Systematic review of the side effects associated with tyrosine kinase inhibitors used in the treatment of gastrointestinal stromal tumours on behalf of the EORTC Quality of Life Group

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Abstract

Tyrosine kinase inhibitors (TKIs) have revolutionised the treatment of advanced gastrointestinal stromal tumours (GISTs). Imatinib is approved as first line therapy and sunitinib is used in cases of imatinib resistance or intolerance. Compared with conventional treatments, TKIs are delivered over longer periods of time and are more specific in their targets (i.e., molecularly targeted), thus presenting different side effect profiles. We review the safety profiles of imatinib and sunitinib, documenting a total of 95 side effects including patient based as well as medically defined outcomes. Gastrointestinal complaints, particularly diarrhoea and nausea, oedema, fatigue and haematological disorders, notably anaemia, are amongst the most prevalent side effects. While there is overlap between the side effect profiles of imatinib and sunitinib, important differences emerge in the frequencies of oedema, hypertension, thyroid functioning, muscle and joint pains, as well as skin and oral conditions. Awareness of potential side effects is informative to both clinician and patient in terms of treatment decision making and can have important implications for treatment adherence and clinical outcome.

Introduction

Gastrointestinal stromal tumours (GISTs) are mesenchymal neoplasms of the gastro-intestinal (GI) tract usually found in the stomach (60%), followed by the jejunum and ileum (30%), duodenum (5%) and colorectum (<5%) [1]. Most GISTs (85–87%) express a mutant protein tyrosine kinase KIT (CD117) while a smaller percentage (5%) harbour mutations in the platelet-derived growth factor receptor-alpha (PDGFR-α) gene [1], [2]. Historically, treatment for advanced GISTs has been limited. While localised GISTs respond well to surgery, large unresectable or metastatic tumours are resistant to conventional chemotherapy and radiotherapy [3]. There have been dramatic improvements in the treatment of advanced GISTs over the last decade due to the development of targeted agents known as tyrosine kinase inhibitors (TKIs) which inhibit a particular target molecule involved in tumour progression rather than targeting cellular machinery common to both malignant as well as normal dividing cells.

The TKI imatinib is now the first line therapy for GIST with a response rate of 68% and median overall survival time of 58 months [4]. Most advanced GISTs respond to imatinib for 12–36 months but secondary resistance develops in more than 80% of patients [5]. The multiple TKI inhibitor sunitinib is recommended for the treatment of GISTs where imatinib resistance or intolerance has developed. A further dual targeted inhibitor, regorafenib has recently received approval as a third line treatment option in the United States. Although TKIs, in particular imatinib, are described as tolerable with manageable side effect profiles [6], [7], [8], [9], [10] nearly all imatinib-treated patients (>95%) experience at least one side effect of any grade of severity [4], [6], [11], [12], [13], [14].

TKIs tend to be administered over a much longer period of time compared with conventional treatments and have different side effect profiles. Although TKIs are selective in their focus of malignant cells, there is some interaction with healthy cells. Treatment side effects may present as symptoms experienced by the patient such as fatigue or nausea. For the purpose of this review, we use the term patient based side effects to indicate physical and psychological outcomes as described by patients. TKI-induced side effects falling within the realm of patient experience might be captured from patient reported outcome measures or quality of life measures or following on from consultation with health care providers. Details on the source of such outcomes are often lacking and in the current review we are not able to ascertain whether or not patient reported measures were used. Outcomes defined by medical examination or investigation such as liver or renal failure, are referred to as medically defined side effects and are based on a more formal diagnosis.

TKI side effects are related to agent (e.g., imatinib, sunitinib) [15] dose [11], [14], [16], treatment duration [7], age [17], sex [17] and cultural differences [18], [19]. Empirical data suggest that patients and physicians do not always agree on symptom severity with the tendency for physicians to rate symptoms as less severe compared with patients [20], [21]. The recent National Cancer Institute (NCI) initiative to create a version of the NCI's Common Terminology Criteria for Adverse Events (PRO-CTCAE) that can be rated by patients was largely driven by this type of scientific evidence (http://outcomes.cancer.gov/tools/pro-ctcae_fact_sheet.pdf) [22]. There is generally lower concordance between patients and physicians for subjective symptoms such as fatigue [21], but again the source of this information is not always clear. In future, use of the PRO-CTCAE (http://outcomes.cancer.gov/tools/pro-ctcae_fact_sheet.pdf) or other PRO measures will enable recording of the patient's own assessment of patient based side effects.

In this review, we systematically document the broad spectrum of TKI-related side effects categorised as symptoms experienced by patients or side effects defined by medical investigation. Within the GIST literature, reports of TKI side effects are often presented as a secondary outcome measure alongside clinical efficacy [23], [24], [25] or as part of management guidelines [26], [27]. Wolter and Schoeffski [15] however offer a comprehensive comparison of the tolerability and safety profiles of imatinib and sunitinib. The current review represents an extension of Wolter and Schoeffski's work to offer a more extensive and updated list of side effects and to highlight the symptoms experienced by patients. The current review also systematically quantifies the frequency of side effect reports in the literature.

Section snippets

Methods

The protocol for this systematic review was informed by the Centre for Reviews and Dissemination Guidance for undertaking reviews in health care [28] and the reporting follows the Preferred Reporting Items of Systematic reviews and Meta-Analyses (PRISMA) guidelines [29]. The protocol for the review is available from the first author.

Literature search

The publication selection process generated 1356 hits, of these, 174 (12.8%) were accepted for review. Of the 174 papers accepted, 27 (16%) papers were subsequently rejected by the third reviewer based on content or source of publication. An additional 29 (17%) papers did not provide information on side effects and one paper [32] reported drug interaction effects. Thus 117 (67%) of the retrieved papers were reviewed with an additional 11 papers identified from cross-referencing leaving 128

Discussion

A total of 95 side effects across 20 broad categories were captured in this review including 65 patient based side effects and 30 medically defined side effects. The majority of side effects were of low grade severity and described as acceptable and manageable. GI complaints and oedema were the most prevalent in terms of paper citations, reported in 57% papers and 56% papers respectively. Within the GI category, diarrhoea and nausea were the most prevalent, affecting 39% and 38% patients

Conclusion

This review has provided a systematic quantification of the side effects experienced by GIST patients treated with imatinib or sunitinib which is informative to both clinicians and patients. Although the toxicity profiles of imatinib and sunitinib are similar, there are some significant differences. The frequencies of recorded side effects will help inform patients before they start treatment. Furthermore, by being alert to potential side effects, clinicians can promptly consider effective

Conflict of interest

The authors declare no conflicts of interest or competing financial interests.

Authors’ contributions

All authors were involved in the conception of the review and made important contributions in revising the manuscript. S.S., A.W. and D.F. screened the papers for review. S.S. and C.J. were involved in extracting and categorising the data.

Reviewers

Piotr Rutkowski, MD, PhD, Professor; Head of Department, Maria Sklodowska-Curie Memorial Cancer Center – Institute, Department of Soft Tissue/Bone Sarcoma and Melanoma, Roentgena Str. 5, PL-02-781 Warsaw, Poland.

Anne Bredart, Clinical psychologist, Institut Curie, Psycho-Oncology Unit, 26 rue d’Ulm, FR-75 005 Paris, France.

Acknowledgement

This study was funded by the European Organisation for Research and Treatment of Cancer Quality of Life (EORTC QOL) Group.

Dr. Samantha C. Sodergren earned a Bachelor of Science Degree in Psychology in 1992 from the University of Southampton and subsequently a Doctor of Philosophy Degree from the University of Plymouth in 2002 in the field of quality of life research. In 2002, Samantha also earned her status as a Chartered Health Psychologist within the British Psychological Society. She has worked as a Research Fellow developing novel approaches to quality of life assessment and is currently co-ordinating studies

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