TY - JOUR
AU - Reynolds, J V
AB - Abstract Background Gastrointestinal stromal tumours (GISTs), previously classified as benign or malignant smooth muscle tumours, are the most common mesenchymal tumours of the gastrointestinal tract. GISTs express a growth factor receptor with tyrosine kinase activity, termed KIT. Mutations of KIT are common in malignant GISTs and lead to constitutional activation of tyrosine kinase function, which causes cellular proliferation and resistance to apoptosis. GISTs are notoriously unresponsive to chemotherapy and, until the recent introduction of the KIT inhibitor imatinib, there has been no effective therapy for advanced, metastatic disease. Methods A Medline literature search was preformed to locate all articles relating to gastrointestinal tumours, GISTs, KIT and imatinib. Results and conclusions The 5-year survival rate after complete resection of GISTs is approximately 50 per cent. The median duration of survival for patients with a metastatic GIST is approximately 20 months, and 9–12 months for patients with local recurrence. Phase II trials have investigated the effect of imatinib on irresectable or metastatic GISTs. In these trials more than 50 per cent of patients responded to imatinib within a few months and approximately 12 per cent had disease progression. Uptake of [18F]fluoro-2-deoxy-d-glucose demonstrated by positron emission tomography has been found to be reduced after starting imatinib. The potential for cure and the optimal length of treatment is currently unknown. Imatinib is the first effective systemic therapy for metastatic and locally irresectable GISTs. Large multi-institutional clinical trials to investigate the efficacy of imatinib as adjuvant or neoadjuvant therapy for GISTs are now required. Introduction Until 20 years ago most gastrointestinal mesenchymal tumours were considered to be of smooth muscle origin. Designations included leiomyoma (benign) or leiomyosarcoma (malignant) for tumours composed primarily of spindle-shaped cells, and benign or malignant leiomyoblastoma for those composed primarily of epithelioid cells. However, gastrointestinal sarcomas had been observed to be relatively resistant to standard doxorubicin-based chemotherapy regimens compared with leiomyosarcomas of the uterus, trunk or limbs1. Mazur and Clark2 reported that many supposed smooth muscle tumours lacked immunohistochemical or electron microscopic evidence of smooth muscle or neural immunoreactivity, and they suggested that the neutral term ‘gastric stromal tumour’ would be more appropriate. Subsequent immunocytochemical studies of gastrointestinal sarcomas documented the frequent lack of, or minimal evidence of muscle differentiation typical of leiomyosarcomas located elsewhere in the body3,4. The term gastrointestinal stromal tumour (GIST) was gradually adopted for a specific category of benign and malignant mesenchymal neoplasms of the gastrointestinal tract with a minimal or incomplete myogenic or neural phenotype (‘uncommitted phenotype’) as defined by immunohistochemistry or electron microscopy. Tumours exhibiting true smooth muscle or Schwann cell (neural) differentiation are excluded. It has since become clear that the tumour cells comprising GISTs are closely related to the interstitial cells of Cajal. These cells constitute a complex cellular network, the likely functions of which are gastrointestinal tract pacemaking and the regulation of intestinal motility3,5. The immunohistochemistry of the interstitial cells of Cajal is similar to that of GIST cells, being positive for c-kit and CD-34, and negative for desmin and S-100. Not all GISTs arise from the interstitial cells of Cajal, however, as some come from the mesentery or omentum which lacks interstitial cells of Cajal, suggesting an origin in multipotential mesenchymal stem cells. Epidemiology and clinical presentation Although relatively rare, GISTs comprise the largest subset of mesenchymal tumours of the gastrointestinal tract3,5. They are reported to constitute about 5 per cent of all sarcomas6 and occur predominantly in middle-aged and older persons, the median age at diagnosis being about 60 years; they are infrequent before the age of 40 years. No significant sex difference has been noted3,5. Approximately 70 per cent of the tumours occur in the stomach, 20–30 per cent in the small intestine and less than 10 per cent elsewhere in the gastrointestinal tract3,7. They occur far less commonly in the oesophagus, colon and rectum, where true myogenic tumours predominate. Small GISTs (2 cm or less) are usually asymptomatic, are detected during investigations or surgical procedures for unrelated disease, and the vast majority are benign. Clinical signs and symptoms (nausea, vomiting, abdominal pain, obstruction, abdominal mass often not initially identifiable as related to the gastrointestinal tract, anaemia and melena) are non-specific. About 50 per cent of GISTs are overtly metastatic at presentation, with the most common sites of metastases being the peritoneum and the liver6. GISTs may be multiple, especially when familial, and they may be associated with cutaneous hyperpigmentation; these patients usually have germline mutations in exon 11 of kit8. Pathology of gastrointestinal stromal tumours Grossly GISTs vary greatly in size, ranging from 1–2 cm to more than 20 cm in diameter. Large tumours may show cystic degeneration, necrosis and focal haemorrhage. The tumours are often well circumscribed and unencapsulated, although a pseudocapsule may occasionally be seen. They occur in the submucosa, muscularis propria or serosa, and not infrequently cause ulceration of the overlying mucosa. They are composed of spindle-shaped cells (60–70 per cent) or epithelioid cells, and are typically more cellular and with less eosinophilic cytoplasm than leiomyomas3 (Fig. 1a). Nuclear atypia, marked cellularity, mixed spindle–epithelioid morphology, mitotic rate above 5 per 50 high-power fields, mucosal invasion and necrosis are associated with malignancy3,9. However, GISTs are not always clearly identifiable as benign or malignant, and many are reported as of low malignant potential. Increasingly, many centres are reluctant to use the term ‘benign’ for any GIST. With prolonged follow-up, it appears that almost any GIST presenting with clinical symptoms or signs leading to treatment has the potential to behave in a malignant fashion. This complex and unsatisfactory situation has led to the development of a scheme based on risk assessment. Suggested definitions of the different risk categories have been compiled by Fletcher et al.10 and are outlined in Table 1. Fig. 1 Open in new tabDownload slide Histopathology and immunohistochemistry of a gastrointestinal stromal tumour (GIST). a GIST with spindle cell phenotype. Note the compact and highly cellular pattern. The cells have paler eosinophilic cytoplasm than smooth muscle neoplasms, with indistinct cell margins and minimal tumour stroma. The nuclei are typically uniform in appearance and spindle or ovoid in shape. The arrow points to an apoptotic tumour cell (× 400 magnification). b KIT immunostaining of a GIST. Most GISTs show diffuse strong cytoplasmic staining as seen here (× 200 magnification) Table 1 Proposed approach for assigning risk to gastrointestinal stromal tumours (adapted from reference10) . Size (cm) . Mitotic count (per 50 HPF) . Very low risk < 2 < 5 Low risk 2–5 < 5 Intermediate risk < 5 6–10 5–10 < 5 High risk > 5 > 5 > 10 Any Any > 10 . Size (cm) . Mitotic count (per 50 HPF) . Very low risk < 2 < 5 Low risk 2–5 < 5 Intermediate risk < 5 6–10 5–10 < 5 High risk > 5 > 5 > 10 Any Any > 10 HPF, high-power field. Open in new tab Table 1 Proposed approach for assigning risk to gastrointestinal stromal tumours (adapted from reference10) . Size (cm) . Mitotic count (per 50 HPF) . Very low risk < 2 < 5 Low risk 2–5 < 5 Intermediate risk < 5 6–10 5–10 < 5 High risk > 5 > 5 > 10 Any Any > 10 . Size (cm) . Mitotic count (per 50 HPF) . Very low risk < 2 < 5 Low risk 2–5 < 5 Intermediate risk < 5 6–10 5–10 < 5 High risk > 5 > 5 > 10 Any Any > 10 HPF, high-power field. Open in new tab In contrast to leiomyomas and leiomyosarcomas, GISTs are typically immunoreactive for CD34, the haematopoietic progenitor cell antigen; they may be focally positive for smooth muscle actin but are negative for desmin. On electron microscopy, GISTs lack the thin actin filaments with periodic densities that are characteristic of smooth muscle tumours. Recent studies have shown that the tumour cells in GISTs express a growth factor receptor with tyrosine kinase activity termed KIT. This receptor, the product of the proto-oncogene c-kit (located on chromosome 4q11-q12), can be detected by immunohistochemical staining for CD117. All GISTs are immunohistochemically positive for KIT (CD117)11 (Fig. 1b). It should be noted that many other tumour types are also CD117 positive, but most do not occur in the gastrointestinal tract and are not in the differential diagnosis. Positive CD117 staining (and in most cases positive CD34 staining) in the appropriate clinical context, with compatible gross features and microscopic findings (highly cellular mesenchymal tumour of the gastrointestinal tract composed of spindle cells, epithelioid cells or a combination of both) are the defining features of these tumours3. Treatment Surgical resection is the treatment of choice for GISTs. Preoperative percutaneous biopsy carries the theoretical risk of peritoneal seeding or tumour rupture, and is indicated only for clearly irresectable disease or when treatment would be altered, as would be the case if the mass proved to be lymphoma or germ cell tumour. The diagnosis of GIST may be suggested by preoperative computed tomography (CT) or at laparotomy by the presence of a large mass without adenopathy that may or may not be associated with liver metastases. All tumours should be approached with the intention of performing complete en bloc removal (R0 resection) of the tumour and surrounding normal tissue, including adjacent organs if involved6,12,13. In a recent report, Langer et al.13 described the outcome of 39 patients following surgery. Complete R0 resection was achieved in 35 of the 39 patients and of these only five died from recurrent disease, compared with three of the four patients with involved margins. Incomplete resection should only be performed for the palliation of pain, bleeding or the symptoms of mass effect. Several reviews have reported that small tumours (5 cm or less) of the stomach can be treated adequately by wedge gastric resection, with a generous margin of gastric wall14. Larger gastric sarcomas may require subtotal or total gastrectomy, including omentectomy. Malignant stromal tumours metastasize to lymph nodes with insufficient frequency to warrant lymph node dissection6,12. Indeed there is no evidence to suggest that procedures more extensive than removal of all gross neoplasm prolong survival or delay recurrence. Complete resection in patients with a primary GIST is associated with a 5-year survival rate of 48–65 per cent (Table 2)6,15–18. GISTs are notoriously unresponsive to chemotherapy and radiation therapy, and there has been no effective treatment for advanced metastatic disease, which is invariably fatal. Table 2 Published series of survival after complete resection of primary gastrointestinal stromal tumours Reference . Study interval . No. of patients . No. of complete resections . 5-year survival after complete resection (%) . Akwari et al.15 1950–1974 108 52 50 Shiu et al.16 1949–1973  38 20 65 McGrath et al.17 1951–1984  51 30 63 Ng et al.18 1957–1997 191 99 48 DeMatteo et al.6 1982–1998 200 80 54 Reference . Study interval . No. of patients . No. of complete resections . 5-year survival after complete resection (%) . Akwari et al.15 1950–1974 108 52 50 Shiu et al.16 1949–1973  38 20 65 McGrath et al.17 1951–1984  51 30 63 Ng et al.18 1957–1997 191 99 48 DeMatteo et al.6 1982–1998 200 80 54 Open in new tab Table 2 Published series of survival after complete resection of primary gastrointestinal stromal tumours Reference . Study interval . No. of patients . No. of complete resections . 5-year survival after complete resection (%) . Akwari et al.15 1950–1974 108 52 50 Shiu et al.16 1949–1973  38 20 65 McGrath et al.17 1951–1984  51 30 63 Ng et al.18 1957–1997 191 99 48 DeMatteo et al.6 1982–1998 200 80 54 Reference . Study interval . No. of patients . No. of complete resections . 5-year survival after complete resection (%) . Akwari et al.15 1950–1974 108 52 50 Shiu et al.16 1949–1973  38 20 65 McGrath et al.17 1951–1984  51 30 63 Ng et al.18 1957–1997 191 99 48 DeMatteo et al.6 1982–1998 200 80 54 Open in new tab Prognosis GISTs are generally thought to be malignant, but they have different degrees of aggressiveness, resulting in varying times to the development of metastases. Predicting the potential biological behaviour of these tumours remains difficult and an analysis of the literature to resolve this issue provides many conflicting reports. Mitotic activity, tumour size, tumour necrosis, histological type and pattern, immunohistochemical profile, staining for proliferating antigens and ploidy status, among others, have all been evaluated extensively in this context without any consensus being established. Age, the mitotic index (fewer than 2 mitoses per 50 high-power fields) and size of the tumour (less than 5 cm versus 5 cm or more) are generally accepted as independent prognostic factors19. Oesophageal tumours as a group have the most favourable long-term survival and small intestinal tumours have the worst20. Patients with leiomyosarcoma have a better survival than those with GIST and the former lesion has a less pronounced drug resistance pattern21. The median survival of patients with metastatic GIST has been estimated at 20 months and for patients with local recurrence it is 9–12 months3. Conventional chemotherapy does not influence survival; in a recently reported series the response rate to doxorubicin was less than 5 per cent22. Although no unequivocal data are as yet available, current efforts focus on establishing whether the presence or absence of KIT mutations, and/or the nature of the mutation, have a bearing on prognosis. KIT mutations in gastrointestinal stromal tumours KIT, a 145-kDa transmembrane glycoprotein, is the product of the c-kit proto-oncogene. A member of the receptor tyrosine kinase family, KIT is closely related to the receptors for platelet-derived growth factor, macrophage colony-stimulating factor, and FMS-like receptor tyrosine kinase (FLT3) ligand8,23. The juxtamembrane and kinase domains of all these receptors are strongly conserved. KIT is expressed by haematopoietic progenitor cells, mast cells, germ cells and by the interstitial cells of Cajal. The extracellular portion of the KIT receptor binds a ligand known as stem-cell factor and the intracellular portion contains the kinase enzymatic domain. KIT activation usually takes place when two adjacent receptors are linked by binding to ligand dimers. This process, known as homodimerization, is accompanied by structural changes in the receptors, leading to activation of the KIT kinase domain. The activated kinases then cross-phosphorylate tyrosine residues in the opposed homodimer partner leading to further activation of the receptor. The phosphotyrosines also serve as binding sites for various cell-signalling proteins, many of which are phosphorylated by KIT or by each other. This leads to activation of the cell-signalling cascades involved in tumorigenesis, including proliferation, adhesion, apoptosis and differentiation8,23. Gain of function mutations of KIT occur in up to 90 per cent of GISTs, the most frequent of which are mutations of exon 11 (57–71 per cent of GISTs)7,24. Mutations in exon 13 and 9 have been found in most of the remaining cases. The mutation leads to constitutional activation (phosphorylation) of the receptor, which in normal circumstances takes place upon binding of the ligand. The activating mutation perpetuates the KIT signal and the downstream phosphorylation cascade in the signal transduction pathway, ultimately leading to activation of cellular proliferation25,26. GISTs with mutant KIT are more likely to be high-grade tumours, characterized by more frequent recurrence and a higher associated mortality rate than gastrointestinal tumours with normal KIT. In one series of more than 100 patients, the presence of an exon 11 mutation was correlated with disease recurrence and predicted for poorer survival (5-year survival rate 86 versus 49 per cent)27. Stable transfection of the mutant gene leads to malignant transformation of murine lymphoid cells (Ba/F3)28. Germline mutations of exon 11 or exon 13 produce an autosomal dominantly inherited susceptibility to the formation of GISTs. Affected individuals develop diffuse hyperplasia of the interstitial cells of Cajal and are affected with the occurrence of multiple GISTs during adulthood29. Thus mutations in KIT seem to serve as a gatekeeper role in the transformation of the interstitial cells of Cajal into a GIST. Protein kinase inhibition and imatinib Protein kinases are enzymes that transfer phosphate from ATP to specific amino acids on substrate proteins. The phosphorylation of these proteins leads to the activation of signal transduction pathways, which have a critical role in a variety of biological processes, including cell growth, differentiation and death30,31. Protein kinases are composed of two subfamilies, the protein serine–threonine kinases and the protein tyrosine kinases. Several protein kinases are deregulated and overexpressed in human cancers and are therefore attractive targets for selective pharmacological inhibitors. Some tyrosine kinases, such as the transmembrane growth factor receptor, have already proved to be excellent targets for successful anticancer drug therapy32. Imatinib (formerly referred to as STI571, and now manufactured as Gleevec® in the USA and Glivec® in Europe; Novartis Pharma AG, Basel, Switzerland) is a powerful and relatively selective and competitive inhibitor of all ABL tyrosine kinases (including c-ABL, bcr-ABL), platelet-derived growth factor receptor (PDGFR) and c-KIT. Imatinib is a multiringed molecule and a 2-phenylaminopyrimidine derivative (Fig. 2) that binds to the ATP-binding site of the target kinase and so prevents the kinase from transferring phosphate from ATP to the tyrosine residues of its substrates. This inhibits downstream signalling from the tyrosine kinase, which switches the balance towards reduced cellular proliferation and increased apoptosis (hence the term ‘signal transduction inhibitor’)8,23,33,34. Fig. 2 Open in new tabDownload slide Structure of imatinib mesylate, designated chemically as 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino-]-phenyl]benzamide methanesulfonate Imatinib is well absorbed after oral administration but, because the drug may cause local irritation, it is taken with food, preferably in the morning. Imatinib is metabolized in the liver by the P450 isoenzyme CYP3A4, and the metabolites are mostly excreted in the stool. The half-life in the circulation ranges from 13–16 h35, which is compatible with administration once daily. Division of the daily dose into two may alleviate nausea after digestion in some patients. Preclinical studies suggest that maintenance of imatinib levels above 1 µmol/l are needed for optimal therapeutic effects, and these serum levels are obtained in patients treated with doses of 300 mg or greater24. Assessment of the efficacy of imatinib as a tyrosine kinase inhibitor, as well as abundant information on its pharmacokinetics and toxicity, has been obtained through studies in patients with chronic myeloid leukaemia (CML). In CML, a chromosomal rearrangement in a haematopoietic stem cell causes the formation of a fusion protein, BCR-ABL, in which the tyrosine kinase component of the ABL portion is constitutively active, a ligand-independent activation similar to the role of KIT in GIST cells. In 1996 Druker et al.36 reported that imatinib specifically inhibited or killed proliferating myeloid cells containing BCR-ABL but was minimally harmful to normal cells. Imatinib impairs BCR-ABL-mediated transfer of phosphate to its substrates. It was found to inhibit the constitutively active fusion product arising from the Philadelphia (Ph) chromosome of CML. Imatinib is highly active and has an acceptable toxicity level when given alone for the treatment of chronic-phase CML. Druker et al.35 reported a complete haematological response in 53 of 54 patients treated with daily imatinib doses of 300 mg or more, and the responses typically occurred in the first 4 weeks of therapy. Importantly, a cytogenetic response occurred in 29 patients (53·7 per cent), and seven (13·0 per cent) achieved a complete cytogenetic response. The toxicity of imatinib was described as minimal in this study, and the most common adverse effects were nausea, myalgia, oedema and diarrhoea. Imatinib also has limited activity against blast-phase CML and relapsed Ph chromosome-positive acute lymphoblastic leukaemia, conditions resistant to standard chemotherapy and even to allogenic stem-cell transplantation4,37. In the USA, imatinib was approved by the Food and Drug Administration (FDA) in May 2001 for the treatment of CML that is refractory to interferon therapy4. Imatinib in the treatment of gastrointestinal stromal tumours GISTs are also potential targets for imatinib because up to 90 per cent of malignant lesions harbour a mutation in KIT, which is specifically inhibited by this drug. Early reports indicate that imatinib is the first effective systemic therapy for metastatic and locally inoperable GIST, although the long-term results are not yet unavailable. Imatinib causes 50 per cent inhibition of KIT at about 100 nmol/l, similar to the concentration required for inhibition of BCR-ABL. In February 2002 the FDA approved imatinib for the treatment of GISTs4. It has also been reported that imatinib has some activity against desmoid tumours, which have recently been shown to express c-kit as well as PDGFR-α and PDGFR-β38. The first patient with a GIST who was treated with imatinib had a progressive, chemotherapy-resistant metastatic lesion carrying a mutation of KIT with a deletion in exon 11. This patient had a rapid and sustained response with 400 mg imatinib daily and is still receiving therapy more than 22 months after its initiation34,39. The European Organization for Research and Treatment of Cancer (soft tissue and sarcoma group) performed a phase I study of imatinib involving 40 patients with advanced soft tissue sarcomas, 36 of whom had a GIST (Table 3). They were treated with oral doses of imatinib ranging from 400 to 1000 mg daily, with therapy continuing until disease progression or unacceptable toxicity occurred, or the patient refused to continue with the drug. Of the 36 patients with GISTs, imatinib inhibited tumour growth in 32, 19 of whom had more than a 50 per cent decrease in tumour volume40. Additionally, most patients with GISTs had major and rapid symptomatic benefit with improvement in performance status. Patients whose lesions were not GIST fared worse, and none had a documented response to the treatment. In responding patients, impressive reductions in [18F]fluoro-2-deoxy-d-glucose uptake were observed on serial positron emission tomography (PET) (within 8 days in most patients) and predicted an objective response by CT after 8 weeks. The investigators recommended a dose of 400 mg twice daily for phase II–III testing. Table 3 Clinical trials of imatinib in locally inoperable or metastatic gastrointestinal stromal tumours Reference . Year . Trial type . No. of patients with GIST . Daily dose (mg) . Objective response . Improvement in clinical symptoms (%) . Minimum follow-up (months) . van Oosterom et al.40 2001 Phase I 36 400–1000 53% partial response 88 9–13 EORTC 17% some response 11% stable 11% progressed Demetri et al.39 2002 Phase II 147 400 or 600 53·7% partial response 89 9 27·9% stable 13·6% progressed Reference . Year . Trial type . No. of patients with GIST . Daily dose (mg) . Objective response . Improvement in clinical symptoms (%) . Minimum follow-up (months) . van Oosterom et al.40 2001 Phase I 36 400–1000 53% partial response 88 9–13 EORTC 17% some response 11% stable 11% progressed Demetri et al.39 2002 Phase II 147 400 or 600 53·7% partial response 89 9 27·9% stable 13·6% progressed GIST, gastrointestinal stromal tumours; EORTC, European Organization for Research and Treatment of Cancer. Partial response is a 50–99% reduction in tumour size; some response is 0–49% reduction. Open in new tab Table 3 Clinical trials of imatinib in locally inoperable or metastatic gastrointestinal stromal tumours Reference . Year . Trial type . No. of patients with GIST . Daily dose (mg) . Objective response . Improvement in clinical symptoms (%) . Minimum follow-up (months) . van Oosterom et al.40 2001 Phase I 36 400–1000 53% partial response 88 9–13 EORTC 17% some response 11% stable 11% progressed Demetri et al.39 2002 Phase II 147 400 or 600 53·7% partial response 89 9 27·9% stable 13·6% progressed Reference . Year . Trial type . No. of patients with GIST . Daily dose (mg) . Objective response . Improvement in clinical symptoms (%) . Minimum follow-up (months) . van Oosterom et al.40 2001 Phase I 36 400–1000 53% partial response 88 9–13 EORTC 17% some response 11% stable 11% progressed Demetri et al.39 2002 Phase II 147 400 or 600 53·7% partial response 89 9 27·9% stable 13·6% progressed GIST, gastrointestinal stromal tumours; EORTC, European Organization for Research and Treatment of Cancer. Partial response is a 50–99% reduction in tumour size; some response is 0–49% reduction. Open in new tab On the basis of these studies, a multicentre phase II trial of imatinib for the treatment of irresectable or metastatic GIST was initiated in July 200039 (Table 3). In this trial 147 patients were randomized to receive 400 or 600 mg imatinib per day. Grade 3 or 4 toxicity (haemorrhage, abdominal pain, electrolyte abnormalities) was noted in 21·1 per cent of patients. With follow-up of more than 9 months for all patients (median 288 days) 120 patients remained in the study. Overall 53·7 per cent had a partial response, defined by a decrease of at least 50 per cent in the size of the lesion, and disease stabilization was noted in an additional 27·9 per cent. With limited follow-up, only 13·6 per cent of patients experienced disease progression. The median time to an objective response was 13 weeks. There were no significant differences in the rate or duration of response between the doses of imatinib tested. The estimated 1-year survival rate for all patients was 88 per cent. In all patients with a response, the uptake of [18F]fluoro-2-deoxy-d-glucose into the tumour detected by PET had decreased markedly from baseline as early as 24 h after a single dose of imatinib, indicating that rapid assessment and prediction of clinical response are possible with this functional imaging modality. Increases in tumour-related glycolytic activity, activity at new sites, or both were seen in all patients with disease progression. PET results correlated with subsequent evidence of a response or progression on CT or magnetic resonance imaging (MRI)38. In a serial follow-up based on CT or MRI, some metastatic lesions became cyst like and, when assessed with serial needle biopsies, these cyst-like lesions consisted mainly of tissue with myxoid degeneration and scarring (Fig. 3)34,39. However, KIT-positive KI-67-negative cells, probably representing non-cycling or dormant GIST cells, may be encountered several months after starting imatinib, even in a responding patient34,39. Fig. 3 Open in new tabDownload slide Computed tomography of a 60-year-old woman with a metastatic gastrointestinal stromal tumour. a Before imatinib, b after 4 months' treatment with imatinib and c after 14 months of treatment. The patient had a dramatic clinical response, with resolution of symptoms of small bowel obstruction and reduction in the size of palpable subcutaneous nodules. b and c demonstrate the cystic like degeneration of the metastatic lesions that occurs with imatinib treatment In both of the above studies the severity and frequency of side-effects were similar to those reported in studies of patients with CML. At twice-daily doses of 500 mg in the European dose-escalation study, nausea and vomiting, oedema and dyspnoea were dose-limiting effects. The most serious adverse events were gastrointestinal or intra-abdominal haemorrhage in patients with large, bulky tumours, which occurred in approximately 5 per cent of patients39,40 (Table 4). Although the long-term results these trials are not yet published, early findings (high objective response rate, low rate of serious toxicity) led to a National Cancer Institute-sponsored phase III intergroup trial of imatinib for metastatic GIST. Accrual for this trial closed September 2001 after exceeding the target goal of 600 patients. A similar phase III trial in Europe is nearing its target accrual. Clinical trials of neoadjuvant and adjuvant use of imatinib are planned. Table 4 Adverse effects with a possible or suspected relation to imatinib in 147 patients with gastrointestinal stromal tumour who took part in a phase II trial (dose 400–600 mg daily)39 Adverse effect . Any grade (%) . Grade 3 or 4 (%) . Any adverse effect 98 21·1 Oedema/fluid retention 74·1 1·4 Nausea 52·4 1·4 Diarrhoea 44·9 2 Myalgia 39·5 0 Fatigue 34·7 0 Dermatitis 30·6 2·7 Headache 25·9 0 Abdominal pain 25·9 0·7 Flatulence 21·8 0 Vomiting 12·9 0·7 Haemorrhage 12·2 4·8 Dyspepsia 10·9 0 Increased lacrimation 9·5 0 Anaemia 8·8 2 Loose stools 8·2 0 Taste disturbance 8·2 0 Neutropenia 6·8 4·8 Abdominal distension 5·4 0 Abnormal liver function tests 5·4 2·7 Leucopenia 4·8 1·4 Arthralgia 4·1 0 Paraesthesia 4·1 0 Oesophageal reflux 4·1 0 Pruritus 4·1 0 Pain (in extremity) 3·4 0 Blurred vision 3·4 0 Photosensitivity 2·7 0 Adverse effect . Any grade (%) . Grade 3 or 4 (%) . Any adverse effect 98 21·1 Oedema/fluid retention 74·1 1·4 Nausea 52·4 1·4 Diarrhoea 44·9 2 Myalgia 39·5 0 Fatigue 34·7 0 Dermatitis 30·6 2·7 Headache 25·9 0 Abdominal pain 25·9 0·7 Flatulence 21·8 0 Vomiting 12·9 0·7 Haemorrhage 12·2 4·8 Dyspepsia 10·9 0 Increased lacrimation 9·5 0 Anaemia 8·8 2 Loose stools 8·2 0 Taste disturbance 8·2 0 Neutropenia 6·8 4·8 Abdominal distension 5·4 0 Abnormal liver function tests 5·4 2·7 Leucopenia 4·8 1·4 Arthralgia 4·1 0 Paraesthesia 4·1 0 Oesophageal reflux 4·1 0 Pruritus 4·1 0 Pain (in extremity) 3·4 0 Blurred vision 3·4 0 Photosensitivity 2·7 0 Open in new tab Table 4 Adverse effects with a possible or suspected relation to imatinib in 147 patients with gastrointestinal stromal tumour who took part in a phase II trial (dose 400–600 mg daily)39 Adverse effect . Any grade (%) . Grade 3 or 4 (%) . Any adverse effect 98 21·1 Oedema/fluid retention 74·1 1·4 Nausea 52·4 1·4 Diarrhoea 44·9 2 Myalgia 39·5 0 Fatigue 34·7 0 Dermatitis 30·6 2·7 Headache 25·9 0 Abdominal pain 25·9 0·7 Flatulence 21·8 0 Vomiting 12·9 0·7 Haemorrhage 12·2 4·8 Dyspepsia 10·9 0 Increased lacrimation 9·5 0 Anaemia 8·8 2 Loose stools 8·2 0 Taste disturbance 8·2 0 Neutropenia 6·8 4·8 Abdominal distension 5·4 0 Abnormal liver function tests 5·4 2·7 Leucopenia 4·8 1·4 Arthralgia 4·1 0 Paraesthesia 4·1 0 Oesophageal reflux 4·1 0 Pruritus 4·1 0 Pain (in extremity) 3·4 0 Blurred vision 3·4 0 Photosensitivity 2·7 0 Adverse effect . Any grade (%) . Grade 3 or 4 (%) . Any adverse effect 98 21·1 Oedema/fluid retention 74·1 1·4 Nausea 52·4 1·4 Diarrhoea 44·9 2 Myalgia 39·5 0 Fatigue 34·7 0 Dermatitis 30·6 2·7 Headache 25·9 0 Abdominal pain 25·9 0·7 Flatulence 21·8 0 Vomiting 12·9 0·7 Haemorrhage 12·2 4·8 Dyspepsia 10·9 0 Increased lacrimation 9·5 0 Anaemia 8·8 2 Loose stools 8·2 0 Taste disturbance 8·2 0 Neutropenia 6·8 4·8 Abdominal distension 5·4 0 Abnormal liver function tests 5·4 2·7 Leucopenia 4·8 1·4 Arthralgia 4·1 0 Paraesthesia 4·1 0 Oesophageal reflux 4·1 0 Pruritus 4·1 0 Pain (in extremity) 3·4 0 Blurred vision 3·4 0 Photosensitivity 2·7 0 Open in new tab The clinical effect of imatinib on GISTs is often rapid, and patients have reported improved well-being and decreased cancer-related symptoms within a few days of starting the drug. It is currently not known for how long imatinib therapy needs to be continued. No responding patient has yet had progression of disease in the series reported so far, but current follow-up is short. The mechanism of resistance to therapy is also unknown, but the lessons from CML suggest that multiple molecular mechanisms may be important, including gene amplification and mutation of the drug-binding site in the kinase domain. Conclusion GISTs account for most mesenchymal tumours arising within the gastrointestinal tract. They express the cell-surface transmembrane receptor KIT that has tyrosine kinase activity and is the protein product of the c-kit proto-oncogene. There are frequent gain-of -function mutations in GISTs that result in activation of KIT signalling, which leads to uncontrolled cell proliferation and resistance to apoptosis. Surgical resection is the treatment of choice for these tumours, which are resistant to chemotherapy. Based on studies of long-term follow-up, up to 85 per cent of patients with GISTs suffer an adverse outcome after surgical resection (recurrence, metastasis, death), although those with a gastric primary fare somewhat better than those with a small bowel or colonic tumour6. Irresectable or metastatic GIST is a fatal disease that resists conventional chemotherapy or radiotherapy6. Imatinib is a selective inhibitor of certain protein kinases including KIT. Results of phase I and II studies indicate that imatinib is the first effective systemic therapy for metastatic and locally inoperable GIST. The treatment is given orally and usually on an outpatient basis. The decision to prescribe imatinib should be made after discussion at a multidisciplinary meeting, which should include a pathologist, radiologist, oncologist and surgeon. The surgeon must be intimately involved, as he or she is responsible for the decision on tumour resectability. The high rate of response to imatinib is not only remarkable but also supports the hypothesis that dysregulated KIT kinase activity is important in human GISTs. PET appears to be a sensitive and reliable indicator of early response or resistance to imatinib. Imatinib is one of the first examples of a drug approved by the FDA that targets an intracellular signalling molecule in cancer therapy. It has been described in a recent editorial as ‘a molecular star in the war against cancer’41. The net cost of imatinib per patient per month is approximately €2600. It is not yet known for how long patients must be treated. Although the results of current trials indicate that imatinib is very effective for many patients with advanced GISTs, resistance to single-agent therapy is common in cancer management. Follow-up so far is short, and it will be years before the answers to many of these questions are known. Based on the results in CML, there is reason to believe that imatinib may be even more effective when given earlier in the management of GIST. It is currently not known whether the remnants of a previously irresectable tumour should be resected after treatment with imatinib. Whether these tumours will remain responsive to imatinib over time is uncertain and so resection should perhaps be considered if technically possible. Imatinib needs to be investigated for locally advanced or high-grade malignant operable GISTs in the adjuvant setting to evaluate its potential role in prolonging disease-free and overall survival. Clinical trials of neoadjuvant and adjuvant use of imatinib are planned. References 1 Edmonson J , Marks R, Buckner J, Mahoney MR. Contrast of response to D-MAP + Sargramostim between patients with advanced malignant gastrointestinal stromal tumours and patients with other advanced leiomyosarcomas . Proc Am Soc Clin Oncol 1999 ; 18 : 541A (Abstract 2088). 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TI - Gastrointestinal stromal tumours
JF - British Journal of Surgery
DO - 10.1002/bjs.4352
DA - 2003-09-22
UR - https://www.deepdyve.com/lp/oxford-university-press/gastrointestinal-stromal-tumours-tKDClg0L10
SP - 1178
EP - 1186
VL - 90
IS - 10
DP - DeepDyve
ER -