Is there a role for surgery in patients with “unresectable” cKIT+ gastrointestinal stromal tumors treated with imatinib mesylate?

doi:10.1016/j.amjsurg.2003.08.023

The American Journal of Surgery

Volume 186, Issue 6, December 2003, Pages 665-669

Presented at the 55th Annual Meeting of the Southwestern Surgical Congress, Tucson, Arizona, April 27–30, 2003

https://doi.org/10.1016/j.amjsurg.2003.08.023 Get rights and content

Abstract

Background

Imatinib mesylate (Gleevec) is being studied as adjuvant chemotherapy for the treatment of cKIT+ gastrointestinal stromal tumors (GISTs). Early reports using Gleevec for the treatment of unresectable GISTs have shown 50% to 60% partial response rates based on radiographic evaluation alone. No study has yet correlated radiographic response with pathologic findings. This retrospective review of patients with cKIT+ GISTs who received Gleevec prior to surgical resection examines the pathologic response to therapy and the feasibility of surgical resection after treatment.

Methods

Patients with cKIT+ GISTs were identified from the institutional sarcoma database. Patients were included if they had pathologic confirmation of cKIT mutation and therapy with Gleevec. The pretreatment and preoperative radiographs, surgeons' operative notes, and pathology reports were reviewed for documentation of the extent of disease.

Results

Between January 2001 and Octorber 2002, 126 patients with unresectable cKIT + GISTs treated with Gleevec were identified. Of these 126 patients, 17 have subsequently undergone surgical resection after a median of 10 months (range 2 to 16) of treatment with Gleevec. Based on computed tomographic (CT) scanning, 1 (6%) patient had evidence of a complete tumor response, 12 (70%) patients had a partial response, 3 (24%) patients had stable disease, and 1 (6%) patient had progressive disease. Posttreatment/preoperative CT imaging documented an overall response rate of 76%. The pathologic review of the operative specimens showed that 2 (12%) patients had a complete response to therapy, 11 (65%) had a partial response to therapy, 3 (18%) patients had no evidence of treatment effect on the excised tumor, 1 patient had progressive disease. Sixteen patients (94%) underwent complete surgical resection of disease, including 3 patients with no pathologic evidence of response to therapy. One patient had progression of disease and was unresectable at surgical exploration.

Conclusions

This series is the first to present pathologic data after the treatment of cKIT+ GISTs with Gleevec. In this series, the majority of responses were limited to partial responses, indicating that surgical resection remains a vital component of the treatment plan for patients with cKIT+ GISTs. This series is consistent with previous reports indicating that complete responses are extremely rare in response to treatment with Gleevec. Patients with advanced disease may benefit from a course of neoadjuvant therapy with Gleevec followed by resection, even when there is evidence of multifocal disease. A prospective evaluation of neoadjuvant Gleevec therapy for advanced cKIT+ GISTs is warranted.

Section snippets

Methods

The institutional sarcoma database was queried for all patients with intraabdominal sarcomas. We then identified all tumor lesions confirmed to be cKIT+ GISTs by CD117 immunohistochemistry. All of these tumors were reviewed and confirmed cKIT+ by a single pathologist (A.K.R.). We included all patients in our study who received therapy with Gleevec and subsequently underwent surgical exploration for tumor resection.

Patient data included age, sex, site of primary tumor, length of treatment with

Results

Between January 2001 and October 2002, 126 patients with unresectable cKIT+ GISTs (either technically inoperable or due to multifocal disease) treated with Gleevec were identified. Radiographs after treatment with Gleevec indicated that 5 (4%) patients were without evidence of disease, 44 (35%) had regression, 46 (37%) had stable disease, 23 (18%) had progression, and 2 (2%) had died of disease. Six (5%) patients did not return for follow-up and were therefore not evaluable. Of these 126

Comments

Gleevec is the first systemic therapy for GISTs with promising evidence of response to therapy. Yet the role for Gleevec in the neoadjuvant and adjuvant setting in the treatment for GISTs remains under investigation. All previous series reporting the efficacy of Gleevec in the treatment of GIST, have based the evaluation of the treatment response on radiographic imaging. Although radiographic response can be helpful in guiding further treatment planning, the pathologic response to treatment is

Conclusions

This series is the first to present complete pathologic data after the treatment of cKIT+ GISTs with Gleevec. In addition, this is the first series to report a pathologic complete response to treatment with Gleevec. The majority of responses were partial, indicating that surgical resection remains a vital component of the treatment plan for patients with cKIT+ GISTs. Patients with advanced disease may benefit from a course of neoadjuvant therapy with Gleevec followed by resection, even when

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Cited by (126)

Impact of surgical resection for gastrointestinal stromal tumor (GIST) patients with initially diagnosed synchronous hepatic metastases on long-term survival outcomes
2023, Digestive and Liver Disease
Citation Excerpt :
Therefore, from a theoretical point of view, surgical resection combined with imatinib therapy seems to be a safe and feasible treatment modality for addressing this problem. Given the lack of high-level clinical studies authenticating the efficacy of the combination compared to imatinib therapy alone, this regimen is still not included in the current NCCN and other guidelines for GISTs [9–12]. To the best of our knowledge, this is the first study using PSM to answer this clinical question by virtue of the data from the SEER database.
The effect of surgical resection on the long-term outcome of GIST patients with initially diagnosed synchronous hepatic metastases in the targeted therapy era is still uncertain. The main aims of this study were to investigate the role of surgery in the treatment of these patients and establish clinical predictive models for assessing prognosis.
We identified these patients from the Surveillance, Epidemiology and End Results (SEER) database between 2010 and 2018. The selection bias in comparisons was minimized by performing propensity score matching (PSM). The risk factors associated with long-term survival outcomes were identified by a Cox proportional hazards model and thus used to establish the nomograms. Nomograms were validated by concordance indexes (C-indexes), time-dependent receiver operator characteristic (ROC) curves, calibration plots, and decision curve analyses (DCA).
Of these 523 eligible patients, there were 187 (35.8%) and 336 (64.2%) patients in the surgical and nonsurgical groups, respectively. Multivariate analysis revealed that surgical resection was an independent prognostic factor for OS (hazard ratio [HR] 0.62; 95% confidence interval [CI] 0.44–0.88, p = 0.0068) and CSS (HR 0.51; 95% CI 0.33 - 0.77, p = 0.0016). After PSM, it was found that surgical resection still showed significantly improved OS (5-year 54.9% vs 38.8%, p = 0.028) and CSS (5-year 65.8% vs 50.3%, p = 0.077). In addition, the C-indexes of the nomograms for OS and CSS prediction were 0.692 and 0.705, respectively, and the nomograms showed good consistency.
This study revealed that surgical resection has a favorable impact on the long-term outcome of patients with synchronous GIST liver metastases, and the nomograms showed remarkable prediction performance for OS and CSS.
Unresectable GIST liver metastases and liver transplantation: A review and theoretical basis for a new indication
2021, International Journal of Surgery
Liver metastases from gastrointestinal stromal tumors (GIST) can be found synchronously to a primary tumor and in the medium/long term after resection of a high-risk GIST. In these cases, treatment with tyrosine kinase inhibitors like imatinib has provided good results, but drug resistance is common after two years of treatment. Liver resection of potentially resectable metastases can improve the results of medical treatment. In cases of unresectability, the role of liver transplantation (LT) has not been well-studied.
A review of the literature was undertaken from January 1995 to December 2020 following the PRISMA and AMSTAR guidelines.
Fifteen cases were identified. In eight cases, the LT was carried out before 2002. Mutational status was only studied in seven cases. LT was performed in 12 cases with a deceased donor and in three cases with a living donor. After a mean follow-up of 52.4 months, overall survival was 86.6% with disease-free survival of 53.3%
LT in the management of unresectable GIST metastases has rarely been performed. Although its application has a solid theoretical basis, its use understood as a radical extension of a standard resection can only be recommended within prospective studies by groups with considerable experience in both GIST and transplantation care.
Staged surgical approach for metastatic GIST, how far should we go? Case report
2021, International Journal of Surgery Case Reports
Gastrointestinal stromal tumor (GIST) is an uncommon mesenchymal neoplasm that commonly arises from the stomach and proximal small intestine but can develop in any part of the gastrointestinal tract. The disease can range from primary localized to an advanced metastatic unresectable disease in up to 30% of patients. Usually, metastasis involves the liver, peritoneum, and occasionally the lungs. The current standard treatment of localized resectable tumors is complete oncological resection, while advanced metastatic GISTs treatment remains contentious.
We report a case of a 34 years old pregnant female presenting with a 3 days history of multiple episodes of hematemesis and melena. Laboratory investigations were unremarkable except for severe anemia (Hgb 4.4 g/dL). After further investigations a diagnosis of duodenal GIST (DGIST) with liver metastasis was made. She received and showed good response to neoadjuvant Imatinib therapy, which was followed by a successful 2-stage surgery in the form of extended right hepatectomy and Whipple procedure with a good survival.
The evolution of Imatinib had a tremendous impact on surgery in metastatic GIST even in initially unresectable cases, thereby providing a better survival. However, the duration of neoadjuvant Imatinib course and the matter of resistance are still unclear those necessitating the use of different agents or the surgical approach.
Although with the advancements in surgical approaches and perioperative care, liver resection might be a curative option. The role of surgery in advanced GIST remains a controversial matter that needs critical selection of cases based on further future research.
Management of Gastrointestinal Stromal Tumors
2017, Surgical Clinics of North America
Indications for surgery in advanced/metastatic GIST
2016, European Journal of Cancer
Gastrointestinal stromal tumours (GISTs) are a relatively rare entity and often present as a locally advanced tumour or with metastatic disease. Complete surgical resection is the only means of cure in localised disease; however, imatinib therapy has greatly advanced the management of GIST and is established as both an adjunct to surgery in high-risk cases and as principle therapy in metastatic disease. Surgery in advanced GIST has undergone a renaissance in recent years with the potential for a combined treatment approach with either neoadjuvant imatinib in locally advanced primary disease or as an adjunct to imatinib in those with metastases or recurrent disease. Neoadjuvant imatinib can render a locally advanced primary GIST resectable, allow less invasive procedures or promote preservation of function, especially if the tumour is located in an anatomically difficult position. The role of surgery in metastatic or recurrent disease is more controversial and case selection is critical. The potential benefit is difficult to quantify, although surgery may have a limited favourable impact on progression-free survival and overall survival for those patients whose disease is responding to imatinib or those with limited focal progression. Patients with imatinib resistant disease should not be offered surgery unless as an emergency where palliative intervention may be justified.
Management of liver metastases of gastrointestinal stromal tumors (GIST)
2015, Annals of Hepatology
Introduction. Liver metastases (LM) are crucial prognostic manifestation of gastrointestinal stromal tumors (GIST). With the advent of tyrosine kinase inhibitors (TKI), management of metastatic GIST has radically changed. Long clinical follow-up provides an increased proportion of GIST patients with LM who are candidates for potentially curative therapy.
Material and methods. Patients who underwent treatment for liver metastases of GIST between 2000-2009 in our department were included in the study. Mean follow-up was 84 months (range 40-145) months. In retrospective analysis we investigated clinical, macro-/microscopic and immunohistochemical criteria, surgical, interventional and TKI therapy as well.
Results. In 87 GIST-patients we identified 25 (29%) patients with metastatic disease. Of these, 12 patients (14%) suffered from LM with a mean age of 60.5 (range, 35-75) years. Primary GIST were located at stomach (n = 4, 33%) or small intestine (n = 8, 67%); all of them expressed CD117 and/or CD34. LM were multiple (83%), distributed in both lobes (67%). They were detected synchronously with primary tumor in 33% and metachronously in 77%. All patients with liver involvement were considered to treatment with TKI. LM were resected (R0) in 4 patients (33%). In recurrent (2/4) and TKI resistant cases, interventional treatment (radiofrequency ablation) and TKI escalation were carried out. During a median follow-up of 84 months (range 30-152), 2 patients died (16.5%) for progressive disease and one patient for other reasons. Nine patients (75%) were alive.
Conclusion. Treatment of LM from GIST needs a multimodal approach. TKI-therapy is required at any case. In case of respectability, surgery must be carried out. In unresectable cases or recurrent/progressive disease, interventional treatment or TKI escalation should be considered. Therefore, these patients need to be treated in experienced centres, where multimodal approaches are established.

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Scientific paperIs there a role for surgery in patients with “unresectable” cKIT+ gastrointestinal stromal tumors treated with imatinib mesylate?

Abstract

Background

Methods

Results

Conclusions

Section snippets

Methods

Results

Comments

Conclusions

Human Pathol

Human Pathol

Lancet

A new acute transforming feline retrovirus and relationship of its oncogene v-kit with the protein kinase gene family

Nature

Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors

Science

Scientific paper
Is there a role for surgery in patients with “unresectable” cKIT+ gastrointestinal stromal tumors treated with imatinib mesylate?