Managing Resistance to Gastrointestinal Stromal Tumours

Managing Resistance to Gastrointestinal Stromal Tumours

Armelle Dufresne, Isabelle Ray-Coquard, Jean-Yves Blay, Jerome Fayette, Laurent Alberti, Philippe Cassier, Pierre Paul Bringuier, Severine Tabone-Eglinger
European Oncological Disease 2006 Issue ll
Published: October 2008
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Incidence and Tumour Characteristics
The incidence of gastrointestinal stromal tumours (GISTs) is reported to be 1.45/100,000 persons per year.1 The most frequent primary sites are gastric (50%) and small bowel (25%). Colorectal, oesophageal and peritoneal GISTs are less frequent. GIST can be diagnosed at any age, with a median of 60 in large series. GISTs may be revealed by an abdominal mass, gastrointestinal (GI) bleeding, anaemia or incidentally. Once tumour material is obtained, the diagnosis of GISTs relies on standard histological examination, with a central review by an expert in sarcoma pathology for equivocal cases.2-5

Immunohistochemical analysis shows that these tumours are CD117-positive (95%), CD34-positive (70%), and smooth muscle actin-positive (40%), while PS100-positive and desmin-positive cases are seen in 5% and 2% of cases, respectively.7 An intraabdominal tumour suspected to be a GIST, in which CD117 immuno-staining is negative, should be considered for molecular analysis for KIT or platelet-derived growth factor receptor-? (PDGFR?) mutations in expert laboratories.3,4 Eighty-five per cent of GISTs exhibit mutations in the KIT and PDGFR? genes.

A mutation in exon 11, 9, 13 and 17 of the KIT gene is observed in 66%, 13%, 1% and 0.6% of the tumours respectively. Within the PDGFR? gene, mutations of exon 18 or 12 are observed in 5% and 1.5% of the cases.2 GISTs occurring during childhood have a lower incidence of KIT and PDGFR? gene mutations.

For localised tumours, risk assessment profile based on the size and mitotic index per 50 high-power fields remains a standard procedure, although prospective evaluation of a large cohort remains to be performed.5 The prognostic value of World Health Organization (WHO) grading is unclear in GISTs. Other histological and molecular characteristics are suspected to be prognostic parameters, i.e. serosal breaching, primary site and the nature of the mutations in the KIT and PDGFR? genes.

Treatment of Localised and Advanced GIST
The treatment of localised GISTs is surgery. In this setting, adjuvant treatment is experimental.3,4 Conversely, for metastatic or relapsing GISTs, imatinib is the standard treatment while the role of surgery is not known.3,4
For localised tumours, wedge resection of the stomach, or segmental resection of the intestine is considered as an adequate treatment, since GISTs tend to grow out of the primary organ. Adjacent organs adherent to the mass should be resected en bloc with the tumour, in order to avoid capsule rupture and intra-abdominal spillage. Though positive resection margins have not been definitely demonstrated to compromise survival, a reexcision should be considered in case of intramural, intra-lesionally excised tumours, without infiltration of the serosal surface.3,4 Adjuvant imatinib should only be given in randomised clinical trials. Neo-adjuvant imatinib should only be given in inoperable tumours, or in tumours when functionsparing surgery is the goal.3,4
For unresectable and/or metastatic disease, treatment with imatinib should be started immediately even if the tumour is not evaluable. It has not been demonstrated that complete surgical removal of the tumour is useful in this setting.3,4 Imatinib at 400mg per day is the currently recommended first-line treatment in advanced phase, since no overall survival improvement has yet been reported in the two large prospective randomised trials that compared first-line treatment with imatinib in doses of either 400mg and 800mg.6,8 It is worth noting, however, that the largest trial trials reported a superiority in terms of progression-free survival (PFS) in the 800mg arm. This benefit may be restricted to the subsets of patients with mutation in exon 9 of the KIT gene.9

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References:
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  2. Corless CL, Fletcher JA, Heinrich MC, “Biology of gastrointestinal stromal tumours”, J Clin Oncol (2004);22: pp. 3813–3825.
  3. Demetri GD, Benjamin RS, Blanke C, et al.,”Optimal management of patients with Gastrointesinal stromal tumours. Expansion and update of NCCN Clinical Practice Guidelines”, JNCCN (2004);2(Suppl. 1): May 2004.
  4. Blay JY, Bonvalot S, Casali P, et al., “GIST consensus meeting panelists. Consensus meeting for the management of gastrointestinal stromal tumours. Report of the GIST Consensus Conference of 20-21 March 2004, under the auspices of ESMO”, Ann Oncol (2005);16: pp. 566–578.
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  14. Polverino A, Coxon A, Starnes C, et al., “AMG 706, an Oral, Multikinase Inhibitor that Selectively Targets Vascular Endothelial Growth Factor, Platelet-Derived Growth Factor, and Kit Receptors, Potently Inhibits Angiogenesis and Induces Regression in Tumour Xenografts”, Cancer Res (2006);66: pp. 8715–8721.
  15. Reichardt P, Pink D, Lindner T, et al., “A phase I/II trial of the oral PKC-inhibitor PKC412 (PKC) in combination with imatinib mesylate (IM) in patients (pts) with gastrointestinal stromal tumour (GIST) refractory to IM”, ASCO Meeting Abstracts (2005);23: p. 3016.
  16. Reichardt P, Casali PG, Blay J, et al., “A phase I study of AMN107 alone and in combination with imatinib in patients (pts) with imatinib-resistant gastrointestinal stromal tumours (GIST)”, ASCO Meeting Abstracts (2006);24: p. 9545.


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