Elsevier

Seminars in Oncology

Volume 36, Issue 4, August 2009, Pages 302-311
Seminars in Oncology

Gastrointestinal Stromal Tumors II: Medical Oncology and Tumor Response AssessmentDisclosures

https://doi.org/10.1053/j.seminoncol.2009.06.003Get rights and content

The finding of mutations of KIT in gastrointestinal stromal tumors (GISTs) and subsequent development of kinase-directed therapy in metastatic GIST serve as a touchstone for the translation of laboratory research into clinical therapeutics. A variety of novel developments have followed the discovery of clinical activity of kinase-directed therapy against GIST. Radiological assessment of GIST challenges the standard of care for assessing tumor responses, ie, Response Evaluation Criteria in Solid Tumors (RECIST). Furthermore, the determination of the relationship of specific KIT mutations and sensitivity and resistance to kinase-directed agents and the assessment of inhibitor levels and the quality of response to those agents have implications beyond the treatment of sarcomas. These discoveries and the next chapters in this developing story are discussed in this review.

Section snippets

State-of-the-Art Tumor Response Assessment

It is clear that patients with gastrointestinal stromal tumors (GIST) do not play by the rules as pertains to response assessment after treatment with tyrosine kinase inhibitors (TKIs). What appeared to be new disease in the liver was actually responding disease that became hypodense after TKIs. Similarly, clear disease progression on imatinib with the “tumor within a tumor” effect is a finding not captured by either Response Evaluation Criteria in Solid Tumors (RECIST) or World Health

Primary and Secondary Resistance to Imatinib

Resistance to imatinib mesylate is a growing clinical problem in the management of GIST. Primary resistance is defined as evidence of clinical progression developing during the first 6 months of TKI treatment. Primary resistance is most commonly seen in patients with tumors carrying mutations in KIT exon 9 or in PDGFRA exon 18, or with tumors that are wild type for both genes.12, 13 Based on in vitro studies, the most common PDGFRA mutation, D842V substitution, which confers primary resistance

Delivering Treatment: Dose Intensity and Dose Density

As we reach the end of the first decade of the use of imatinib for patients with GIST (the first patient with GIST being treated with imatinib in March 2000),25 it is worthwhile reviewing the dosing of this remarkable drug. Specifically, given the use of scaled dosing of most chemotherapy agents, ie, dosing by body surface area or by weight, and the widespread use of weight-based dosing of medications in the pediatric setting, why is a flat dose of imatinib typically given to GIST patients (ie,

Delivering Treatment: Pharmacology-Driven Therapy

As holds true for all drugs that are orally administered, the pharmacokinetics of imatinib are largely determined by the absorption of the drug, the binding to blood components, its metabolism, and its elimination. With respect to absorption, imatinib has an excellent bioavailability, exceeding 95%, which is unaffected by food intake.42 It is thought that ATP-binding cassettes (ABC) pumps such as p-glycoprotein and breast cancer resistance (BCR) protein can influence the absorption of imatinib.

New Avenues in Gist Treatment

A variety of questions remain active issues for patients with recurrent GIST. Since only imatinib has been tested as first-line therapy in patients with metastatic GIST, we do not yet know the “best” first-line agent for this clinical situation. We are increasingly trying to target patients' therapies based on the clinical and genetic characteristics of their tumors. We are searching for ways to maximize the benefit from the drugs we have at hand presently. We do not know how best to treat

Where are We, in the End?

The management of GIST has improved during the past decade with a rapidity that rivals virtually any other type of human cancer. Yet, a majority of patients diagnosed with advanced GIST are still not cured with the currently available therapies.10, 26, 29 Therefore, new treatment options need to be explored.

A large group of novel TKIs related to imatinib and sunitinib are currently under clinical evaluation or recently evaluated. Several of these agents are listed in Table 1. Some of these have

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      Resistance to treatment with imatinib can be primary or secondary. Primary resistance to imatinib occurs in the first 6 months of therapy and encountered in GISTs with KIT exon 9, PDGFRA exon 18, SDH-deficient and wild-type GISTs.46 Primary resistance to treatment is suspected on imaging when there are no typical density changes or decline in metabolic activity on the first restaging CT or PET/CT.

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      After initiation of therapy, patients are assessed at short intervals to determine therapeutic effect. Non‐responders, especially those with documented mutations in KIT exon 9, may benefit from dose escalation[4-6] of imatinib mesylate depending upon clinical tolerance, whereas others may benefit from approved second‐line therapy with sunitinib malate.[7] This approach of preoperative TKI therapy followed by resection in patients with localized disease is based on observations of different investigators: patients with stable or responsive tumours achieved 12‐month overall survival (OS) of 95% in one study[8] and 2‐year actuarial survival approaching 100% in another.[9]

    • Resistance to treatment in gastrointestinal stromal tumours: What radiologists should know

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      Imatinib has dramatic efficacy in advanced GIST and was approved by the United States Food and Drug Administration (US FDA) and European Union in 2002 as the first line of treatment in patients with such tumours. Nevertheless, a subset of GISTs are inherently resistant to imatinib as they harbour different kinds of mutations.3 Additionally, GISTs may develop secondary resistance to imatinib during the course of treatment.4

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      However, not all GISTs respond to TKI therapy, and approximately 20% of patients do not tolerate specific TKI agents [2,9,10]. In addition, different exon mutations, wild-type status, and the development of tumor mutations during therapy can result in treatment resistance to TKIs [2,11,12]. Resection remains an option for patients with metastatic GIST.

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    Disclosures

    R.S. Benjamin: Novartis (consulting, speaker's bureau)

    M. Debiec-Rychter: Novartis (research support)

    A. Le Cesne: Novartis (honoraria)

    S. Sleijfer: Pfizer, Novartis (research support)

    G.D. Demetri: Novartis, Pfizer, Ariad, Johnson & Johnson, Genentech, Plexxikon, Bristol Meyers Squibb Research, Infinity Pharmaceuticals, Ziopharm, Alnylam, Idera, Bayer, Serono, Amgen (research support, consulting)

    H. Joensuu: Novartis, Bayer-Schering Pharma (honoraria), testimony (Pfizer)

    P. Schöffski: Novartis (research funding and honoraria); Pfizer (research funding and honoraria)

    A. Poveda: none

    1,2

    These authors contributed equally to this work.

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