Surgical Resection of Gastrointestinal Stromal Tumors After Treatment with Imatinib

Background Surgical resection of gastrointestinal stromal tumors (GISTs) has been the most effective therapy for these rare tumors. Imatinib has been introduced as systemic therapy for locally advanced and metastatic GIST. In this study, the surgical resection rates and long-term outcomes of patients treated with preoperative imatinib for locally advanced primary, recurrent, or metastatic GISTs were evaluated. Methods Patients were retrospectively assessed for completeness of surgical resection and for disease-free and overall survival after resection. Results Forty-six patients underwent surgery after treatment with imatinib. Eleven were treated for locally advanced primary GISTs for a median of 11.9 months, followed by complete surgical resection. All eleven were alive at a median of 19.5 months, and ten were free of disease. Thirty-five patients were treated for recurrent or metastatic GIST. Of these, eleven underwent complete resection. Six of the eleven patients had recurrent disease at a median of 15.1 months. All eleven patients were alive at a median of 30.7 months. Patients with a partial radiographic tumor response to imatinib had significantly higher complete resection rates than patients with progressive disease (91% vs. 4%; P < .001). Of the 24 patients with incomplete resection, 18 initially responded to imatinib but were unable to undergo complete resection after they progressed before surgery. Conclusions Preoperative imatinib can decrease tumor volume and is associated with complete surgical resection in locally advanced primary GISTs. Early surgical intervention should be considered for imatinib-responsive recurrent or metastatic GIST, since complete resection is rarely achieved once tumor progression occurs. Presented in part at the Annual Meeting of the Society of Surgical Oncology, Atlanta, GA, March 2005.     

Optimizing Surgical and Imatinib Therapy for the Treatment of Gastrointestinal Stromal Tumors

Introduction

The discovery of activating KIT and PDGFRα mutations in gastrointestinal stromal tumors (GISTs) represented a milestone as it allowed clinicians to use tyrosine kinase inhibitors, like imatinib, to treat this sarcoma. Although surgery remains the only potentially curative treatment, patients who undergo complete resection may still experience local recurrence or distant metastases. Therapeutic strategies that combine surgical resection and adjuvant imatinib may represent the best treatment to maximize patient outcomes. In addition to the use of imatinib in the adjuvant and metastatic settings, neoadjuvant imatinib, employed as a cytoreductive therapy, can decrease tumor volume, increase the probability of complete resection, and may reduce surgery-related morbidities. Thus, selected patients with metastatic disease may be treated with a combination of preoperative imatinib and metastasectomy. However, it is critical that patients with GIST be evaluated by a multidisciplinary team to coordinate surgery and targeted therapy in order to maximize clinical outcomes.

Discussion

Following a systematic literature review, we describe the presentation, diagnosis, and treatment of GIST, with a discussion of the risk assessment for imatinib therapy. The application of surgical options, combined with adjuvant/neoadjuvant or perioperative imatinib, and their potential impact on survival for patients with primary, recurrent, or metastatic GIST are discussed.     

Complete Remission of Recurrent Gastrointestinal Stromal Tumors After Treatment with Imatinib: Report of a Case

A 49-year-old man underwent partial resection of the jejunum for an abdominal tumor, which was histologically confirmed to be a gastrointestinal stromal tumor (GIST). Immunohistochemistry revealed that the tumor cells were positive for c-kit, p52, and MIB-1. He underwent resection of a total of 83 recurrent tumors over the next 36 months. A computed tomography (CT) scan done a few months later showed multiple tumor recurrences. The patient was started on imatinib mesylate 400 mg/day, and 3 months later, a CT image showed an increase in tumor size but a decrease in tumor density. Subsequent CT scans showed a marked decrease in tumor size 3 months later and no evidence of tumor recurrence 9 and 12 months after the commencement of imatinib treatment. The patient remains in complete remission 31 months after the start of treatment.     

Preoperative Imatinib Treatment in Patients With Advanced Gastrointestinal Stromal Tumors: Patient Experiences and Systematic Review of 563 Patients

Preoperative IM therapy for GIST is now a research focus. Due to the low incidence of the disease, there are few RCTs on the preoperative treatment for advanced GIST, let alone relevant meta-analysis. Efficacy of this therapy and targeting population are still undetermined. Therefore, the first part of this article is composed of a controlled retrospective study and demonstrates that preoperative therapy with IM can significantly improve the outcome of advanced GIST. In the second part of the paper, we further investigated what portion of advanced GIST patients benefit more from the therapy, based on a meta-analysis. As the disease is relatively rare, we involved 563 cases in the meta-analysis, much higher than in the controlled clinical studies (51 cases). The objective of this paper is to investigate effects of surgical resection on imatinib-treated advanced GIST. Twenty-two consecutive advanced GIST patients (Group A) with preoperative IM treatment were compared to 29 patients (Group B) who underwent initial tumor resection during the same period. Subsequently, a systematic review of 563 patients was applied to identify the benefit of the advanced GIST patients receiving imatinib before surgery. Compared with Group B, less patients in Group A underwent multivisceral resection (18.2% versus 48.3%, P = 0.026) or suffered tumor rupture at time of surgery (0% versus 17.2%, P = 0.04). The 3-year estimated progression-free survival of Group A (94.4%) was also superior to that of Group B (61.4%; P = 0.045). Subsequent meta-analysis indicated that primarily unresectable patients had higher complete resection and 2-year PFS rates than recurrent/metastasis patients (P = 0.005 and 0.20, respectively); (b) stable disease (SD) patients had better outcome in resection including resectability rate (P < 0.0001), PFS (P < 0.00001) and OS (P = 0.0008) than progressive disease (PD) patients; (c) in recurrent/metastatic PD patients, surgery played a minor role, because they had a higher bulky residual disease rate (P = 0.0005) and higher progression risk (P < 0.00001) within 2 years after surgery. Preoperative IM treatment improves prognosis of advanced GISTs. Among recurrent/metastatic patients, postimatinib surgery may benefit those who have SD after IM treatment but not those resistant to IM.Key words: Gastrointestinal stromal tumors, Imatinib, Targeted therapy, Surgical resectionGastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasia of the digestive tract, with a worldwide incidence of approximately 15 per 1 million people. Between 15% and 50% of GISTs are advanced at the time of diagnosis.¹ Historically, owing to the low response rate of GISTs to conventional chemotherapy or radiation therapy (overall response rate < 5%),² surgery was the only recognized treatment for GIST before the advent of imatinib. However, surgery has historically had poor outcomes, so surgery alone is seldom sufficient for advanced GIST. Even if patients with locally advanced GIST undergo complete resection, tumor recurrence occurs frequently, and the 5-year survival can be as low as 54%. In patients with locally nonresectable, recurrent or metastatic disease, the outcomes are even poorer, with a median survival of 12–19 months and a 5-year survival rate of < 5–10%.³In 2000, imatinib mesylate (IM), a tyrosine kinase inhibitor, was first reported to have been used in one patient with metastatic GIST, and it achieved remarkable success.⁴ Currently, IM is the first-line palliative treatment for advanced GIST.^5,6 Nevertheless, although IM confers clinical benefits to more than 80% of patients with advanced disease, complete response to IM therapy is restricted to a few patients. Furthermore, while the majority of patients initially benefit from IM, the development of resistance to the drug still limits long-term IM use. Clinical trials have shown that two-thirds of the patients with metastatic disease who use IM develop progression, with a median progression-free survival (PFS) of approximately 20 to 24 months.⁷ These flaws in IM treatment led us to investigate the value of potential multimodal approaches combining surgery and IM therapy. Several multi-institutional trials have described the successful use of postoperative IM treatment,^8,9 which was approved for adjuvant treatment of patients with primary GIST in December 2008 by the US Food and Drug Administration (FDA). In addition, surgery following primary IM treatment is feasible in advanced GIST.^10,11 However, limited by low case numbers, most of these studies have been based on the results of isolated cases or small joint institutions, and they do not include randomized controlled clinical trials. Therefore, little is known about the exact effects of postimatinib surgical resection on outcomes of patients with locally advanced primary, recurrent or metastatic GIST. In the present study, we retrospectively analyzed the outcomes of patients with advanced GISTs who received preoperative IM treatment at our institution and compared their outcomes with the prognostic results of patients with high-risk GIST (according to the NIH risk stratification system¹²) who did not receive preoperative IM. Then, we performed a meta-analysis in which we further divided advanced patients into an unresectable and a metastasis group or a stable disease and a progressive disease group to identify which portion of the advanced patients benefit more from the surgery following IM therapy. By combining our findings with the results of our meta-analysis, we evaluated the role of postimatinib surgical intervention in patients with advanced GISTs.     

143例胃肠道间质瘤的外科诊治及预后分析

目的:探讨胃肠道间质瘤的临床病理特征及外科诊治情况,分析影响预后相关因素。方法:回顾性分析经手术治疗的143例患者的临床资料。结果:发生于胃42.7%,小肠35.0%,腹痛不适44.1%,消化道出血或贫血28.0%。131例手术完整切除,免疫组化表型CD117阳性率为98.5%。中位生存时间为64.0个月,1、3、5年生存率分别为89.7%,72.4%和53.4%。手术切除的完整性和危险程度分级是影响预后的独立因素(P0.05)。结论:胃肠道间质瘤术前确诊率较低,手术完整切除是主要治疗手段,伊马替尼治疗晚期患者有一定疗效。影响患者预后的独立因素是肿瘤危险程度分级、手术切除的完整性和伊马替尼治疗。     

Effect of Imatinib (STI571) on Metastatic Gastrointestinal Stromal Tumors: Report of a Case

The prognosis for advanced gastrointestinal stromal tumor (GIST) is poor. However, recent reports from Europe have described the effects of imatinib against metastatic GIST. We herein report the case of a Japanese patient treated with imatinib for advanced GIST. Imatinib at 400mg daily was given to an adult with multiple liver and peritoneal metastases 17 months after undergoing a GIST resection. The sum of the diameter of all target lesions decreased from 37.7 to 10.9cm at 6 months. Tinnitus (grade 2), which has not been reported elsewhere as an adverse effect, developed at 2 months. However, it did not require any treatment. Other adverse effects, nausea (grade 2) and anemia (grade 2), resolved spontaneously. Our results are consistent with previous reports that show imatinib to be effective for the treatment of metastatic GIST, and also suggest that imatinib at 400mg daily for more than 7 months is well tolerated in Japanese adults.     

A Review of Resistance Patterns and Phenotypic Changes in Gastrointestinal Stromal Tumors Following Imatinib Mesylate Therapy

Gastrointestinal stromal tumors are neoplastic lesions that arise from the interstitial cells of Cajal and are associated with somatic mutations in the tyrosine kinase receptor, KIT. The only known curative therapy is complete surgical resection. Unfortunately, postsurgical recurrence rates exceed 50% and most tumors are resistant to standard chemotherapy and radiation. Imatinib mesylate, a novel tyrosine kinase inhibitor, holds promise as a potential adjuvant therapy to prevent recurrence and improve long-term survival. However, as resistance data emerge, it appears that a potential “escape pathway” may originate from secondary mutations in the KIT receptor. This paper reviews the historical clinical experience with imatinib mesylate and discusses resistance patterns following targeted therapy. We highlight this review with an interesting case report that illustrates unique phenotypic tumoral changes associated with imatinib mesylate resistance. Drs. Bickenbach and Wilcox share joint first authorship     

胃肠道间质瘤35例诊治体会

目的探讨胃肠道间质瘤的临床病理特点及治疗方法。方法回顾性分析我院2005年7月至2010年7月期间收治的35例患者的临床资料。结果 35例患者病变分别位于胃部18例(51.4%),其中胃体15例(42.9%)、胃窦3例(8.6%);回肠16例(45.7%);小肠系膜根部1例(2.9%)。35例均进行手术治疗,其中行胃楔形切除术15例(42.9%),胃大部切除术3例(8.6%),小肠部分切除术16例(45.7%),肠系膜肿块切除加大部分小肠切除术1例(2.9%)。术后病理报告均为间质瘤;免疫组织化学染色结果:CD117阳性33例(94.3%),CD34阳性26例(74.3%)。35例术后均获随访,随访时间6个月至5年,平均25.6个月。1例术后10个月死于肿瘤复发,1例术后4个月死于短肠综合征、营养不良,余33例无肿瘤复发。结论胃肠道间质瘤确诊依赖于病理组织学检查及免疫组化染色,完整切除病灶是最有效的治疗手段。     

The Outcome of Gastrointestinal Stromal Tumors (GISTs) After a Surgical Resection in Our Institute

PURPOSE: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract arising from Cajal's cells and expressing c-kit. In a consensus report, the clinical behavior of GISTs was categorized into risk classes according to the tumor size and mitotic count. We analyzed the risk categories based on GIST patients who underwent a surgical resection at our institute during a period of 15 years. METHODS: We evaluated the risk categories of GISTs and analyzed the outcome and risk categories retrospectively. We presented the MIB-1 score of the tumor instead of mitotic counts for the evaluation of cellular growth because of inaccuracies regarding the mitotic counts. RESULTS: Patients were classified into 4 cases of very low risk, 11 of low risk, 8 of intermediate risk, and 5 of high risk. Four high-risk patients showed recurrence as either liver metastasis or peritoneal dissemination. In addition, local recurrence occurred in one low-risk and one intermediate-risk patient each. CONCLUSION: Our cases confirmed the correlation between the risk categories and the prognosis. A complete resection with sufficient margin must be confirmed even in low-risk cases to prevent local recurrence. Since high-risk patients showed poor prognosis, the adjuvant treatment with chemotherapeutic regimens must therefore be further studied for high-risk patients.     

Serum Midkine Correlates with Tumor Progression and Imatinib Response in Gastrointestinal Stromal Tumors

Background

A previous study identified midkine (MK) expression in primary gastrointestinal stromal tumor (GIST) as a prognostic marker. The aim of the current study was to compare serum midkine (S-MK) concentrations of GIST patients with those of healthy controls and to determine if MK can serve as a prognostic serum marker for these patients.

Materials and Methods

S-MK concentrations were measured by enzyme-linked immunosorbent assay in GIST patients (n = 96) and healthy controls (n = 148). S-MK levels were then correlated with clinicopathological data and the administration of imatinib therapy. In addition, MK expression was evaluated in 39 surgically resected GIST and in 17 leiomyoma specimens on a tissue microarray.

Results

S-MK concentrations in GIST patients were significantly higher than in healthy controls: median (25th and 75th percentiles) S-MK concentration was 235 (139 and 376) pg/ml in the GIST patients and 99 (33 and 198) pg/ml in the controls (P < 0.001; Mann–Whitney U test). Significantly higher median S-MK concentrations were found in GIST with recurrence compared with those without (295 vs 230; P = 0.009). GIST patients with S-MK levels higher than 400 pg/ml showed a significantly worse recurrence-free survival (P = 0.026; log-rank test). Patients receiving imatinib therapy had decreased median S-MK concentrations compared with those who were not treated with imatinib (331 vs 201; P < 0.001).

Conclusions

S-MK concentration is a potential marker for evaluating the progression and prognosis of GIST, especially during imatinib therapy. Further studies could focus on the role of midkine in the tumorigenesis of GIST and responsiveness toward imatinib therapy.     

Treatment of Gastrointestinal Stromal Tumors with Imatinib Mesylate:A Major Breakthrough in the Understanding of Tumor-specific Molecular Characteristics

A specific treatment for gastrointestinal stromal tumors (GIST) has been found through improved understanding of the molecular mechanism of carcinogenesis. GIST are radio and chemo-resistant (less than 10 objective responses). Stromal tumors originate from the multiplication of the cells of Cajal, which intervene in intestinal motility and express the c-Kit gene, also called CD117, on their surface. CD117 is a protein with tyrosine kinase activity, and can be demonstrated through immunohistochemical staining techniques.Treatment with Imatinib mesylate (Glivec), a recently discovered selective inhibitor of tyrosine kinases already used in chronic myeloid leukemia (in which an overexpression of tyrosine kinase is observed) was associated with tumor regression of more than 50% in the initial series of patients with GIST treated in 2001. Since then, approximately 2,000 patients have been included in therapeutic trials, with an objective response rate between 60% and 70% 12 to 18 months after inclusion. The clinical benefit has been estimated at 80% to 90% in patients whose chance of survival until now has been less than 30% at one year (median survival 18 months). Nonetheless, imatinib mesylate has not shown any activity in CD117-negative sarcoma (10% of sarcoma). The therapeutic importance of this drug in the treatment of solid GI tumors deemed inoperable is considerable.     

肛门直肠间质瘤治疗体会(附12例报告)

目的探讨肛门直肠间质瘤的诊断和治疗。方法回顾性分析我院2008年至2013年收治的12例间质瘤患者的临床资料。结果 12例其中男5例,女7例。年龄40~84岁,平均53.33±13.44岁。肿瘤大小在1~5cm之间,平均2.0±1.37cm。其中高危3(25%)例,中危4(33.3%)例,极低危5(41.6%)例。病理核分裂象5/50HP为7例。CD117阳性10(91.67%)例,CD34阳性8(75%)例。目前患者均存活,随访时间27.75±15.21个月,复发4(33.33%)例。结论对肛门直肠间质瘤应进行规范化的诊断和治疗,尽量减少复发。     

Choices of Surgical Approaches for Gastrointestinal Stromal Tumors of the Stomach: Laparoscopic versus Open Resection

Aims: The aim of this study is to explore the optimal surgical approach for gastrointestinal stromal tumors (GISTs) of the stomach in terms of the perioperative outcomes and long-term relapse-free survival. Methods: From January 2004 to July 2011, 156 patients who underwent either laparoscopic (LAP group, n = 68) or open surgery (OPEN group, n = 88) were included in the final analysis following the eligibility criteria. Results: Clinicopathological characteristics of the selected patients were similar between the two groups. The LAP group was associated with less blood loss (50 vs. 180 ml, p < 0.001), shorter operating time (90 vs. 125 min, p < 0.001), earlier oral intake (3 vs. 5 days, p < 0.001), shorter postoperative hospital stay (8 vs. 10 days, p < 0.001), and low risk of postoperative complications (5.9 vs. 22.7%, p = 0.004) compared with the OPEN group. No significant difference was observed in 5-year relapse-free survival between the LAP and OPEN groups (94.2 vs. 94.0%, p = 0.807). The subgroup analysis of patients who underwent wedge resection showed similar results with the original comparison except that difference in complication rate between the two groups lost significance. Conclusions: Laparoscopic wedge resection for gastric GISTs ≤7 cm could get preferable short-term postoperative outcomes and similar long-term relapse-free survival compared with open surgery.     

Gastrointestinal Stromal Tumor of the Rectum: Results of Surgical and Multimodality Therapy in the Era of Imatinib

Background

The rectum is a rare site of gastrointestinal stromal tumor (GIST), and factors determining long-term outcome remain unclear. In a population study, we assessed the outcome of rectal GIST patients treated at two referral centers.

Methods

A total of 39 patients diagnosed with rectal GIST between January 2002 and December 2010 were identified in prospective databases. Tumor and patient characteristics, treatment details, and outcome were evaluated. Median follow-up was 41 (3–110) months.

Results

A male predominance was noticed (M/F = 29/10). Median age was 53 years (range, 32–80 years). The cohort included, of 39 patients, 12 low-risk, 26 high-risk, and 1 with M1 disease. Of 38 patients with nonmetastatic disease, 36 underwent surgery as transabdominal (15 of 36) or local (21 of 36) resection. There were 21 patients who received preoperative and/or postoperative imatinib treatment. Patients with preoperative imatinib (16 of 36) had a significantly higher rate of R0 resections (p = .02). Five patients developed local recurrences. All of them had undergone local tumor excision with positive margins and without perioperative imatinib. Also, five patients suffered from distant metastases. All belonged to the high-risk group and underwent tumor surgery (3 R0, 2 R1) without receiving perioperative imatinib. A total of three patients died of disease. Perioperative imatinib was associated with improved local disease-free, disease-free, and overall survival (p < .01, p < .01, and p = .03, respectively). Local disease-free survival was significantly improved by negative resection margins (p < .01).

Conclusions

Complete resection is recommended to achieve local disease control. Preoperative imatinib was associated with improved surgical margins. Perioperative imatinib was associated with improved local disease-free, disease-free, and overall survival.     

Surgical Outcomes of Patients with Gastrointestinal Stromal Tumors in the Era of Targeted Drug Therapy

Background  The discovery of the c-KIT mutation and the advent of targeted drug therapy with imatinib mesylate have revolutionized the management of gastrointestinal stromal tumors (GISTs). The outcome of patients with surgically treated GISTs treated in the era of targeted drug therapy was assessed and factors associated with adverse outcomes determined. Materials and Methods  Patients with GISTs requiring surgery at a tertiary care center from 2002 to 2007 were reviewed and prognostic factors determined. Results  Forty patients were surgically treated for GISTs. The median age at presentation was 59 years. The stomach (55%) was the main site of primary disease. The median tumor size was 7 cm. Eleven (28%) patients had metastatic disease at presentation. Surgery was undertaken in all patients with curative intent. Multi-organ resection was required in 10 (25%) patients. Imatinib mesylate was administered postoperatively in 68% of cases. Median follow-up was 24 months. There was a 40% recurrence rate with 63% undergoing repeat surgical resection. The peritoneum and liver were the main sites of recurrent disease. The 5-year disease-specific survival and disease-free survival (DFS) were 65% and 35%, respectively. High mitotic rate (P = 0.017) and tumor size greater than 10 cm (P = 0.009) were the only prognostically significant adverse factors of DFS on multivariate analysis, independent of imatinib mesylate treatment. Conclusion  Aggressive surgical treatment and follow-up of GISTs, combined with targeted drug therapy, leads to long-term DFS survival. Tumor recurrence is independently associated with a high tumor mitotic rate and size greater than 10 cm, despite the use of adjuvant targeted drug therapy.     

Patterns of Care, Prognosis, and Survival in Patients with Metastatic Gastrointestinal Stromal Tumors (GIST) Refractory to First-Line Imatinib and Second-Line Sunitinib

Background

Data regarding the management and outcome of patients with metastatic gastrointestinal stromal tumors (GIST) refractory to 1st-line imatinib and 2nd-line sunitinib are limited.

Methods

Medical records of 223 imatinib-resistant and sunitinib-resistant GIST who were treated in 11 major referral centers were reviewed.

Results

The three most frequent drugs used in the 3rd-line setting were: nilotinib n?=?67 (29.5%), sorafenib n?=?55 (24.5%), and imatinib n?=?40 (17.5%). There were 18 patients (8%) who received best supportive care (BSC) only. The median progression-free survival (PFS) and overall survival (OS) on 3rd-line treatment were 3.6?months [95% confidence interval (95% CI), 3.1?C4.1] and 9.2?months (95% CI, 7.5?C10.9), respectively. Multivariate analysis showed that, in the 3rd-line setting, albumin level and KIT/PDGFRA mutational status were significantly associated with PFS, whereas performance status and albumin level were associated with OS. After adjustment for prognostic factors, nilotinib and sorafenib provided the best PFS and OS. Rechallenge with imatinib was also associated with improved OS in comparison with BSC.

Conclusion

In the 3rd-line setting, rechallenge with imatinib provided limited clinical benefit but was superior to BSC. Sorafenib and nilotinib have significant clinical activity in imatinib-resistant and sunitinib-resistant GIST and may represent an alternative for rechallenge with imatinib.     

Emergence of Imatinib Resistance Associated with Downregulation of C-Kit Expression in Recurrent Gastrointestinal Stromal Tumor (GIST): Optimal Timing of Resection

Introduction  

Gastrointestinal stromal tumors (GISTs) are the most common gastrointestinal mesenchymal tumors. The activating mutation in the KIT (c-kit; CD117) proto-oncogene with subsequent tyrosine kinase activation plays a central role in the pathogenesis of GIST. Tyrosine kinase inhibitors are an integral part of GIST therapy. Initial response to neoadjuvant imatinib can be expected in up to 70% of the patients, thus offering an opportunity to surgically treat those with locally advanced primary or recurrent GIST. This favorable response to imatinib, however, is plagued with development of secondary resistance during the course of therapy.