All statistical retrospectively compared the clinical outcomes and adverse analyses were performed using the SPSS software, version 16.0 events of 91 advanced GIST patients with disease (SPSS Inc., Chicago, IL, USA). All p-values <0.05 were considered progression treated with IM escalation or a direct switch to statistically significant. sunitinib administration. Results Materials and Methods Clinical features. Table I summarizes the clinicopathological Patients, treatments and evaluations. The GIST Team at Chang-Gung characteristics of 91 metastatic GIST patients (divided into Memorial Hospital (CGMH) prospectively collected data about the IM escalation and sunitinib groups) with disease progression clinicopathological features, treatment courses and clinical outcomes at, or intolerance of 400 mg/day IM. There were 63 patients of patients with metastatic GISTs who were treated in this in the IM escalation group and 28 patients in the sunitinib Institution. This study enrolled 214 patients with histologically- confirmed metastatic GISTs with measurable lesions (as per the group. There were no significant differences in age, gender, Response Evaluation Criteria in Solid Tumors (RECIST) guidelines) second-line treatment causes and gene mutations between the (20) and expression of CD117 (c-KIT) antigen between August 2001 groups. In the IM escalation group, 21 patients received and 2012. Other eligibility criteria included an Eastern Cooperative 600 mg/day IM and 42 patients received 800 mg/day IM. Oncology Group performance score of 3 or less and adequate hematological, renal and hepatic function. The patients received 400 Treatment outcomes. None of the patients in the IM escalation mg IM in the form of 4 capsules of 100 mg each per day with food. group (N=63), achieved a CR, but 16 patients (25.4%) Patients underwent regular physical examinations and evaluations of performance status, body weight, complete blood count and serum achieved a PR and 20 patients (31.7%) had SD resulting in a biochemistry. In total, 91 out of 214 patients with disease progression response rate ((RR)=CR+PR) of 31.7% and a tumor control were treated with IM escalated to between 600 and 800 mg daily (IM rate ((TCR)=CR+PR+SD) of 57.1%. In the sunitinib group

5030 Hsu et al: Imatinib-escalation and Sunitinib for Progressive GIST

Table I. Characteristics of 91 metastatic GIST patients. Table II. Clinical responses and outcomes of IM escalation and sunitinib treatment in 91 patients with progressive GIST. IM escalation Sunitinib p-Value (N=63) (N=28) IM escalation Sunitinib p-Value (N=63) (N=28) Age, median (range, years) 57 (24-83) 59 (15-91) 0.646 Gender (Male: Female) 42:21 15:13 0.233 Response 0.289 Indications for TKI use CR 0 1 (3.6%) Progression after IM 400 mg/day PR 16 (25.4%) 10 (35.7%) (600 mg:800 mg escalated IM) 63 (20:43) 25 0.027 SD 20 (31.7%) 6 (21.4%) IM intolerance 0 3 PD 27 (42.9%) 11 (39.3%) KIT/PDGFRA mutations 0.436 Response rate (CR+PR) 16 (25.4%) 11 (39.3%) 0.209 KIT exon 9 11 3 Tumor control rate KIT exon 11 29 13 (CR+PR+SD) 36 (57.1%) 17 (60.7%) 0.753 Others 6 5 Median PFS 7.4 months 9.9 months 0.316 Median OS 30.0 months 35.5 months 0.599 GIST, Gastrointestinal stromal tumor; IM, imatinib mesylate; PDGFRA, platelet-derived growth factor receptor alpha; TKI, tyrosine kinase CR, Complete response; GIST, gastrointestinal stromal tumor; IM, inhibitor. imatinib mesylate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease.

(N=28), 1 patient (3.6%) achieved a CR, 10 patients (35.7%) achieved a PR and 6 patients (21.4%) had SD, resulting in a group, patients who underwent surgery had better PFS than RR of 39.3% and a TCR of 60.7% (Table II). patients who did not (15.3 vs. 6.4 months, p=0.006, Figure There were no significant differences between the IM 5). The number of patients in the sunitinib groups who escalation group and the sunitinib group with respect to PFS underwent surgery was limited, thus, outcomes with or (7.4 vs. 9.9 months, p=0.316) and OS (30.0 vs. 35.5 months, without surgery were not analyzed in these groups. p=0.599) (Figure 1). Adverse events. The most common adverse events were Outcomes of both groups with different gene mutations. We hematological. More than 60% of patients in both groups performed sub-group analysis to discern whether there was experienced anemia of any grade. Patients in the sunitinib evidence that the choice of second-line treatment should take group more frequently experienced leukopenia, neutropenia account of different gene mutations. In patients with KIT exon and thrombocytopenia of any grade compared to patients in 9 mutations, the IM escalation group had a trend toward a the IM escalation group. Grade 3 and 4 hematological adverse favorable PFS (12.3 vs. 3.6 months, p=0.421, Figure 2A) and effects were uncommon, with the exception of anemia. OS (41.9 vs. 15.2 months, p=0.553, Figure 2B) compared to The most common non-hematological adverse events of the sunitinib group. In contrast, the sunitinib group had any grade in the IM escalation group were edema (23.8%) significantly better PFS (14.3 vs. 6.2 months, p=0.037, Figure and bleeding (22.2%), while patients in the sunitinib group 2C) and a trend toward better OS (not reached vs. 16.4 mainly experienced diarrhea (50%), hand-foot syndrome months, p=0.161, Figure 2D) compared to the IM escalation (HFS, 50%) and hypertension (50%). Most non- group in patients without KIT exon 9 mutations. hematological adverse events were mild and manageable, with the most common grade 3 or 4 adverse event being HFS Prognostic factors for PFS. We performed survival analyses in 25% of the patients in the sunitinib group. Detailed to determine whether factors such as tumor response and adverse events are showed in Table III. surgery were prognostic factors for PFS in either group. In the IM escalation group, patients with a PR had significantly Discussion better PFS compared to patients with SD and PD (40.1 vs. 9.0 vs. 2.2 months, p<0.01, Figure 3A). Similarly, in the When patients with metastatic GIST experience disease sunitinib group, patients with a response (either CR or PR) progression or therapy intolerance after 400 mg/day IM had significantly better PFS than patients with SD and PD treatment, the options for systemic treatment include IM (not reached vs. 9.9 vs. 3.1 months, p<0.01, Figure 3B). escalation or switching to sunitinib administration. This Patients with KIT exon 9 mutations had better PFS study found that groups of patients who received escalated compared to patients with exon 11 mutations (12.3 vs. 6.4 IM or sunitinib did not have significant differences in RR, months, p=0.043, Figure 4A) in the IM escalation group, but TCR, PFS or OS. The IM escalation group had a trend not in the sunitinib group (Figure 4B). In the IM escalation toward favorable PFS and OS in patients with KIT exon 9

5031 ANTICANCER RESEARCH 34: 5029-5036 (2014) mutations, while the sunitinib group had a significantly longer PFS and a trend towards a favorable OS in patients without KIT exon 9 mutations. Patients with responses and clinical benefits in both groups, as well as patients who underwent surgery or who had KIT exon 9 mutations in the IM escalation group, all had a longer PFS on average. In the current study, the median PFS of the 63 patients who received escalated IM was 7.4 months. This result was better than outcomes reported by 2 previous trials (81 days in EORTC 62005 and 4 months in S0033) (16, 17). A likely explanation for this is that 17 of the 63 patients (27.0%) in the IM escalation group in the current study underwent tumor resection, which could prolong PFS (19). Attention to side-effect management and improvement of patient compliance could also explain this difference. Patients treated with sunitinib and who had KIT exon 11 mutations and other mutations had a longer PFS and a trend toward better OS compared to patients with these same mutations in the IM escalation group. In contrast, patients with KIT exon 9 mutations in the IM escalation group might have a longer PFS compared to those in the sunitinib group. Although we did not perform analysis of secondary mutations, Heinrich et al. (12) reported that GISTs with primary KIT exon 11 mutations had significantly more secondary kinase mutations than GISTs with KIT exon 9 mutations (73% vs. 19%, p<0.01). A higher rate of secondary KIT exon 13 or 14 mutations was observed in the patients with primary KIT exon 11 mutations, and these patients had on average a longer PFS when treated with sunitinib. This could explain why, in our study, sunitinib led to a favorable PFS in patients with KIT exon 11 mutations and other mutations but not in patients with exon 9 mutations. Sunitinib also had antitumor activity in patients Figure 1. Patients with disease progression or IM intolerance treated with KIT exon 9 mutations, although the patients included in with either IM escalation (N=63) or sunitinib (N=28) had similar PFS (A) and OS (B). the current study were relatively few. Gene mutation status might help physicians decide between IM escalation and sunitinib as a second-line therapy. Changes in exon mutation status contributed to In contrast to the results of previous reports (9, 11), our differences in the PFS of patients in the IM escalation study showed that patients treated with IM escalation or group. Similarly to Heinrich’s study (21), patients in the IM second-line sunitinib who had an objective response achieved escalation-group in the current study with KIT exon 9 better PFS than patients with SD. Both the B2222 study (9) mutations had significantly longer PFS than those with KIT and our previous study (11) found that patients with exon 11 mutations (median PFS=12.3 versus 6.4 months; objective responses had similar survival outcomes to those p=0.04). This observation is also supported by the with SD after first-line IM treatment. This discordance is MetaGIST study, which demonstrated that patients with KIT probably due to the different settings and situations of these oncoproteins encoded by exon 9 should be treated with studies. This work was a second-line study that compared 2 escalated IM doses (18). different therapeutic strategies. The patients in this study had Survival analysis showed no differences in PFS among a greater tumor burden, suffered from more tumor-related GIST patients with different exon mutation statuses treated complications and were treated with more cytotoxic agents with sunitinib. Henrich et al. (12) reported that sunitinib compared to patients receiving first-line 400 mg/day IM. treatment could lead to significantly longer PFS, or even OS, Therefore, the patients in the current study had different in patients with primary KIT exon 9 mutations or wild-type responses and distinct outcomes compared to patients in the genotypes compared to patients with KIT exon 11 mutations. previous studies. Contrary to Henrich’s report, the current study found no

5032 Hsu et al: Imatinib-escalation and Sunitinib for Progressive GIST

Figure 2. PFS (A, C) and OS (B, D) in patients with KIT exon 9 mutations (A, B) and other mutations (C, D) who were treated with either IM escalation or sunitinib.

differences in the PFS of patients with primary KIT exon 9 The analysis of differences in adverse events between mutations, wild-type genotypes or KIT exon 11 mutations. metastatic GIST patients receiving escalated imatinib versus However, this study included a limited number of cases and sunitinib may give physicians more information about thus lacked the statistical power needed to draw a selection of the second-line treatment regimen. This study conclusion, especially in the sunitinib group. found that the two therapeutic regimens had distinct features IM escalation and surgery is a potential combination in terms of adverse events. Similar to a previous large-scale treatment modality for patients with GIST progression. We phase III trial, the current study found that anemia was the previously demonstrated that surgery could prolong PFS of most common hematological adverse event for both treatment some patients with progressive GIST, especially those with regimens. Out of the non-hematological adverse events, edema limited progression (LP) (19). Therefore, surgery may be was the most common adverse event of any grade in the IM- viewed as a salvage option and used in combination with escalation group. This finding was consistent with previous other local ablative procedures to prolong PFS of patients studies. In the sunitinib group, HFS and hypertension were the with LP. Surgery can also enable delayed use of next- most common adverse events of any grade, each occurring in generation drugs and, in the current study, it significantly 50% of the patients of this group. HFS was the most common improved the PFS of GIST patients receiving escalated IM. grade 3 adverse event in our study, which is a different finding The value of surgery for patients receiving sunitinib from studies involving Western GIST patients. The reason for treatment is still debated, so further investigation of the role this difference in the incidence of HFS is still unknown and of surgery in these patients is warranted (22). justifies further study. Potential explanations for this

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Figure 3. PFS of patients treated with IM escalation (A) or sunitinib (B) Figure 4. PFS of patients treated with IM escalation (A) or sunitinib (B) with respect to treatment response. with respect to mutation status. observation include differences in drug metabolism or pharmacokinetics between different ethnic groups (23). Furthermore, Lee et al. (24) reported a higher frequency of HFS in Asian patients treated at Asian sites compared to Asian patients treated at non-Asian sites in a study involving more than 4,000 non-Asian renal cell carcinoma patients treated with sunitinib. Recent evidence suggests that heterogeneity in toxicity and efficacy among patients receiving anti-vascular endothelial growth factor therapy can be partially explained by genomic variability, including single nucleotide polymorphisms. This provides a possible explanation for the differences in adverse event frequencies between Asian and non-Asian patients in this analysis (24). In contrast to the previous report, the present study found that hypertension was the most common adverse event in patients treated with sunitinib. This study did confirm the previous finding that hypertension develops in 11% or more Figure 5. PFS of patients treated with IM escalation with or without (28% continuous dosing) of GIST patients treated with surgery.

5034 Hsu et al: Imatinib-escalation and Sunitinib for Progressive GIST

Table III. Adverse events in the IM escalation and sunitinib groups.

IM escalation (N=63) Sunitinib (N=28)

All grades Grade 3/4 All grades Grade 3/4

Hematological Anemia 38 (64.4%) 22 (40.7%) 19 (67.9%) 8 (26.9%) Leukopenia 17 (27%) 0 17 (60.7%) 2 (7.1%) Neutropenia 17 (27%) 0 16 (57.1%) 2 (7.1%) Thrombocytopenia 11 (17.5%) 1 (1.6%) 16 (57.1%) 4 (14.2%) Non-hematological Edema 15 (23.8%) 2 (3.2%) 1 (3.6%) 0 Anorexia 7 (11.1%) 2 (3.2%) 4 (14.2%) 1 (3.8%) Vomiting 9 (14.3%) 1 (1.6%) 3 (10.7%) 0 Diarrhea 12 (19.0%) 3 (4.8%) 14 (50.0%) 1 (3.6%) Fatigue 5 (7.9%) 0 3 (10.7%) 0 Dermatitis 4 (6.3%) 0 4 (14.2%) Yellow skin 0 0 3 (10.7%) 0 HFS 0 0 14 (50.0%) 7 (25.0%) Neuropathy 1 (1.6%) 0 0 0 Mucositis 0 0 3 (10.7%) 0 Bleeding 14 (22.2%) 9 (14.3%) 3 (10.7%) 1 (3.6%) AST/ALT 3 (4.8%) 1 (1.6%) 3 (10.7%) 1 (3.6%) Infection 8 (12.7%) 7 (11.1%) 3 (10.7%) 1 (3.6%) Hypertension 1 (1.6%) 0 14 (50.0%) 1 (3.6%) Hypothyroidism 0 0 2 (7.1%)0

AST/ALT, Aspartate aminotransferase/alanine aminotransferase; HFS, hand-foot syndrome; IM, imatinib mesylate.

sunitinib (Grade 3/4, 3%) (25, 26), whereas imatinib Author Contribution treatment was not associated with high blood pressure. Hypertension is probably a class effect of vascular These Authors contributed equally to this study (Chih-Chieh Hsu endothelial growth factor receptor inhibitors, which increase and Chiao-En Wu) hypertension via several mechanisms, including alteration of endothelial cell nitrous oxide metabolism (25). Acknowledgements Our study indicates that comparable results were seen in patients treated with IM escalation or a direct switch to We appreciate the financial support provided by Novartis Co., Ltd. sunitinib after IM failure. However, there were limitations (Taiwan) for genetic analysis. inherent to this study. This was the retrospective nature of the study where patient selection could not be randomized. References Although all data were collected prospectively and the characteristics of both groups were similar and 1 Tzen CY, Wang JH, Huang YJ , Wang MN, Lin PC, Lai GL and homogeneous, selection and recall bias could not be Wu CY: Incidence of gastrointestinal stromal tumor: a retrospective study based on immunohistochemical and completely prevented. Furthermore, the number of patients mutational analyses. Dig Dis Sci 52: 792-797, 2007. in the sunitinib group was too small to yield strong evidence 2 Blanke CD and Corless CL: State-of-the art therapy for and conclusions. To overcome these limitations, our results gastrointestinal stromal tumors. Cancer Invest 23: 274-280, should be confirmed by future prospective randomized 2005. controlled trials. 3 Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, In conclusion, IM escalation and a direct switch to Ishiguro S, Kawano K, Hanada M, Kurata A, Takeda M, sunitinib after IM failure yielded comparable results. Muhammad Tunio G, Matsuzawa Y, Kanakura Y, Shinomura Y and Kitamura Y: Gain-of-function mutations of c-kit in human Physicians can choose either treatment after IM failure, and gastrointestinal stromal tumors. Science 279: 577-580, 1998. they should consider the specific kinase mutations and 4 Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, distinct adverse events associated with the two treatments Fanning S, Zimmermann J and Lydon NB: Effects of a selective when deciding which to use. Prospective randomized trials inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl are still required to validate these findings. positive cells. Nat Med 2: 561-566, 1996.

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I, Tassell V, Cohen DP and Demetri GD: Clinical evaluation of 14 Chen YY, Yeh CN, Cheng CT, Chen TW, Rau KM, Jan YY and continuous daily dosing of sunitinib malate in patients with Chen MF: Sunitinib for Taiwanese patients with gastrointestinal advanced gastrointestinal stromal tumour after imatinib failure. stromal tumor after imatinib treatment failure or intolerance. Eur J Cancer 45: 1959-1968, 2009. World J Gastroenterol 17: 2113-2119, 2011. 15 Group. TEESNW: Gastrointestinal stromal tumors: ESMO Received June 5, 2014 Clinical Practice Guidelines for diagnosis, treatment and follow- Revised July 8, 2014 up. Ann Oncol 23(Suppl 7): vii49-55, 2012. Accepted July 9, 2014

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