Towards Global Consensus in the Treatment of GIST
The contemporary clinical landscape of gastrointestinal stromal tumor (GIST) has evolved rapidly over the past several years. Widely used treatment guidelines – from the European Society of Medical Oncology (ESMO) and the National Comprehensive Cancer Network – have recently been updated and represent the most up-to-date, comprehensive tools guiding the optimal management of GIST. In these, and in other published guidelines, close alignment among recommendations now exists for many of the clinical issues relevant to GIST management – surgery, use of the tyrosine kinase inhibitors imatinib and sunitinib and the role of pre- and post-operative imatinib, among others. This trend towards a global consensus in the treatment of GIST is the result of a relatively large amount of new data across the spectrum of its management. However, for some clinical considerations, recommendations still partially deviate. This review examines clinical recommendations and opinions on the management of GIST in the context of the latest data in the field and with an eye towards a multidisciplinary approach including surgical oncology, medical oncology, pathology and diagnostic radiology. Points of consensus are highlighted. Expert opinion is presented on management areas where no scientific evidence or firm recommendations currently exist; lingering and unresolved questions or issues are included. Within this framework, we present an evaluation of current global guidelines on the following areas in GIST management: surgery in the metastatic setting; neoadjuvant therapy; adjuvant therapy; mutational analysis; maintenance tyrosine kinase inhibitor therapy; and radiological imaging in GIST. A summary of consensus across these guidelines based on clinical trial data is juxtaposed with expert opinion where gaps in data still remain.
In a therapeutic area once poorly understood, the experience with gastrointestinal stromal tumor (GIST) over the recent past has been said to help "…transform solid tumor oncology…". Changes in management practices influenced by advances in diagnosis, assessments of response to surgical and medical treatment, definitions of drug resistance, and notably, in the understanding of the role of specific mutations of the genes involved in the pathogenesis of GIST, have led to the creation of a variety of guidelines in order to help clinicians who may be facing the treatment of GIST keep pace with these improvements in healthcare delivery.
Guidelines from the European Society of Medical Oncology (ESMO) and the National Comprehensive Cancer Network (NCCN) in the USA, are among the more widely recognized and consulted for the management of patients with GIST. These were both updated in 2009 to reflect the continually evolving clinical landscape for patients with this tumor type. Still, it is important to recognize that other guidelines have also been developed with the expressed goal of providing summary recommendations for GIST management in specific countries, for example, Canada, Switzerland and Japan. These were developed to address particular clinical concerns and/or health regulatory authorities' treatment requirements. For example, according to the authors of Japanese practice guidelines, two unique conditions exist in that country: a substantial proportion of GIST is incidentally found as submucosal tumor (SMT) during routine endoscopic screening examinations; and the relatively high incidence of SMT-like gastric cancer make the differential diagnosis of GIST from that of gastric cancer resembling SMT clinically important.
The science of GIST has evolved from that of a poorly characterized mesenchymal neoplasm of the GI tract and mesentery with an ambiguous pathobiology to one of an archetype of molecularly targeted malignancies. The discovery that approximately 85% of GISTs are driven by oncogenic mutations that occur, to varying degrees, in two mutually exclusive pivotal tyrosine kinase receptors intricately involved in cell signaling pathways – KIT and PDGF receptor-α (PDGFRA) – spurred the current management paradigm for advanced GIST that relies on the use of imatinib mesylate and other tyrosine kinase inhibitors (TKIs). These agents inhibit the function of the GIST-associated, mutated tyrosine kinase receptor proteins. In the face of such 'activating mutations', both cell proliferation and apoptotic pathways become aberrantly altered. Nevertheless, surgery remains the cornerstone of therapy for primary localized, resectable GIST. Recently, the role of surgery has been investigated even in advanced/metastatic cases. The use of post- and/or pre-operative imatinib – that is, adjuvant and/or neoadjuvant therapy – have each been shown to improve surgical outcomes, and their effects on rates of recurrence and, perhaps, overall survival, continue to be evaluated.
Updated guidelines are beginning to offer consistent recommendations, especially in areas where new data from randomized trials are available, for example, on the use of adjuvant imatinib; yet there remain gaps in the continually evolving field of GIST. Emerging data now exist that could not be fully considered during the development of existing guidelines, and other data regarding, for example, the potential role of second-generation TKI therapies, such as nilotinib, are still needed.
The goals of this review are to integrate established and late-breaking data in GIST, identify unresolved questions/issues, and juxtapose expert opinion where no scientific evidence or firm recommendations currently exist. A main goal is to highlight the global consensus that has emerged in major treatment guidelines, reflecting in part the accumulation of mature trial data as well as the growing worldwide clinical experience in this field. The vast majority of clinical data and management recommendations relate to the use of first-line imatinib and it is on these that this review focuses.
It is widely recognized that the successful management of GIST clearly relies on a multidisciplinary approach comprised of medical oncologists, surgical oncologists, pathologists and diagnostic radiologists. With this in mind, topics include: surgery in metastatic GIST; neoadjuvant and adjuvant therapy with imatinib; role of mutational analysis; maintenance TKI therapy; and radiological assessments of treatment response. While not intended to offer yet another set of guidelines, it is nevertheless hoped that the information provided herein might help resolve some of the potential confusion clinicians may face as they approach a diagnosis of GIST, as well as contribute to future iterations of such recommendations.
Abstract and Introduction
Abstract
The contemporary clinical landscape of gastrointestinal stromal tumor (GIST) has evolved rapidly over the past several years. Widely used treatment guidelines – from the European Society of Medical Oncology (ESMO) and the National Comprehensive Cancer Network – have recently been updated and represent the most up-to-date, comprehensive tools guiding the optimal management of GIST. In these, and in other published guidelines, close alignment among recommendations now exists for many of the clinical issues relevant to GIST management – surgery, use of the tyrosine kinase inhibitors imatinib and sunitinib and the role of pre- and post-operative imatinib, among others. This trend towards a global consensus in the treatment of GIST is the result of a relatively large amount of new data across the spectrum of its management. However, for some clinical considerations, recommendations still partially deviate. This review examines clinical recommendations and opinions on the management of GIST in the context of the latest data in the field and with an eye towards a multidisciplinary approach including surgical oncology, medical oncology, pathology and diagnostic radiology. Points of consensus are highlighted. Expert opinion is presented on management areas where no scientific evidence or firm recommendations currently exist; lingering and unresolved questions or issues are included. Within this framework, we present an evaluation of current global guidelines on the following areas in GIST management: surgery in the metastatic setting; neoadjuvant therapy; adjuvant therapy; mutational analysis; maintenance tyrosine kinase inhibitor therapy; and radiological imaging in GIST. A summary of consensus across these guidelines based on clinical trial data is juxtaposed with expert opinion where gaps in data still remain.
Introduction
In a therapeutic area once poorly understood, the experience with gastrointestinal stromal tumor (GIST) over the recent past has been said to help "…transform solid tumor oncology…". Changes in management practices influenced by advances in diagnosis, assessments of response to surgical and medical treatment, definitions of drug resistance, and notably, in the understanding of the role of specific mutations of the genes involved in the pathogenesis of GIST, have led to the creation of a variety of guidelines in order to help clinicians who may be facing the treatment of GIST keep pace with these improvements in healthcare delivery.
Guidelines from the European Society of Medical Oncology (ESMO) and the National Comprehensive Cancer Network (NCCN) in the USA, are among the more widely recognized and consulted for the management of patients with GIST. These were both updated in 2009 to reflect the continually evolving clinical landscape for patients with this tumor type. Still, it is important to recognize that other guidelines have also been developed with the expressed goal of providing summary recommendations for GIST management in specific countries, for example, Canada, Switzerland and Japan. These were developed to address particular clinical concerns and/or health regulatory authorities' treatment requirements. For example, according to the authors of Japanese practice guidelines, two unique conditions exist in that country: a substantial proportion of GIST is incidentally found as submucosal tumor (SMT) during routine endoscopic screening examinations; and the relatively high incidence of SMT-like gastric cancer make the differential diagnosis of GIST from that of gastric cancer resembling SMT clinically important.
The science of GIST has evolved from that of a poorly characterized mesenchymal neoplasm of the GI tract and mesentery with an ambiguous pathobiology to one of an archetype of molecularly targeted malignancies. The discovery that approximately 85% of GISTs are driven by oncogenic mutations that occur, to varying degrees, in two mutually exclusive pivotal tyrosine kinase receptors intricately involved in cell signaling pathways – KIT and PDGF receptor-α (PDGFRA) – spurred the current management paradigm for advanced GIST that relies on the use of imatinib mesylate and other tyrosine kinase inhibitors (TKIs). These agents inhibit the function of the GIST-associated, mutated tyrosine kinase receptor proteins. In the face of such 'activating mutations', both cell proliferation and apoptotic pathways become aberrantly altered. Nevertheless, surgery remains the cornerstone of therapy for primary localized, resectable GIST. Recently, the role of surgery has been investigated even in advanced/metastatic cases. The use of post- and/or pre-operative imatinib – that is, adjuvant and/or neoadjuvant therapy – have each been shown to improve surgical outcomes, and their effects on rates of recurrence and, perhaps, overall survival, continue to be evaluated.
Updated guidelines are beginning to offer consistent recommendations, especially in areas where new data from randomized trials are available, for example, on the use of adjuvant imatinib; yet there remain gaps in the continually evolving field of GIST. Emerging data now exist that could not be fully considered during the development of existing guidelines, and other data regarding, for example, the potential role of second-generation TKI therapies, such as nilotinib, are still needed.
The goals of this review are to integrate established and late-breaking data in GIST, identify unresolved questions/issues, and juxtapose expert opinion where no scientific evidence or firm recommendations currently exist. A main goal is to highlight the global consensus that has emerged in major treatment guidelines, reflecting in part the accumulation of mature trial data as well as the growing worldwide clinical experience in this field. The vast majority of clinical data and management recommendations relate to the use of first-line imatinib and it is on these that this review focuses.
It is widely recognized that the successful management of GIST clearly relies on a multidisciplinary approach comprised of medical oncologists, surgical oncologists, pathologists and diagnostic radiologists. With this in mind, topics include: surgery in metastatic GIST; neoadjuvant and adjuvant therapy with imatinib; role of mutational analysis; maintenance TKI therapy; and radiological assessments of treatment response. While not intended to offer yet another set of guidelines, it is nevertheless hoped that the information provided herein might help resolve some of the potential confusion clinicians may face as they approach a diagnosis of GIST, as well as contribute to future iterations of such recommendations.
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