ABSTRACT. Imatinib is a highly effective treatment for patients with metastatic gastrointestinal stromal tumours (GIST). In most instances, response to imatinib ...
The British Journal of Radiology, 79 (2006), e40–e44
CASE REPORT
Response evaluation in gastrointestinal stromal tumours treated with imatinib: misdiagnosis of disease progression on CT due to cystic change in liver metastases 1
K M LINTON,
MBChB, MRCP,
2
M B TAYLOR,
MBChB, MRCP, FRCR
and 1J A RADFORD,
MBChB, MD, FRCP
1
Cancer Research UK Department of Medical Oncology and 2Department of Diagnostic Radiology, Christie Hospital NHS Trust, Wilmslow Road, Withington, Manchester M20 4BX, UK ABSTRACT. Imatinib is a highly effective treatment for patients with metastatic gastrointestinal stromal tumours (GIST). In most instances, response to imatinib treatment is assessed with CT. We present two cases where CT demonstrated the appearance of new low density liver lesions after 8–12 weeks of imatinib treatment. While this finding is consistent with progressive disease due to new lesions appearing at a previously uninvolved site, we hypothesise that the appearance of new liver lesions is in fact due to cystic change within previously occult, solid metastases. These untreated solid metastases were not visible on conventional portal phase CT due to their small size and vascular nature. Our hypothesis is supported by the observation that extrahepatic sites of disease had reduced in size over the same period of imatinib treatment and by the subsequent disease outcomes of these two cases. One patient, who continued imatinib because of significant symptomatic improvement despite the CT findings, remained stable on the same dose of imatinib for 18 months. The other patient, whose disease progressed when imatinib was withdrawn, had a dramatic response to treatment when imatinib was restarted at the same dose 2 years later. It is important that radiologists and oncologists who are involved in the management of GIST recognize that the appearance of new, lowdensity liver lesions on CT may represent a response to treatment. This finding must be correlated with symptomatic response and with tumour sites outside the liver before erroneously withdrawing effective imatinib treatment.
Gastrointestinal stromal tumours (GISTs) are rare tumours of mesenchymal origin, which can occur anywhere in the gastrointestinal tract, but most commonly arise in the stomach or small intestine [1]. GISTs were recently reclassified after discovering that these tumours harbour pathogenetically important mutations of the c-kit proto-oncogene (which encodes the KIT receptor) [2, 3]. Mutated KIT in turn leads to unchecked activation of the KIT tyrosine kinase pathway and downstream upregulation of cell growth and survival signals, resulting in GIST formation [4]. Imatinib mesylate (formerly STI-571, Glivec/Gleevec; Novartis, Basel, Switzerland) is a specifically designed tyrosine kinase receptor inhibitor, which targets, among others, the KIT receptor and interrupts neoplastic growth messages to the cell [5]. Imatinib has revolutionized the management of metastatic or unresectable GIST, which is largely resistant to conventional chemotherapy and radiotherapy, and remains the only effective licensed therapy available to these patients [6]. Assessment of tumour response to treatment with CT is the most common end-point for evaluating the clinical efficacy of imatinib and is the main determinant for continuation or discontinuation of therapy for individual patients. We report two cases of imatinib-treated e40
Received 19 May 2005 Revised 27 July 2005 Accepted 10 August 2005 DOI: 10.1259/bjr/62872118 ’ 2006 The British Institute of Radiology
metastatic and unresectable GIST where CT evaluation of the liver following imatinib showed the appearance of new low-density lesions, which were misinterpreted as disease progression.
Case 1 A 56-year-old man presented with weakness, anorexia, fever and upper abdominal pain due to a large, unresectable, c-kit positive duodenal GIST with synchronous liver metastases. CT showed a 9.3 cm predominantly solid mass involving the third part of the duodenum and the pancreatic head (Figure 1a). There was also a 2.0 cm ring enhancing lesion in the liver and 3 subtle, solid, low-density liver lesions. The largest of the low density lesions measured 1.6 cm and had a density of 95 Hounsfield Units (HU). Imatinib 400 mg daily was started in 2002. Within 1 week of starting treatment, he experienced a dramatic improvement of his tumour symptoms and performance status. A response evaluation CT after 8 weeks of imatinib showed that the mass in the duodenum and pancreas had reduced to 7.4 cm and remained solid (Figure 1c). However, between 40 and 50 new low-density liver The British Journal of Radiology, August 2006
Case report: Misdiagnosis in GIST after imatinib
(a)
(b)
(c)
(d)
Figure 1. Patient 1: contrast enhanced CT prior to treatment with imatinib. (a) The primary gastrointestinal stromal tumour (GIST) (outlined) involves the duodenum and pancreatic head and measures 9.3 cm. (b) No liver metastases are visible at this level, although three subtle lesions were seen elsewhere in the liver. Patient 1: contrast enhanced CT after 8 weeks of treatment with imatinib. (c) The duodenal mass (outlined) has reduced in size to 7.4 cm. (d) Multiple small low-density lesions are now seen within the liver (same level as Figure 1b). These were initially reported as being new metastases, but subsequently were considered as being due to cystic change in pre-existing metastases.
lesions were apparent on contrast-enhanced CT, the largest measuring 1.0 cm. The previously identified low density liver lesions had become cystic (density 28 HU). They had also slightly increased in size and the largest now measured 2.0 cm. The ring enhancing lesion was unchanged. The appearance of multiple new liver lesions on CT (Figure 1b,d) was initially reported as disease progression (PD). However, as he had experienced significant symptomatic benefit and because the primary tumour was smaller, imatinib was continued. A repeat CT after a further 8 weeks of treatment showed no further change and all sites of disease remained stable on the same dose of imatinib for the next 2 years.
Case 2 A 67-year-old woman underwent resection of a jejunal leiomyosarcoma in 1993. In 1999 she developed liver The British Journal of Radiology, August 2006
metastases and underwent left hemi-hepatectomy. Within 6 months of surgery she developed a pelvic mass and omental nodules. Biopsy of the pelvic mass confirmed metastatic sarcoma. Shortly afterwards, a metastasis in the second lumbar vertebra as well as new liver metastases were diagnosed. The disease failed to respond to sequential single-agent chemotherapy with doxorubicin and ifosfamide. Her original biopsy was re-examined and found to be c-kit (CD117) and CD34 positive. The diagnosis was therefore revised to GIST and imatinib 400 mg daily was commenced in 2002. The pre-treatment CT showed an 8.0 cm solid pelvic mass (Figure 2a), 2 cystic liver metastases measuring 4.5 cm and 3.0 cm and small omental nodules. The cystic liver metastases had densities of 23–25 HU and the larger metastasis showed enhancing nodules within its wall. A response evaluation CT after 12 weeks of imatinib treatment showed that the mass in the pelvis had e41
K M Linton, M B Taylor and J A Radford
(a)
(b)
(c)
(d)
Figure 2. (a,b) Contrast enhanced. Patient 2: contrast enhanced CT prior to treatment with imatinib. (a) There is an 8 cm solid pelvic mass (outlined). (b) No liver metastases are visible on this section. Note surgical clips from previous hepatic resection (arrow) and L2 vertebral metastasis (*). Patient 2: contrast enhanced CT after 12 weeks of treatment with imatinib. (c) The pelvic mass has reduced in size to 5.1 cm. (d) (At the same level as Figure 2b) A low lesion (arrow) is one of eight newly visible lesions in the liver.
reduced to 5.1 cm (Figure 2c). The density had fallen slightly, but the lesion remained solid. The omental nodules were also slightly smaller. The cystic liver metastases, however, had slightly enlarged to 5.1 cm and 3.1 cm, respectively, and 8 new low-density liver lesions, measuring between 3 mm and 8 mm, were seen on CT (Figure 2b,d). The larger cystic metastases were unchanged in density, but the enhancing nodules within the wall of the larger lesion had resolved. Since starting imatinib she developed new abdominal pain and anaemia, which required hospital admission. Because of this, and the appearance of new liver lesions on CT, disease progression was diagnosed and imatinib was stopped. A restaging CT performed 18 months later showed enlargement of the pelvic mass to 14.4 cm. There were also several new bone metastases, including a large destructive sternal metastasis. The liver lesions were relatively unchanged from before. At this time, her previous CT examinations were reviewed. In the light of our experience with the first case, it was considered that the development of new lowdensity liver lesions on the first response evaluation CT e42
may also have been due to cystic response within previously occult metastases. Imatinib was therefore restarted at the same dose of 400 mg daily, almost 2 years after her first exposure to the drug. A repeat CT after 8 weeks of treatment showed a dramatic improvement. The pelvic mass had reduced to 9.4 cm and the sternal metastasis was also significantly smaller. The liver lesions were little changed. On this occasion, her tumour symptoms and performance status improved significantly. She has now been followed-up for over 12 months and her disease has continued to respond to imatinib.
Discussion Cystic change is a well recognized feature of certain tumours that are responding to treatment (such as nonseminomatous germ cell tumours) [7]. In their paper of 2002, Chen et al first reported how previously solid metastases from GIST can become cystic on contrastenhanced CT following successful treatment with The British Journal of Radiology, August 2006
Case report: Misdiagnosis in GIST after imatinib
imatinib. They observed that treated metastases had a slightly higher density (in the range of 21–29 HU) than would be expected for simple cysts [8]. Another study examined the serial histological changes in GIST treated with imatinib and confirmed that treatment-induced cystic change is associated with tumour response: compared with their previously solid counterparts, cystic metastases had lower mitotic counts, lower proliferation indices, loss of cellular cohesion and shrinkage of tumour tissue [9]. It is recognized that liver metastases from GIST are frequently hypervascular prior to treatment [10]. These lesions may therefore not be visible on conventional portal venous phase CT, which is the most common CT technique used in oncology patients. In both of our cases only portal venous phase CT was used and small untreated solid liver metastases were not visible. The appearance of new lesions in the liver after imatinib treatment was therefore interpreted as PD. According to conventional RECIST criteria, PD is defined as >20% increase in the sum of the long axis of up to 10 target lesions, or the appearance of new lesions [11]. After continuation of imatinib, we observed no further change in the cystic liver metastases and at extrahepatic tumour sites, either tumour stabilization (case 1) or shrinkage (case 2) occurred. These successful clinical outcomes gave retrospective evidence that initial treatment with imatinib was effective. They also corroborate our observation that the appearance of new liver lesions on CT in the first 8–12 weeks after starting treatment is due to increased lesion conspicuity following cystic change and not due to disease progression. The decision to continue treatment in the first case was based largely on the fact that the patient experienced considerable clinical improvement of tumour symptoms after imatinib treatment. Conversely, treatment was stopped in the second case where a symptomatic benefit was not apparent. Symptomatic improvement as a marker of response may be valuable. However, as our second case illustrates, the interpretation of symptoms that develop as a result of imatinib treatment may be misleading. This patient developed new symptoms of abdominal pain and anaemia soon after commencing imatinib, which were thought at the time to be due to underlying disease progression. GISTs are very vascular tumours and intratumoural haemorrhage following effective imatinib treatment is not uncommon [9]. Therefore, in retrospect, we conclude that in this case the development of pain and anaemia occurred because of imatinib-related haemorrhage into liver or pelvic metastases, and not because of underlying disease progression. Several other side effects of imatinib can overlap with tumour symptoms and should not be misdiagnosed as PD, including nausea, vomiting and oedema formation (especially if associated with the development of ascites) [6]. The development of new symptoms following imatinib must therefore be carefully evaluated to avoid a misdiagnosis of disease progression, especially in the context of apparently corroborative radiological evidence. The radiological techniques used in the initial staging and in the treatment response evaluation of imatinib must be critically evaluated. Functional imaging modalities such as PET (positron emission tomography) have The British Journal of Radiology, August 2006
been shown to provide significantly more accurate assessments of response to imatinib than CT, especially in the early post-treatment stage (first 8 weeks) [12, 13]. However, this modality is not widely available in the non-research setting. Due to the vascular nature of GISTs, it has been suggested that triple phase CT (including non-contrast, arterial phase and portal phase acquisitions) is more sensitive in the initial staging of patients [12]. Our experience has also found that untreated solid liver metastases may not be detectable on single portal venous phase CT, although we have not evaluated dual (arterial and portal venous phase) or triple phase techniques. There is evidence that dynamic gadolinium enhanced MRI may be superior to single phase CT in early disease assessment [10] but, to our knowledge, this technique has not been fully evaluated and has not been compared with the results from triple phase CT. According to strict RECIST criteria, cystic lesions should be regarded as non-measurable [11]. However, this may be difficult in GIST when target lesions, which are initially solid, only become cystic following imatinib exposure. Modified objective criteria using a combination of tumour size and density on CT have therefore been proposed for early response evaluation in GIST [14]. Despite its limitations, CT remains the most common means of evaluating treatment response to imatinib in GIST. Based on the current evidence, including our experience, we propose evaluating dual phase CT (arterial and portal venous phases) and gadolinium enhanced MRI in the initial staging and treatment assessment of GIST, using modified objective criteria to evaluate response to imatinib. Currently, neither NICE (National Institutes for Clinical Excellence, UK) nor NCCN (National Comprehensive Cancer Network, USA) GIST treatment guidelines recognize symptomatic improvement as a marker of response [15, 16]. In light of our experience, we furthermore propose that these guidelines should be amended to include symptomatic improvement as a response criterion, especially when the interpretation of radiological findings is in doubt. Guidelines should also emphasise that response may be associated with the appearance of new cystic liver lesions, especially if single phase CT is used. It is essential that clinicians and radiologists who are involved in the treatment of GIST are aware of the limitations of CT response evaluation in order to avoid inappropriate withdrawal of imatinib treatment. Furthermore, we are obliged to review the radiology of all patients with GIST who may have stopped imatinib prematurely due to a misinterpretation of their response evaluation CTs, as these patients may benefit from the reintroduction of imatinib even after long periods off treatment.
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The British Journal of Radiology, August 2006
