New frontiers in the medical management of gastrointestinal stromal tumours

Mazzocca, Alessandro; Napolitano, Andrea; Silletta, Marianna; Ceruso, Mariella Spalato; Santini, Daniele; Tonini, Giuseppe; Vincenzi, Bruno

doi:10.1177/1758835919841946

Cited by 40 publications

(32 citation statements)

References 88 publications

(122 reference statements)

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“…For third-line treatment, top-line results of the phase III VOYAGER trial comparing avapritinib to regorafenib has shown no statistical difference in PFS, although ORR was higher in the avapritinib cohort. A recent review has suggested a complete shift in second-line and third-line treatment with sunitinib and regorafenib being replaced by ripretinib and avapritinib [28]. In the same publication, an alternative flow chart is presented in which both drugs are followed by 'other tyrosine kinase inhibitors' in fourth line and beyond [28].…”

Section: Imatinib Reintroductionmentioning

confidence: 99%

“…A recent review has suggested a complete shift in second-line and third-line treatment with sunitinib and regorafenib being replaced by ripretinib and avapritinib [28]. In the same publication, an alternative flow chart is presented in which both drugs are followed by 'other tyrosine kinase inhibitors' in fourth line and beyond [28]. However, the overwhelming responses of PDGFRA D842V-mutated GISTs to avapritinib were not included.…”

Section: Imatinib Reintroductionmentioning

confidence: 99%

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Revolutions in treatment options in gastrointestinal stromal tumours (GISTs): the latest updates

Farag

Smith

Fotiadis

et al. 2020

Curr. Treat. Options in Oncol.

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Anastasia Constantinidou and Robin L. Jones contributed equally to this work. This article is part of the Topical Collection on Sarcoma Keywords Gastrointestinal stromal tumour I GIST I Tyrosine kinase inhibitors I TKI I Avapritinib I Ripretinib Opinion statement The treatment of advanced GIST is rapidly evolving with the development of novel molecular compounds such as avapritinib and ripretinib, but also promising results have been achieved with cabozantinib in a phase II trial. The availability of over five lines of treatment for patients with advanced GIST is likely to completely shift the current second-line and third-line treatment options, and will also potentially enable a personalised approach to treatment. Imatinib will most likely remain as the first-line treatment of choice for the vast majority of GIST patients. However, for GIST patients with tumours harbouring a D842V mutation in PDGFRA exon 18, avapritinib has shown efficacy and will become first-line therapy for this molecular subgroup. For second-and third-line treatment, results are awaited of a number of clinical trials. However, second-line and further treatment could potentially be tailored depending on secondary mutations found in imatinib-resistant GISTs. As secondary resistance to TKIs remains the biggest challenge in the treatment of GIST and despite negative results

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Section: Imatinib Reintroductionmentioning

confidence: 99%

Section: Imatinib Reintroductionmentioning

confidence: 99%

Revolutions in treatment options in gastrointestinal stromal tumours (GISTs): the latest updates

Farag

Smith

Fotiadis

et al. 2020

Curr. Treat. Options in Oncol.

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“… 1 , 2 Clinical benefits from the administration of REG were initially observed in metastatic colorectal cancer (CRC) and gastrointestinal stromal tumour (GIST), as stated by the three randomized controlled clinical trials (RCTs) CORRECT, GRID and CONCUR. 3 – 5 More recently, REG gained approval in hepatocellular carcinoma (HCC), on the basis of data from the RESORCE trial, 6 where REG showed a survival benefit in patients affected by advanced or metastatic HCC who progressed on sorafenib treatment. Currently, REG is approved as a single agent for the treatment of CRC, GIST and HCC at a dose of 160 mg orally once daily on days 1–21 of each 28 days cycle.…”

Section: Introductionmentioning

confidence: 99%

“…Prompt identification of AEs is fundamental to guarantee that patients can be treated as safely as possible and, in order to ensure that anticancer treatment is effective, maintaining the optimal dose levels represents a major issue. 15 , 16 …”

Section: Introductionmentioning

confidence: 99%

Dose reduction and discontinuation of standard-dose regorafenib associated with adverse drug events in cancer patients: a systematic review and meta-analysis

et al. 2020

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Background: Regorafenib (REG) is an oral multikinase inhibitor used in colorectal cancer, gastrointestinal stromal tumour and hepatocellular carcinoma. Several adverse events (AEs) are commonly reported during REG administration, and strategies for managing AEs in everyday clinical practice include supportive care, dose modifications and, when necessary, treatment withdrawal. We performed a systematic review and meta-analysis to assess the schedule treatment modifications of REG associated with AEs across randomized controlled clinical trials (RCTs). Methods: Eligible studies included RCTs assessing standard dose REG versus placebo. Outcomes of interest included: AE-related permanent discontinuation, dose interruptions and dose reductions. Results: We retrieved all the relevant RCTs through PubMed/Med, Cochrane library and EMBASE: 7 eligible studies involving a total of 2099 patients (Regorafenib: 1362; placebo: 737) were included in our analysis. The use of REG was associated with higher incidence and risk of all outcomes of interest when compared with placebo. The incidences of permanent discontinuation, dose interruptions and dose reductions in patients receiving REG were 9.7%, 57.2% and 47%, respectively, versus 3.3%, 16.7% and 7.7% of placebo group; compared with placebo, the summary relative risks (RRs) of permanent discontinuation, dose interruptions and dose reductions in REG arm were 2.80 (95% CI 1.85–4.22), 3.21 (95% CI 2.59–3.99) and 6.02 (95% CI 3.28–11.03), respectively. Conclusions: Treatment with REG at the standard dose of 160 mg is associated with a significant increase in AE-related permanent discontinuation, dose interruptions and dose reductions. Prompt identification and management of AEs seem mandatory to obtain maximal benefit from REG treatment. In the current landscape, dose personalization of REG may have the potential to improve quality of life, minimize treatment discontinuation and maximize patient outcomes.

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“…2 GIST responds to treatment with targeted KIT/PDGFRA inhibitors such as imatinib mesylate. [3][4][5] However, up to 40-50% of GISTs develop secondary resistance after an average of 24 months of imatinib treatment. Based on the natural evolution of the disease, the patient could be placed on a higher dose of imatinib or a tyrosine kinase inhibitor such as ripretinib, though resistance can be a challenge.…”

Section: Introductionmentioning

confidence: 99%

<p>Chloroquine Combined with Imatinib Overcomes Imatinib Resistance in Gastrointestinal Stromal Tumors by Inhibiting Autophagy via the MAPK/ERK Pathway</p>

Zheng¹,

Shu

et al. 2020

OTT

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Background: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. However, up to 40-50% of GISTs develop secondary resistance after an average of 24 months of imatinib treatment. It has been reported that autophagy can promote the survival of GIST cells and induce drug resistance. Presently, the specific mechanism of autophagy in GISTs with imatinib resistance is not clear. Materials and Methods: The cell-counting kit (CCK)-8 method and flow cytometry were used for in vitro drug sensitivity testing and autophagy level detection. Detection of the apoptosis level was by flow cytometry with the annexin V Kit. Western blotting was used to analyze the role of autophagy and apoptosis in GIST cells with CQ alone, imatinib alone, or in combination, and to analyze MAPK pathway expression. In vitro results were confirmed by in vivo experiments using the mice model. Hematoxylin and eosin and immunohistochemical staining were used to detect the pathological characteristics and immunophenotype of the transplanted tumor. Detection of KIT and PDGFRA gene mutations in the transplanted imatinib-resistant GIST was done by denaturing high performance liquid chromatography (DHPLC) and direct sequencing. ERK and KIT expression and regulation levels were detected by Western blotting. Results: In vitro and vivo experiments, the autophagy level of imatinib-resistant cells was higher than that of normal cells; CQ combined with imatinib can promote apoptosis by blocking autophagy of imatinib-resistant cells. In the meanwhile, we found that the phosphorylation level of ERK may be related to autophagy. Conclusion: Our data suggest that autophagy through the MAPK/ERK pathway may play a pivotal role in imatinib-resistant GIST proliferation. Moreover, combining an autophagy inhibitor with imatinib may be a potential valuable strategy in overcoming acquired resistance in GIST patients.

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New frontiers in the medical management of gastrointestinal stromal tumours

Cited by 40 publications

References 88 publications

Revolutions in treatment options in gastrointestinal stromal tumours (GISTs): the latest updates

Revolutions in treatment options in gastrointestinal stromal tumours (GISTs): the latest updates

Dose reduction and discontinuation of standard-dose regorafenib associated with adverse drug events in cancer patients: a systematic review and meta-analysis

<p>Chloroquine Combined with Imatinib Overcomes Imatinib Resistance in Gastrointestinal Stromal Tumors by Inhibiting Autophagy via the MAPK/ERK Pathway</p>

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