Impact of Surgery on Advanced Gastrointestinal Stromal Tumors (GIST) in the Imatinib Era

Background The role for surgery in patients with “unresectable” gastrointestinal stromal tumors (GIST) treated with imatinib is still not defined. The objective of this retrospective study was to evaluate the feasibility and benefit of this secondary surgery.Methods Progression-free survival (PFS) in a group of patients who underwent secondary surgery was compared to that of patients treated exclusively with imatinib.Results Of 180 patients with unresectable GIST treated with Imatinib, 22 (12%) underwent secondary surgery, following which one patient achieved a complete radiological response, 19 achieved a partial response (PR), in one patient the disease was stable, and in one patient there was reactivation of local occlusive disease after an initial PR. No patient with overall progression was to undergo surgery. At the beginning of imatinib therapy, five patients with metastases underwent emergency surgery [hemorrhage (n = 3) due to rupture of large necrotic masses], which ultimately resulted in three of the five patients dying postoperatively. A macroscopically complete resection was achieved in all primary tumors (5/5) and in ten of the 17 metastases. Pathological analysis revealed two complete response (CR) and 17 PR, and no treatment effect was evidenced in three patients. Two-year overall survival after surgery was 62%. The median PFS calculated from the initiation of imatinib therapy was 18.7 months for all operated patients and 23.4 months after planned surgery.Conclusion Primary tumors that become amenable to surgery with prior imatinib therapy, evolving necrosis and localized progression (to avoid life-threatening complications) could benefit from this secondary surgery. For the majority of other residual lesions, the potential benefit of secondary surgery should be evaluated in randomized studies in the future since PFS is similar to that reported among non-operated patients.     

Extraabdominal Lymph Node Metastasis in Gastrointestinal Stromal Tumors (GIST)

Background  

The two principal ways of metastases in gastrointestinal stromal tumors (GISTs) are diffuse intraabdominal spread and liver metastasis whereas lymph node metastases (LNM) are extremely rare. Accordingly, nodal dissection is generally not recommended for GISTs’ surgical treatment.     

胃肠道间质细胞肿瘤43例临床及病理分析

目的:探讨胃肠道间质瘤临床表现和良性、潜在恶性、恶性的病理诊断标准,及其对临床评估预后的价值.方法:选用43例临床资料完整的病例,经免疫组化S-P方法测定CD117、CD34、SMA、S-100、NSE及组织化学Masson染色.结果:43例免疫组化阳性率CD117 40/43例(93.0%);CD34 34/43例(79.1%);CD117及CD34皆阳性30/43(69.8%),SMA 16/43例(37.2%)向平滑肌分化;S-100阳性或兼有NSE阳性14/43例(32.6%)向神经鞘分化;6/43例(14.0%)双向分化.良性5例,潜在恶性10例,恶性28例,预后与肿瘤病理判定密切相关.结论:胃肠道间质瘤的病理诊断除结合临床各项检查外,仍需依靠免疫组化测定(CD117及/或CD34),其中必须一项呈阳性者方能确定诊断.     

Giant Gastric Gastrointestinal Stromal Tumor (GIST)

Journal of Gastrointestinal Surgery - Gastrointestinal stromal tumors (GIST) represent 0.1–3 % of gastrointestinal malignancy. Surgery is the mainstay of treatment, but in high-risk tumors,...     

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。     

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.     

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.     

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.     

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.     

Surgical Management After Neoadjuvant Imatinib Therapy in Gastrointestinal Stromal Tumours (GISTs) with Respect to Imatinib Resistance Caused by Secondary KIT Mutations

Background In metastasized GISTs, resistance to imatinib after initial tumour response has been associated with observation of secondary mutations in the activation loop of KIT. The aim of the current study was to evaluate the tumour response and observance of secondary KIT mutations in a case of GIST undergoing neoadjuvant imatinib therapy. Methods We report on a case of an initially unresectable gastric GIST with curative resection after 10 months of neoadjuvant imatinib therapy. Mutation analysis of KIT was performed on a pretherapeutic biopsy specimen, as well as on the resected tumour specimen. Results The pretherapeutic biopsy revealed cKit positive tumour cells with mutation of KIT exon 11 Del 560–576. The remaining tumour mass after neoadjuvant imatinib therapy almost exclusively consisted of hypocellular myxohyalinale stroma with rare microfoci of cKit positive tumour cells. Laser microdissection of several tumour microfoci revealed two additional point mutations located in the activation loop of KIT exon 17, C809G and N822Y, each observed separately in a distinct microfocus. Neither of these two point mutations has been reported in a GIST so far. Conclusions Neoadjuvant imatinib therapy successfully reduces tumour size in GISTs. Since resistance relevant secondary mutations of the activation loop of KIT may be observed after neoadjuvant imatinib therapy, the time elapse with preoperative imatinib therapy should be chosen as short as curative tumour resection or function sparing surgery can be carried out. The determination of the optimal time point for surgery is therefore a critical event and will be discussed.     

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.     

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.     

Score prediction of metastatic risk in Gastrointestinal Stromal Tumours (GIST)

The purpose was to generate a score targeted at the metastatic risk potentially reflecting oncogenic activation in Gastrointestinal Stromal Tumours (GIST). In 41 patients size and location of the primary, mitotic index, initial symptoms, and histological appearance were rated with 0 to 1 or 2 points. The course of the disease was recorded as incidental, symptomatic, locally recurrent, with peritoneal dissemination, or with hepatic spread. The parameters tumour size (p < 0.001), mitotic index (p < 0.001), localisation of the primary (p < 0.001) and symptoms (p < 0.05) correlated with the course of the disease. This correlation was highly significant (p < 0.0005) when the overall score was applied, the median being 0 in incidental, 3 in symptomatic, 4 in locally recurrent, 4.5 in peritoneal, and 5 points in hepatic spreading GIST. Results were compared with those of an established risk stratification. The sensitivity and specificity of a score > 4 for the occurrence of liver metastases were 100 and 73.5 % compared with 85.7 and 82.4 % for a high risk profile according to Franquemont's classification. The results indicate the ability of routinely recorded data to predict the metastatic outcome of GIST.     

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.     

胃肠道间质瘤伊马替尼术前治疗进展

目的 探讨伊马替尼术前治疗胃肠道间质瘤（gastrointestinal stromal tumor,GIST）的作用。 方法 采用文献复习的方法,对研究伊马替尼术前治疗GIST的文献加以综述。 结果 伊马替尼术前治疗是进展期GIST的有效治疗手段,能显著提高患者的手术切除率,延长总体生存时间。 结论 术前伊马替尼治疗转移性或局部进展期GIST疗效较好,应参考GIST基因分型结果个体化术前给药,值得进一步深入临床研究。