Metastatic Gastrointestinal Stromal Tumors Patients Research Articles

Metastatic gastrointestinal stromal tumor: A regional cancer center experience of 44 cases

Background:Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Historically, a poor prognosis for metastatic disease has been reported with systemic chemotherapy. Significant advances have been made in the last decade, since the introduction of different tyrosine kinase inhibitors (TKIs). Unfortunately, even though the TKIs have been used for a long time, there are very few published data of the experience of TKI therapy in metastatic GIST from India.Materials and Methods:Patients diagnosed with metastatic GIST from January 2005 to October 2016 at our center, who received first-line therapy with imatinib 400 mg/day, were reviewed retrospectively. Patients’ profile, response to treatment, toxicity of TKI therapy, time to progression, and survival were evaluated.Results:Of the 44 metastatic GIST patients, 23 (52.2%) were males. Median age at diagnosis was 48 years. The most common presenting symptom was an abdominal pain (52%), followed by weight loss (23%). Most frequently affected metastatic site was liver (57%), followed by peritoneum (16%), and lungs (4.5%). Metastases to both liver and peritoneum were found in 10 patients (22.5%). All patients were initially treated with imatinib at a dose of 400 mg/day. Disease stabilization was documented in 21 cases (48%), and 13 patients (29%) achieved a partial response. TKI therapy was well-tolerated in most cases. Median progression-free survival (PFS) was 26 months, and estimated median survival was 48 months. Patients with lung metastases have a significantly inferior median PFS and overall survival, in comparison to patients with other metastatic sites (P < 0.05).Conclusions:Imatinib therapy was well tolerated and induced a sustained clinical benefit in more than half of the patients with metastatic GIST. Lung metastases seemed to be a poor prognostic factor in this patient population.

Surgical management of patients with progressing metastatic gastrointestinal stromal tumors receiving sunitinib treatment: A prospective cohort study

BackgroundFor selected patients with metastatic gastrointestinal stromal tumor (GIST) who have received first-line imatinib (IM) and are undergoing cytoreductive surgery, response to IM at time of surgery correlates with resection completeness as well as favorable progression-free survival (PFS) and overall survival (OS). However, surgical impact in GIST patients receiving second-line sunitinib (SU) is still not well clarified. Materials and methodsBetween 2001 and 2014, 86 of 311 metastatic GIST patients received SU. Among them, 69 patients eventually experienced progression. Twenty-six patients who experienced local progression (LP) and underwent surgeries were investigated. Each tumor was assessed for genetic alterations before and after surgery. ResultsTwenty-six GIST patients receiving SU who experienced LP underwent surgery after a median of 6.2 months of SU use. Nineteen patients (73.1%) had undergone prior surgery on IM. The complication rate was 15.3%, and no additional operation was required for GIST patients receiving SU and experiencing LP who underwent surgery. The median PFS and OS times after surgery and start of SU were 5.2 and 18.9 months, respectively, and 16.4 and 26.0 months, respectively (median follow-up of 15.2 months). GIST patients receiving SU with LP (N = 26) may gain a significant PFS and OS benefit with surgery when compared with those not undergoing surgery (N = 43) (p = 0.003 and p = 0.02, respectively). Secondary exon 17 mutation occurred commonly and might explain SU resistance (8/23; 34.8%). ConclusionSurgery is feasible in highly selected patients with metastatic GIST who are receiving SU and experiencing LP. Those patients may also have significantly prolonged PFS and OS after surgery. Secondary exon 17 mutation might explain SU resistance.

Efficacy analysis of targeted therapy combined with surgery in the treatment of recurrent and metastatic gastrointestinal stromal tumor

To investigate the efficacy of targeted therapy combined with surgery in the treatment of recurrent and metastatic gastrointestinal stromal tumor(GIST). Clinicopathological and followed-up data of 318 patients with recurrent and metastatic GIST admitted in Zhongshan Hospital between January 2000 and December 2015 were analyzed retrospectively. According to different treatment methods, the patients were divided into four groups: surgery group (operation alone, 44 cases), target therapy group (imatinib alone, 108 cases), target therapy combined with surgery group (imatinib plus operation, 139 cases), other therapy group (chemotherapy, Chinese medicine and others, 27 cases). The progression-free survival (PFS) and overall survival (OS) of four groups were compared. The baseline informations, such as age, gender, primary site, et al, were not significantly different (all P>0.05), but the recurrent and metastatic site was significantly different among 4 groups (P=0.000). The medial PFS of surgery group, target therapy group, target therapy combined with surgery was 16(95%CI: 4.9 to 27.0) months, 44 (95%CI: 30.9 to 57.1) months, 35 (95%CI: 26.5 to 43.5) months, respectively, and the latter 2 groups had significantly longer PFS than surgery group(P=0.000), while no significant difference was found between target therapy group and target combined with surgery group (P=0.251). The median OS of surgery group, target therapy group, target therapy combined with surgery, and other therapy group was 24 (95%CI: 9.0 to 39.0) months, 69(95%CI: 40.8 to 97.2) months, 92(95%CI: 78.0 to 106.0) months, 12(95%CI: 9.5 to 14.5) months. Target therapy group and target therapy combined with surgery group had significantly longer OS than surgery and other therapy groups (P=0.000), while the target therapy combined with surgery group had significantly longer OS than target therapy group(P=0.028). Target therapy combined with surgery can prolong the survival of recurrent and metastatic GIST patients.

Molecular mechanism of gastrointestinal stromal tumors and progress in drug research

The functional mutation of c-kit and platelet-derived growth factor receptor α (PDGFRA) which encode proto-oncogene receptor tyrosine kinase are the crucial pathogeneses of gastrointestinal stromal tumors(GISTs). 80%-85% c-kit gene mutation including exon 11,exon 9,exon 13,exon 17 and 5%-10% PDGFRA gene mutation such as exon 18, exon 12 are examined in GISTs. Neither of c-kit or PDGFRA gene mutation are called wide type GISTs. The pathogeneses of wild type GISTs are not clear. The deficiency of succinate dehydrogenase B(SDHB)-related insulin-like growth factor 1(IGF-1R) activation, BRAF gene mutation and neurofibromatosis type 1 may be related to progression of wild type GISTs. More than half of metastatic GISTs patients receiving imatinib treatment can develop to c-kit secondary mutations, which are responsible for secondary resistance. However, the reasons of imatinib resistance in GISTs without c-kit secondary mutation need to be explored. At present, many clinical trials are ongoing to evaluate new drugs in GISTs treatment, including nilotinib, masitinib, pazopanib, dovitinib, ponatinib, dasatinib, crenolanib, linsitinib and immunotherapy, which may bring resistance GISTs treatment to new hope. Next generation sequencing (NGS) and liquid biopsy will be very important in GISTs research and clinical practice.

NKp30 isoforms and NKp30 ligands are predictive biomarkers of response to imatinib mesylate in metastatic GIST patients

ABSTRACTDespite effective targeted therapy acting on KIT and PDGFRA tyrosine kinases, gastrointestinal stromal tumors (GIST) escape treatment by acquiring mutations conveying resistance to imatinib mesylate (IM). Following the identification of NKp30-based immunosurveillance of GIST and the off-target effects of IM on NK cell functions, we investigated the predictive value of NKp30 isoforms and NKp30 soluble ligands in blood for the clinical response to IM. The relative expression and the proportions of NKp30 isoforms markedly impacted both event-free and overall survival, in two independent cohorts of metastatic GIST. Phenotypes based on disbalanced NKp30B/NKp30C ratio (ΔBClow) and low expression levels of NKp30A were identified in one third of patients with dismal prognosis across molecular subtypes. This ΔBClow blood phenotype was associated with a pro-inflammatory and immunosuppressive tumor microenvironment. In addition, detectable levels of the NKp30 ligand sB7-H6 predicted a worse prognosis in metastatic GIST. Soluble BAG6, an alternate ligand for NKp30 was associated with low NKp30 transcription and had additional predictive value in GIST patients with high NKp30 expression. Such GIST microenvironments could be rescued by therapy based on rIFN-α and anti-TRAIL mAb which reinstated innate immunity.

Diffusion-weighted magnetic resonance imaging in metastatic gastrointestinal stromal tumor (GIST): a pilot study on the assessment of treatment response in comparison with 18F-FDG PET/CT

Diffusion-weighted magnetic resonance imaging (MRI) is increasingly being used for assessing the treatment succes in oncology, but the real clinical value needs to evaluated by comparison with other, already established, metabolic imaging techniques. To prospectively evaluate the clinical potential of diffusion-weighted MRI with apparent diffusion coefficient (ADC) mapping for gastrointestinal stromal tumor (GIST) response to targeted therapy compared with 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). Eight patients (mean age, 56 ± 11 years) known to have metastatic GIST underwent 18F-FDG PET/CT and MRI (T1Gd, DWI [b = 50,300,600], ADC mapping) simultaneously, before and after change in targeted therapy. MR and PET/CT examinations were first analyzed blindly. Second, PET/CT images were co-registered with T1Gd-MR images for lesion detection. Only 18F-FDG avid lesions were considered. Maximum standardized uptake value (SUVmax) and the corresponding minimum ADCmin were measured for the six largest lesions per patient, if any, on baseline and follow-up examinations. The relationship between changes in SUVmax and ADCmin was analyzed (Spearman's correlation). Twenty-four metastases (12 hepatic, 12 extra-hepatic) were compared on PET/CT and MR images. SUVmax decreased from 7.7 ± 8.1 g/mL to 5.5 ± 5.4 g/mL (P = 0.20), while ADCmin increased from 1.2 ± 0.3 × 10(-3)mm(2)/s to 1.5 ± 0.3 × 10(-3)mm(2)/s (P = 0.0002). There was a significant association between changes in SUVmax and ADCmin (rho = - 0.62, P = 0.0014), but not between changes in lesions size (P = 0.40). Changes in ADCmin correlated with the response of 18F-FDG avid GIST to targeted therapy. Thus, diffusion-weighted MRI may represent a radiation-free alternative for follow-up treatment for metastatic GIST patients.

Patterns of care, prognosis, and survival of patients with metastatic gastrointestinal stromal tumors (GIST) refractory to first-line imatinib and second-line sunitinib.

10044 Background: Data regarding the management and outcome of metastatic GIST patients (pts) refractory to 1st line imatinib (I) and 2nd sunitinib (S) are limited. Methods: Eleven institutions par...

Overall survival benefit with masitinib mesylate in imatinib-naive, locally advanced, or metastatic gastrointestinal stromal tumor (GIST): 4-years follow-up of the French Sarcoma Group phase II trial.

85 Background: Masitinib is a novel tyrosine kinase inhibitor which, in vitro, has greater activity and selectivity than imatinib (IM) against both wild-type KIT receptor and its mutated form in the juxtamembrane region (IC 50=100 nM versus 200 nM for IM, 3 nM versus 27nM and 40 nM versus 120nM, respectively, for exons 9,11, and 13). This multicenter phase II study evaluated efficacy and safety of masitinib as a first-line treatment of advanced GIST. Methods: IM-naïve patients with inoperable, locally advanced or metastatic GIST received oral masitinib (7.5 mg/kg/day) until progression, refusal or toxicity. Efficacy variables included response rate, best response (RECIST), progression-free survival (PFS) and overall survival (OS). Initial results were previously reported in EJC 2010. We present here the same series with updated PFS and OS (median follow up of 48 months). Results: 30 patients with a median age of 58 years (60% of males) were included from June 2005 to April 2007 in five French institutions. At the cut-off date (31 august 2010), 9 patients are still under treatment with a median treatment duration of 41 months (min=33, max=52). Two additional progressions have been reported for a total of 14 events (13 progressions and 1 death). Updated median PFS is 41 months (95% CI: [17.5; NR]) with PFS rates of 60% [39; 77], 56% [35; 73] and 45% [24; 64] respectively at 2, 3 and 4 years. With 8 patients dead, median OS is not yet reached with OS rates of 90% [72; 97], 87% [68; 95] and 74% [52; 87], respectively, at 2, 3, and 4 years. The main frequent relevant grade 3 toxicities were: rash (10%), neutropenia (7%) and abdominal pain (7%) with one patient presented a grade 4 skin exfoliation. No other relevant long-term toxicities were reported and no more patients discontinued treatment due to suspected toxicity. Conclusions: The long term results observed with masitinib confirm a very interesting activity with prolonged PFS and OS. These results support the head to head comparison with imatinib in the currently ongoing phase III randomized clinical trial in first line locally advanced or metastatic GIST patients. [Table: see text]

Surgical management in metastatic gastrointestinal stromal tumor (GIST) patients after imatinib mesylate treatment

Imatinib mesylate (IM) demonstrates substantial efficacy in most patients with metastatic gastrointestinal stromal tumors (GISTs). However, progression of GIST eventually develops and emerges as a challenge. To assess the role of surgery in the multidisciplinary management of GISTs, we studied the surgical outcomes in GIST patients receiving IM. Between 2001 and May 2009, 161 metastatic GIST patients received IM. Among them, 35 patients undergoing 38 surgeries were investigated. Patients were categorized based on extent of disease before surgery (responsive or stable disease (PR, SD), local progression (LP), and generalized progression (GP)). Each tumor was investigated for genetic alteration before and after surgery. Disease status before surgery was significantly associated with surgical result. Gross tumor clearance was achieved in 42.9% of patients with responsive disease, but only 4.8% of those with focal resistance and 0% of those with disease progression (P = 0.022). GIST patients with PR, SD, and LP had significant better 2-year progression-free survival and overall survival than those with GP. Secondary mutations tended to be found more frequently in GIST patients with LP after surgery than those with response (10/21 (47.6%) vs. 2/14 (14.3%); P = 0.07), indicating that surgery may prevent potential development of secondary mutation in GIST patients with response. Secondary kit mutations were also found more frequently with primary exon 11 mutation than those with exon 9 mutation (38.7% vs. 16.7%; P = 0.394). Surgery may benefit selected GIST patients with PR, SD, and LP, especially for patients with LP because patients with LP had comparable survival to that of patients with responsive lesion. Surgery may prevent potential development of secondary mutations in selected patients with response after IM treatment. Secondary kit mutation was found more frequently in GIST patients with a primary kit exon 11 mutation than those with a primary kit exon 9 mutation.

Gastrointestinal stromal tumor (GIST) recurrence following surgery: review of the clinical utility of imatinib treatment

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. Surgery with complete removal of the tumor is the primary treatment for resectable GIST and the only chance of cure. However, recurrence after surgery is common. The 2 main prognostic factors are the mitotic activity and the size of the tumor. Tumor rupture is also a risk factor for postoperative recurrence, and extra care should be taken while manipulating this soft and friable tumor. Imatinib mesylate (IM, Gleevec®, Novartis, Basel, Switzerland) is a tyrosine kinase inhibitor and was first studied in the palliative setting for metastatic GIST patients in the year 2000. It is now the cornerstone of metastatic GIST treatment. IM also plays an important role as an adjuvant treatment for resectable GIST and has been shown to increase the recurrence-free survival in phase III studies. However, some points remain to be clarified. Notably, the ideal duration of adjuvant IM after surgery is still unclear. It is also difficult to determine the exact place of surgery in metastatic or recurrent GIST patients in the IM era. A multidisciplinary approach is, therefore, mandatory to offer GIST patients the best treatment available.

A phase I study of AMN107 alone and in combination with imatinib in patients (pts) with imatinib-resistant gastrointestinal stromal tumors (GIST)

9545 Background: Although imatinib induces durable clinical benefit in pts with metastatic GIST, resistance may emerge. AMN107 is a novel agent rationally designed to inhibit the PDGFR, KIT and Bcr-Abl tyrosine kinases. It has been shown to inhibit the proliferation of both imatinib-sensitive and imatinib-resistant GIST cells in vitro. Methods: Cohorts of imatinib-resistant GIST pts with radiological progressive disease (PD) were treated with AMN107 alone (400 mg p.o. bid) or with escalating doses of AMN107 (200 mg qd, 400 mg qd, or 400 mg bid) in combination with imatinib (400 mg p.o. bid). Pharmacokinetic (PK) analyses were performed for both AMN107 and imatinib. Serial tumor assessments included CT and 18FDG-PET scans. Results: As of 30 November 2005, 30 pts (13 women and 17 men), median age 51 yr (range 24–83) received AMN107 alone (n=18) or in combination up to 400 mg qd with imatinib (n=12) for 7 to 98 days (median 49 days). This study continues to accrue. Serious adverse events (SAE’s) reported in four patients deemed related to disease included abdominal pain, peritonitis and anemia. Grade 1/2 drug-related adverse events included hyperbilirubinemia, myalgias, peripheral edema and skin rash. Dose-limiting toxicity (Grade 3 elevated bilirubin) was reported in one pt on AMN107 alone. Efficacy data available for 18 patients show that three patients experienced progressive disease and 15 patients had stable disease, although the duration of follow-up was short. PK results in a limited number of patients showed that the effect of imatinib co-administration on AMN107 PK appears to be minimal, while AMN107 increases imatinib exposure on the average by 50%. Conclusions: AMN107 alone or in combination with imatinib has acceptable tolerability in patients with imatinib-resistant GIST. These initial data suggest there may be relevant activity of AMN107 alone and in combination with imatinib in imatinib-resistant metastatic GIST patients. [Table: see text]

Tyrosine kinase inhibitor as a therapeutic drug for chronic myelogenous leukemia and gastrointestinal stromal tumor.

The Philadelphia chromosome found in leukemia cells of chronic myelogenous leukemia (CML) patients is produced by translocation between chromosomes 9 and 22, resulting in expression of a chimera protein of Bcr and Abl kinase in the cytoplasm. Bcr-Abl kinase attracted oncology researchers as a molecular target for CML therapy, and a variety of small Abl kinase inhibitors were synthesized. STI571 (imatinib mesylate) was produced by modification of 2-phenylaminopyrimidine, a core structure of protein kinase C inhibitor, to improve selectivity, stability, solubility, and bioavailability. STI571 competitively binds to the ATP binding site of Bcr-Abl kinase and inhibits Abl tyrosine kinase activity. STI571 showed significant efficacy in the clinical study with CML patients at all stages: chronic phase, accelerated phase, and blast crisis. More than 90% of the patients showed good hematologic response to STI571. STI571 is also a potent inhibitor of a receptor-type c-Kit tyrosine kinase. Therefore, STI571 was examined for therapeutic efficacy against malignant Gastro-Intestinal Stromal Tumors (GIST), which are mainly caused by aberrant expression of a mutated c-Kit that is constitutively active without binding of a ligand, stem cell factor (SCF). More than a half of the metastatic GIST patients enrolled in the clinical study responded to STI571. Thus, STI571 is now used as a therapeutic drug for both CML and GIST in more than 80 countries worldwide. Certain point mutations in the ATP binding site were found to be a cause of resistance to STI571 in both Bcr-Abl and c-Kit kinases. Therefore, it would be better to make a precise therapeutic strategy with STI571 based on the gene analysis data. It is also expected that it will be possible to design an inhibitor to overcome such resistance by using the structural information on the mutants.