Imatinib rechallenge in patients with advanced gastrointestinal stromal tumors

BackgroundImatinib is the standard of care for patients with advanced gastrointestinal stromal tumors (GIST).DesignThis article reviews recent data on the impact of imatinib treatment interruption and subsequent rechallenge in patients with advanced GIST.ResultsThe randomized BFR14 trial showed that (i) interruption of imatinib after 1, 3, or 5 years of treatment in patients with nonprogressive GIST was associated with a high risk of progression even in patients with a complete response; (ii) rechallenge with imatinib restored tumor control in most patients, but the tumor response seldom reached that before treatment interruption; (iii) patients receiving continuous imatinib had a high rate of prolonged tumor control, which increased with longer imatinib treatment. The findings in the metastatic setting have important implications regarding the duration of adjuvant imatinib in GIST.ConclusionsDiscontinuation of imatinib in responding patients with advanced GIST is associated with a high risk of progression and is therefore not recommended. Although rechallenge is a strategy for treating patients who relapse after stopping imatinib, suboptimal tumor response indicates that continuous kinase suppression is necessary to achieve the best clinical outcome. Three-year adjuvant imatinib is recommended for patients with resected ‘high-risk’ GIST; however, a longer duration may provide additional benefits.     

甲磺酸伊马替尼治疗复发或转移性胃肠间质瘤

目的 评价甲磺酸伊马替尼进行术前辅助治疗及治疗术后复发和(或)转移性胃肠间质瘤(GISTs)的临床疗效及不良反应。方法 经病理组织学证实的GISTs 30例,其中29例CD117阳性。行术前辅助化疗2例,术后复发或已转移并失去手术机会者28例,给予甲磺酸伊马替尼200～600mg／d口服。结果 30例患者中,3例失访,25例可评价客观疗效。部分缓解(PR)15例,占60．0％;病情稳定(SD)5例,占20．0％;疾病进展(PD)5例,占20．0％。患者获益(CR PR SD)率80．0％,获益者中位无进展生存期(TTP)超过13个月。随访1年以上者22例,1年生存率为86．4％。27例可评价不良反应,其中轻度水肿23例(85.2％),Ⅰ、Ⅱ度白细胞减少11例(40．7％),Ⅰ、Ⅱ度乏力8例(29．6％),轻度腹痛4例(14．8％),Ⅰ、Ⅱ度恶心呕吐5例(18．5％),轻度皮疹3例(11．1％),出血2例(7．4％)。结论 甲磺酸伊马替尼治疗进展期GISTs疗效肯定,不良反应较轻．患者能够耐受,可以较长时期用于转移性和(或)不能手术的GISTs治疗。     

伊马替尼治疗晚期胃肠道间质瘤

背景与目的:胃肠道间质瘤(gastrointestinal stromal tumors,GISTs)是胃肠道最常见的间叶源性肿瘤,对传统的化疗耐药.本研究评价选择性的酪氨酸激酶抑制剂伊马替尼治疗晚期胃肠道间质瘤的效果.方法:入组60例患者,男性43例,女性17例,95.0%的患者体能状况评分(ECOG)0～2分.中位年龄53岁(23～80岁).所有患者口服伊马替尼400 mg/d,评价抗肿瘤疗效和安全性,主要的入选标准是晚期胃肠道间质瘤,有可测量病灶.结果:1例无法评价疗效,无CR,PR 35例(59.3%,35/59),SD持续6个月以上者13例(22.0%,13/59),6个月内PD 11例(18.6%,11/59).不良反应较轻,最常见的Ⅲ～Ⅳ度毒性有出血(6.7%,4/60)、贫血 (5.0%,3/60)、水肿(3.3%,2/60)、腹痛 (3.3%,2/60)、腹泻 (3.3%,2/60)和恶心(3.3%,2/60).结论:酪氨酸激酶抑制剂伊马替尼治疗晚期胃肠道间质瘤有一定疗效,且毒性可耐受.     

Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor.

PURPOSE: Most gastrointestinal stromal tumors (GISTs) express constitutively activated mutant isoforms of KIT or kinase platelet-derived growth factor receptor alpha (PDGFRA) that are potential therapeutic targets for imatinib mesylate. The relationship between mutations in these kinases and clinical response to imatinib was examined in a group of patients with advanced GIST. PATIENTS AND METHODS: GISTs from 127 patients enrolled onto a phase II clinical study of imatinib were examined for mutations of KIT or PDGFRA. Mutation types were correlated with clinical outcome. RESULTS: Activating mutations of KIT or PDGFRA were found in 112 (88.2%) and six (4.7%) GISTs, respectively. Most KIT mutations involved exon 9 (n = 23) or exon 11 (n = 85). All KIT mutant isoforms, but only a subset of PDGFRA mutant isoforms, were sensitive to imatinib, in vitro. In patients with GISTs harboring exon 11 KIT mutations, the partial response rate (PR) was 83.5%, whereas patients with tumors containing an exon 9 KIT mutation or no detectable mutation of KIT or PDGFRA had PR rates of 47.8% (P =.0006) and 0.0% (P <.0001), respectively. Patients whose tumors contained exon 11 KIT mutations had a longer event-free and overall survival than those whose tumors expressed either exon 9 KIT mutations or had no detectable kinase mutation. CONCLUSION: Activating mutations of KIT or PDGFRA are found in the vast majority of GISTs, and the mutational status of these oncoproteins is predictive of clinical response to imatinib. PDGFRA mutations can explain response and sensitivity to imatinib in some GISTs lacking KIT mutations.     

Imatinib mesylate for the treatment of gastrointestinal stromal tumor

Gastrointestinal stromal tumors (GISTs) are rare neoplasms of mesenchymal origin arising in the GI tract. These tumors are characterized by activating mutations of either receptor tyrosine kinase KIT or PDGFRA, which are found in 85% of cases. The introduction of imatinib mesylate (IM), which targets the kinases presenting with these molecular alterations, has dramatically changed the management of these rare tumors, which were resistant to conventional cytotoxic chemotherapy, both in advanced and localized phases. IM is orally available, has a favorable safety profile and induces partial responses and disease stabilization in up to 80% of patients with advanced GIST. Recently, IM was approved for the postoperative treatment of patients with completely resected localized GIST.     

KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours

A recent randomized EORTC phase III trial, comparing two doses of imatinib in patients with advanced gastrointestinal stromal tumours (GISTs), reported dose dependency for progression-free survival. The current analysis of that study aimed to assess if tumour mutational status correlates with clinical response to imatinib. Pre-treatment samples of GISTs from 377 patients enrolled in phase III study were analyzed for mutations of KIT or PDGFRA by combination of D-HPLC and direct sequencing of tumour genomic DNA. Mutation types were correlated with patients' survival data. The presence of exon 9-activating mutations in KIT was the strongest adverse prognostic factor for response to imatinib, increasing the relative risk of progression by 171% (P<0.0001) and the relative risk of death by 190% (P<0.0001) when compared with KIT exon 11 mutants. Similarly, the relative risk of progression was increased by 108% (P<0.0001) and the relative risk of death by 76% (P=0.028) in patients without detectable KIT or PDGFRA mutations. In patients whose tumours expressed an exon 9 KIT oncoprotein, treatment with the high-dose regimen resulted in a significantly superior progression-free survival (P=0.0013), with a reduction of the relative risk of 61%. We conclude that tumour genotype is of major prognostic significance for progression-free survival and overall survival in patients treated with imatinib for advanced GISTs. Our findings suggest the need for differential treatment of patients with GISTs, with KIT exon 9 mutant patients benefiting the most from the 800 mg daily dose of the drug.     

Treatment outcomes in older patients with advanced gastrointestinal stromal tumor (GIST)

Background

The aim of the study was to analyze the treatment results of advanced GIST in the largest, homogenous series of older patients.

Motesanib inhibits Kit mutations associated with gastrointestinal stromal tumors

Background

To compare the biological characteristics of three types of human hepatocellular carcinoma multi-drug resistant cell sub-lines Bel-7402/ADM models established by three methods.

Methods

Established human hepatocellular carcinoma adriamycin (ADM) multi-drug resistant cell sub-lines models Bel-7402/ADM_V, Bel-7402/ADM_L and Bel-7402/ADM_S by three methods of in vitro concentration gradient increased induction, nude mice liver-implanted induction and subcutaneous-implanted induction respectively. Phase contrast microscopy was used to observe the cells and the MTT (methyl thiazolyl tetrazolium) method was used to detect drug resistance of the three different sub-lines of cells.

Results

The three groups of drug resistant cells, Bel-7402/ADM_V, Bel-7402/ADM_L and Bel-7402/ADM_S generated cross-resistance to ADM and CDDP (cis-Diaminedichloroplatinum), but showed a significant difference in resistance to Bel-7402 IC₅₀ value (P < 0.01). The doubling times were significantly extended compared to the parent cell line (39 h) and were 65 h (Bel-7402/ADM_V), 46 h (Bel-7402/ADM_L), and 45 h (Bel-7402/ADM_S). The excretion rates of ADM were significantly increased compared with the parent cell (34.14%) line and were 81.06% (Bel-7402/ADM_V), 66.56% (Bel-7402/ADM_L) and 61.56% (Bel-7402/ADM_S). Expression of P-gp and MRP in the three groups of resistant cells was significantly enhanced (P < 0.01). There was no significant variation in the expression of GSH/GST (P > 0.05).

Conclusions

Stable resistance was involved in the resistant cell line model established by the above three methods. Liver implantation was a good simulation of human hepatocellular and proved to be an ideal model with characteristics similar to human hepatocellular biology and the pharmacokinetics of anticancer drugs.     

Imatinib induced severe skin reactions and neutropenia in a patient with gastrointestinal stromal tumor

Background

Imatinib mesylate has been used for the treatment of unresectable or metastatic gastrointestinal stromal tumors (GIST). The current recommended dose of imatinib is 400 mg/day that is increased to 800 mg/day in cases with disease progression. However, imatinib can be associated with diverse adverse events, which has limited its use. We report a case of severe adverse skin reactions with neutropenic fever during imatinib treatment in a patient with GIST.

Case presentation

A 71-year-old man was admitted with a one month history of epigastric pain and a palpable mass in the right upper quadrant. An abdominal CT scan revealed a 20 × 19 cm intraabdominal mass with tumor invasion into the peritoneum. Needle biopsy was performed and the results showed spindle shaped tumor cells that were positive for c-KIT. The patient was diagnosed with unresectable GIST. Imatinib 400 mg/day was started. The patient tolerated the first eight weeks of treatment. However, about three months later, the patient developed a grade 4 febrile neutropenia and a grade 3 exfoliative skin rash. The patient recovered from this serious adverse events after discontinuation of imatinib with supportive care. However, the skin lesions recurred whenever the patient received imatinib over 100 mg/day. Therefore, imatinib 100 mg/day was maintained. Despite the low dose imatinib, follow up CT showed a marked partial response without grade 3 or 4 toxicities.

Conclusion

The recommended dose of imatinib for the treatment of GIST is 400 mg/day but patients at risk for adverse drug reaction may benefit from lower doses. Individualized treatment is needed for such patients, and we may also try sunitinib as a alternative drug.     

Imatinib plus low‐dose doxorubicin in patients with advanced gastrointestinal stromal tumors refractory to high‐dose imatinib

BACKGROUND:

In KIT‐expressing Ewing sarcoma cell lines, the addition of doxorubicin to imatinib increases apoptosis, compared with imatinib or doxorubicin alone. On the basis of these in vitro data, the authors conducted a phase 1‐2 trial of doxorubicin with imatinib in patients with gastrointestinal sarcoma tumors refractory to high‐dose imatinib therapy.

METHODS:

Patients with metastatic gastrointestinal sarcoma tumor resistant to imatinib at 400 mg by mouth (p.o.) twice a day were eligible for this multicenter study, and received imatinib (400 mg p.o. every day [q.d.]) concomitantly with doxorubicin 15‐20 mg/m²/weekly for 4 cycles (monthly cycles), followed by imatinib (400 mg p.o. q.d.) maintenance in nonprogressive patients. Spiral computed tomography and positron emission tomography with F18‐fluorodeoxyglucose were done basally and after 2 months of therapy to evaluate response. An in vitro study assessed the effect of combining imatinib and doxorubicin.

RESULTS:

Twenty‐six patients with progressive gastrointestinal sarcoma tumor were entered in the study. Treatment was well tolerated. Three (14%) of 22 evaluable patients had partial responses per Response Evaluation Criteria in Solid Tumors, and 8 (36%) had clinical benefit (partial response or stable disease for ≥6 months). Median progression‐free survival (PFS) was 100 days (95% confidence interval [CI], 62‐138), and median survival was 390 days (95% CI, 264‐516). Interestingly, PFS was 211 days (95% CI, 52‐370) in patients with wild type (WT) KIT and 82 days (95% CI, 53‐111) in non‐WT patients (10 mutant, 6 not assessed). A synergistic effect on cell line proliferation and apoptosis was found with imatinib and doxorubicin combination.

CONCLUSIONS:

Low‐dose chemobiotherapy combination showed promising activity in heavily pretreated gastrointestinal sarcoma tumor patients, especially in those with WT‐KIT genotype. Cancer 2010. © 2010 American Cancer Society.     

非小细胞肺癌EGFR基因突变及与疗效的相关性研究

目的:研究晚期非小细胞肺癌(NSCLC)患者表皮生长因子受体(EGFR)基因突变情况,探讨其与NSCLC临床病理学特征及吉非替尼疗效的关系。方法:PCR扩增和基因测序的检测60例NSCLC患者EGFR基因第18、19、20和21外显子突变情况。靶向治疗组14例吉非替尼治疗;化疗组46例以GP方案(顺铂联合吉西他滨方案)治疗。结果:60例晚期NSCLC中,EGFR基因突变率30.00%,19外显子突变12例,21外显子突变6例。腺癌、无吸烟史和女性患者EGFR基因突变率分别为36.89%、50.00%和57.14%。14例EGFR突变阳性患者口服吉非替尼组,CR 1例,PR 10例,SD 2例和PD 1例,客观有效率为78.57%,疾病控制率为92.85%;4例EGFR突变阳性患者GP方案化疗组,CR 0例,PR 2例,SD 2例和PD 0例,客观有效率为50.00%。42例EGFR突变阴性GP方案化疗组,客观有效率为38.10%。结论:晚期NSCLC患者EGFR基因突变率较高,EGFR基因的突变与肿瘤的病理类型、性别、年龄、民族、吸烟指数相关。EGFR基因突变KTI治疗,可有效提高患者的疾病缓解率,并较好地预测TKI治疗晚期非小细胞肺癌的疗效。     

Comparison of RECIST and Choi criteria for computed tomographic response evaluation in patients with advanced gastrointestinal stromal tumor treated with sunitinib

BackgroundControversies exist about computed tomography (CT) response evaluation criteria for patients with gastrointestinal stromal tumor (GIST).Patients and methodsFifty-one patients with advanced GIST treated second line with sunitinib were evaluated with contrast-enhanced CT every 3 months. Response was rated according to RECIST and Choi criteria. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan–Meier analysis.ResultsAccording to RECIST, patients were categorized as complete response (CR; n = 0; 0%), partial remission (PR; n = 1; 2.0%), stable disease (SD; n = 37; 72.5%), and progressive disease (PD; n = 13; 25.5%) at 3 months. When Choi criteria were applied responses were CR (n = 0; 0%), PR (n = 16; 31.4%), SD (n = 21; 41.1%), and PD (n = 14; 27.5%). Despite these discrepancies, patients rated as SD with RECIST and PR as well as SD according to Choi criteria displayed similar PFS (41.3, 40.7, and 41.3 weeks, respectively) and OS (100.4, 91.6, and 108.0 weeks, respectively). Patients with PD had significantly shorter PFS (10.1 weeks for both criteria) and OS (29.1 weeks for RECIST; 28.9 weeks for Choi) regardless of the response classification applied.ConclusionIn contrast to absence of progression, discrimination of PR from SD with Choi criteria was of no predictive value.     

晚期胃肠间质瘤药物治疗进展

作为胃肠道较罕见的肿瘤,胃肠道间质瘤(gastrointestinal stromal tumor,GIST)的恶化率通常很高.靶向药物酪氨酸激酶抑制剂(tyrosine kinase inhibitor,TKI)已成为晚期GIST治疗的基石.近年来,随着新型TKI(如瑞派替尼和阿伐替尼等)相继问世,晚期GIST治疗模...     

胃肠道间质瘤术后复发转移的治疗

  胃肠间质瘤（GIST）是消化道最常见的间叶组织来源的肿瘤。手术虽然是GIST的主要治疗方法，但不能治愈复发转移的GIST。如NCCN建议，复发转移的GIST应首选伊马替尼（STI571）。晚期和复发转移的GIST患者应该长期服用STI571，直到患者出现耐药而不能控制肿瘤。虽然复发转移再手术的效果很差，几乎100％会再复发转移，但病变能切除时或在能观察的病变在STI571治疗后一旦取得最大疗效反应时仍要外科手术或建议手术。关于STI571的新辅助和辅助治疗的试验正在研究中。另一种多靶点的酪氨酸激酶抑制剂SU11248正在临床试验中，对STI571无效或耐药的患者中约65 %获益。总之，合理的治疗方法和治疗时机对减少GIST复发转移、有效地控制疾病、提高生活质量以及生存率至关重要。