Unresectable Gastrointestinal Stromal Tumors Research Articles

Positive immunohistochemical staining of KIT in solid-pseudopapillary neoplasms of the pancreas is not associated with KIT/PDGFRA mutations

Solid-pseudopapillary neoplasms of the pancreas are uncommon neoplasms of low malignant potential and of uncertain histogenesis. A small percentage of patients develop metastatic disease and some succumb to disease. The management of patients with metastatic disease or unresectable tumor, and patients who are just not good surgical candidates is problematic. Novel therapy targets are needed. Successful treatment of metastatic and unresectable gastrointestinal stromal tumors with KIT kinase inhibitor, imatinib mesylate (Gleevec), makes it intriguing to look at the status of KIT in solid-pseudopapillary neoplasms of the pancreas. In this study, we investigated KIT expression in 50 solid-pseudopapillary neoplasms by immunohistochemical staining. Of the 50 (50%) solid-pseudopapillary neoplasms, 25 showed diffuse expression (in >50% neoplastic cells) of KIT and additional five (10%) cases showed focal staining (in 10–50% neoplastic cells). Expression of KIT was not associated with tumor behavior and prognosis. A subset of 11 cases showing diffuse KIT expression detected by immunohistochemical staining were further evaluated for the presence of activating mutations in KIT exons 9, 11, 13 and 17, and PDGFRA exons 12 and 18 using PCR amplification followed by direct sequencing. However, no KIT or PDGFRA mutations were identified in any of these 11 cases tested, suggesting that the overexpression of KIT is probably not due to activating mutations in KIT or PDGFRA. The exact mechanism of KIT overexpression in solid-pseudopapillary neoplasms remains to be elucidated. One possible mechanism is gene dose effect (increased copies of KIT gene). Experience in gastrointestinal stromal tumors and other tumors have shown that mutation-mediated activation of KIT or PDGFRA is a prerequisite for clinical response with imatinib mesylate. Thus, lack of mutations in KIT or PDGFRA in solid-pseudopapillary neoplasms suggests that imatinib mesylate is less likely to be effective in the treatment for patients with metastatic disease or unresectable tumor, and patients who are just not good surgical candidates.

Sunitinib

Sunitinib and its active metabolite (SU012662) are selective inhibitors of multiple receptor tyrosine kinases associated with tumour growth and angiogenesis. The clinical efficacy of oral sunitinib has been demonstrated in patients with advanced gastrointestinal stromal tumours (GIST). In a phase III, randomised, double-blind, placebo-controlled, multicentre trial in patients with metastatic and/or unresectable GIST following unsuccessful imatinib therapy, the median time to tumour progression and median progression-free survival time were > or =4-fold longer in patients receiving sunitinib 50 mg/day than in those receiving placebo, in 6-week cycles consisting of 4 weeks of treatment followed by a 2-week rest period. Sunitinib also exhibited antitumour activity in patients with advanced renal cell carcinoma (RCC) following unsuccessful cytokine therapy. In two multicentre, single-arm, phase II clinical trials in patients with cytokine-refractory metastatic RCC, partial responses were reported in 40% and 43% of patients receiving sunitinib 50 mg/day for 4 weeks followed by 2 weeks without treatment in 6-week cycles; 27% and 22% of patients achieved stable disease for > or =3 months. Sunitinib was more effective than interferon-alpha as a first-line therapy in patients with metastatic RCC. In a large, well designed, phase III trial in previously untreated patients, progression-free survival was significantly longer in patients receiving sunitinib 50 mg/day in 6-week cycles (4 weeks of treatment followed by a 2-week rest period) compared with those receiving interferon-alpha 9MU three times weekly (47.3 vs 24.9 weeks). In general, sunitinib was well tolerated in patients with GIST and RCC, with adverse events usually being of mild or moderate severity.

Pathology of gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors in the gastrointestinal tract. It was found that most GIST expressed KIT, a receptor tyrosine kinase encoded by protooncogene c-kit. In normal gastrointestinal wall, KIT is expressed by interstitial cells of Cajal (ICC), which are a pacemaker for autonomous gastrointestinal movement. Because both GIST and ICC are double-positive for KIT and CD34, and because familial and multiple GIST appear to develop from diffuse hyperplasia of ICC, GIST are considered to originate from ICC or their precursor cells. It was also found that approximately 90% of the sporadic GIST have somatic gain-of-function mutations of the c-kit gene, and that the patients with familial and multiple GIST have germline gain-of-function mutations of the c-kit gene. These facts strongly suggest that the c-kit gene mutations are a cause of GIST. Approximately half of the sporadic GIST without c-kit gene mutations were demonstrated to have gain-of-function mutations in platelet-derived growth factor receptor-alpha (PDGFRA) gene that encodes another receptor tyrosine kinase. Because KIT is immunohistochemically negative in a minority of GIST, especially in PDGFRA gene mutation-harboring GIST, mutational analyses of c-kit and PDGFRA genes may be required to diagnose such GIST definitely. Imatinib mesylate was developed as a selective tyrosine kinase inhibitor. It inhibits constitutive activation of mutated KIT and PDGFRA, and is now being used for KIT-positive metastatic or unresectable GIST as a molecular target drug. Confirmation of KIT expression by immunohistochemistry is necessary for application of the drug. The effect of imatinib mesylate is different in various types of c-kit and PDGFRA gene mutations, and the secondary resistance against imatinib mesylate is often acquired by the second mutation of the identical genes. Mutational analyses of c-kit and PDGFRA genes are also significant for prediction of effectiveness of drugs including newly developed agents.

Management of Gastrointestinal Stromal Tumors in the Imatinib Era: Selected Case Studies

The introduction of imatinib, an orally administered inhibitor of the KIT receptor tyrosine kinase, is prompting revision of the management algorithms that have traditionally guided the treatment of gastrointestinal stromal tumor (GIST). Historically, patients with GISTs have had substantial rates of relapse as well as limited long-term survival even after complete surgical resection of a primary tumor. Imatinib has been shown to induce durable tumor responses in more than half of the patients with malignant metastatic or unresectable GISTs and to halt disease progression in an additional third. These encouraging results have led to the initiation of clinical trials of imatinib as an adjuvant or neoadjuvant therapy with surgery. Until relevant data are reported to provide definitive direction for the management of operable or potentially operable GISTs, treatment decisions must be made on the basis of the available evidence and clinical experience with imatinib. This paper presents selected case studies describing approaches to the combined use of surgery and systemic therapy that have been applied in the treatment of individual GIST patients. The management of GIST in these cases required a coordinated, multidisciplinary approach involving medical oncologists, diagnostic radiologists, gastroenterologists, surgeons, and pathologists.

Patterns of Progression in Gastrointestinal Stromal Tumor Treated with Imatinib Mesylate

Although most patients with gastrointestinal stromal tumor (GIST) treated with imatinib mesylate achieve remission or disease stabilization, a significant proportion show progressive disease (PD) with or without initial favorable responses. We evaluated and categorized the patterns of progression of metastatic or unresectable GIST treated with imatinib to identify the prognostic significance and contribution to further treatment decision-making. We prospectively gathered clinical data from 62 GIST patients treated with imatinib mesylate (400 mg/day) over a median period of 26 months. Twenty-one of these patients showed evidence of PD based on Response Evaluation Criteria in Solid Tumor criteria. Four patterns of PD were defined: focal progression (FP, N = 4), general progression (GP, N = 6), new cystic lesion (NCL, N = 6) and new solid lesion (NSL, N = 5). The groups were found to differ in terms of time to progression and prior response to imatinib. The proportion of patients who responded to escalated doses of imatinib (600-800 mg/day) was significantly higher in NCL patients (P = 0.04). Overall survival and survival from the confirmation of PD were significantly better in NCL or FP patients compared with NSL or GP patients (P = 0.0157, P = 0.0013). We identified four patterns of disease progression based on radiographic criteria with different clinical characteristics and impact on survival. Knowledge of these patterns was relevant for early detection and may be helpful in further treatment decision-making.

Tumeurs stromales gastro-intestinales : définition, caractéristiques histologiques, immunohistochimiques et génétiques, stratégie diagnostique

Gastrointestinal stromal tumors (GISTs) are the most frequent mesenchymal tumors of the gastrointestinal tract. Major advances in their definition and classification and the understanding of their molecular mechanisms have recently been made. These advances have resulted in the delineation of a treatment that has become a model of targeted therapy in oncology. GISTs are defined as tumors of the gastrointestinal tract, but also of the mesentery and peritoneum, constituted by a proliferation of usually spindle-shaped, rarely epithelioid cells, usually, but not consistently expressing the KIT protein. Most GISTs are associated with molecular abnormalities in two target genes: KIT (which encodes the KIT protein) and PDGFRA (which encodes the A chain of the PDGF receptor). The diagnosis of GIST relies on histological arguments (proliferation of spindle-shaped cells in 70% of cases, of epithelioid cells in 20%; histological variants are rare and sometimes misleading) and on immunohistochemical arguments (expression of KIT in 95%, usually associated with CD34 expression in 60%-70% of cases). The demonstration of mutations in target genes is required only in cases that are histologically suggestive but KIT-negative; beyond this indication, this is only undertaken in research protocols. The differential diagnosis of GIST includes the other mesenchymal tumors of the gastrointestinal tract, such as leiomyomas and leiomyosarcomas, and the digestive locations of some sarcomas; it relies on both histological and immunohistochemical arguments. The evaluation of the prognosis is essential. According to the current concept, every GIST carries a risk of malignancy, which may vary from very low to very high. Prognosis is based on a simple algorithm using two histoprognostic parameters, i.e., tumor size and mitotic index. The treatment of localized GIST is surgical resection, which must be complete; that of advanced or unresectable GIST is based on the use of a targeted therapy, imatinib, which is a pharmacological antagonist of the KIT protein. Proper understanding and utilisation of the diagnostic criteria and classification of GIST by pathologists are essential for good patient management.

Gastrointestinal stromal tumor: 5 years later

There is now considerable interest in gastrointestinal stromal tumor (GIST) because it can be treated effectively with a targeted molecular agent. The majority of GISTs contain an activating mutation in the KIT protooncogene or, occasionally, in the platelet-derived growth factor-alpha (PDGFRA) gene. Five years ago, imatinib mesylate, a specific molecular inhibitor of the protein products of these 2 genes, was applied to metastatic GIST. Approximately 80% of patients with metastatic GIST benefit from imatinib, although acquired resistance to the agent may develop. For patients with primary GIST, surgery remains the treatment of choice, and whether outcome is improved by adjuvant imatinib is currently under broad investigation. A combination of imatinib therapy and surgery also may be effective in a subset of patients with metastatic or unresectable primary GIST. In this review, the authors summarize the new multimodality approach to GIST. The integration of surgery and molecular therapy in GIST will serve as a prototype for the management of other solid tumors for which targeted agents become available.

Follow-up of gastro-intestinal stromal tumours (GIST) during treatment with imatinib mesylate by abdominal MRI

Typical MRI findings for gastro-intestinal stromal tumours (GIST) under treatment with imatinib were evaluated. MRI was performed in 45 patients (25 responders, 20 non-responders) with metastatic or locally advanced, unresectable GIST. Target lesions were selected and re-evaluated after 2, 4, and 6 months of therapy with imatinib. The target tumour response (TTR) was classified according to RECIST criteria. TTR, signal intensity in the centre and border of the lesion and the presence and the extension of a hypervascular rim were analysed. The mean diameter of the marker lesions decreased significantly (P<0.001) from 7.1+/-2.6 cm to 5.9+/-2.3 cm after 6 months. Accuracy of RECIST criteria was 51%, 69% and 73% on MRI 2, 4 and 6 months for response assessment. In addition, responders had higher signal-to-noise ratios on T2-w images after 2 months (P<0.05) and a decrease of vascularised areas in the lesion 4 and 6 months after treatment (each P<0.01), when compared with non-responders. Beyond the size measurement for response assessment, MRI provides additional information of tumour response using SI of T2-w images and quantification of vascularised areas of GIST manifestations.

Imatinib for the treatment of patients with unresectable and/or metastatic gastrointestinal stromal tumours: systematic review and economic evaluation

To assess the clinical and cost-effectiveness of imatinib in the treatment of unresectable and/or metastatic, KIT-positive, gastrointestinal stromal tumours (GISTs), relative to current standard treatments. Electronic databases. As there were no randomised trials that have directly compared imatinib with the current standard treatment in patients with advanced GIST, this review included non-randomised controlled studies, cohort studies, and case series that reported effectiveness results of treatment with imatinib and/or other interventions in patients with advanced GIST. The effectiveness assessment was based on the comparison of results from imatinib trials and results from studies of historical control patients. Economic evaluation was mainly based on an assessment and modification (when judged necessary) of a model submitted by Novartis. Evidence from published uncontrolled trials involving 187 patients, and from abstracts reporting similar uncontrolled trials involving 1700 patients, indicates that approximately 50% of imatinib-treated individuals with advanced GIST experience a dramatic clinical response in terms of at least a 50% reduction in tumour mass. At present, although useful data are accumulating, it is not possible to predict which patients may respond in this way. Fifteen studies where possible GIST patients had been treated with therapies other than imatinib or best supportive care were also identified. All imatinib-treated patients experienced adverse effects, although they were relatively mild. Overall, imatinib was reported to be well tolerated. The most common serious events included unspecified haemorrhage and neutropenia. Skin rash, oedema and periorbital oedema were the common adverse events observed. Patients on the highest dose regimen (1000 mg per day in one trial) may experience dose-limiting drug toxicity. A structured assessment was carried out of the Novartis economic evaluation of imatinib for unresectable and/or metastatic GIST. The model was clearly presented and well written, its structure and input data were transparent, and the level of simplification was reasonable in terms of the objectives and data availability. However, the original Novartis model overestimated the cost-effectiveness of imatinib because of disproportion of survival and time-to-treatment failure in the imatinib arm, and the use of a possibly biased survival curve for patients in the control arm. The original Novartis model was modified to correct these two important shortcomings, which made it less sensitive to the choice of the survival curve for the control patients. According to the modified Novartis model, the estimated cost per quality-adjusted life-year (QALY) was 85,224 UK pounds (range 51,515--98,889 UK pounds) after 2 years, 41,219 UK pounds (27,331--44,236 UK pounds) after 5 years and 29,789 UK pounds (21,404--33,976 UK pounds) after 10 years. The results from a new Birmingham model were also within the range of estimates from the modified Novartis model. Evidence from uncontrolled studies indicates that the treatment with imatinib brings about clinically significant shrinkage of tumour mass in about half of patients with unresectable and/or metastatic, KIT-positive GIST. Results of modelling based on data from uncontrolled studies suggest that imatinib treatment improves survival in patients with unresectable and/or metastatic GIST. The economic evaluation modelling suggests that the cost per QALY gained ranges from 51,515 to 98,889 UK pounds after 2 years, from 27,331 to 44,236 UK pounds after 5 years, and from 21,404 to 33,976 UK pounds after 10 years. Further research is needed into quality of life within trials involving patients with advanced malignancy, and long-term follow-up of adverse events is needed. Subgroup analysis of which, if any, patient types have a better or worse response to imatinib is also required. Analysis of individual patient data may be a good way of exploring these issues. There are many uncertainties surrounding imatinib prescription, such as the length of time patients should be on imatinib, the dose, drug resistance and the optimum time-point in the disease course at which to give the drug. Secondary research such as an update of this systematic review and a reassessment of the model is highly recommended when ongoing trials reach completion.

Imatinib mesylate STI571 therapy for five patients with advanced gastrointestinal stromal tumors

To explore the therapeutic effect of STI571(imatinib mesylate) on advanced gastrointestinal stromal tumors (GISTs). Clinical data of 5 cases with advanced GISTs were analyzed retrospectively. The expression of c- kit (CD117) was detected by immunohistochemical method in five patients with advanced GISTs . All patients failed to systematic chemotherapy or radiofrequency and operation because of extensive and multiple metastases (4 cases underwent 1 to 3 times of exploratory surgery). Tumor size was markedly decreased one to six months after STI571 given without serious drug- related side effects. STI571 is an effective chemotherapy for advanced unresectable or metastatic GISTs. Inhibitor of the Kit signal- transduction pathway is a promising regimen that is different from conventional chemotherapy for advanced GISTs.

Surgical Resection Combined with Systemic Imatinib Therapy for the Treatment of Advanced Gastrointestinal Stromal Tumor

The results of surgical treatment of advanced gastrointestinal stromal tumor (GIST) are poor due to low resectability and high recurrence. This situation has been improved by the use of novel targeted molecular therapy with imatinib. For unresectable advanced GIST, the neo-adjuvant role of imatinib relies on cytoreduction and tumor shrinkage. The operability is increased and further definite surgery is facilitated. In cases with postoperative relapse, adjuvant imatinib therapy still provides the benefits of postponing tumor progression and enabling subsequent surgeries. We report two cases of advanced GISTs treated with surgery and imatinib. The first case was an inoperable advanced GIST with peritoneal sarcomatosis which became resectable after systemic imatinib therapy for 10 months. The second case had recurrent GIST after en bloc resection seven months earlier and resulted in stable disease status with continuous imatinib therapy. The timing, duration and dosage of imatinib remain inconclusive and demand further studies. Lifelong follow-up of advanced GISTs is mandatory.

Imatinib mesylate acts in metastatic or unresectable gastrointestinal stromal tumor by targeting KIT receptors--a review.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal malignancy of the gastrointestinal tract. This tumor is resistant to conventional chemotherapy and radiotherapy. Although surgery has been the only effective treatment for GIST to date, it is not enough to manage metastatic GIST. Imatinib mesylate, a KIT tyrosine kinase inhibitor, is an oral agent that has been found to have a dramatic antitumor effect on metastatic GIST with either wild-type or mutant KIT. Although imatinib mesylate has been used in GIST treatment for several years, its use marks a new era of molecular targeting therapy. While several issues remain, they should be clarified by the current clinical trials and associated laboratory studies.

Phase II clinical study of STI571 in Japanese (Jpn) patients (pts) with malignant gastrointestinal stromal tumors (GIST): results of the B 1201 study

4078 Background: STI 571, (Gleevec), is a specific inhibitor of BCR-ABL, c-kit, and PDGFR tyrosine kinases. After demonstration of efficacy against KIT- positive GISTs, STI571 was approved for the treatment of GISTs in the US and the EU. This Phase II open-labelled, multicenter trial investigated the efficacy, tolerability, and PK of STI571 in Japanese pts with unresectable and/or metastatic malignant GISTs. Methods:The inclusion criteria were KIT-positive and unresectable and/or metastatic GISTs with measurable lesions, adequate organ function, PS (ECOG)of 0–2, and a life expectancy >2 months. Pts were randomized to either 400 or 600 mg/day of STI571. For PD, the dose was increased. Efficacy was assessed by SWOG criteria, and toxicity was reported by NCI-CTC v2.0. PK was examined in 21 patients. Results: 74 pts were enrolled (400 mg /600 mg = 28/46, M/F = 48/26, PS 0/1/2=57/14/3, median age=56 years (range 24–74)). C-kit mutations in exon 11 was the most common mutational abnormality (79.7 %) and mutation in exon 9 was the next most common (10.3 %). The overall response rate was 55.4% (CR/PR/SD/PD = 0/41/30/1).The percentage of pts with PR was higher in the 600 mg dose group than in the 400 mg dose group (60.9% vs 46.4%) however this was not statistically significant. All pts experienced AE with a suspected relationship to STI571, 90 % of which were grade 1 or 2 (nausea, vomiting, diarrhoea, facial edema, etc). A relatively high number (>5% of incidents) of grade 3/4 toxicities were observed including neutropenia (17.6%) and dermatitis (6.8%), which were higher in the 600 mg dose group (21.7 % vs.10.9 %) than in the 400 mg dose group (10.7 % vs. 0 %). More patients in the 600 mg dose group required dose interruptions (39% vs. 67%) and reductions(39% vs.70%). PK analysis revealed a dose-proportional increase of Cmax and AUC0–24 as similarly reported in previous studies. Conclusions: STI571 has substantial objective effects against unresectable and/or metastatic GISTs in Jpn pts, with considerable safety and tolerability. An optimal dose of 400 mg daily is recommended for pts with malignant GIST based on the results of this study. No significant financial relationships to disclose.

Phase II clinical study of STI571 in Japanese (Jpn) patients (pts) with malignant gastrointestinal stromal tumors (GIST): results of the B 1201 study

4078 Background: STI 571, (Gleevec), is a specific inhibitor of BCR-ABL, c-kit, and PDGFR tyrosine kinases. After demonstration of efficacy against KIT- positive GISTs, STI571 was approved for the treatment of GISTs in the US and the EU. This Phase II open-labelled, multicenter trial investigated the efficacy, tolerability, and PK of STI571 in Japanese pts with unresectable and/or metastatic malignant GISTs. Methods:The inclusion criteria were KIT-positive and unresectable and/or metastatic GISTs with measurable lesions, adequate organ function, PS (ECOG)of 0–2, and a life expectancy >2 months. Pts were randomized to either 400 or 600 mg/day of STI571. For PD, the dose was increased. Efficacy was assessed by SWOG criteria, and toxicity was reported by NCI-CTC v2.0. PK was examined in 21 patients. Results: 74 pts were enrolled (400 mg /600 mg = 28/46, M/F = 48/26, PS 0/1/2=57/14/3, median age=56 years (range 24–74)). C-kit mutations in exon 11 was the most common mutational abnormality (79.7 %) and mutation in exon 9 was the next most common (10.3 %). The overall response rate was 55.4% (CR/PR/SD/PD = 0/41/30/1).The percentage of pts with PR was higher in the 600 mg dose group than in the 400 mg dose group (60.9% vs 46.4%) however this was not statistically significant. All pts experienced AE with a suspected relationship to STI571, 90 % of which were grade 1 or 2 (nausea, vomiting, diarrhoea, facial edema, etc). A relatively high number (>5% of incidents) of grade 3/4 toxicities were observed including neutropenia (17.6%) and dermatitis (6.8%), which were higher in the 600 mg dose group (21.7 % vs.10.9 %) than in the 400 mg dose group (10.7 % vs. 0 %). More patients in the 600 mg dose group required dose interruptions (39% vs. 67%) and reductions(39% vs.70%). PK analysis revealed a dose-proportional increase of Cmax and AUC0–24 as similarly reported in previous studies. Conclusions: STI571 has substantial objective effects against unresectable and/or metastatic GISTs in Jpn pts, with considerable safety and tolerability. An optimal dose of 400 mg daily is recommended for pts with malignant GIST based on the results of this study. No significant financial relationships to disclose.

GIST: overview and recent advances in treatment with imatinib mesylate

The treatment of advanced and metastatic gastrointestinal stromal tumours (GIST) has been revolutionised by the development of the drug imatinib mesylate (Glivec), one of the first targeted molecular therapies available for the treatment of cancer. However, little has been previously documented about this rare tumour. The aim of this article is to provide an overview of GIST and its treatment, and discuss the nursing management of GIST patients. This is particularly timely given that the National Institute for Clinical Excellence is expected to publish its guidance for the use of Glivec in the treatment of unresectable and/or metastatic GISTs this September.

Surgery and imatinib in the management of GIST: emerging approaches to adjuvant and neoadjuvant therapy.

Gastrointestinal stromal tumor (GIST) is a neoplasm of the gastrointestinal tract, mesentery, or omentum that expresses the protein-tyrosine kinase KIT (CD117) and is the most common mesenchymal tumor arising at these sites. Surgical resection is the first-line intervention for operable GISTs, particularly localized primary tumors, and it was historically the only effective treatment. However, more than half of all GIST patients present with locally advanced, recurrent, or metastatic disease. The 5-year survival rate ranges from 50% to 65% after complete resection of a localized primary GIST and decreases to approximately 35% for patients with advanced disease who undergo complete surgical resection. A total of 40% to 90% of all GIST surgical patients subsequently have postoperative recurrence or metastasis. Imatinib is a potent, specific inhibitor of KIT that has demonstrated significant activity and tolerability in the treatment of malignant unresectable or metastatic GIST, inducing tumor shrinkage of 50% or more or stabilizing disease in most patients. A key strategy for prolonging the survival of patients with GIST is to improve the outcome of surgery. It is possible that the adjuvant and neoadjuvant use of imatinib (e.g., rendering initially inoperable tumors resectable) in the overall management approach to advanced GIST may contribute to surgeons' success in attaining this objective.

A pilot study of imatinib mesylate (STI571) on gastrointestinal stromal tumors in Japanese patients.

Gastrointestinal stromal tumor (GIST) is the most common type of nonepithelial tumor in the gastrointestinal tract. The gastrointestinal stromal tumor is defined immunohistologically as a c-Kit-positive tumor. For those GISTs that are malignant, the only effective treatment modality has been surgical. Early clinical reports have shown that imatinib mesylate (STI571) produces substantial anticancer activity in patients with metastatic or unresectable GIST. Nine Japanese patients who were found clinically and immunohistochemically to have inoperable GISTs were entered into this study. These patients were given 400 mg STI571 orally once daily. We then evaluated the tumor response and the safety of the drug. Five of the nine patients achieved partial responses, two had stable disease, and two had progressive disease. The main side effects were skin rash, edema, periorbital edema, diarrhea, nausea, and vomiting. Mild anemia, leukocytopenia, and neutropenia were also noted. No patients required dose reduction or cessation because of adverse events. This study demonstrates that STI571 might be an active agent against malignant GIST in Japanese patients with manageable toxicities. Gastrointestinal stromal tumor (GIST) is the most common type of nonepithelial tumor in the gastrointestinal tract. The gastrointestinal stromal tumor is defined immunohistologically as a c-Kit-positive tumor. For those GISTs that are malignant, the only effective treatment modality has been surgical. Early clinical reports have shown that imatinib mesylate (STI571) produces substantial anticancer activity in patients with metastatic or unresectable GIST.

A patient with unresectable gastrointestinal stromal tumor responded to STI571

A patient with unresectable gastrointestinal stromal tumor responded to STI571

Role of imatinib mesylate (Gleevec®/Glivec®) in gastrointestinal stromal tumors

Gastrointestinal stromal tumors are soft tissue sarcomas of the gastrointestinal tract that originate from mesenchymal cells. Advances in the systemic therapy of gastrointestinal stromal tumors are highlighted by the rapid development and approval of the molecularly targeted therapy imatinib mesylate (Gleevec®/Glivec®). Mutations of the KIT gene are known to be present in most gastrointestinal stromal tumors and result in gain of function, with permanent activation of the expressed KIT receptor in the absence of binding of the stem cell factor ligand. Imatinib is the first rationally designed selective inhibitor of specific protein tyrosine kinases, including KIT. Inhibiting the downstream signaling of KIT switches the cell balance into apoptosis. Although complete responses have seldom been seen up until now, imatinib has proven to be extremely effective in the treatment of patients with unresectable and/or metastatic gastrointestinal stromal tumors.

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

Background Imatinib mesylate (Gleevec) is being studied as adjuvant chemotherapy for the treatment of c KIT+ 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 c KIT+ 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 c KIT+ GISTs were identified from the institutional sarcoma database. Patients were included if they had pathologic confirmation of c KIT 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 c KIT + 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 c KIT+ 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 c KIT+ 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 c KIT+ GISTs is warranted.