Fast track — ArticlesDevelopment and validation of a prognostic nomogram for recurrence-free survival after complete surgical resection of localised primary gastrointestinal stromal tumour: a retrospective analysis
Introduction
Gastrointestinal stromal tumours (GIST) typically arise from the gastrointestinal tract, but also can be seen in the mesentery, omentum, and retroperitoneum.1, 2 They commonly contain a mutation in the KIT proto-oncogene, or less frequently, in platelet-derived growth factor receptor alpha (PDGFRA).3, 4, 5 GIST have received considerable attention because of their sensitivity to tyrosine kinase inhibitors. Imatinib mesylate (Novartis Pharmaceuticals, Basel, Switzerland) is a specific inhibitor of the KIT and PDGFRA proteins (as well as of ABL and BCR-ABL). Imatinib causes regression or stabilisation of disease in over 80% of patients with metastatic GIST, with a median survival of 5 years.6 However, acquired resistance to imatinib occurs at a median treatment duration of less than 2 years.6, 7 The other US Food and Drug Administration (FDA)-approved targeted agent for advanced GIST is sunitinib maleate (Pfizer, New York, USA), which inhibits KIT, PDGFRA, vascular endothelial growth factor receptors, fms-like tyrosine kinase-3 receptor (FLT3), and the RET receptor. When given to patients who are intolerant to imatinib or have refractory disease, sunitinib achieves a median progression-free survival (PFS) of 6 months.8
The gold standard for localised primary GIST is surgical resection. However, tumour recurrence is common and usually occurs in the liver, the peritoneum, or both.9 Almost all GIST, with the possible exception of very small tumours (<1 cm) found incidentally, seem to have the potential to recur after surgical resection. However, assessment of the risk of recurrence in a patient has been difficult. The rarity of the tumour and the recent recognition of GIST as a distinct pathological entity among soft tissue tumours have limited the identification of prognostic variables and the establishment of staging systems. Overexpression of KIT (CD117) and widespread use of immunohistochemical staining for KIT have now enabled precise diagnosis of GIST.
The American College of Surgeons Oncology Group (ACOSOG) has recently reported the results of study Z9001—an intergroup, randomised, double-blind, placebo-controlled trial assessing the efficacy of adjuvant imatinib for patients with primary GIST larger than 3 cm. Adjuvant imatinib therapy prolonged recurrence-free survival (RFS) compared with placebo.10 With a median follow-up of 19 months, RFS at 1 year was 98% (95% CI 96–100) in the imatinib group versus 83% (78–88) in the placebo group (hazard ratio [HR] 0·35 [0·22–0·53], p<0·0001). On the basis of this trial, the FDA approved the use of adjuvant imatinib in December, 2008, and the European Medicines Agency (EMEA) in March, 2009.11, 12 EMEA approval is restricted to patients at significant risk of relapse, without reference to what criteria should be used to make this determination. Because of the potential toxic effects and the financial cost of the treatment, the ability to measure the risk of recurrence for individual patients is important.
Risk stratification in GIST based on tumour size, mitotic activity, and tumour location has been suggested, but an optimal staging system has not been established and validated.13, 14, 15, 16, 17, 18, 19, 20, 21 Two commonly used staging systems for prognosis were developed at a 2001 US National Institutes of Health (NIH) workshop (table 1).14, 15 A modification of one of these staging systems was then suggested in 2006 (table 1).18 None of these staging systems provides a quantifiable risk of recurrence for individual patients. Although an American Joint Committee on Cancer (AJCC) tumour-node-metastasis (TNM) staging system for sarcoma exists, it is not specific enough for GIST and therefore has not been used. Prognostic nomograms for assessment of postoperative outcome in sarcomas and other malignancies have been developed at Memorial Sloan-Kettering Cancer Center (MSKCC, New York, NY, USA) and elsewhere.22, 23, 24, 25, 26 A nomogram is a graphical interface for a statistical model using variables with additive prognostic importance to predict precisely a patient outcome. Nomograms are typically more accurate than staging systems, such as AJCC groupings.24, 25 Our aim was to establish a nomogram to predict the risk of tumour recurrence after gross surgical resection of a localised primary GIST in the absence of tyrosine kinase inhibitor therapy.
Section snippets
Patients
We used three databases of patients who underwent complete gross resection of a localised primary GIST without adjuvant therapy. Within each dataset, an expert pathologist confirmed diagnosis of GIST and calculated the mitotic index (number of mitoses per 50 randomly selected high-power microscopic fields [HPFs]). The pathologist measured tumour size either before or after formalin fixation. The nomogram was constructed based on 127 patients treated at MSKCC between 1983 and 2002. The
Results
We constructed a nomogram using 127 patients from MSKCC. The median follow-up of patients free of recurrence in this series was 4·7 years, with 42 patients having recurrence. RFS is shown in figure 1. Nomogram construction was based on previous analysis of this series, showing that tumour mitotic rate (with a breakpoint of <5 or ≥5 mitoses per 50 HPFs), size (assessed as a continuous variable), and tumour site independently predict RFS.27 The nomogram assigned points based on tumour size in a
Discussion
This study describes the development and validation of a prognostic nomogram to predict RFS after resection of localised primary GIST. The nomogram—which takes into account tumour size, site of origin, and mitotic index—had better predictive accuracy, as determined by concordance probabilities, than had two commonly used staging systems developed at the US NIH GIST workshop in 2001. The nomogram had a concordance probability higher, but not statistically different, than that of a third staging
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