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Gastrointestinal stromal tumors: ESMO Clinical Recommendations for diagnosis, treatment and follow-up
clinical recommendations
Annals of Oncology 18 (Supplement 2): ii27–ii29, 2007 doi:10.1093/annonc/mdm024
Gastrointestinal stromal tumors: ESMO Clinical Recommendations for diagnosis, treatment and follow-up staging and risk assessment
The only study reporting the incidence of gastrointestinal stromal tumors (GISTs) indicates a rate of 1–2/100 000 persons per year [1]. The most frequent primary sites are gastric (50%) and small bowel (25%). Colorectal, esophageal, and peritoneal GISTs are less frequent. GIST can be diagnosed at any age, with a median of 60 years in large series.
Imaging techniques to evaluate GIST include endoscopy, endoscopic ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), and fluorine-18fluorodeoxyglucose (FDG) positron emission tomography (PET). When a small tumor is found incidentally during endoscopy, the local extent of the tumor should be evaluated using endoscopic ultrasonography. Contrast-enhanced CT scan is currently the imaging modality of choice for patients with suspected abdominal mass or biopsy-proven GIST [II, B] for both staging and surgical planning [3, 4]. For rectal GIST, MRI provides better preoperative staging information than CT scan [3, 4]. Most metastases arise in the liver and peritoneal cavity, while pleural, lung, or lymph node metastases are rare (<10%). Evaluation of FDG uptake using PET scan is recommended only when early detection of tumor response to imatinib treatment is required for purposes of planning surgery or response evaluation is equivocal [3, 4]. For localized tumors, risk assessment based on the size and mitotic index per 50 high-power fields is generally accepted, although prospective validation of a large cohort remains to be carried out (Table 1) [5]. Clinical and molecular characteristics may be better prognostic parameters than World Health Organization (WHO) grading, i.e. serosal breaching, primary site, and the nature of the mutations in the KIT and PDGFRA genes.
diagnosis GIST may present as an abdominal mass, gastrointestinal bleeding, hemoperitoneum, anemia, perforation, or incidentally. A biopsy before definitive surgery in sarcomas is favored by most experts. In GIST, this is not always possible, e.g. when tumors are diagnosed in an emergency setting. Because GISTs are submucosal tumors, endoscopic biopsies do not always provide representative material. The use of transperitoneal biopsies is not accepted by all experts because of the theoretical risk of tumor dissemination [3, 4]. Once tumor material is obtained, the diagnosis of GIST relies on standard histological examination, with a central review by an expert in sarcoma pathology for equivocal cases [II, B] [5]. Immunohistochemical analysis shows that these tumors are generally CD117+ (95%) and CD34+ (70%), may be smooth muscle actin+ (40%), but are rarely PS100+ (5%) or desmin+ (2%) [II, B] [7]. Immunohistochemistry should be carried out without antigen retrieval since this may result in falsepositive CD117 staining. Bouin fixation should be avoided since it may impair the feasibility of molecular analysis on fixed samples [II, B] [3, 4]. Intra-abdominal tumors suspected to be a GIST in which CD117 immunostaining is negative should be considered for molecular analysis of KIT or PDGFRA mutations in expert laboratories [II, B] [3, 4]. Eighty-five percent of GISTs exhibit mutations in the KIT or PDGFRA genes. A mutation in exon 11, 9, 13, and 17 of the KIT gene is observed in 66%, 13%, 1%, and 0.6% of the tumors, respectively; within the PDGFRA gene, mutations of exon 18 or 12 are observed in 5% and 1.5% of the cases [2]. GISTs occurring during childhood have a lower incidence of KIT and PDGFRA gene mutations. Correspondence to: ESMO Guidelines Working Group, ESMO Head Office, Via La Santa 7, CH-6962 Viganello-Lugano, Switzerland Approved by the ESMO Guidelines Working Group: December 2006
ª 2007 European Society for Medical Oncology
treatment The treatment of localized GIST is surgery [II, A]. In this setting, adjuvant treatment is experimental [3, 4]. Conversely, for metastatic or relapsing GIST, imatinib is the standard treatment [II, A], while the role of surgery is not known [3, 4]. For localized tumors, wedge resection of the stomach, or segmental resection of the intestine, is considered to be adequate treatment since GISTs tend to be expophytic and do not involve regional lymph nodes [III, B]. For esophageal, duodenal, and rectal primaries, however, wedge resections are often not feasible, and therefore wide resections are the treatment of choice. In case of omental or mesenteric GIST, a complete en-bloc resection of visible disease is recommended. Adjacent organs adherent to the mass should be resected en-bloc with the tumor, in order to avoid capsule rupture and intra-abdominal spillage. Though positive resection
Downloaded from http://annonc.oxfordjournals.org/ at University of California, Santa Cruz on March 31, 2015
incidence
clinical recommendations
Annals of Oncology
Table 1. Prognostic factors Prognosis
Favorable
Intermediate
Unfavorable
Histological type Mitoses/HPF Type of KIT mutation Tumor size Gender
Spindel cell <3 Missense exon 11 <5 cm Female
Epitheloid cell >3 to <15 Deletion, insertion exon 11 5–10 cm –
Mixed >15 Mutations exon 9 or 13 >10 cm Male
response evaluation CT scan is currently the imaging modality of choice in response evaluation [III, B]. RECIST or WHO response criteria do not always accurately identify responders. In addition to patients in PR according to RECIST, imatinib is also beneficial for patients with stable disease (i.e. size variation between ÿ30% and +20%) according to conventional tumor response (RECIST) criteria, and even in a subset of patients who undergo an initial increase >20% in tumor volume within the first 6 months in conjunction with significant clinical symptomatic improvement or FDGPET response. FDG-PET has proven to be highly sensitive in detecting early tumor response, but is costly and still limited in availability. When a GIST responds to imatinib, the mass rapidly becomes hypo-attenuated on contrast-enhanced CT while a reduction in overall size may not occur for months, if it occurs at all. This reduction in tumor density, as measured by Hounsfield Units, reflects a loss of tumor vessels and is generally associated with a reduction in tumor metabolic activity on PET scan (decreased glucose uptake) [II, A]. Clinical symptomatic improvement, reduction in tumor density on CT scan and PET scan response are all predictors of tumor control by imatinib [3, 4].
ii28 | ESMO Guidelines Working Group
follow-up There are no data in the published literature that could support specific recommendations for follow-up frequency or the nature of the investigations. Relapses most often occur in the peritoneum or in the liver. Whether earlier treatment of advanced GIST with imatinib improves the outcome of these patients is unknown. For high risk and intermediate risk (Table 1) [5], follow-up with a CT scan every 3–4 months for 3 years, then every 6 months until 5 years, and yearly afterward is deemed reasonable, since although the recurrence rate is high, at least for high-risk GIST, late relapse is not unusual [V, D] [3, 4]. For low-risk or very low risk tumors (Table 1) [5], regular follow-up using CT scan every 6 months for 5 years is an acceptable option [V, D] [3, 4]. At the present time, there is, however, no evidence indicating that these are the optimal intervals, and whether follow-up with CT is beneficial or not in these patients.
note Levels of evidence [I–V] and grades of recommendation [A–D] as used by the American Society of Clinical Oncology are given in square brackets. Statements without grading were considered justified standard clinical practice by the experts and the ESMO faculty.
literature 1. Kindblom LG, Meis KindBlom J, Bumming P et al. Incidence, prevalence, phenotype and biologic spectrum of gastrointestinal stromal tumors (GIST): a population based study of 600 cases. Ann Oncol 2003; 13: 157. 2. Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol 2004; 22: 3813–3825. 3. Demetri GD, Benjamin RS, Blanke C et al. Optimal management of patients with Gastrointesinal stromal tumors. Expansion and update of NCCN Clinical Practice Guidelines. J Natl Compr Cancer Netw 2004; 2 (Suppl 1). 4. Blay JY, Bonvalot S, Casali P et al. GIST consensus meeting panelists. Consensus meeting for the management of gastrointestinal stromal tumors. Report of the GIST Consensus Conference of 20-21 March 2004, under the auspices of ESMO. Ann Oncol 2005; 16: 566–578. 5. Fletcher CDM, Berman JJ, Corless CL et al. Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol 2002; 33: 459–465. 6. Demetri GD, von Mehren M, Blanke CD et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002; 347: 472–480. 7. Verweij J, Casali P, Zalcberg J et al. Improved progression free survival in gastrointestinal stromal tumors with high dose Imatinib. Results of a randomized phase III study of the EORTC, ISG and AGITG. Lancet 2004; 364: 1127–1134.
Volume 18 | Supplement 2 | April 2007
Downloaded from http://annonc.oxfordjournals.org/ at University of California, Santa Cruz on March 31, 2015
margins have not been definitely demonstrated to compromise survival, re-excision should be considered in case of intramural, intralesionally excised tumors, without infiltration of the serosal surface [IV, C] [3, 4]. Adjuvant imatinib should only be given in randomized clinical trials. Preoperative imatinib for cytoreduction should only be given for inoperable tumors or when function-sparing surgery is the goal [3, 4]. For unresectable and/or metastatic disease, treatment with imatinib should be started immediately even if the tumor is not evaluable [IV, C]. It is not proven that complete surgical removal of the tumor after response to imatinib is useful in this setting [3, 4]. Imatinib at 400 mg per day is the currently recommended first-line treatment in advanced phase, since no overall survival improvement has yet been reported in the two large prospective randomized trials comparing first-line treatment with imatinib doses of 400 and 800 mg (I, A) [6–8]. Of note, however, the largest trial reported a trend for superior progression-free survival in the 800 mg arm; this benefit may be restricted to the subset of patients with a mutation in exon 9 of the KIT gene [9]. Imatinib interruption is associated with a high risk of relapse, even for patients in complete remission [10]. Although most (but not all patients) responded to imatinib reintroduction, the drug should not be discontinued outside of a clinical trial (II, B).
Annals of Oncology
clinical recommendations
8. Rankin C, von Mehren M, Blanke C et al. Continued prolongation of survival by imatinib in patients with metastatic GIST. Update of Results from North American Intergroup Phase III Study S0033. Proc Am Soc Clin Oncol 2004; 23: 815 (Abstr 9005). 9. Debiec-Rychter M, Sciot R, Le Cesne A et al. KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumors. Results of mutation analysis in 377 patients entered into a randomized study. Eur J Cancer 2006; 42 (8): 1093–1103. 10. Blay JY, Berthaud P, Perol D et al. Continuous vs intermittent imatinib treatment in advanced GIST after one year: a prospective randomized
phase III trial of the French Sarcoma Group. Proc Am Soc Clin Oncol 2004 (Abstr 9006).
Coordinating authors for the ESMO Guidelines Working Group: J.-Y. Blay1, A. Le Cesne2 1 Invited author, Unite´ INSERM 590, Centre Le´on Be´rard, Lyon & Hopital Edouard Herriot, Lyon, France 2 Invited author, Institut Gustave Roussy, Oncology, Villejuif, France
Downloaded from http://annonc.oxfordjournals.org/ at University of California, Santa Cruz on March 31, 2015
Volume 18 | Supplement 2 | April 2007
doi:10.1093/annonc/mdm024 | ii29
Annals of Oncology 18 (Supplement 2): ii27–ii29, 2007 doi:10.1093/annonc/mdm024
Gastrointestinal stromal tumors: ESMO Clinical Recommendations for diagnosis, treatment and follow-up staging and risk assessment
The only study reporting the incidence of gastrointestinal stromal tumors (GISTs) indicates a rate of 1–2/100 000 persons per year [1]. The most frequent primary sites are gastric (50%) and small bowel (25%). Colorectal, esophageal, and peritoneal GISTs are less frequent. GIST can be diagnosed at any age, with a median of 60 years in large series.
Imaging techniques to evaluate GIST include endoscopy, endoscopic ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), and fluorine-18fluorodeoxyglucose (FDG) positron emission tomography (PET). When a small tumor is found incidentally during endoscopy, the local extent of the tumor should be evaluated using endoscopic ultrasonography. Contrast-enhanced CT scan is currently the imaging modality of choice for patients with suspected abdominal mass or biopsy-proven GIST [II, B] for both staging and surgical planning [3, 4]. For rectal GIST, MRI provides better preoperative staging information than CT scan [3, 4]. Most metastases arise in the liver and peritoneal cavity, while pleural, lung, or lymph node metastases are rare (<10%). Evaluation of FDG uptake using PET scan is recommended only when early detection of tumor response to imatinib treatment is required for purposes of planning surgery or response evaluation is equivocal [3, 4]. For localized tumors, risk assessment based on the size and mitotic index per 50 high-power fields is generally accepted, although prospective validation of a large cohort remains to be carried out (Table 1) [5]. Clinical and molecular characteristics may be better prognostic parameters than World Health Organization (WHO) grading, i.e. serosal breaching, primary site, and the nature of the mutations in the KIT and PDGFRA genes.
diagnosis GIST may present as an abdominal mass, gastrointestinal bleeding, hemoperitoneum, anemia, perforation, or incidentally. A biopsy before definitive surgery in sarcomas is favored by most experts. In GIST, this is not always possible, e.g. when tumors are diagnosed in an emergency setting. Because GISTs are submucosal tumors, endoscopic biopsies do not always provide representative material. The use of transperitoneal biopsies is not accepted by all experts because of the theoretical risk of tumor dissemination [3, 4]. Once tumor material is obtained, the diagnosis of GIST relies on standard histological examination, with a central review by an expert in sarcoma pathology for equivocal cases [II, B] [5]. Immunohistochemical analysis shows that these tumors are generally CD117+ (95%) and CD34+ (70%), may be smooth muscle actin+ (40%), but are rarely PS100+ (5%) or desmin+ (2%) [II, B] [7]. Immunohistochemistry should be carried out without antigen retrieval since this may result in falsepositive CD117 staining. Bouin fixation should be avoided since it may impair the feasibility of molecular analysis on fixed samples [II, B] [3, 4]. Intra-abdominal tumors suspected to be a GIST in which CD117 immunostaining is negative should be considered for molecular analysis of KIT or PDGFRA mutations in expert laboratories [II, B] [3, 4]. Eighty-five percent of GISTs exhibit mutations in the KIT or PDGFRA genes. A mutation in exon 11, 9, 13, and 17 of the KIT gene is observed in 66%, 13%, 1%, and 0.6% of the tumors, respectively; within the PDGFRA gene, mutations of exon 18 or 12 are observed in 5% and 1.5% of the cases [2]. GISTs occurring during childhood have a lower incidence of KIT and PDGFRA gene mutations. Correspondence to: ESMO Guidelines Working Group, ESMO Head Office, Via La Santa 7, CH-6962 Viganello-Lugano, Switzerland Approved by the ESMO Guidelines Working Group: December 2006
ª 2007 European Society for Medical Oncology
treatment The treatment of localized GIST is surgery [II, A]. In this setting, adjuvant treatment is experimental [3, 4]. Conversely, for metastatic or relapsing GIST, imatinib is the standard treatment [II, A], while the role of surgery is not known [3, 4]. For localized tumors, wedge resection of the stomach, or segmental resection of the intestine, is considered to be adequate treatment since GISTs tend to be expophytic and do not involve regional lymph nodes [III, B]. For esophageal, duodenal, and rectal primaries, however, wedge resections are often not feasible, and therefore wide resections are the treatment of choice. In case of omental or mesenteric GIST, a complete en-bloc resection of visible disease is recommended. Adjacent organs adherent to the mass should be resected en-bloc with the tumor, in order to avoid capsule rupture and intra-abdominal spillage. Though positive resection
Downloaded from http://annonc.oxfordjournals.org/ at University of California, Santa Cruz on March 31, 2015
incidence
clinical recommendations
Annals of Oncology
Table 1. Prognostic factors Prognosis
Favorable
Intermediate
Unfavorable
Histological type Mitoses/HPF Type of KIT mutation Tumor size Gender
Spindel cell <3 Missense exon 11 <5 cm Female
Epitheloid cell >3 to <15 Deletion, insertion exon 11 5–10 cm –
Mixed >15 Mutations exon 9 or 13 >10 cm Male
response evaluation CT scan is currently the imaging modality of choice in response evaluation [III, B]. RECIST or WHO response criteria do not always accurately identify responders. In addition to patients in PR according to RECIST, imatinib is also beneficial for patients with stable disease (i.e. size variation between ÿ30% and +20%) according to conventional tumor response (RECIST) criteria, and even in a subset of patients who undergo an initial increase >20% in tumor volume within the first 6 months in conjunction with significant clinical symptomatic improvement or FDGPET response. FDG-PET has proven to be highly sensitive in detecting early tumor response, but is costly and still limited in availability. When a GIST responds to imatinib, the mass rapidly becomes hypo-attenuated on contrast-enhanced CT while a reduction in overall size may not occur for months, if it occurs at all. This reduction in tumor density, as measured by Hounsfield Units, reflects a loss of tumor vessels and is generally associated with a reduction in tumor metabolic activity on PET scan (decreased glucose uptake) [II, A]. Clinical symptomatic improvement, reduction in tumor density on CT scan and PET scan response are all predictors of tumor control by imatinib [3, 4].
ii28 | ESMO Guidelines Working Group
follow-up There are no data in the published literature that could support specific recommendations for follow-up frequency or the nature of the investigations. Relapses most often occur in the peritoneum or in the liver. Whether earlier treatment of advanced GIST with imatinib improves the outcome of these patients is unknown. For high risk and intermediate risk (Table 1) [5], follow-up with a CT scan every 3–4 months for 3 years, then every 6 months until 5 years, and yearly afterward is deemed reasonable, since although the recurrence rate is high, at least for high-risk GIST, late relapse is not unusual [V, D] [3, 4]. For low-risk or very low risk tumors (Table 1) [5], regular follow-up using CT scan every 6 months for 5 years is an acceptable option [V, D] [3, 4]. At the present time, there is, however, no evidence indicating that these are the optimal intervals, and whether follow-up with CT is beneficial or not in these patients.
note Levels of evidence [I–V] and grades of recommendation [A–D] as used by the American Society of Clinical Oncology are given in square brackets. Statements without grading were considered justified standard clinical practice by the experts and the ESMO faculty.
literature 1. Kindblom LG, Meis KindBlom J, Bumming P et al. Incidence, prevalence, phenotype and biologic spectrum of gastrointestinal stromal tumors (GIST): a population based study of 600 cases. Ann Oncol 2003; 13: 157. 2. Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol 2004; 22: 3813–3825. 3. Demetri GD, Benjamin RS, Blanke C et al. Optimal management of patients with Gastrointesinal stromal tumors. Expansion and update of NCCN Clinical Practice Guidelines. J Natl Compr Cancer Netw 2004; 2 (Suppl 1). 4. Blay JY, Bonvalot S, Casali P et al. GIST consensus meeting panelists. Consensus meeting for the management of gastrointestinal stromal tumors. Report of the GIST Consensus Conference of 20-21 March 2004, under the auspices of ESMO. Ann Oncol 2005; 16: 566–578. 5. Fletcher CDM, Berman JJ, Corless CL et al. Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol 2002; 33: 459–465. 6. Demetri GD, von Mehren M, Blanke CD et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002; 347: 472–480. 7. Verweij J, Casali P, Zalcberg J et al. Improved progression free survival in gastrointestinal stromal tumors with high dose Imatinib. Results of a randomized phase III study of the EORTC, ISG and AGITG. Lancet 2004; 364: 1127–1134.
Volume 18 | Supplement 2 | April 2007
Downloaded from http://annonc.oxfordjournals.org/ at University of California, Santa Cruz on March 31, 2015
margins have not been definitely demonstrated to compromise survival, re-excision should be considered in case of intramural, intralesionally excised tumors, without infiltration of the serosal surface [IV, C] [3, 4]. Adjuvant imatinib should only be given in randomized clinical trials. Preoperative imatinib for cytoreduction should only be given for inoperable tumors or when function-sparing surgery is the goal [3, 4]. For unresectable and/or metastatic disease, treatment with imatinib should be started immediately even if the tumor is not evaluable [IV, C]. It is not proven that complete surgical removal of the tumor after response to imatinib is useful in this setting [3, 4]. Imatinib at 400 mg per day is the currently recommended first-line treatment in advanced phase, since no overall survival improvement has yet been reported in the two large prospective randomized trials comparing first-line treatment with imatinib doses of 400 and 800 mg (I, A) [6–8]. Of note, however, the largest trial reported a trend for superior progression-free survival in the 800 mg arm; this benefit may be restricted to the subset of patients with a mutation in exon 9 of the KIT gene [9]. Imatinib interruption is associated with a high risk of relapse, even for patients in complete remission [10]. Although most (but not all patients) responded to imatinib reintroduction, the drug should not be discontinued outside of a clinical trial (II, B).
Annals of Oncology
clinical recommendations
8. Rankin C, von Mehren M, Blanke C et al. Continued prolongation of survival by imatinib in patients with metastatic GIST. Update of Results from North American Intergroup Phase III Study S0033. Proc Am Soc Clin Oncol 2004; 23: 815 (Abstr 9005). 9. Debiec-Rychter M, Sciot R, Le Cesne A et al. KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumors. Results of mutation analysis in 377 patients entered into a randomized study. Eur J Cancer 2006; 42 (8): 1093–1103. 10. Blay JY, Berthaud P, Perol D et al. Continuous vs intermittent imatinib treatment in advanced GIST after one year: a prospective randomized
phase III trial of the French Sarcoma Group. Proc Am Soc Clin Oncol 2004 (Abstr 9006).
Coordinating authors for the ESMO Guidelines Working Group: J.-Y. Blay1, A. Le Cesne2 1 Invited author, Unite´ INSERM 590, Centre Le´on Be´rard, Lyon & Hopital Edouard Herriot, Lyon, France 2 Invited author, Institut Gustave Roussy, Oncology, Villejuif, France
Downloaded from http://annonc.oxfordjournals.org/ at University of California, Santa Cruz on March 31, 2015
Volume 18 | Supplement 2 | April 2007
doi:10.1093/annonc/mdm024 | ii29