Elsevier

The Lancet Oncology

Volume 10, Issue 11, November 2009, Pages 1045-1052
The Lancet Oncology

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Development and validation of a prognostic nomogram for recurrence-free survival after complete surgical resection of localised primary gastrointestinal stromal tumour: a retrospective analysis

https://doi.org/10.1016/S1470-2045(09)70242-6Get rights and content

Summary

Background

Adjuvant imatinib mesylate prolongs recurrence-free survival (RFS) after resection of localised primary gastrointestinal stromal tumours (GIST). We aimed to develop a nomogram to predict RFS after surgery in the absence of adjuvant therapy to help guide patient selection for adjuvant imatinib therapy.

Methods

A nomogram to predict RFS based on tumour size (cm), location (stomach, small intestine, colon/rectum, or other), and mitotic index (<5 or ≥5 mitoses per 50 high-power fields) was developed from 127 patients treated at Memorial Sloan-Kettering Cancer Center (MSKCC), New York, NY, USA. The nomogram was tested in patients from the Spanish Group for Research on Sarcomas (GEIS; n=212) and the Mayo Clinic, Rochester, MN, USA (Mayo; n=148). The nomogram was assessed by calculating concordance probabilities and testing calibration of predicted RFS with observed RFS. Concordance probabilities were also compared with those of three commonly used staging systems.

Findings

The nomogram had a concordance probability of 0·78 (SE 0·02) in the MSKCC dataset, and 0·76 (0·03) and 0·80 (0·02) in the validation cohorts. Nomogram predictions were well calibrated. Inclusion of tyrosine kinase mutation status in the nomogram did not improve its discriminatory ability. Concordance probabilities of the nomogram were better than those of the two NIH staging systems (0·76 [0·03] vs 0·70 [0·04, p=0·04] and 0·66 [0·04, p=0·01] in the GEIS validation cohort; 0·80 [0·02] vs 0·74 [0·02, p=0·04] and 0·78 [0·02, p=0·05] in the Mayo cohort) and similar to those of the AFIP-Miettinen staging system (0·76 [0·03] vs 0·73 [0·004, p=0·28] in the GEIS cohort; 0·80 [0·02] vs 0·76 [0·003, p=0·09] in the Mayo cohort). Nomogram predictions of RFS seemed better calibrated than predictions made with the AFIP-Miettinen system.

Interpretation

The nomogram accurately predicts RFS after resection of localised primary GIST and could be used to select patients for adjuvant imatinib therapy.

Funding

National Cancer Institute, Bethesda, MD, USA.

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

References (59)

  • J Andersson et al.

    Gastrointestinal stromal tumors with KIT exon 11 deletions are associated with poor prognosis

    Gastroenterology

    (2006)
  • CY Tzen et al.

    Spectrum and prognostication of KIT and PDGFRA mutation in gastrointestinal stromal tumors

    Eur J Surg Oncol

    (2008)
  • N Nakamura et al.

    Prognostic significance of expressions of cell-cycle regulatory proteins in gastrointestinal stromal tumor and the relevance of the risk grade

    Hum Pathol

    (2005)
  • SE Steigen et al.

    Diagnostic and prognostic markers for gastrointestinal stromal tumors in Norway

    Mod Pathol

    (2008)
  • M Miettinen et al.

    Gastrointestinal stromal tumors/smooth muscle tumors (GISTs) primary in the omentum and mesentery: clinicopathologic and immunohistochemical study of 26 cases

    Am J Surg Pathol

    (1999)
  • S Hirota et al.

    Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors

    Science

    (1998)
  • MC Heinrich et al.

    PDGFRA activating mutations in gastrointestinal stromal tumors

    Science

    (2003)
  • MC Heinrich et al.

    Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III Trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group

    J Clin Oncol

    (2008)
  • CD Blanke et al.

    Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT

    J Clin Oncol

    (2008)
  • RP DeMatteo et al.

    Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival

    Ann Surg

    (2000)
  • FDA Food and Drug Administration. http://www.fda.gov/aboutFDA/CentersOffices/CDER/ucm129210.htm (accessed Sept 18,...
  • Evaluation of medicines for human use

  • DW Franquemont

    Differentiation and risk assessment of gastrointestinal stromal tumors

    Am J Clin Pathol

    (1995)
  • B Nilsson et al.

    Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era—a population-based study in western Sweden

    Cancer

    (2005)
  • M Miettinen et al.

    Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis

    Arch Pathol Lab Med

    (2006)
  • BK Goh et al.

    Which is the optimal risk stratification system for surgically treated localized primary GIST? Comparison of three contemporary prognostic criteria in 171 tumors and a proposal for a modified Armed Forces Institute of Pathology risk criteria

    Ann Surg Oncol

    (2008)
  • MW Kattan et al.

    Postoperative nomogram for disease recurrence after radical prostatectomy for prostate cancer

    J Clin Oncol

    (1999)
  • MW Kattan et al.

    Postoperative nomogram for 12-year sarcoma-specific death

    J Clin Oncol

    (2002)
  • MW Kattan et al.

    Postoperative nomogram for disease-specific survival after an R0 resection for gastric carcinoma

    J Clin Oncol

    (2003)
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