scholarly journals Gastrointestinal Stromal Tumors (GIST)—Paving the Way for Modern Oncology—Epidemiology, Diagnosis, Treatment

2015 ◽  
Vol 11 (1) ◽  
pp. 57
Author(s):  
Elena Tsvetkova ◽  
E Celia Marginean ◽  
Carolyn Nessim ◽  
Shailendra Verma ◽  
◽  
...  
Keyword(s):  
Metastatic Disease ◽  
Gastrointestinal Stromal Tumors ◽  
Kinase Inhibitor ◽  
Locally Advanced ◽  
Neoadjuvant Treatment ◽  
Line Treatment ◽  
Borderline Resectable ◽  
Secondary Resistance ◽  
Stromal Tumors ◽  
Unresectable Disease

Gastrointestinal stromal tumors (GIST) are relatively rare tumors arising in the gastrointestinal tract. Clinical presentations of GIST are related to the site of origin, tumor size, and presence of ulceration. Surgery followed by adjuvant treatment with the BCR-ABL tyrosine kinase inhibitor, imatinib, for 3 years, in high-risk tumors is the only curative modality. Neoadjuvant treatment with imatinib may be considered in the setting of locally advanced primary borderline resectable/unresectable disease. Treatment with imatinib in patients with metastatic or unresectable disease is associated with significant improvements in overall survival (OS) from 18 to 57 months. In patients with metastatic disease, those responding to imatinib therapy may be considered for surgery and this may be beneficial if resection of the primary and metastatic disease is feasible and if imatinib is continued post resection. Other locoregional treatments such as radiofrequency ablation (RFA) and hepatic artery embolization (HAE) with or without chemotherapy may achieve long-lasting disease control and may be considered in highly selected patients. In patients with primary or secondary resistance to imatinib, second-line treatment with sunitinib and third-line treatment with regorafenib is recommended. However, despite all of these advances, few patients with metastatic disease are cured and further trials of novel agents or combinations are required.

scholarly journals Gastrointestinal Stromal Tumors (GIST)—Paving the Way for Modern Oncology—Epidemiology, Diagnosis, Treatment

2015 ◽  
Vol 11 (01) ◽  
pp. 74
Author(s):  
Elena Tsvetkova ◽  
E Celia Marginean ◽  
Carolyn Nessim ◽  
Shailendra Verma ◽  
◽  
...  
Keyword(s):  
Metastatic Disease ◽  
Gastrointestinal Stromal Tumors ◽  
Kinase Inhibitor ◽  
Locally Advanced ◽  
Neoadjuvant Treatment ◽  
Line Treatment ◽  
Borderline Resectable ◽  
Secondary Resistance ◽  
Stromal Tumors ◽  
Unresectable Disease

Gastrointestinal stromal tumors (GIST) are relatively rare tumors arising in the gastrointestinal tract. Clinical presentations of GIST are related to the site of origin, tumor size, and presence of ulceration. Surgery followed by adjuvant treatment with the BCR-ABL tyrosine kinase inhibitor, imatinib, for 3 years, in high-risk tumors is the only curative modality. Neoadjuvant treatment with imatinib may be considered in the setting of locally advanced primary borderline resectable/unresectable disease. Treatment with imatinib in patients with metastatic or unresectable disease is associated with significant improvements in overall survival (OS) from 18 to 57 months. In patients with metastatic disease, those responding to imatinib therapy may be considered for surgery and this may be beneficial if resection of the primary and metastatic disease is feasible and if imatinib is continued post resection. Other locoregional treatments such as radiofrequency ablation (RFA) and hepatic artery embolization (HAE) with or without chemotherapy may achieve long-lasting disease control and may be considered in highly selected patients. In patients with primary or secondary resistance to imatinib, second-line treatment with sunitinib and third-line treatment with regorafenib is recommended. However, despite all of these advances, few patients with metastatic disease are cured and further trials of novel agents or combinations are required.

Imatinib mesylate therapy in advanced gastrointestinal stromal tumors—A Regional cancer centre experience

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 19505-19505
Author(s):  
K. M. Patel ◽  
P. M. Shah ◽  
S. N. Shukla ◽  
B. J. Parikh ◽  
A. S. Anand ◽  
...  
Keyword(s):  
Local Recurrence ◽  
Imatinib Mesylate ◽  
Metastatic Disease ◽  
Gastrointestinal Stromal Tumors ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Free Survival ◽  
Stromal Tumors ◽  
Post Surgery

19505 Background: The treatment of gastrointestinal stromal tumors has been revolutionised by the advent of Imatinib, a specific tyrosine kinase inhibitor. Post operative local and metastatic recurrences of this tumor have been effectively managed by Imatinib. Here we present our experience of Imatinib in recurrent locally advanced/metastatic gastrointestinal stromal tumors (GIST). Methods: From Nov 2001 to Sep 2005, 33 patients with metastatic and / or locally advanced inoperable CD-117 positive GIST were offered imatinib mesylate therapy at 400 mg/day p.o. A total of 21 patients were evaluable for tumor response. Follow up period ranged from 4 months to 38 months with median follow up period being 18 months. Median age is 58 yrs, M:F ratio is 6:4. ECOG performance status was 0–1 in 70% (23 patients) and 2 in 30% (10 patients). 70% patients had post surgery recurrence. 2 patients (6%) had received adjuvant chemotherapy prior to recurrence. 30% (10 patients) had local recurrence, 40% (13 patients) had metastatic disease while 30% (10 patients) had local recurrence as well as metastatic disease. Results: Response evaluation was done by RECIST criteria. 15% (5 patient) showed CR while PR rates were 30% (10 patients). The overall major response (CR+PR) was 45%. The overall progression free survival was as high as 80%. All the patients who had a progression free survival also had a significant improvement in quality of life. Conclusions: Imatinib mesylate therapy shows significant survival benefits in locally advanced inoperable/metatstatic gastrointestinal stromal tumors. It will be a very long time before PET scan for evaluation and follow up becomes feasible in developing country setting. No significant financial relationships to disclose.

Intraoperative radiotherapy (IORT) in the era of intensive neoadjuvant chemotherapy and chemoradiotherapy for locally advanced and borderline resectable adenocarcinoma of the pancreas (PDAC).

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 393-393 ◽  
Author(s):  
Florence K. Keane ◽  
Jennifer Yon-Li Wo ◽  
Cristina Ferrone ◽  
Jeffrey W. Clark ◽  
Lawrence Scott Blaszkowsky ◽  
...  
Keyword(s):  
Frozen Section ◽  
Locally Advanced ◽  
Neoadjuvant Treatment ◽  
Intraoperative Radiotherapy ◽  
Distant Metastases ◽  
Borderline Resectable ◽  
Surgical Exploration ◽  
Positive Margins ◽  
Unresectable Disease ◽  
Significant Difference

393 Background: Improved outcomes with FOLFIRINOX or gemcitabine with nab-paclitaxel in the treatment of metastatic PDAC have prompted incorporation of these regimens into neoadjuvant treatment of PDAC. While some patients are still found to be unresectable after neoadjuvant treatment, others are able to undergo resection. Our aims are to evaluate outcomes and toxicities associated with use of IORT in this setting. Methods: We retrospectively analyzed records of 85 patients with locally advanced/ borderline resectable PDAC who received neoadjuvant treatment with chemotherapy and/or chemoradiotherapy followed by surgical exploration in an IORT-equipped operating suite between 2010-2015. Descriptive statistics were used to compare surgical outcomes. Survival analysis was used to calculate overall survival (OS). Results: Of 85 patients, 49 (57.6%) underwent resection after neoadjuvant treatment, 27 (31.8%) were unresectable, and 9 (10.6%) were found to have distant metastases. 24 of 49 patients who underwent resection received IORT for close/positive margins on intraoperative frozen section. There was no significant difference in operative times, postoperative complications, or operative morbidity in patients who underwent resection and IORT vs those who underwent resection alone. Median OS was 31.1 months in patients who underwent resection alone and 35.1 months in patients who underwent resection and IORT. Despite the increased incidence of close/ positive margins in patients who underwent resection and IORT, the rates of local recurrence were similar to those who underwent resection alone. 26 of 27 patients with unresectable disease upon exploration received IORT. Median OS was 20.5 months. IORT was associated with increased hospital stay (4 vs. 3.5 d), but no significant difference in operative time or morbidity. Conclusions: IORT is not associated with increased toxicity when used in conjunction with resection or surgical exploration after neoadjuvant therapy. IORT resulted in median OS of 35 months for patients with close or positive margins and of 20.5 months for patients with unresectable disease.

Use of ponatinib to inhibit kinase mutations associated with drug-resistant gastrointestinal stromal tumors (GIST).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 10509-10509 ◽  
Author(s):  
Michael C. Heinrich ◽  
Jonathan A. Fletcher ◽  
Rana Anjum ◽  
Cesar Serrano-Garcia ◽  
Sadanand Vodala ◽  
...  
Keyword(s):  
Cell Lines ◽  
Gastrointestinal Stromal Tumors ◽  
Kinase Activity ◽  
Binding Pocket ◽  
Drug Resistant ◽  
Line Treatment ◽  
Resistance Mutations ◽  
Secondary Resistance ◽  
Stromal Tumors ◽  
Exon 11

10509 Background: Ponatinib (PO) is a multi-targeted tyrosine kinase inhibitor with potent pan-BCR-ABL activity that has recently been approved for treatment of CML and Ph+ ALL. PO also inhibits the kinase activity of KIT. Approximately 80% of gastrointestinal stromal tumors (GIST) contain primary activating KIT mutations, the majority of which cluster in exon 11. Imatinib (IM) is approved for the 1st line treatment of GIST; however, patients frequently relapse due to the acquisition of secondary resistance mutations located in either the KIT ATP-binding pocket or the activation (A) loop. Sunitinib (SU) is approved for 2nd line treatment of GIST but does not effectively inhibit A-loop mutants. Here we explored the activity of PO against major primary and secondary KIT mutants found in GIST. Methods: The drug sensitivity of KIT mutants was determined using engineered Ba/F3 cells harboring mutant forms of KIT exon 11 with or without ATP binding pocket or A-loop mutations. The abilities of PO, IM, SU, and regorafenib (RE) to inhibit viability and/or KIT kinase activity were compared using this system as well as an isogenic CHO cell system. We also profiled these same drugs using a panel of GIST cell lines, including cell lines with IM-resistant secondary KIT mutations. Results: In all in vitro systems, PO potently inhibited KIT exon 11 mutant kinases, with an IC50 of < 30 nM. PO also potently inhibited a range of secondary KIT mutants, including multiple A-loop mutant kinases. PO induced substantial tumor regression in Ba/F3 tumor models expressing a KIT exon 11 mutant with or without an A-loop mutation (D816H). Using GIST cell lines, PO inhibited the viability of those harboring primary KIT exon 11 and secondary resistance mutations more effectively than IM, SU, and RE. Importantly, in patients dosed once daily with 45 mg ponatinib, plasma concentrations achieved are predicted to lead to inhibition of all KIT mutants tested with the possible exception of V654A. Conclusions: PO potently inhibits the majority of clinically relevant KIT mutant kinases and has a broader spectrum of activity compared to IM, SU, or RE. Based on these data, a phase 2 study of PO in drug-resistant GIST is being initiated.

A phase II open-label study of cpi-613 in combination with modified (m)FOLFIRINOX in patients with locally advanced pancreatic cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS4176-TPS4176
Author(s):  
David Lawrence Bajor ◽  
AMR MOHAMED ◽  
J. Eva Selfridge ◽  
Erin E. Anderson ◽  
Jeffrey Hardacre ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase Ii ◽  
Metastatic Disease ◽  
Locally Advanced ◽  
Neoadjuvant Treatment ◽  
Advanced Pancreatic Cancer ◽  
Locally Advanced Pancreatic Cancer ◽  
Open Label ◽  
Borderline Resectable ◽  
Nccn Guidelines

TPS4176 Background: For patients with locally advanced pancreatic cancer, neoadjuvant trials are the preferred strategy. The goals of neoadjuvant treatment are to diminish the size of the primary tumor to allow for safe surgical resection and to limit the chance of developing metastatic disease. mFOLFIRINOX is the gold-standard for treatment in the adjuvant setting and an acceptable regimen in the neoadjuvant setting with many ongoing neoadjuvant trials using it as a chemotherapeutic backbone. CPI-613 (devimistat) is a small-molecule inhibitor of pyruvate dehydrogenase and alpha-ketogluterate dehydrogenase that has been studied in combination with mFOLFIRINOX in a phase I trial of patients with metastatic pancreas cancer and shown to be safe at the proposed phase II dose. Methods: This is a single-center, single-arm phase II trial for patients with locally advanced pancreatic cancer; defined as either borderline resectable or unresectable according to NCCN guidelines and interpreted by the primary investigator. Patients with metastatic disease are excluded. Patients will receive treatment with CPI-613 and mFOLFIRINOX per the table below. The primary endpoint is overall survival. Secondary endpoints are progression free survival and resection rate. At the time of submission this study has completed initial accrual with 37 patients enrolled. Clinical trial information: NCT03699319. [Table: see text]

Molecular Correlates of Imatinib Resistance in Gastrointestinal Stromal Tumors

2006 ◽  
Vol 24 (29) ◽  
pp. 4764-4774 ◽  
Author(s):  
Michael C. Heinrich ◽  
Christopher L. Corless ◽  
Charles D. Blanke ◽  
George D. Demetri ◽  
Heikki Joensuu ◽  
...  
Keyword(s):  
Gastrointestinal Stromal Tumors ◽  
Molecular Mechanisms ◽  
Clonal Evolution ◽  
Clinical Problem ◽  
Primary Resistance ◽  
Imatinib Resistance ◽  
Secondary Resistance ◽  
Stromal Tumors ◽  
Rnai Technology ◽  
Imatinib Resistant

Purpose Gastrointestinal stromal tumors (GISTs) commonly harbor oncogenic mutations of the KIT or platelet-derived growth factor alpha (PDGFRA) kinases, which are targets for imatinib. In clinical studies, 75% to 90% of patients with advanced GISTs experience clinical benefit from imatinib. However, imatinib resistance is an increasing clinical problem. Patients and Methods One hundred forty-seven patients with advanced, unresectable GISTs were enrolled onto a randomized, phase II clinical study of imatinib. Specimens from pretreatment and/or imatinib-resistant tumors were analyzed to identify molecular correlates of imatinib resistance. Secondary kinase mutations of KIT or PDGFRA that were identified in imatinib-resistant GISTs were biochemically profiled for imatinib sensitivity. Results Molecular studies were performed using specimens from 10 patients with primary and 33 patients with secondary resistance. Imatinib-resistant tumors had levels of activated KIT that were similar to or greater than those typically found in untreated GISTs. Secondary kinase mutations were rare in GISTs with primary resistance but frequently found in GISTs with secondary resistance (10% v 67%; P = .002). Evidence for clonal evolution and/or polyclonal secondary kinase mutations was seen in three (18.8%) of 16 patients. Secondary kinase mutations were nonrandomly distributed and were associated with decreased imatinib sensitivity compared with typical KIT exon 11 mutations. Using RNAi technology, we demonstrated that imatinib-resistant GIST cells remain dependent on KIT kinase activity for activation of critical downstream signaling pathways. Conclusion Different molecular mechanisms are responsible for primary and secondary imatinib resistance in GISTs. These findings have implications for future approaches to the growing problem of imatinib resistance in patients with advanced GISTs.

PLX9486 shows anti-tumor efficacy in patient-derived, tyrosine kinase inhibitor-resistant KIT-mutant xenograft models of gastrointestinal stromal tumors

2018 ◽  
Vol 19 (2) ◽  
pp. 201-210 ◽  
Author(s):  
Yemarshet K. Gebreyohannes ◽  
Elizabeth A. Burton ◽  
Agnieszka Wozniak ◽  
Bernice Matusow ◽  
Gaston Habets ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Gastrointestinal Stromal Tumors ◽  
Kinase Inhibitor ◽  
Stromal Tumors ◽  
Xenograft Models

Adjuvant and Neoadjuvant Therapy for Pancreatic Adenocarcinoma

2017 ◽  
Author(s):  
Gregory C Wilson ◽  
Brent T Xia ◽  
Syed A Ahmed
Keyword(s):  
Pancreatic Cancer ◽  
Adjuvant Therapy ◽  
Neoadjuvant Therapy ◽  
Pancreatic Adenocarcinoma ◽  
Locally Advanced ◽  
Neoadjuvant Treatment ◽  
Advanced Pancreatic Cancer ◽  
Treatment Strategies ◽  
Ductal Adenocarcinoma ◽  
Borderline Resectable

Despite decades of advancement and research into the multimodal care of pancreatic cancer, mortality after the diagnosis of pancreatic ductal adenocarcinoma remains grim. The role of adjuvant therapy following surgical resection has been well established in the literature. However, adjuvant therapy is imperfect, and outside of a clinical trial, there are high rates of omission or delayed initiation of therapy. Neoadjuvant treatment strategies continue to be explored in the management of resectable, borderline-resectable, and locally advanced unresectable pancreatic adenocarcinoma. With improved resection rates and the possibility for tumor downstaging, neoadjuvant therapy has become standard for patients with borderline-resectable and locally advanced unresectable tumors. Additional benefits of neoadjuvant therapy in the treatment of resectable tumors include improved completion rates of systemic therapy and R0 resection rates. Future clinical trials, including the use of novel treatment agents and combination treatment strategies in both neoadjuvant and adjuvant regimens, will add value to the treatment of pancreatic adenocarcinoma. Key words: adjuvant therapy, borderline-resectable pancreatic cancer, locally advanced pancreatic cancer, neoadjuvant therapy, pancreatic adenocarcinoma, resectable disease 

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