Gastrointestinal stromal tumours: ESMO–EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up
Authors: P.G. Casali, N. Abecassis, S. Bauer, R. Biagini, S. Bielack, S. Bonvalot, I. Boukovinas, J.V.M.G. Bovee, T. Brodowicz, J.M. Broto, A. Buonadonna, E. De Álava, A.P. Dei Tos, X.G. Del Muro, P. Dileo, M. Eriksson, A. Fedenko, V. Ferraresi, A. Ferrari, S. Ferrari, A.M. Frezza, S. Gasperoni, H. Gelderblom, T. Gil, G. Grignani, A. Gronchi, R.L. Haas, A. Hannu, B. Hassan, P. Hohenberger, R. Issels, H. Joensuu, R.L. Jones, I. Judson, P. Jutte, S. Kaal, B. Kasper, K. Kopeckova, D.A. Krákorová, A. Le Cesne, I. Lugowska, O. Merimsky, M. Montemurro, M.A. Pantaleo, R. Piana, P. Picci, S. Piperno-Neumann, A.L. Pousa, P. Reichardt, M.H. Robinson, P. Rutkowski, A.A. Safwat, P. Schöffski, S. Sleijfer, S. Stacchiotti, K. Sundby Hall, M. Unk, F. Van Coevorden, W. Van der Graaf, J. Whelan, E. Wardelmann, O. Zaikova, J.Y. Blay
Journal: Annals of Oncology (2018)

Gastrointestinal stromal tumours (GISTs) are rare tumours, with an estimated unadjusted incidence of around 1/100 000/year [1.Nilsson B. Bümming P. Meis-Kindblom J.M. 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; 103: 821-829Crossref PubMed Scopus (1027) Google Scholar]. This only covers clinically relevant GISTs, since, if investigated, a much higher number of lesions ≤ 1 cm in diameter (microGISTs) can be found at histopathological examination of stomach tissue in middle-aged and elderly individuals. There is a slight prevalence in males. The median age is around 60–65 years, with a wide range. Occurrence in children is very rare. Paediatric GIST represents a clinically and molecularly distinct subset, marked by female predominance, absence of KIT/platelet-derived growth factor alpha (PDGFRA) mutations, frequent mutations or silencing of the four genes that encode the subunits of the succinate dehydrogenase (SDH) enzyme complex, gastric multicentric location and possible lymph node metastases [2.Pappo A.S. Janeway K.A. Pediatric gastrointestinal stromal tumors.Hematol Oncol Clin North Am. 2009; 23 (vii): 15-34Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar]. Some syndromes are linked to GISTs: •The Carney triad syndrome, marked by gastric GISTs, paraganglioma and pulmonary chondromas (these may occur at different ages) [3.Zhang L. Smyrk T.C. Young Jr, W.F. et al.Gastric stromal tumors in Carney triad are different clinically, pathologically, and behaviorally from sporadic gastric gastrointestinal stromal tumors: findings in 104 cases.Am J Surg Pathol. 2010; 34: 53-64Crossref PubMed Scopus (167) Google Scholar];•Carney–Stratakis syndrome, marked by a dyad of GIST and paraganglioma [4.Gaal J. Stratakis C.A. Carney J.A. et al.SDHB immunohistochemistry: a useful tool in the diagnosis of Carney–Stratakis and Carney triad gastrointestinal stromal tumors.Mod Pathol. 2011; 24: 147-151Crossref PubMed Scopus (162) Google Scholar, 5.Pasini B. McWhinney S.R. Bei T. et al.Clinical and molecular genetics of patients with the Carney–Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD.Eur J Hum Genet. 2008; 16: 79-88Crossref PubMed Scopus (363) Google Scholar]; and•Neurofibromatosis type 1(NF1), possibly leading to wild-type (WT), often multicentric GIST, predominantly located in the small bowel [6.Miettinen M. Fetsch J.F. Sobin L.H. Lasota J. Gastrointestinal stromal tumors in patients with neurofibromatosis 1: a clinicopathologic and molecular genetic study of 45 cases.Am J Surg Pathol. 2006; 30: 90-96Crossref PubMed Scopus (377) Google Scholar]. Families with germline autosomal dominant mutations of KIT are an extremely rare finding, presenting with multiple GISTs at an early age, possibly along with other associated features such as pigmented skin macules, urticaria pigmentosa and diffuse hyperplasia of the interstitial cells of Cajal in the gut wall. When small oesophagogastric or duodenal nodules < 2 cm in size are detected, endoscopic biopsy may be difficult and laparoscopic/laparotomic excision may be the only way to make a histological diagnosis. Many of these small nodules, if diagnosed as GISTs, will be either low-risk or entities whose clinical significance remains unclear. Therefore, the standard approach to patients with oesophagogastric or duodenal nodules < 2 cm is endoscopic ultrasound assessment and then follow-up, reserving excision for patients whose tumour increases in size or becomes symptomatic [IV, C]. As an option, the patient can choose to undergo a histological assessment, also depending on age, life expectancy and comorbidities. If follow-up is the choice, an evidence-based, optimal surveillance policy is lacking. A logical approach may be to have a short-term first control (e.g. at 3 months) and then, in the case of no evidence of growth, a more relaxed follow-up schedule may be selected. In a histologically proven small GIST, standard treatment is excision, unless major morbidity is expected. Alternatively, in the case of a likely low-risk GIST on biopsy, the decision can be made with the patient to follow up the lesion. However, an exception is the standard approach to rectal nodules represented by biopsy or excision after endorectal ultrasound assessment and pelvic magnetic resonance imaging (MRI), regardless of the tumour size and mitotic rate. In fact, the progression risk of a clinically significant GIST at this site is higher, its prognosis is significantly worse compared with most gastric GISTs and the local implications for surgery are more critical. A follow-up policy may be an option, to be discussed with the patient, in the case of small lesions and whenever the surgical risk is particularly high (comorbidities, age, etc.). The standard approach to tumours ≥2 cm in size is biopsy/excision, because they are associated with a higher risk of progression if confirmed as GIST [IV, C]. If there is an abdominal nodule not amenable to endoscopic assessment, laparoscopic/laparotomic excision is the standard approach. If there is a mass, especially if surgery is likely to be a multivisceral resection, multiple core needle biopsies are the standard approach. They should be obtained through endoscopic ultrasound guidance, or through an ultrasound/computed tomography (CT)-guided percutaneous approach. This may allow the surgeon to plan the best approach according to the histological diagnosis and avoid surgery for diseases which might not benefit (e.g. lymphomas, mesenteric fibromatosis and germ cell tumours). The risk of peritoneal contamination is negligible if the procedure is properly carried out. Moreover, lesions at risk in this regard (e.g. cystic masses) should be biopsied only in specialised centres. Immediate laparoscopic/laparotomic excision is an option on an individualised basis, especially if surgery is limited. If a patient presents with obvious metastatic disease, a biopsy of the metastatic focus is sufficient and the patient usually does not require a laparotomy for diagnostic purposes. The tumour sample should be fixed in 4% buffered formalin (Bouin fixative should not be used, since it prevents molecular analysis). Pathologically, the diagnosis of GIST relies on morphology and immunohistochemistry, the latter being positive for CD117 (KIT) and/or DOG1 (see Table 1) [7.Rubin B.P. Blanke C.D. Demetri G.D. et al.Protocol for the examination of specimens from patients with gastrointestinal stromal tumor.Arch Pathol Lab Med. 2010; 134: 165-170Crossref PubMed Google Scholar, 8.Novelli M. Rossi S. Rodriguez-Justo M. et al.DOG1 and CD117 are the antibodies of choice in the diagnosis of gastrointestinal stromal tumours.Histopathology. 2010; 57: 259-270Crossref PubMed Scopus (147) Google Scholar]. A proportion of GISTs (in the range of 5%) are CD117-negative. The mitotic count has a prognostic value and should be expressed as the number of mitoses on a total area of 5 mm2 [which replaces the former 50 high-power field (HPF) area]. Mutational analysis for known mutations involving KIT and PDGFRA can confirm the diagnosis of GIST, if doubtful (particularly in rare CD117/DOG1-negative suspect GIST). Mutational analysis has a predictive value for sensitivity to molecular-targeted therapy and to prognostic value. Its inclusion in the diagnostic work-up of all GISTs should be considered standard practice [II, A] (with the possible exclusion of < 2 cm non-rectal GISTs, which are very unlikely ever to be candidates for medical treatment). Centralisation of mutational analysis in a laboratory enrolled in an external quality assurance programme and with expertise in the disease may be useful. Centralised pathological diagnosis is more strongly recommended for KIT/PDGFRA WT GIST, to confirm the diagnosis of GIST with an expert pathologist at a reference centre. In KIT/PDGFRA/BRAF WT GIST, immunohistochemistry for SDHB is done to identify SDH-deficient GIST. In quadruple-negative GIST (KIT/PDGFRA/BRAF/SDH), an unrecognised underlying NF1 syndrome should be excluded [9.Gasparotto D. Rossi S. Polano M. et al.Quadruple-negative GIST is a sentinel for unrecognized neurofibromatosis type 1 syndrome.Clin Cancer Res. 2017; 23: 273-282Crossref PubMed Scopus (53) Google Scholar]. The collection of fresh frozen tissue is encouraged, to allow new molecular pathology assessments to be made at a later stage. Informed consent for tumour storage (adhering to local and international guidelines) should be sought, enabling later analyses and research.Table 1Personalised medicine synopsis tableBiomarkerMethodUseLoEGoRMitotic indexPathologyDisease classification Prognostic relevanceUsed for medical treatment decisionsIVAKIT/PDGFRA/ BRAFSanger sequencing or NGSDisease classification Prognostic relevance Predictive relevance Used for medical treatment decisions Currently actionable/targetableIASDHIHCDisease classification Prognostic relevance Predictive relevance Used for medical treatment decisionsIIIAGoR, grade of recommendation; IHC, immunohistochemistry; LoE, level of evidence; NGS, next generation sequencing; PDGFRA, platelet-derived growth factor receptor alpha; SDH, succinate dehydrogenase. Open table in a new tab GoR, grade of recommendation; IHC, immunohistochemistry; LoE, level of evidence; NGS, next generation sequencing; PDGFRA, platelet-derived growth factor receptor alpha; SDH, succinate dehydrogenase. Multidisciplinary treatment planning is needed, involving pathologists, radiologists, surgeons and, medical oncologists, as well as gastroenterologists, nuclear medicine specialists, etc., as applicable. Management should be carried out in reference centres for sarcomas and GISTs and/or within reference networks sharing multidisciplinary expertise and treating a high number of patients annually. The revised Union for International Cancer Control tumour, node and metastasis classification of malignant tumours (UICC TNM 8), incorporates the main prognostic factors in GIST (see Table 2) [10.TNM Classification of Malignant Tumours.in: Brierley J.D. Gospodarowicz M.K. Wittekind C. 8. John Wiley & Sons, Inc, Oxford2016Google Scholar].Table 2Prognostic factors for GIST UICC TNM 8 (modified from [10.TNM Classification of Malignant Tumours.in: Brierley J.D. Gospodarowicz M.K. Wittekind C. 8. John Wiley & Sons, Inc, Oxford2016Google Scholar])Prognostic factorsTumour relatedHost relatedEnvironment relatedEssentialAnatomical siteHistological typeSize of tumourDepth of invasionGrade (well to poorly differentiated)M categoryMitotic rateAdditionalPresence of KIT mutationMutational site in KIT or PDGFRA geneSurgical resection marginsPresentation status (primary versus recurrence)NF1AgeQuality of surgeryNew and promisingTP53Ki‐67Tumour hypoxiaGIST, gastrointestinal stromal tumour; NF1, neurofibromatosis type 1; PDGFRA, platelet-derived growth factor alpha; TNM, tumour, node, metastasis; TP53, tumour protein 53; UICC, Union for International Cancer Control.Modified from [10.TNM Classification of Malignant Tumours.in: Brierley J.D. Gospodarowicz M.K. Wittekind C. 8. John Wiley & Sons, Inc, Oxford2016Google Scholar] with permission from John Wiley & Sons, Inc. Open table in a new tab GIST, gastrointestinal stromal tumour; NF1, neurofibromatosis type 1; PDGFRA, platelet-derived growth factor alpha; TNM, tumour, node, metastasis; TP53, tumour protein 53; UICC, Union for International Cancer Control. Modified from [10.TNM Classification of Malignant Tumours.in: Brierley J.D. Gospodarowicz M.K. Wittekind C. 8. John Wiley & Sons, Inc, Oxford2016Google Scholar] with permission from John Wiley & Sons, Inc. Prognostic factors are the mitotic rate, tumour size and tumour site (gastric GISTs have a better prognosis than small bowel or rectal GISTs). Tumour rupture is an additional adverse prognostic factor and should be recorded, regardless of whether it took place before or during surgery. Mutational status has not been incorporated in any risk classification at present, although some genotypes have a distinct natural history and, above all, KIT/PDGFRA WT GISTs have peculiar clinical presentations and course. Localised GIST with PDGFR D842V mutation are generally associated with a good prognosis and resistance to imatinib. Several risk classifications have been proposed. A widely used risk classification was proposed by the Armed Forces Institute of Pathology, which incorporates the primary mitotic count, tumour size and tumour site, i.e. the three main prognostic factors in localised GISTs [11.Miettinen M. Lasota J. Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis.Arch Pathol Lab Med. 2006; 130: 1466-1478Crossref PubMed Google Scholar, 12.Miettinen M. Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites.Semin Diagn Pathol. 2006; 23: 70-83Crossref PubMed Scopus (1418) Google Scholar]. A nomogram utilising all three criteria has been developed on another series [13.Gold J.S. Gönen M. Gutiérrez A. et al.Development and validation of a prognostic nomogram for recurrence-free survival after complete surgical resection of localised primary gastrointestinal stromal tumour: a retrospective analysis.Lancet Oncol. 2009; 10: 1045-1052Abstract Full Text Full Text PDF PubMed Scopus (382) Google Scholar]. When using these tools, it is important to appreciate that the mitotic index and tumour size are non-linear, continuous variables, so that thresholds are interpreted wisely. Prognostic contour maps were generated through a pool of series of GIST patients not treated with adjuvant therapy, which incorporate the mitotic index and tumour size as continuous non-linear variables, while tumour rupture is considered in addition to tumour site [14.Joensuu H. Vehtari A. Riihimäki J. et al.Risk of recurrence of gastrointestinal stromal tumour after surgery: an analysis of pooled population-based cohorts.Lancet Oncol. 2012; 13: 265-274Abstract Full Text Full Text PDF PubMed Scopus (648) Google Scholar]. They have been validated against a reference series. Staging procedures consider that most relapses affect the peritoneum and the liver. Contrast-enhanced abdominal and pelvic CT scan is the investigation of choice for staging and follow-up. MRI may be an alternative. For rectal GISTs, MRI provides better preoperative staging information. Chest CT scan and routine laboratory testing complement the staging work-up of the asymptomatic patient. The evaluation of fluorodeoxyglucose (FDG) uptake using an FDG-positron emission tomography (PET) scan, or FDG-PET–CT/MRI, is useful mainly when early detection of the tumour response to molecular-targeted therapy is of special interest. The standard treatment of localised GISTs is complete surgical excision of the lesion, with no dissection of clinically negative lymph nodes [III, A]. If laparoscopic excision is planned, the technique needs to follow the principles of oncological surgery [III, A] [15.Ohtani H. Maeda K. Noda E. et al.Meta-analysis of laparoscopic and open surgery for gastric gastrointestinal stromal tumor.Anticancer Res. 2013; 33: 5031-5041PubMed Google Scholar]. A laparoscopic approach is clearly discouraged in patients who have large tumours, because of the risk of tumour rupture, which is associated with a very high risk of relapse. R0 excision is the goal (i.e. an excision whose margins are clear of tumour cells). When R0 surgery implies major functional sequelae, and preoperative medical treatment is not effective, the decision can be made with the patient to accept possible R1 (microscopically positive) margins [IV, B]. This is even more acceptable for low-risk lesions, given the lack of any formal demonstration that R1 surgery is associated with a worse overall survival (OS). If R1 excision was already carried out, re-excision may be an option, provided the original site of lesion can be found, and major functional sequelae are not foreseen. The risk of relapse can be substantial, as defined by available risk classifications. Adjuvant treatment with imatinib for 3 years was associated with a relapse-free survival (RFS) and OS advantage in comparison with 1 year of therapy in high-risk patients in a randomised trial [16.Joensuu H. Eriksson M. Sundby Hall K. et al.Adjuvant imatinib for high-risk GI stromal tumor: analysis of a randomized trial.J Clin Oncol. 2016; 34: 244-250Crossref PubMed Scopus (147) Google Scholar]. Previously, a placebo-controlled trial demonstrated that imatinib dosed for a planned duration of 1 year can prolong RFS in localised GISTs having a diameter ≥ 3 cm with a macroscopically complete resection [17.Dematteo R.P. Ballman K.V. Antonescu C.R. et al.Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial.Lancet. 2009; 373: 1097-1104Abstract Full Text Full Text PDF PubMed Scopus (1057) Google Scholar]. Therefore, adjuvant therapy with imatinib for 3 years is the standard treatment for patients with a significant risk of relapse [I, A]. A shared decision-making process is needed when the risk is intermediate [18.Gronchi A. Judson I. Nishida T. et al.Adjuvant treatment of GIST with imatinib: solid ground or still quicksand? A comment on behalf of the EORTC Soft Tissue and Bone Sarcoma Group, the Italian Sarcoma Group, the NCRI Sarcoma Clinical Studies Group (UK), the Japanese Study Group on GIST, the French Sarcoma Group and the Spanish Sarcoma Group (GEIS).Eur J Cancer. 2009; 45: 1103-1106Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar]. Randomised clinical studies are ongoing to test longer durations of adjuvant therapy in GISTs. The benefit associated of adjuvant imatinib may vary according to the type of KIT/PDGFRA mutation, being greater in patients with KIT exon 11 deletion mutations [19.Joensuu H. Wardelmann E. Sihto H. et al.Effect of KIT and PDGFRA mutations on survival in patients with gastrointestinal stromal tumors treated with adjuvant imatinib: an exploratory analysis of a randomized clinical trial.JAMA Oncol. 2017; 3: 602-609Crossref PubMed Scopus (114) Google Scholar, 20.Corless C.L. Ballman K.V. Antonescu C.R. et al.Pathologic and molecular features correlate with long-term outcome after adjuvant therapy of resected primary GI stromal tumor: the ACOSOG Z9001 trial.J Clin Oncol. 2014; 32: 1563-1570Crossref PubMed Scopus (207) Google Scholar]. Mutational analysis is critical to make a clinical decision about adjuvant therapy. There is a consensus that PDGFRA D842V-mutated GISTs should not be treated with any adjuvant therapy, given the lack of sensitivity of this genotype both in vitro and in vivo [IV, D]. Given the data supporting the use of a higher dose of imatinib (800 mg daily) in the case of an exon 9 KIT mutation in advanced GIST, some expert clinicians prefer to use this dose even in the adjuvant setting for this genotype [II, B] [21.Debiec-Rychter M. Sciot R. Le Cesne A. et al.KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours.Eur J Cancer. 2006; 42: 1093-1103Abstract Full Text Full Text PDF PubMed Scopus (742) Google Scholar, 22.Heinrich M.C. Owzar K. Corless C.L. 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; 26: 5360-5367Crossref PubMed Scopus (481) Google Scholar, 23.Heinrich M.C. Corless C.L. Demetri G.D. et al.Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor.J Clin Oncol. 2003; 21: 4342-4349Crossref PubMed Scopus (1956) Google Scholar]. Regulatory constraints may limit this practice, which is currently not supported in the adjuvant setting by controlled trials. With regard to so called KIT/PDGFRA/BRAF WT GIST, there is a consensus on avoiding adjuvant treatment in NF1-related and SDH expression-negative GISTs [IV, D]. This reflects their lack of sensitivity to imatinib and other approved tyrosine kinase inhibitors (TKIs) in the advanced setting, as well as their peculiar natural history, which is often more indolent. Subgroup analyses of available randomised trials are, however, too limited to provide sufficient evidence. European and international cooperation would be vital to determine best practices in the exceedingly rare paediatric GIST. In case of tumour rupture at the time of surgery, there is spillage of tumour cells into the peritoneal cavity; therefore, occult peritoneal disease can be assumed to exist. This puts the patient at a very high risk of peritoneal relapse [24.Hohenberger P. Ronellenfitsch U. Oladeji O. et al.Pattern of recurrence in patients with ruptured primary gastrointestinal stromal tumour.Br J Surg. 2010; 97: 1854-1859Crossref PubMed Scopus (158) Google Scholar]. Therefore, these patients should be considered for imatinib therapy [IV, A]. The optimal duration of treatment in these cases is unknown, given the uncertainty whether these cells should be considered as metastatic. If R0 surgery is not feasible, or it could be achieved through less mutilating/function-sparing surgery in the case of volumetric reduction (this includes total gastrectomy and all other major procedures), pre-treatment with imatinib is standard [III, A] [25.Eisenberg B.L. Harris J. Blanke C.D. et al.Phase II trial of neoadjuvant/adjuvant imatinib mesylate (IM) for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumor (GIST): early results of RTOG 0132/ACRIN 6665.J Surg Oncol. 2009; 99: 42-47Crossref PubMed Scopus (313) Google Scholar, 26.Rutkowski P. Gronchi A. Hohenberger P. et al.Neoadjuvant imatinib in locally advanced gastrointestinal stromal tumors (GIST): the EORTC STBSG experience.Ann Surg Oncol. 2013; 20: 2937-2943Crossref PubMed Scopus (149) Google Scholar]. This may also be the case if the surgeon believes that the surgical resection is safer after cytoreduction (e.g. the risk of bleeding and tumour rupture is decreased). A shortcoming may be the lack of reliable mitotic counting for accurate risk stratification for adjuvant postoperative therapy. A biopsy with histological and mutational analyses is recommended to confirm the histological diagnosis, to exclude resistant genotypes to therapy with imatinib (e.g. PDGFRA D842V mutations) and to propose the 800 mg imatinib dose for less sensitive KIT exon 9 mutations. Following maximal tumour response, generally after 6–12 months, surgery is carried out. Early tumour response assessment is required to avoid delaying surgery in the case of non-responding disease. Functional imaging makes it possible to assess the tumour response very rapidly, within a few weeks, particularly in the absence of mutational analysis. There are limited data to guide the physician on when to stop imatinib treatment before surgery; however, it can be safely stopped a few days or even one day before surgery and can be resumed promptly when the patient recovers from surgery. Imatinib is the standard treatment for locally advanced inoperable and metastatic disease [I, A] [27.Blanke C.D. Demetri G.D. von Mehren M. 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; 26: 620-625Crossref PubMed Scopus (830) Google Scholar, 28.Blanke C.D. Rankin C. Demetri G.D. et al.Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033.J Clin Oncol. 2008; 26: 626-632Crossref PubMed Scopus (853) Google Scholar, 29.Verweij J. Casali P.G. Zalcberg J. et al.Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial.Lancet. 2004; 364: 1127-1134Abstract Full Text Full Text PDF PubMed Scopus (1430) Google Scholar, 30.Zalcberg J.R. Verweij J. Casali P.G. et al.Outcome of patients with advanced gastro-intestinal stromal tumours crossing over to a daily imatinib dose of 800 mg after progression on 400 mg.Eur J Cancer. 2005; 41: 1751-1757Abstract Full Text Full Text PDF PubMed Scopus (330) Google Scholar], as well as for patients previously treated with adjuvant imatinib who did not relapse while receiving it. Imatinib is also the standard treatment for patients with metastatic disease who have had all lesions removed surgically, although surgery is not recommended as a primary approach in the metastatic setting. The standard dose of imatinib is 400 mg daily [I, A]. However, data have shown that patients with tumours harbouring the KIT exon 9 mutation have significantly better progression-free survival (PFS) on a higher dose level, i.e. 800 mg daily, which is therefore held as standard treatment in this subgroup [III, B] [31.Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST) Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients.J Clin Oncol. 2010; 28: 1247-1253Crossref PubMed Scopus (388) Google Scholar]. Patients with a PDGFRA D842V mutation are generally insensitive to imatinib [32.Farag S. Somaiah N. Choi H. et al.Clinical characteristics and treatment outcome in a large multicentre observational cohort of PDGFRA exon 18 mutated gastrointestinal stromal tumour patients.Eur J Cancer. 2017; 76: 76-83Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar] and other TKIs and are, therefore, candidates for clinical studies on new agents targeting this mutation. It is doubtful whether patients with so-called WT SDH-deficient GIST benefit from available TKIs, though there are reports of activity of sunitinib [33.Janeway K.A. Albritton K.H. Van Den Abbeele A.D. et al.Sunitinib treatment in pediatric patients with advanced GIST following failure of imatinib.Pediatr Blood Cancer. 2009; 52: 767-771Crossref PubMed Scopus (127) Google Scholar]. In the metastatic setting, treatment with imatinib should be continued indefinitely, since treatment interruption is generally followed by relatively rapid tumour progression, even when lesions have been previously surgically excised [I, A] [34.Le Cesne A. Ray-Coquard I. Bui B.N. et al.Discontinuation of imatinib in patients with advanced gastrointestinal stromal tumours after 3 years of treatment: an open-label multicentre randomised phase 3 trial.Lancet Oncol. 2010; 11: 942-949Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar]. When treatment is started, the patient should be alerted to the importance of compliance with therapy, as well as interactions with concomitant medications and foods, and the best ways to handle side effects. Dose intensity should be maintained by proper management of side effects, and a correct policy of dose reductions and interruptions should be applied in the case of excessive, persistent toxicity. Retrospective data suggest that suboptimal plasma levels of imatinib are associated with a worse outcome, although a correlation with the outcome has never been established prospectively [35.Demetri G.D. Wang Y. Wehrle E. et al.Imatinib plasma levels are correlated with clinical benefit in patients with unresectable/metastatic gastrointestinal stromal tumors.J Clin Oncol. 2009; 27: 3141-3147Crossref PubMed Scopus (309) Google Scholar]. Aside from its potential use to tailor the imatinib dose, assessment of plasma level may be useful in the case of: (i) patients receiving concomitant medications that put them at a risk of major interactions or patients with previous surgical resections able to decrease plasma levels; (ii) unexpected observed toxicities; and (iii) progression on 400 mg, to rationally lead the physician to increase the dose to 800 mg daily. Close monitoring of the tumour response should be carried out in the early phases of treatment. Follow-up should be continued throughout the treatment, since the risk of secondary progression persists over time. Complete excision of residual metastatic disease has been shown to be associated with a good prognosis, provided the patient is responding to imatinib, but it has never been demonstrated prospectively whether this is due to surgery or to patient selection [36.Mussi C. Ronellenfitsch U. Jakob J. et al.Post-imatinib surgery in advanced/metastatic GIST: is it worthwhile in all patients?.Ann Oncol. 2010; 21: 403-408Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 37.Raut C.P. Posner M. Desai J. et al.Surgical management of advanced gastrointestinal stromal tumors after treatment with targeted systemic therapy using kinase inhibitors.J Clin Oncol. 2006; 24: 2325-2331Crossref PubMed Scopus (360) Google Scholar, 38.Wang D. Zhang Q. 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