A review of the surgical management of metastatic gastrointestinal stromal tumours (GISTs) on imatinib mesylate (Glivecä)

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1 International Journal of Surgery (2005) 3, 206e212 REVIEW A review of the surgical management of metastatic gastrointestinal stromal tumours (GISTs) on imatinib mesylate (Glivecä) G. Barnes a, V.R. Bulusu b, *,1, R.H. Hardwick a,1, N. Carroll b,1, H. Hatcher b, H.M. Earl b,1, V.E. Save c,1, K. Balan d,1, N.V. Jamieson a a Directorate of Surgery, Addenbrooke s Hospital, Cambridge, CB2 2QQ, UK b Department of Radiology, Addenbrooke s Hospital, Cambridge CB2 2QQ, UK c Department of Pathology, Addenbrooke s Hospital, Cambridge, CB2 2QQ, UK d Department of Nuclear Medicine, Addenbrooke s Hospital, Cambridge, CB2 2QQ, UK KEYWORDS Metastatic GISTs; Imatinib mesylate; Role of surgery Abstract Gastrointestinal stromal tumours (GISTs) are defined as a group of C-KIT positive mesenchymal tumours of the gastrointestinal tract. Although they may arise throughout the gut, the commonest sites are stomach and small intestine. Over 80% of metastases are to the liver and omentum. Targeted therapy (imatinib) can inhibit C-KIT and thereby aberrant tumoural proliferation. Imatinib may induce shrinkage of lesions and cystic change. Such physical changes often correspond with reduced metabolic activity demonstrated by 18-FDG PET scans. These changes may enable metastatectomy reducing tumour pain and the risk of haemorrhage and rupture in the short term. In the long term, resection may lessen the risk of recurrence by removing potentially resistant clones. The precise role of palliative resection for GIST metastases on imatinib remains unclear. Imatinib has changed the natural history of metastatic GISTs, with increased survival times. Surgery remains an important management strategy in the metastatic setting because complete pathological responses are rare with imatinib. Surgery is likely to provide the best palliation, greatest reduction in tumour burden and eliminate resistant clones. A multidisciplinary team approach with expertise concentrated in a few centres specialising in the management of these rare tumours is vital to the successful outcome. Future issues regarding the management of differential response of the metastases to imatinib are highlighted. With the emergence of techniques enabling identification of the precise mutational status of the C-KIT * Corresponding author. Tel.: C ; fax: C address: ramesh.bulusu@addenbrookes.nhs.uk (V.R. Bulusu). 1 Bulusu VR, Hardwick RH, Carroll N, Earl HM, Save VE and Balan K are members of the Cambridge GIST Study Group /$ - see front matter ª 2005 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved. doi: /j.ijsu

2 Surgical management of metastatic GISTs on imatinib mesylate 207 oncogene, the imatinib/surgery sequence could be tailored to the type of C-KIT mutation. ª 2005 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved. Introduction Gastrointestinal stromal tumours (GISTs) are rare tumours and account for 0.1e0.3% of all gastrointestinal cancers and 5% of all soft tissue sarcomas. 1 GISTs predominantly occur in middle aged and older patients (fifth to seventh decades) with no significant difference in the sex incidence. 2 They are the most prevalent mesenchymal tumours of the gastrointestinal tract, occurring throughout the gut. The most common sites are stomach (60%) and small intestine (20e30%), but they can also arise from the large bowel and rectum (10%). 3,4 Ten per cent of patients present with metastatic disease. The most frequent metastatic sites are liver (65%) and omentum (21%); in over 50%, liver is the sole site of spread (Figs. 1 and 2). Lymph node (6%), bone (6%) and lung metastases (2%) are uncommon at presentation. 5 The term GIST was coined by Mazur and Clark. 6 Recent advances in molecular research have enabled the differentiation of GISTs from smooth muscle tumours such as leiomyoma and leiomyosarcoma. This distinction is important due to the availability of targeted therapy for GISTs: Imatinib mesylate (Glivec). Imatinib inhibits the C-KIT tyrosine kinase and other kinases. GISTs are now defined as a group of C-KIT tyrosine kinase receptor (CD117) positive mesenchymal tumours of the gastrointestinal tract (Fig. 3). Ninety per cent of GISTs express the mutated form of the C-KIT proto-oncogene. This mutation results in constitutive activation of the C-KIT tyrosine kinase receptor and signal transduction pathway, causing unregulated cell growth. 7,8 This is the crucial event in their pathogenesis. It is now thought that these tumours may originate from the interstitial cells of Cajal, the pacemaker cells of the gastrointestinal tract. 9,10 Role of surgery in the management of metastatic GISTs Surgery remains the treatment of choice for primary GISTs. All primary GISTs should be approached with the aim of performing a complete en bloc (R0) resection (Fig. 4). 11,12 The 5 year survival rate in patients with resected primary GISTs ranges from 48% to 65% in published series. 13e15 In the MSKCC series 40% of patients relapsed after a median follow up of 24 months, mostly with metastatic disease. 5 Imatinib is the only effective treatment available at present for patients with metastatic GISTs. The overall response is reported to be as high as 80% and the median duration of response is in excess of 24 months. 16e18 Imatinib is given orally 400 mg once daily until progression. At present multi-slice CT is considered to be the imaging Figure 1 Transaxial CT images showing liver metastases from a primary gastric GIST resected 2 years previously. Figure 2 Transaxial CT images showing multiple omental metastases from a primary gastric GIST resected 6 years previously.

3 208 G. Barnes et al. Figure 3 Primary gastric GIST: immunostaining for KIT (CD 117). Note the strongly positive staining tumour cells (brown colouration). modality of choice to assess response. 18-FDG PET imaging may become the standard for the future, with the wider availability of scanners. A proposed algorithm for the management of metastatic GISTs is shown in Fig. 5. At present, the role of palliative resection in patients with metastatic GISTs on imatinib is unclear. In the pre-imatinib era, survival following surgical resection for recurrent disease was poor, with a median survival of less than 16 months. 5 In the imatinib era, the median survival of patients with metastatic GISTs has improved to beyond 24 months. Imatinib may be able to downsize the metastatic lesion(s) to enable resection of previously unresectable disease. Such tumour shrinkage may allow a less radical resection, thereby lessening surgical morbidity. Following imatinib Figure 4 En bloc resection of a primary gastric GIST (removal of the stomach, spleen and omentum) to achieve R0 resection. treatment, cystic change in metastatic GISTs is a common imaging finding with or without any reduction in the size of the tumours 19,20 (Fig. 6). Following a period of imatinib administration, 18-FDG PET study can be used to confirm that the metastatic lesions are metabolically inactive and there is no other active disease elsewhere (Fig. 7). These imaging findings may make surgical resection technically feasible. In the short term, operative resection eliminates tumour pain and potential risk of rupture and haemorrhage. In the long term, resection may lessen the risk of tumour recurrence through the emergence of resistant clones. Although imatinib may facilitate resection by reducing the volume and vascularity of metastases, in some instances the tumours may undergo myxoid and/or hyaline change which may make their resection more technically demanding. 21 Histopathological analysis of resected specimens may reveal residual active tumour or hyalinised, myxoid areas with necrosis (Fig. 8). In general, the cystic changes on CT imaging and the hypometabolic areas on 18-FDG PET correspond to necrotic areas in the tumour. Pathological complete response with absence of CD117 positivity has been noted in some resected tumours postimatinib therapy 22 (Fig. 9). Close liaison between the surgeon, oncologist and radiologist is vital to optimize the timing of resection. After stopping imatinib, resection should be undertaken promptly. Rapid progression of metastatic GIST, accompanied by a marked clinical deterioration, has been noted after a long interval between cessation and surgery. 23 Hepatic resection and peritoneal/omental debulking are the commonest procedures performed for metastatic GIST. It is the predominant pattern of metastatic spread to the liver and omentum that enables multiple surgical resections to be undertaken without significant morbidity, should these be necessary. At operation, every effort should be made to remove metastatic lesions intact. Careful dissection should be undertaken to minimise the risk of cystic rupture in view of the changes induced by imatinib therapy. There had been concern that targeted therapy might impair wound healing post-operatively. No increased risk of postoperative complications in these patients has been reported. Imatinib can be safely discontinued a day before surgery and recommenced within two weeks after surgery with no adverse effects on wound healing. 21 Experience from the MD Anderson Cancer Centre suggests that a proportion of patients with metastatic GISTs who are on imatinib may benefit from surgical resection. In that series, 16/17

4 Surgical management of metastatic GISTs on imatinib mesylate 209 Figure 5 Proposed algorithm for management of GIST tumours. Algorithm for metastatic GISTs is highlighted (GIST Advisory board UK 11 ). patients treated with imatinib underwent complete surgical resection of their disease and two patients had a pathological complete response at surgery. The majority of patients (11/17) had a partial pathological response to imatinib, with variable amounts of viable tumour still present after therapy, indicating that surgery remains an important part of the treatment for patients with c kit positive GISTs. 22 A German group has reported its experience of post-imatinib resection in 11 patients. R0 resection was achieved in 10 patients with one patient achieving a pathological complete response. Hepatic metastatectomy was performed in six patients and in five patients peritoneal metastases were resected. All patients were alive with a median follow up of 45.9 months. 24 In another series, 3/35 patients with liver metastases treated with imatinib had complete resection of the hepatic metastases. 25 Successful resection of initially inoperable liver metastases from a gastric GIST following imatinib treatment was described in a 25 year old woman in Other groups have attempted to combine hepatic resections with microwave coagulation or chemoembolization and believe that aggressive surgery may have an impact on survival. 27 Multiple hepatic resections for recurrent metastases from GISTs have also been reported. 28 A particular subset of patients can be defined by the differential response of their GIST metastases to imatinib. Some lesions respond, while others remain stable or show progression. Accordingly, 18-FDG PET imaging often shows varying uptake between the lesions. There is currently discussion among GIST specialists as to which lesions should be resected in patients on imatinib. Pain, rupture

5 210 G. Barnes et al. Figure 7 Coronal 18-FDG PET image showing a hepatic GIST metastasis after 12 months on imatinib. The lesion is metabolically inactive. Figure 6 Transaxial CT images showing a large right lobe hepatic GIST metastasis, and smaller splenic lesion. (a) At diagnosis of metastases 3 years after resection of a primary gastric GIST. (b) After 9 months of imatinib therapy: note the characteristic cystic appearance induced by imatinib. and haemorrhage may be indications for resection in both 18-FDG PET hot and 18-FDG PET cold lesions. Another rationale exists for resecting 18-FDG PET hot lesions early; they are likely to possess mutations that may have conferred resistance to imatinib. Here, surgery aims to eliminate resistant clonal proliferation, whilst allowing continued exposure to imatinib in the responding 18-FDG PET cold lesions. This approach may be useful in a small minority of patients with metastatic GISTs who remain fit candidates for surgery and whose lesions remain technically respectable. 12 A proportion of patients progress while on imatinib, presumably as a result of innate or acquired resistance. This is thought to be due to unfavourable mutations which make the tumour less responsive to imatinib. 29,30 In the future, elucidating the precise mutational status of C-KIT may have an influence on the imatinib/surgery sequencing in patients with metastatic GISTs. It may make sense to optimize cytoreduction with imatinib first and then consider surgical resection in patients with favourable mutational status. On the contrary, patients with unfavourable mutations may benefit from early surgical intervention. These approaches remain experimental at present but may become incorporated into the management algorithm in future. 21 Figure 8 Hepatic metastasis: high power haematoxylin & eosin staining of resected specimen post-imatinib therapy. Liver tissue separates nodules of hypocellular tumour containing bland spindle cells (arrows).

6 Surgical management of metastatic GISTs on imatinib mesylate 211 References Figure 9 Hepatic metastasis: immunostaining for KIT (CD117). Sparsely positive tumoural cells following imatinib therapy. Conclusions The role of surgery in metastatic GISTs remains unclear. Imatinib has changed the natural history of metastatic GISTs. In a proportion of patients with initially unresectable disease, imatinib treatment may now enable surgical resection. We believe that surgical resection should be explored at every stage in the natural history of metastatic GISTs. Close liaison between oncology, radiology and the surgical teams is essential. Each case should undergo careful ongoing review by a multidisciplinary team which has the experience of managing these rare tumours. Surgical resection, when feasible, is likely to provide the best palliation, greatest reduction in tumour burden and may potentially eliminate resistant clones. It cannot be overemphasized that difficult decisions regarding surgical intervention need to be made on a case by case basis, taking into account the patients wishes and their physiological ability to withstand surgical trauma with palliative goals. The question for the GIST oncological and surgical community is how to integrate surgery in patients with unresectable/metastatic GISTs, with targeted therapy. When does one recommend surgery in patients with unresectable or metastatic GISTs? Does surgical debulking preceded by targeted therapy at any stage improve the overall survival? Should one continue imatinib after complete resection of metastatic disease? These questions can only be answered by prospective international multicentre randomized controlled studies, a number of which are already in progress. 1. Miettinen M, Lasota J. Gastrointestinal stromal tumours e definition, clinical, histological, immunohistochemical and molecular genetic features and differential diagnosis. 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