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Gastrointestinal Cancer |
Departments of aSurgery, bPathology, and cInternal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
Key Words. Imatinib mesylate • Tyrosine kinase inhibitor • Gastrointestinal stromal tumor • Gastrointestinal bleeding Palliative resection • Surgical resection • GIST
Correspondence: Faek R. Jamali, M.D., F.A.C.S., American University of Beirut Medical Center, P.O. Box 11-0236, Beirut, Lebanon. Telephone: 961-3750954; Fax: 961-1363291; e-mail: fj03{at}aub.edu.lb
Received November 11, 2006; accepted for publication January 29, 2007.
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ABSTRACT |
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We report on the surgical management of an unusual and clinically significant complication following progression of disease secondary to imatinib resistance. The role of surgical therapy in the management of GIST complications following resistance to imatinib and the integration of surgical and molecular therapy of locally advanced or metastatic GISTs are discussed.
Disclosure of potential conflicts of interest is found at the end of this article.
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CASE PRESENTATION |
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Upper endoscopy revealed a raised 5-cm x 6-cm hard, submucosal mass extending from the cardia/fundus into the lesser curve. Endoscopic ultrasonography (EUS) was performed, revealing that the hypoechoic mass was arising from the fourth layer of the gastric wall (corresponding to the muscularis propria), highly suggestive of gastrointestinal stromal tumor (GIST). Deep well endoscopic biopsies were obtained and showed a stromal cell tumor with high malignant potential (>20 mitoses per 10 high-power fields). Immunostaining for CD117 was diffusely positive and c-kit mutation analysis by polymerase chain reaction demonstrated a deletion of 15 bp from exon 11, confirming the diagnosis of GIST.
Because of the patient's advanced disease, imatinib mesylate (Gleevec®; Novartis Pharmaceuticals, Basel Switzerland), 400 mg once daily, was initiated. The patient demonstrated rapid clinical improvement and progressive disappearance of the palpable abdominal mass. A repeat CT scan of the abdomen 2 months after the initiation of therapy revealed a significant decrease in the size of the gastric mass as well as the metastatic deposits in the liver. The patient reached her maximal response at 6 months and her disease remained stable thereafter on imaging. An upper endoscopy done at the time showed marked shrinkage of the gastric component of the tumor, but with visible residual disease. Despite the excellent clinical response, the patient was not felt to be a surgical candidate in light of her multiple liver metastases, and she was continued on the same dose of imatinib for another 6 months while she demonstrated stable disease.
One year after the initiation of imatinib therapy, the patient started to have recurrent episodes of severe melena. An upper GI endoscopy was performed, showing a large, very deep bleeding ulcer in the center of the mass on the lesser curvature of the stomach. Endoscopic hemostasis was not successful. These repeated episodes of bleeding necessitated three hospital admissions and multiple (>20) blood transfusions over a 2-month period. CT scan evaluation at this time confirmed disease progression, with an increase in the size of the liver lesions despite continued treatment with imatinib and showed evidence of direct liver invasion (segments II and III) by the lesion along the lesser curvature of the stomach (Fig. 1C). The patient was referred after multidisciplinary consultation for surgical treatment and underwent an en bloc total gastrectomy and left lateral segmentectomy (II, III) with a Roux-Y reconstruction. Intraoperative findings were those of a large GIST with areas of central necrosis, effectively bridging the stomach and liver together as one unit. Pathology confirmed the previously established diagnosis of GIST, with necrosis giving rise to a fistula between a necrotic cavity in the tumor and the gastric lumen (Fig. 2).
Postoperatively the patient was maintained on imatinib at a dose of 400 mg daily. She was advised to increase the dose to 800 mg as she had shown evidence of progression preoperatively, but the patient could not do so for financial reasons. On follow-up imaging 4 months later, the patient had developed extensive liver metastases (Fig. 1D) and succumbed to her disease 6 months following her surgery, 2 years from the date of her initial diagnosis.
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DISCUSSION |
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) mutation [6]. Recent data from registries in Sweden and the Netherlands indicate that, on the basis of CD117 testing, the annual incidence of GISTs has been largely underestimated [7, 8]. In the Dutch study, the incidence of GISTs increased from 2.1 per million inhabitants in 1995 to 12.7 per million inhabitants in 2003 [7]. The clinical presentation of GISTs is variable and is related to the presence of a mass effect or bleeding. Because of the nonspecific nature of the symptoms, the diagnosis of GISTs is often delayed by a mean of 6 months form the time of onset of symptoms. Several imaging modalities have been reported to be useful in the investigation of GISTs including CT scan and magnetic resonance imaging [9, 10]. Diagnosis rests on tissue biopsy, which is best performed endoscopically. Because endoscopic biopsy may not be revealing as a result of the submucosal nature of the tumor, EUS has recently evolved as a vital diagnostic modality for GISTs [11]. The ability to perform EUS fine-needle aspiration has been associated with a diagnostic accuracy of 80%–85% [12, 13]. Percutaneous biopsy should rarely be used because it is associated with a significant risk for tumor rupture, dissemination, and hemorrhage. It is only indicated in cases where it may alter the management or to confirm metastatic disease prior to imatinib therapy. Fluorodeoxyglucose positron emission tomography (FDG–PET) scanning of GISTs is increasingly being used, particularly for the evaluation of metastatic disease as well as for the early detection of tumor response to imatinib treatment if surgery is being considered following cytoreductive therapy [14].
Surgical resection remains the primary and most definitive treatment option for localized GISTs. Resection of GISTs can usually be accomplished with a wedge resection of the stomach or a segmental resection of the small intestine. GISTs are soft and friable, so special care needs to be taken to avoid intraoperative rupture, which increases the risk for recurrence. As GISTs rarely metastasize to lymph nodes, lymphadenectomy is not routinely indicated. Complete gross resection is possible in approximately 85% of patients with primary, localized tumors [15–17]. Complete surgical resection is associated with a 54% 5-year disease-specific survival rate. Despite successful surgical therapy however, GISTs exhibit a high risk for metastatic relapse. The initial site of recurrence involves the liver in 65% of cases, the peritoneal surfaces in 50% of cases, and both in about 20% of cases [18, 19].
GIST resistance to conventional chemotherapy has led to a search for more effective systemic therapy in the setting of advanced disease. Imatinib mesylate, a tyrosine kinase inhibitor blocking most mutated activated Kit proteins of GISTs, demonstrated excellent results by controlling tumor growth in up to 85% of advanced GISTs in the phase I, II, and III trials reported to date [20–24]. This excellent response rate led to the establishment of imatinib as the treatment modality of choice for metastatic GISTs and allowed investigation of its use in a neoadjuvant fashion for the management of marginally resectable primary tumors when, because of the size and location of the tumor, resection would require the risk for severe organ dysfunction or when negative margins would be difficult to achieve. Recent reports are demonstrating an increasingly important role for surgery in the multimodality management of GISTs following initial imatinib therapy [25, 26].
Primary resistance to imatinib is rare, affecting only 15% of patients. Half the patients who initially respond, however, become resistant by 2 years after imatinib initiation. The most common mechanism of acquired resistance is secondary kit mutation [27–30]. The other identified mechanism of imatinib resistance is Kit or PDGFR- amplification, but this occurs infrequently. Resistance in GISTs is associated with disease progression and represents a therapeutic challenge. Surgeons are often confronted with having to intervene in a palliative role for patients with metastatic or locally advanced GISTs. For patients with indolent disease, debulking large lesions that produce significant pain or symptoms is generally felt to be beneficial. Patients with a good performance status also benefit from surgery to control tumor-associated bleeding, intestinal perforation, or fistula formation.
In patients who develop focal resistance, with some tumors progressing on imatinib and others remaining stable, surgery can be considered for the progressive disease component. By resecting clones of disease that have acquired drug resistance, surgical debulking may prolong survival in patients with metastatic disease, as long as the remaining disease remains drug responsive. In a recently published study, Raut et al. [31] reported on 69 patients with advanced or metastatic GISTs that were treated with imatinib or sunitinib followed by surgical resection. For patients with limited disease progression, surgical debulking combined with kinase-directed therapy resulted in a median postoperative progression-free survival (PFS) time of 7.7 months and an overall survival time of 29.8 months. The authors concluded that patients with limited disease progression may benefit from debulking procedures by prolonging PFS, particularly if surgery achieves either the complete extirpation of all tumors or a reduction in tumor burden such that no individual nodule is >1 cm in diameter.
In this case, we are reporting on the surgical management of an unusual and clinically significant complication following progression of disease secondary to imatinib resistance. Our patient presented with a metastatic large gastric GIST that was arising from the lesser curvature of the stomach. The patient responded well to imatinib for a period of 1 year then exhibited resistance evidenced by progression of the disease. The tumor invaded the left lobe of the liver, leading to communication between a necrotic cavity in the tumor and the gastric lumen. This led to clinically significant recurrent episodes of GI bleeding that were not amenable to endoscopic hemostasis modalities. This bleeding may have been originating from the liver itself, oozing into the stomach through the necrotic tumor cavity. In retrospect, the patient may have been referred for angiography and possible embolization of the feeding left lobe vessels, possibly sparing her a major noncurative surgical resection. She was treated surgically, and postoperatively was restarted on imatinib despite her resistance. She would have been ideally suited for the use of sunitinib if it were available to us.
In conclusion, although rare, the incidence of GISTs is on the rise because of improved diagnostic accuracy, awareness, and endoscopic detection. While the treatment of primary localized GISTs remains surgical, the integration of surgery and molecular therapy for primary or metastatic GISTs is under intense investigation and will serve as the basis for combined therapy in other malignancies. Current studies are ongoing to better refine the timing and indication for surgical intervention in curative as well as palliative treatments.
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