Adjuvant imatinib therapy for gastrointestinal stromal tumors

Surgery is the standard of care for primary resectable gastrointestinal stromal tumors (GISTs), but half of surgically treated patients relapse. Imatinib (IM) has been shown to prolong recurrence-free survival after complete surgery and is now approved as adjuvant therapy (400 mg/day) for high-risk GIST patients. IM is well tolerated, with mild to moderate side effects observed. Whether adjuvant IM prolongs overall survival is under evaluation in two ongoing clinical trials.     

Adherence to imatinib therapy in patients with gastrointestinal stromal tumors

Imatinib mesylate, an oral tyrosine kinase inhibitor, is indicated for first-line treatment of patients with unresectable and/or metastatic gastrointestinal stromal tumors (GIST). Imatinib also is approved as adjuvant therapy for patients following resection of primary GIST. Despite the efficacy of imatinib for the treatment of patients with GIST, adherence to treatment can prove difficult.     

Surgical intervention for imatinib and sunitinib-resistant gastrointestinal stromal tumors

Imatinib mesylate is an effective treatment for recurrent or metastatic gastrointestinal stromal tumors (GISTs), but secondary resistance has been reported. The tyrosine kinase inhibitor sunitinib malate has shown efficacy in imatinib-resistant GISTs, and has been used as second-line therapy for recurrent or metastatic GISTs. However, it is often difficult to treat patients with imatinib- and sunitinib-resistant GISTs. In this report, we describe a case of surgically resected liver and peritoneal recurrences of GISTs that arose polyclonally and were resistant to imatinib and sunitinib. A 67-year-old man was referred to our hospital with multiple recurrent GISTs after failed imatinib treatment. Sunitinib was administered at 50 mg/day for 4 weeks with 2-week intervals between treatments. Some of the recurrent GISTs were sensitive, but others were resistant, and progressive disease was diagnosed. Extended left hepatectomy and peritoneal tumorectomy were performed. Histologically, tumors sensitive to sunitinib showed degenerative changes, while the resistant tumors consisted of KIT-positive, viable GIST cells. The primary mutation in all the tumors consisted of a deletion at nucleotides 555–560 with an E554D point mutation at exon 11 of the c-kit gene. The sunitinib-resistant liver and peritoneal tumors had different point mutations: T to G and T to A, respectively, although both resulted in an N822K amino acid alteration, indicating the polyclonal evolution of recurrent GISTs. Thus, if R0 resection is expected, surgical intervention under the control of imatinib or sunitinib should be considered for the control of metastatic or recurrent GISTs.     

伊马替尼治疗胃肠道间质瘤的继发性耐药机制

甲磺酸伊马替尼是一种高效的酪氨酸激酶抑制剂,在临床上用于进展期或手术不能切除胃肠道间质瘤(GIST)的患者.虽然取得了很好的疗效,但是容易产生耐药,耐药机制主要有原发性耐药和继发性耐药,其中继发性耐药成为近些年研究的焦点.通过对继发性耐药机制的研究,可探讨新的治疗策略.     

伊马替尼治疗胃肠道间质瘤的继发性耐药机制

甲磺酸伊马替尼是一种高效的酪氨酸激酶抑制剂,在临床上用于进展期或手术不能切除胃肠道间质瘤(GIST)的患者.虽然取得了很好的疗效,但是容易产生耐药,耐药机制主要有原发性耐药和继发性耐药,其中继发性耐药成为近些年研究的焦点.通过对继发性耐药机制的研究,可探讨新的治疗策略.     

Combining imatinib with surgery in gastrointestinal stromal tumors: rationale and ongoing trials

Gastrointestinal stromal tumor (GIST) has become a well-recognized pathologic entity defined by expression of the KIT protein and often associated with gain of function mutations of the c-KIT oncogene. Imatinib, a specific inhibitor of the aberrant KIT protein, is an approved, well-tolerated oral drug for the management of metastatic or inoperable GIST. Traditional radical surgery resection for locally advanced, recurrent, or metastatic GIST is associated with a poor outcome. The rationale for combining imatinib with surgery for GIST, either as an adjuvant agent in the situation of primary resection for patients at high risk or in the neoadjuvant setting for patients with locally advanced, recurrent, or metastatic disease, is compelling in the continuous effort to improve disease-free and overall survival. Several clinical trials are addressing these issues as well as timing of surgery, assessment of drug response, and the addition of surgical resection in the situation of focal progressive disease on imatinib. The results of these studies will be meaningful in future standard therapy consideration.     

Simultaneously occurring chronic myelogenous leukemia and gastrointestinal stromal tumors treated with imatinib

Imatinib mesylate (imatinib, STI571, Gleevec; Novartis Pharma) is an orally administered competitive inhibitor of BCR-ABL tyrosine kinase that has demonstrated significant efficacy in chronic myelogenous leukemia (CML). Imatinib is also a potent inhibitor of the receptor-type KIT tyrosine kinase with demonstrated benefits in KIT-expressing gastrointestinal stromal tumors (GISTs). This article presents the case of a patient with simultaneous occurrence of CML and GIST who was treated with the single agent imatinib. To our knowledge, this is the first report of simultaneous occurrence of these two malignancies and of the efficacy of imatinib in concurrent treatment of both neoplasms in a single patient.     

Systemic therapy for advanced gastrointestinal stromal tumors: beyond imatinib

Progression on first-line therapy with imatinib in gastrointestinal stromal tumors (GIST) is caused by either initial resistance or more often a secondary mutation in tyrosine kinases KIT or PDGFR. Therapies in development for imatinib-resistant GIST include agents that target KIT/PDGFR with greater potency or possess broader kinase inhibition profiles including VEGFR. To circumvent secondary mutations in KIT/PDGFR, inhibition of the downstream signaling in PI3K/Akt/mTOR pathway and enhanced degradation of KIT/PDGFR are also under investigation.     

胃间质瘤术前辅助伊马替尼治疗的临床意义

目的 胃肠间质瘤(Gastrointestinal stromal tumor,GIST)是胃肠道最常见的间叶来源性肿瘤,根治性手术是GIST获得治愈的唯一希望。为了提高手术根治性切除率,降低手术风险,提高生活质量,伊马替尼(IM)开始被尝试应用于GIST的术前治疗。方法 本研究回顾8例GIST术前辅助治疗后手术的诊疗经过。IM每日一次400mg口服,严密随访,评价疗效,并通过多学科讨论确定手术时机。用药时间12周~40周。对IM术前辅助治疗的临床疗效和安全性予以评价。结果 术前治疗部分缓解率62.5%。本组病例未出现不可耐受的不良反应。全部病例均获R₀切除,未出现术中肿瘤破裂。术后恢复顺利。结论 针对进展期胃部巨大GIST及近贲门区GIST,在多学科诊疗团队的监护下,术前辅助IM治疗安全有效,值得临床推广应用。     

Some lessons learned from imatinib mesylate clinical development in gastrointestinal stromal tumors

Imatinib mesylate is a molecular-targeted agent, shown to be effective in chronic myeloid leukemia and gastrointestinal stromal tumors (GIST). The latter may currently serve as a model on which speculating how the future of molecular-targeted therapy in solid tumors will be. So far, some lessons have been learnt. 1) Molecular-targeted therapy can be effective in the advanced disease setting, resulting in major tumor responses. 2) Patterns of tumor responses may be peculiar, radiologically and pathologically. 3) Anti-tumor activity may be highly predictable by assessing tumor molecular biology. 4) The methodology of clinical development of molecular-targeted agents may differ from standard chemotherapy in some respects, because, say, the preclinical rationale may be stronger, thus increasing the Bayesian prior probability of efficacy, or the optimal dose cannot be determined separately from the assessment of activity and efficacy. 5) Molecular-targeted agents will hardly remain "orphan drugs", if effective. 6) While an obvious impact on survival in the advanced disease setting has been clearly demonstrated, the biologic and clinical impact of molecular-targeted therapy still needs to be elucidated. Its eradicating capabilities, as well as the implications of secondary resistance, are to be understood. 7) Integrated, multimodality approaches, including surgery, may still be of value in the molecular-targeted therapy era.     

Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate.

Gastrointestinal stromal tumors (GIST) are characterized by a strong KIT receptor activation most often resulting from KIT mutations. In a smaller subgroup of tumors without KIT mutations, analogous activating mutations are found in the platelet-derived growth factor receptor alpha (PDGFRalpha) gene. Both PDGFRalpha and KIT receptors are targets of the tyrosine kinase inhibitor imatinib (Glivec) which has improved the treatment of advanced GISTs significantly. However, a subgroup of tumors show a secondary progress under therapy with imatinib after initial response. One possible mechanism of secondary resistance is the development of newly acquired KIT mutations. In the present study, we evaluated the frequency of such secondary KIT mutations in a series of GIST patients in which tumor tissue was resected under treatment. We examined one to seven different tumor areas in 32 cases (total of 104 samples) and found up to four newly acquired KIT mutations in 14 patients (43.8%). These were always located in exons encoding the first or second tyrosine kinase domain (exon 13, 14, or 17). Mutations were found only in a subset of samples analyzed from each case whereas others retained the wild-type sequence in the same region. There was never more than one new mutation in the same sample. Consistent with a secondary clonal evolution, the primary mutation was always detectable in all samples from each tumor. According to our results, the identification of newly acquired KIT mutations in addition to the primary mutation is dependent on the number of tissue samples analyzed and has high implications for further therapeutic strategies.     

Effect of angiosonography to monitor response during imatinib treatment in patients with metastatic gastrointestinal stromal tumors.

PURPOSE: Gastrointestinal stromal tumor (GIST) metastases are typically intra-abdominal and hypervascular. We assessed the effect of angiosonography with a second-generation contrast agent to monitor response during imatinib treatment in patients with metastatic KIT+ GIST. EXPERIMENTAL DESIGN: Ten consecutive patients with known advanced KIT+ GIST were investigated with angiosonography and computerized tomography (CT). We also monitored the serum levels of the major angiogenic growth factor, vascular endothelial growth factor. RESULTS: Angiosonography showed a reduction in tumor vascularization of liver metastases during imatinib treatment in all cases. We observed a reduction in tumor vascularization before a reduction in tumor size. The tumor perfusion appeared reduced in the central part of the liver metastases. With a median follow-up of 18 months (range 3-33), a reduction in tumor vascularization was initially observed in all patients, but progressive disease was documented in four patients following imatinib treatment. CT documented tumor response according to standardized criteria in six patients, stable disease in four, and progressive disease according to angiosonography. The reduction of tumor perfusion at angiosonography correlated with the pseudocystic appearance at CT. The "nodule(s) within a mass" pattern of recurrence occurred in two patients with no difference observed between angiosonography and CT. Early decreasing serum vascular endothelial growth factor levels were observed in the two cases with higher pretreatment levels. CONCLUSIONS: Imatinib could induce antiangiogenic and/or antivascular effects in GIST, and this effect could be easily monitored with angiosonography. Angiosonography might be a useful complement for monitoring the therapeutic effect of imatinib in these patients.     

Correlation of immunophenotype with progression-free survival in patients with gastrointestinal stromal tumors treated with imatinib mesylate

BACKGROUND: The therapy for gastrointestinal stromal tumor (GIST) has been revolutionized by imatinib mesylate (IM). It is unknown whether the levels of KIT expression or the presence of CD34, smooth muscle actin (SMA), desmin, or S-100 protein predicts patient outcome from IM therapy. In the current study, the prognostic effects for KIT and other proteins (CD34, SMA, desmin, S-100) were analyzed in a series of GISTs in which protein expression was evaluated by immunohistochemical analysis (IHC). METHODS: The cases of 106 patients with GIST who were uniformly treated with IM at the study institution between December 15, 2000, and January 13, 2002 were evaluated retrospectively. The association between KIT intensity, CD34, desmin, SMA, S-100 protein, and progression-free survival (PFS) was studied. Kaplan-Meier analysis and the Cox proportional hazards regression model were used for statistical analysis. RESULTS: The majority of tumors arose from the stomach (37%), small intestine (35%), and colorectum (14%). KIT expression as determined by IHC was categorized as weak (10%), intermediate (32%), or strong (58%). Patient tumors expressed CD34 (75%), SMA (56%), desmin (1%), and S-100 protein (32%). Patients whose GIST had weak, intermediate, or strong KIT expression were found to have an 18-month PFS rate of 80%, 84%, and 69%, respectively (P = .30). The presence or absence of CD34, SMA, desmin, or S-100 protein did not appear to correlate with PFS after IM. CONCLUSIONS: Patients with the appropriate clinical presentation and KIT-positive GIST tumors appear to benefit from IM independent of the level of KIT or the expression of CD34, SMA, desmin, or S-100 protein by IHC.     

Imaging gastrointestinal stromal tumors.

BACKGROUND: Because of the recent reclassification of mesenchymal tumors, which was based on a better understanding of the genetics and immunophenotype of gastrointestinal stromal tumors (GISTs), only a limited number of studies have described the radiologic appearance of GISTs. METHODS: This study reviews the imaging characteristics of GISTs, with an emphasis on differentiating benign and malignant tumors using positron emission tomography (PET), computed tomography (CT), and magnetic resonance imaging (MRI). We reviewed the data from 53 cases of GISTs treated at our institute. The imaging studies from these cases, which were recorded at our institute from January 1998 through June 2003, included PET, CT, and MRI. RESULTS: Of the 53 GIST cases, stomach and small bowel tumors accounted for 80% of the tumors. Malignant lesions were larger and more heterogeneous, had ulcerations, and were PET positive. Peritoneal and liver metastases were most common. CONCLUSIONS: PET, CT, and MRI appear to be useful in differentiating nonmetastasizing from malignant GISTs.     

甲磺酸伊马替尼治疗胃肠间质瘤毒副作用的深化研究*

目的　进一步观察甲磺酸伊马替尼治疗胃肠间质瘤（ＧＩＳＴ）患者的毒副反应。方法　入组１２８例患者,均口服甲磺酸伊马替尼剂量４００ｍｇ／天,病情进展患者部分加量至６００ｍｇ／天。自服药起观察毒副反应,直至患者死亡或随访结束。结果　甲磺酸伊马替尼毒副反应多发生于治疗的最初１年内,大多数长期服药患者的毒副反应发生率及严重程度增加不显著。常见毒副反应多为１～２级,高剂量组毒副反应未见明显增加。新观察到的毒副反应包括记忆力下降、语言迟缓、阴囊水肿、指甲凸凹不平、皮下瘀斑、肾病综合征样表现,未出现消化道大出血及肿瘤溶解综合征。原发部位、剂量水平、有无肝转移对毒副反应的发生率无显著影响（Ｐ＞０.０５）;性别和年龄对毒副反应的发生率有显著影响（Ｐ＜０.０５）。结论　甲磺酸伊马替尼毒副反应轻微,患者耐受性较好,但药物说明书和文献未提及的毒副反应尤其值得关注。     

Pleomorphic phenotypes of gastrointestinal stromal tumors at metastatic sites with or without imatinib treatment

Secondary resistance of gastrointestinal stromal tumors (GISTs) to tyrosine kinase inhibitors occurs after several years’ administration. However, the mechanism of resistance has not been fully clarified. In this study, we analyzed the genotypes and the histologic and immunohistochemical phenotypes of metastatic GISTs with and without imatinib treatment, and clarified the pleomorphic nature of metastatic GISTs. We examined 31 autopsy cases in which the patients died of multiple metastases of GISTs, and two surgically resected specimens with and without imatinib treatment. A total of 152 primary and metastatic lesions in 33 cases of GISTs were examined for histologic and immunohistochemical expression of KIT and CD34. We analyzed the expression of other receptor tyrosine kinases (RTKs) in KIT‐negative lesions, including human EGFR‐related 2 (HER2), epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (MET), platelet‐derived growth factor receptor‐α (PDGFRA), and platelet‐derived growth factor receptor‐β (PDGFRB). Fifteen lesions in seven cases (9.9%) lacked KIT expression, and 74 (49%) in 22 cases lacked CD34 expression. Eight KIT‐negative lesions in five cases expressed PDGFRB, one of which also expressed EGFR, and three lesions in one case expressed MET. Results for the other RTKs were negative. Missense point mutations at PDGFRB gene exon 12 were detected in one PDGFRB‐positive case. Our results indicate that histomorphology, immunohistochemical phenotypes, and genotypes of metastatic GISTs vary among lesions, even in cases without imatinib treatment. A KIT‐independent mechanism, such as activation of other RTKs, might participate in the proliferation of late‐stage GISTs and might be a cause of secondary imatinib resistance. (Cancer Sci 2010; 101: 1270–1278)     

Phase I study of panobinostat and imatinib in patients with treatment-refractory metastatic gastrointestinal stromal tumors

Background:

Panobinostat, a pan-deacetylase inhibitor, overcomes imatinib resistance in preclinical models of gastrointestinal stromal tumours (GIST). Here we determined the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of panobinostat in combination with imatinib (IM) for treatment of patients with refractory GIST.

Methods:

Following a 7-day run-in phase of IM (400 mg per day), escalating doses of panobinostat were added following a ‘3 plus 3'' design. Twelve heavily pretreated GIST patients were enrolled in two dose levels.

Results:

Most common adverse events were thrombocytopenia, anaemia, fatigue, creatinine elevation, nausea, emesis and diarrhoea. Twenty micrograms of panobinostat and 400 mg IM were declared the MTD. Pharmacologically active concentrations of panobinostat and IM were achieved as evidenced by histone H3 acetylation in blood mononuclear cells in vivo and inhibition of the IM-resistant KIT (D816) mutation in vitro. In FDG-PET-CT scans after IM run-in and following 3 weeks panobinostat treatment, 1 out of 11 evaluable patients showed a metabolic partial response, 7 patients were metabolically stable and 3 patients progressed. Longest treatment duration was 17 weeks (median 6).

Conclusion:

Panobinostat and IM can be administered at doses achieving target inhibition in vivo. Further clinical exploration of patients with treatment-refractory GIST is warranted. Correlative studies in this trial may help to optimise dosing schedules in GIST.