Gastrointestinal Cancer

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1 This material is protected by U.S. Copyright law. Unauthorized reproduction is prohibited. For reprints contact: Gastrointestinal Cancer Management of Gastrointestinal Stromal Tumors in the Imatinib Era: Selected Case Studies Robert S. Benjamin, a Charles D. Blanke, b Jean-Yves Blay, c Sylvie Bonvalot, d Burton Eisenberg e a University of Texas MD Anderson Cancer Center, Houston, Texas, USA; b Oregon Health & Science University, Portland, Oregon, USA; c Hôpital Edouard Herriot and Centre Léon Bérard, Lyons, France; d Institut Gustave Roussy, Paris, France; e Norris Cotton Cancer Center, Lebanon, New Hampshire, USA Key Words. Gastrointestinal stromal tumor therapy GIST KIT CD117 Tyrosine-kinase inhibition Imatinib Abstract The introduction of imatinib, an orally administered inhibitor of the KIT receptor tyrosine kinase, is prompting revision of the management algorithms that have traditionally guided the treatment of gastrointestinal stromal tumor (GIST). Historically, patients with GISTs have had substantial rates of relapse as well as limited long-term survival even after complete surgical resection of a primary tumor. Imatinib has been shown to induce durable tumor responses in more than half of the patients with malignant metastatic or unresectable GISTs and to halt disease progression in an additional third. These encouraging results have led to the initiation of clinical trials of imatinib as an adjuvant or neoadjuvant therapy with surgery. Until relevant data are reported to provide definitive direction for the management of operable or potentially operable GISTs, treatment decisions must be made on the basis of the available evidence and clinical experience with imatinib. This paper presents selected case studies describing approaches to the combined use of surgery and systemic therapy that have been applied in the treatment of individual GIST patients. The management of GIST in these cases required a coordinated, multidisciplinary approach involving medical oncologists, diagnostic radiologists, gastroenterologists, surgeons, and pathologists. The Oncologist 2006;11:9 20 Introduction Remarkable progress has been made during the last several years in the diagnosis and treatment of gastrointestinal stromal tumor (GIST). Understanding that the molecular pathogenesis of GIST is linked to deregulated KIT tyrosine-kinase activity has resulted in the successful application of a novel systemic tyrosine-kinase inhibitor, imatinib (Gleevec ; Novartis Pharmaceuticals Corporation, East Hanover, NJ, in the treatment of GIST patients with malignant metastatic or unresectable disease. Approaches to management that may potentially Correspondence: Robert S. Benjamin, M.D., Sarcoma Medical Oncology, University of Texas, MD Anderson Cancer Center, 1515 Holcombe Boulevard., Box 0450, Houston, Texas, 77030, USA. Telephone: ; Fax: ; rbenjami@mdanderson.org Received July 12, 2005; accepted for publication October 20, AlphaMed Press /2006/$12.00/0 The Oncologist 2006;11: improve outcomes in GIST patients through the use of imatinib at earlier stages are only beginning to be investigated, including the possible role of imatinib as an adjuvant or a neoadjuvant agent with surgery. Understanding the molecular pathogenesis of GIST has also improved diagnosis, such that GIST is now more frequently identified. GISTs are the most common nonepithelial tumors of the gastrointestinal tract [1]. Surgical resection is the mainstay of treatment for patients with operable tumors and was the only effective intervention prior to the introduction of imatinib, since GISTs are highly resistant to chemotherapeu-

2 10 Case Studies in GIST Management tic agents, including newer approved (e.g., temozolomide [Temodar ; Schering-Plough Corporation, Kenilworth, NJ, and investigational (e.g., ecteinascidin-743) drugs [2 5]. However, surgery is not curative in many cases. Historically, the 5-year survival rate has been approximately 35% 65% among patients able to undergo complete resection. Among patients with unresectable disease, the median survival time is months [6 10]. These observations suggest that microscopic disease often persists despite surgical resection of solid tumors. Imatinib is a potent and specific inhibitor of the KIT protein-tyrosine kinase, which is constitutively activated in more than 90% of GISTs as a result of gain-of-function mutations in the KIT proto-oncogene [11 15]. The presence of KIT is readily detected through reactivity with the CD117 antigen on immunohistochemical assay, a marker that establishes the diagnosis in a gastrointestinal tract mesenchymal neoplasm with characteristic histologic features [16]. Oncogenic activating mutations in the gene for the platelet-derived growth factor receptor alpha tyrosine kinase, another target of imatinib, have recently been identified in approximately one third of the small subset of GISTs (less than 5% 10%) that appear to lack KIT mutations [17, 18]. Imatinib has been shown to induce complete remission in 4% 5%, partial remission (decrease of at least 50% in tumor burden) in 47% 67%, and stable disease in 18% 32% of patients with advanced CD117-positive GISTs studied in clinical trials for which data based on at least 9 13 months of observation have been published [19 23]. Imatinib is approved for the treatment of KIT (CD117) positive unresectable and/or metastatic malignant GIST, as well as the first-line treatment of chronic myeloid leukemia in all phases [24]. Imatinib is administered orally in tablet form. The standard dosage for the treatment of GISTs is 400 or 600 mg once daily. Recently reported results of a European phase III trial showed that initial treatment with 400 mg twice daily significantly prolonged progression-free survival, in comparison with 400 mg/day, and was generally tolerated fairly well [22]. The authors of that report suggested that, in patients with widespread metastatic disease, the progression-free survival benefit seen with the 400-mg twice-daily dose might prompt consideration of this dosage. In the clinical trials of imatinib in GIST overall, the most common adverse effects included periorbital and peripheral edema, nausea, muscle cramps, diarrhea, headache, rash, fatigue, anemia, and neutropenia [25]. Most side effects were mild to moderate in severity at the standard dosages. The dramatic results of imatinib therapy in patients with metastatic or unresectable GIST suggest a possible benefit in GIST patients who are, or potentially might become, candidates for surgery. New evidence-based treatment guidelines recommend imatinib as first-line therapy in cases of marginally resectable pathology-confirmed GISTs, with surgery and postoperative imatinib administration advised if imatinib response improves resectability [26]. The following cases illustrate emerging approaches to the practical management of GIST in the new era of multimodality, multidisciplinary treatment of this disease. Clinical practice guidelines for GIST will need to be integrated with actual clinical experience, as exemplified by these cases, and treatment must be tailored to individual cases. Case Studies Case Study 1: A 69-Year-Old Woman with a Primary Gastric GIST and Unifocal Hepatic Metastasis The patient presented with a history of 3 months of anorexia, upper abdominal discomfort, and weight loss of 7 kg (15 lb), initially suggesting the diagnosis of gastric ulcer. Upper gastrointestinal endoscopy revealed a friable, exophytic mass in the greater curvature of the stomach. A biopsy was reported as showing only inflammation. Spiral computed tomography (CT) scanning of the abdomen demonstrated the presence of a 5-6-cm gastric mass (Fig. 1). At laparoscopy, a 2-cm lesion on the liver was also detected. Biopsy of the hepatic lesion, which was documented as CD117 (KIT)-positive by immunohistochemistry, confirmed the diagnosis of GIST. The patient received neoadjuvant therapy with imatinib, 600 mg/day, for 8 weeks as a participant in the Radiation Therapy Oncology Group (RTOG) Study S-0132 (Table 1). The positron-emission tomography (PET) scan obtained at 8 weeks revealed a near absence of [ 18 F]fluorodeoxyglucose (FDG) uptake, a marker of intratumoral metabolic activity; comparison with the patient s pretreatment FDG-PET scan demonstrated significant tumor response (Fig. 2). The patient underwent surgical resection with partial gastrectomy. Extension of the gastric GIST into the upper retroperitoneum was noted, as well as several tumor nodules in the lesser sac and omentum. All apparent tumor was excised. Postoperative pathology examination revealed a tumor mass of approximately cm (compared with the initial gastric mass measurement of 5 6 cm by CT scan), with 80% 90% tumor necrosis. The original liver lesion was not visible at surgery, and the results of intraoperative ultrasonography of the liver were negative for lesions. The patient resumed imatinib therapy, 600 mg/day, at approximately 3 weeks postoperatively and was to continue receiving adjuvant imatinib for 2 years, according to the study protocol. The Oncologist

3 Benjamin, Blanke, Blay et al. 11 Figure 1. Baseline spiral computed tomography scan of the patient in case 1. (Courtesy of Burton Eisenberg, M.D.) This patient presented with a bulky primary GIST and a liver metastasis. In the past, patients with similar disease had a median survival time of <2 years, and complete resection was achieved in only 31% [7]. Today, the availability of imatinib raises the question as to what options may be offered to patients who present with large, marginally resectable or initially unresectable primary GISTs and to those with recurrent or metastatic disease that appears to be resectable, and what effects these options may have on Figure 2. Positron-emission tomography scan with [ 18 F]fluorodeoxyglucose tracer obtained from the patient in case 1 before (left) and after (right) 8 weeks of neoadjuvant therapy with imatinib, 600 mg/day. (Courtesy of Burton Eisenberg, M.D.) survival. Results from the adjuvant and neoadjuvant trials of imatinib currently under way, including RTOG Study S- 0132, are expected to provide guidance. Promising results of surgery to remove residual GIST masses in patients who had an objective response to initial therapy with imatinib have already been reported in a small study [27]. Of eight patients who underwent GIST resection during imatinibinduced partial remission of their disease, seven had his- Table 1. Radiation Therapy Oncology Group (RTOG) Study S-0132 Title Objectives Entry criteria Projected accrual Outline Evaluations Follow-up Sponsors Phase II study of neoadjuvant and adjuvant imatinib mesylate in patients with primary or recurrent potentially resectable malignant gastrointestinal stromal tumors Determine progression-free survival, objective response rate, and safety Histologically confirmed malignant GIST: potentially resectable primary disease or potentially resectable recurrent disease, local, or intra-abdominal/pelvic metastatic disease Documented KIT (CD117) expression by immunohistochemistry Visceral or abdominal origin of primary disease At least one unidimensionally measurable lesion: primary disease, 5 cm; recurrent disease, 2 cm No extra-abdominal metastatic disease 63 patients within 2 years All patients receive imatinib, 600 mg/day, for 4 weeks Patients with progressive disease considered for immediate surgical resection Patients with responding or stable disease continue 600 mg/day imatinib for four additional weeks, then undergo surgical resection to debulk all gross tumor (complete resection not required) Once-daily imatinib therapy resumed 2 4 weeks postoperatively, continuing for 2 years CT FDG-PET: pretreatment, day 1 7, 4 weeks, 8 weeks Tumor specimens: pretreatment (core biopsy 4), surgical specimen Every 3 months for 2 years, then every 6 months for 3 years National Cancer Institute (U.S.), RTOG, American College of Radiology Imaging Network Abbreviations: CT, computed tomography; FDG-PET, 18 fluorodeoxyglucose positron-emission tomography; GIST, gastrointestinal stromal tumor.

4 12 Case Studies in GIST Management tologically complete excisions; GIST progression had occurred in only one of these patients at the time the investigators presented their findings. In case 1, the presence of a malignant bulky primary in conjunction with metastatic GIST warranted initiation of imatinib as the first-line treatment. A further consideration was whether the patient might benefit from a trial of imatinib administration designed specifically for the neoadjuvant setting. The presence of a potentially reducible primary tumor and a single, localized, intra-abdominal metastasis suggested the possibility that complete excision might be achievable after pharmacologic debulking. In this case, the patient s hepatic lesion showed a complete response to neoadjuvant imatinib therapy, and the bulky primary tumor was rendered completely resectable. Case 1 illustrates one approach to combining systemic therapy with surgical intervention to potentially eradicate signs of viable GIST. Before the introduction of imatinib, GIST treatment was mainly the responsibility of surgeons. Today, the combined expertise of medical oncologists and surgeons is likely to provide the best prospects for cure or for prevention of disease progression. Similarly, the integrated use in this case of CT and FDG-PET imaging as well as postoperative pathology study underscores the importance of multimodality monitoring for the assessment of tumor response to imatinib and the selection and timing of further treatment. Case Study 2: A 44-Year-Old Man with Recurrent Metastatic GIST The patient presented with a large mesenteric mass, bilobar hepatic metastases, and peritoneal implants 7 months following previous resection of a GIST of the small intestine (Fig. 3). Histopathologic findings and positivity for CD117 (KIT) on immunohistochemical staining confirmed the diagnosis of recurrent GIST. The patient received imatinib and had a significant response after 8 weeks of treatment. The large liver lesion decreased in size from 6.5 cm 2 at baseline to 2.3 cm 2 and exhibited a 66% decrease in density on CT scans, whereas the lower abdominal mass decreased from 48 cm 2 to 27.8 cm 2 and showed a greater than threefold reduction in density (Fig. 4). Further tumor response was demonstrated by CT scanning after 24 weeks of imatinib therapy, with the hepatic lesion appearing totally cystic (Fig. 5). Persistent abnormalities in the mesentery and left lobe of the liver were also apparent on imaging studies at this time. The patient underwent resection of the left hepatic lobe and the large mesenteric mass as well as several smaller mesenteric nodules. The area of metastasis in the right hepatic lobe was localized intraoperatively and treated by radiofrequency ablation to avoid bilobar resection. On pathology study, only one of the resected liver specimens was found to contain a viable focus of disease, measuring 8 mm in diameter. Thus, the composite masses demonstrated by the patient s preoperative CT scans measured 15 cm, whereas the findings at surgery revealed a viable tumor focus of only 8 mm, consistent with the CT-demonstrated reduction in lesion density. The remainder of the liver lesion showed myxoid degeneration. Postoperatively, the patient continued imatinib therapy for 4 months. The significant tumor response to imatinib in this case suggests that recurrent disease with metastases more extensive than those in case 1 may likewise potentially become resectable with neoadjuvant therapy. Consequently, accurate assessment of response to treatment is essential in considering the selection and timing of further intervention for patients whose optimal first-line therapy is imatinib. The darkening of a GIST lesion observed on a CT scan, for example, might make a lesion appear larger or even as a new lesion. It is not necessarily a sign of disease progression in an imatinib-treated patient, however. CT-demonstrated lesion darkening, and even enlargement, may instead indi- Figure 3. Baseline computed tomography scans from the patient in case 2. (A) and (B) show the liver with metastatic lesions, and an abdominal mass below. (C) and (D) show a large mesenteric mass. (Courtesy of Robert S. Benjamin, M.D.) The Oncologist

5 Benjamin, Blanke, Blay et al. 13 cate that the tumor is becoming necrotic and showing fluidvolume expansion signs that the tumor is responding. In case 2, measurement of density (change in Hounsfield units) as well as size in evaluating the results of CT were important in detecting and evaluating degenerative changes in the patient s tumors. Moreover, the CT-based preoperative estimate of hepatic GIST size considerably exceeded the extent of viable disease found in the resected surgical specimens. Studies of imatinib-treated GIST patients have demonstrated that functional imaging with FDG-PET is highly predictive of subsequent anatomic response documented by CT or magnetic resonance imaging and can show treatment effects (i.e., reduction in tumor metabolic activity) as early as 24 hours after the start of therapy [20, 28, 29]. Combinedmodality PET/CT was demonstrated to be superior to PET and CT in detecting GIST metastases and correctly characterizing response to imatinib therapy [30]. However, PET scanning is not available at all clinical facilities. In a correlative analysis of CT and PET scanning results, a decrease in tumor size of 10% or more and a decrease in tumor density of 15% or more documented by CT scan had a sensitivity of 94% and a specificity of 100% in detecting patients with a complete response by PET scanning [31]. Case Study 3: A 57-Year-Old Man with a Massive Primary GIST The patient presented with a huge abdominal mass extending from the pelvis to the diaphragm (Fig. 6). On confirmation of the diagnosis of GIST by CD117 (KIT) immunohistochemistry, he began treatment with imatinib, requiring coadministration of an i.v. antiemetic with his first dose because of near-complete obstruction at the gastric outlet. After 2 days of treatment, however, rapid response to imatinib eliminated the need for the antiemetic agent. The patient continued to experience rapid tumor shrinkage and symptomatic relief during the subsequent 6 months of imatinib therapy. At that point, the tumor began to enlarge, although it appeared to consist largely of fluid (Fig. 7). Because of increasing tumor volume and abdominal swelling, the patient underwent surgery after 39 weeks of treatment. The surgical team evacuated seven liters of intratumoral fluid, facilitating removal of a residual compressed tumor mass measuring cm. Pathology examination revealed that approximately 50% of the cells in the resected specimen were viable. Following surgery, the patient was instructed to resume his imatinib therapy immediately, but because of a misunderstanding, he inadvertently failed to do so. He returned to the clinic 2 months later with evidence of rapidly progressive disease in the liver and the appearance of a possible peritoneal implant. Treatment with imatinib, 800 mg/day, was reinstituted. One month later, there was definite regression of the liver metastases and disappearance of the possible peritoneal implant on CT. The patient underwent further surgery and remains free of disease on continued imatinib. Figure 4. Computed tomography scans from the patient in case 2 obtained at baseline (left panels) and after 8 weeks of therapy with imatinib (right panels). The superimposed density and size measurements indicate the treatment responses in the hepatic lesion (A, B) and the mesenteric mass (C, D). Abbreviations: HU, Hounsfield units; sd, standard deviation. (Courtesy of Robert S. Benjamin, M.D.) Figure 5. Computed tomography scans from the patient in case 2 obtained at baseline (A) and after 24 weeks of therapy with imatinib (B). The 24-week scan demonstrates further response in the hepatic lesion, which now appears totally cystic, compared with the 8-week scan (Fig. 4B). (Courtesy of Robert S. Benjamin, M.D.)

6 14 Case Studies in GIST Management Figure 6. Sagittal T2 (right) and coronal T2 fast spin echo (left) magnetic resonance imaging scans from the patient in case 3 demonstrating massive gastrointestinal stromal tumor. (Courtesy of Robert S. Benjamin, M.D.) The presence of multiple risk factors in case 3 most notably massive tumor size, tumor rupture, and postoperative evidence of residual viable disease suggests that consideration of adjuvant treatment with imatinib may be warranted for patients after surgery for GIST whose disease has characteristics associated with a high risk for recurrence or spread. The rationale for adjuvant therapy may be particularly compelling in cases such as this one, in which the GIST exhibits responsiveness or stabilization during preoperative imatinib administration. A principal of surgical management of GIST is to avoid rupture, which facilitates intra-abdominal seeding and reduces survival even in cases in which the resection is complete [23]. However, the unusual size of the tumor in case 3 necessitated intentional rupture and drainage during surgery to achieve decompression of the fluid-bearing mass that had developed as the patient responded to imatinib treatment. Excision of the mass was then possible, providing symptomatic relief. The development of rapidly progressive disease soon after surgery in the absence of imatinib therapy, and the prompt restoration of response after imatinib administration was resumed, underscore the importance of uninterrupted treatment with imatinib for this patient. Data are awaited from ongoing adjuvant trials of imatinib in GIST, which include high-risk patients. Case Study 4: A 57-Year-Old Man with Low- Grade GIST and a PDGFRA Exon Deletion In May 1996, this patient presented with abdominal pain. CT scanning of the abdomen showed a 17-cm perigastric mass. The patient underwent surgical resection. The mass proved to be a low-grade GIST, and no adjuvant therapy was administered. In 1998 and again in 1999, the patient underwent resection of multiple hepatic lesions. Results of immunological staining were positive for CD117 and negative for CD34. Genetic analysis revealed KIT wild-type exons Figure 7. Computed tomography scans from the patient in case 3 obtained after 8 weeks (left) and 24 weeks (right) of therapy with imatinib. The superimposed density measurement indicates that the mass is almost entirely liquid in consistency. Abbreviations: HU, Hounsfield units; sd, standard deviation. (Courtesy of Robert S. Benjamin, M.D.) 8, 9, 10, 11, 13, and 17, and a PDGFRA exon 18 deletion (DIMH ). In January 2000, the patient presented again with hepatic lesions. Gene therapy and experimental chemotherapy were administered but were ineffective. In October 2000, the patient was started on a regimen of imatinib 400 mg/day. He achieved a partial response, which has been sustained. The improvement seen in this case again demonstrates the relevance of molecular oncogenic mechanisms in the selection of and response to targeted therapies such as imatinib. As already indicated, a small subset of GISTs lack KIT mutations but have PDGFRA mutations, some sensitive, but others insensitive, to imatinib. PDGFRA isoforms V561D, deldimh , and del1845 have been found to be sensitive to imatinib, whereas the D842V mutation has been shown to be relatively resistant to this agent [32]. Thus, it is not surprising that the patient described in case 4, who had a PDGFRA exon 18 DIMH deletion, achieved a clinical response. Thus, it appears reasonable to initiate a trial of imatinib in patients whose GISTs lack demonstrable KIT mutations or do not express KIT protein. This case also demonstrates the overall importance of genetic analysis in patients with GISTs as a strategy for predicting clinical response to imatinib as part of the process of choosing therapeutic options. Case Study 5: A 58-Year-Old Man with an Advanced GIST and an Abdominal Aortic Aneurysm In 1978, this patient had undergone resection of an ileal hamartoma, which on later review proved to be a GIST with an exon 11 KIT gene mutation. He was being moni- The Oncologist

7 Benjamin, Blanke, Blay et al. 15 tored for an abdominal aortic aneurysm (AAA) when he was noted to have a recurrent (or new primary) gastric GIST. Results of PET scanning were positive for hepatic and intraabdominal metastases. At surgery, the gastric tumor was removed, but the metastatic lesions were not amenable to resection. Pathology study of the tumor excised from the stomach showed classic ulcerated GIST (Fig. 8). By this point in the patient s course, the AAA had become significantly enlarged. The surgeons, however, decided not to attempt to repair the AAA on the grounds that the patient was dying of his underlying malignancy. He was enrolled in Study B2222 and began treatment with imatinib, 600 mg/day. After 3 months of therapy, he achieved a radiographically demonstrated partial remission. In April 2001, the patient survived emergency surgery for rupture of the AAA. The vascular surgeon noted that the patient apparently had numerous omental metastases of his GIST. However, limited pathologic examination revealed only fat necrosis. Treatment with imatinib, 600 mg/day, was continued. Three months later, the patient required a Roux-en-Y revision, performed by an oncologic surgeon, because of complications from the emergency operation. The surgeon reported multiple nodules on the liver, peritoneum, and other abdominal sites on gross inspection, and biopsy specimens were obtained. The main pathology findings were organizing hemorrhage and scar tissue (Fig. 9). Other sections contained scant cellular material; immunohistochemistry results were negative for CD117 (KIT) staining. This is one of the first known instances of a complete response (absence of residual active GIST) after therapy with imatinib. Additional reports of complete responses in imatinib-treated GIST patients have appeared recently [21, 22, 33]. In light of the eradication of all signs of viable tumor in case 5, a noteworthy aspect of the case is the discrepancy between the surgeons reports of observing widespread lesions intraoperatively and the subsequent negative pathology and immunohistochemistry findings. This experience again highlights the importance of accurate assessment of GIST response in patients receiving imatinib. Evaluation for residual viable disease in imatinib-responsive patients who have apparent GIST lesions is becoming a critical component of treatment monitoring. GIST mutation status, if known, may be a contributing factor in determining the choice and timing of surgical and medical management. In case 5, the tumor harbored a KIT exon 11 mutation, which is associated with a higher probability of response to imatinib [32]. Benefit from imatinib therapy could, therefore, be anticipated in this patient and was seen in the achievement of complete remission following surgery that reduced his tumor burden. Patients with a mutation other than KIT exon 11 or with no detectable mutation have had lower rates of response to imatinib and might be considered for early, aggressive surgical management [32, 34]. Finally, case 5 serves as a cautionary example of the dangers of therapeutic nihilism in the imatinib era. With the patient s GIST under control on imatinib therapy, Figure 8. Histopathology study of a biopsy specimen from the recurrent gastric gastrointestinal stromal tumor resected in case 5. The features are characteristic of classic ulcerated disease. (Courtesy of Charles D. Blanke, M.D.) Figure 9. Histopathology study of a specimen taken from a mesenteric gastrointestinal stromal tumor (GIST) nodule in the patient in case 5. The specimen was obtained during a Roux-en-Y revision after abdominal aortic aneurysm repair. At the time of the corrective surgery, the patient had been receiving therapy with imatinib, 600 mg/day, for several months. The specimen shows organizing hemorrhage and no viable GIST cells. (Courtesy of Charles D. Blanke, M.D.)

8 16 Case Studies in GIST Management the AAA unexpectedly became the life-threatening condition and led to complications that subjected the patient to further, corrective surgery. Case Study 6: A 70-Year-Old Man with Relapsing Gastric GIST This elderly male patient presented in April 2000 with a gastric GIST in relapse and complaints of abdominal pain and swelling. At surgery, a 6-cm, CD117 (KIT)-positive, CD34-negative peritoneal GIST was completely resected. Another relapse, with multiple peritoneal metastases, occurred 4 months later. The patient again underwent resection, reported as microscopically complete. Three months later, the patient again presented in relapse, with multiple peritoneal tumors; the largest mass of which measured 22 cm. By February 2001, imatinib had become available, and the patient began investigational treatment at a dosage of 800 mg/day. The dosage was reduced to 600 mg/day at 4 months because of side effects. After 6 months of imatinib therapy, the patient achieved a partial remission, was in good physical condition, and was deemed by the surgical team to have an operable principal tumor, whereas other tumor sites were still present in the liver. After discussion, the patient preferred to postpone surgery. In December 2001, the patient again complained of abdominal swelling and moderate pain. CT scan revealed an increase of <20% in the largest peritoneal metastasis, which did not meet the formal criteria for disease progression. Resection of this metastasis was performed and was reported to be macroscopically complete. A pathology study, with CD117 (KIT) immunohistochemical assay, revealed numerous residual tumor cells expressing KIT (Fig. 10). Treatment with imatinib, 800 mg/day, was restarted. Between the time of surgery and the resumption of imatinib therapy 10 days postoperatively, a tumor nodule developed in the abdominal scar. Following reinstitution of imatinib treatment, the nodule remained stable for 6 months (Fig. 11). Thereafter, progression manifested itself as multiple subcutaneous nodules in the abdominal wall. The patient died 3 months later and at the time was refractory to third-line chemotherapy with vinorelbine (Navelbine ; GlaxoSmithKline, Philadelphia, In patients with relapsing GISTs, the disease has become systemic and, historically, has had a rapidly progressive, fatal course [6, 7]. Today, however, the ability to address advanced (systemic) GIST with a systemic therapy is prompting reconsideration of the role of metastasectomy in GIST management. Case 6 raises several questions, which await definitive answers from increasing clinical experience and research studies: a) Should imatinib be given as adjuvant therapy after complete resection of a first GIST metastasis? b) Should a patient with recurrence of metastatic disease that is rendered operable by imatinib therapy be considered a candidate for repeat resection? c) If an imatinib-treated patient with metastatic GIST and a history of prior surgeries has multiple tumors but only a single growing mass, should resection of the growing mass be considered? d) If surgery in such a patient yields evidence of viable, progressive disease, should imatinib therapy be reinstituted postoperatively? To date, the use of surgical resection for recurrent or metastatic GIST has been limited mainly to select patients with single-site disease or multiple small lesions (e.g., low-volume peritoneal surface foci) [35]. Multiple intraabdominal organ resection and tumor debulking have not generally been indicated except in unusual cases for palliation of symptoms in patients with good performance status. Recently, some authors have suggested that resection of progressive GIST lesions in patients whose disease is otherwise responsive or stable during treatment with imatinib may be a feasible approach to GIST control [36, 37]. In case 6, a patient with serial relapses of metastatic peritoneal GIST achieved a 6-month remission in which he enjoyed reasonably good health, was kept alive beyond 2 years, and was able to undergo resection for recurrence of GIST-related symptoms through combined medical and surgical management. Case Study 7: Timing of Post-Imatinib Surgery in Two Patients with Initially Inoperable GISTs From February 2001 to September 2002, 120 patients with confirmed CD117 (KIT)-positive unresectable GISTs were enrolled in three consecutive studies of imatinib therapy, two European Organization for Research and Treatment of Figure 10. Peritoneal metastatic gastrointestinal stromal tumor surgically resected in March 2002 from the patient in case 6. (Courtesy of Jean-Yves Blay, M.D, Ph.D.) The Oncologist

9 Benjamin, Blanke, Blay et al. 17 Cancer trials and one French national trial. Patients benefited from treatment in approximately 85% of cases, with partial remission achieved in 60%. All patients had macroscopic evidence of residual disease after 6 12 months of imatinib administration, 400 mg/day, but significant improvement in tumor status in a number of cases prompted consideration of adjuvant surgery. The death of three patients from complications following emergency operations for GIST rupture provided further support for the investigation of surgery as a planned intervention to potentially reduce tumor-related morbidity and mortality. Two patients with huge necrotic masses were among the imatinib-treated GIST patients (n = 4) who underwent elective surgery after prolonged remission and before expected complications. Since the size of the tumors and the evidence of myxoid degeneration on CT scans indicated that these two patients were at risk for tumor rupture, the decision was made to perform scheduled resection to avoid emergency surgery (Fig. 12). Postoperative dissection of the excised masses revealed necrotic and hemorrhagic contents within heavily vascularized tumor walls, confirming the preoperative assessment of a high risk for bleeding complications (Fig. 13). Pathology study of the tumors before and after imatinib treatment demonstrated that the sparse remaining viable GIST cells were confined principally to the periphery of the walls of the cystic masses. Pre- and post-imatinib immunohistochemical assays for CD117 (KIT) showed nearly complete histologic responses in the residual masses, as well as in unresected hepatic metastases. Neither patient experienced surgery-related morbidity. GISTs are highly vascularized tumors that are prone to bleeding [21]. Hemorrhage is a frequent presenting symptom as well as a complication of the disease and was observed in a small subset of patients (5%) with bulky tumors in a phase II trial of imatinib in GIST, probably as a consequence of tumor degeneration in response to therapy [20, 25]. As case 7 illustrates, consideration of the timing of surgery may prove to be advisable for GIST patients who become candidates for resection because of tumor response to imatinib and appear to be at a higher risk for rupture or emergent bleeding complications. Optimal management of such patients requires ongoing consultation between the medical and surgical teams, with support from diagnostic radiologists for disease staging and monitoring of tumor viability. Figure 11. Computed tomography scans from the patient in case 6 obtained in January 2002 (A) and June 2002 (B, C). The patient was being treated with imatinib and underwent resection of a peritoneal metastasis in March Note the metastatic gastrointestinal stromal tumor nodule that developed in the abdominal scar during a perioperative break in imatinib administration (C). (Courtesy of Jean-Yves Blay, M.D, Ph.D.) Conclusion Contemporary management of GIST appears to be poised for evolution toward the combined use of systemic tyrosine kinase inhibitor therapy and surgical resection to optimize treatment outcomes. As illustrated by the preceding cases, a multidisciplinary-team approach that integrates the expertise of surgeons, medical oncologists, pathologists, diagnostic radiologists, and gastroenterologists is evolving as a new paradigm for GIST diagnosis, treatment, and monitoring. GIST is no longer principally within the purview of the surgeon alone. Clearly, data from adjuvant and neoadjuvant clinical trials of imatinib are needed before any definitive conclusions can be drawn about the effects of this therapy on

10 18 Case Studies in GIST Management Figure 12. Huge necrotic gastrointestinal stromal tumors conferring high risk for rupture and hemorrhagic complications in two patients with prolonged imatinib-induced remissions. (Courtesy of Sylvia Bonvalot, M.D.) Figure 13. Dissection of the excised tumors presented in Figure 12, revealing hemorrhagic and necrotic contents. (Courtesy of Sylvie Bonvalot, M.D.) disease response and survival in GIST patients with operable tumors. However, the high rates of major response and freedom from progression achieved to date in the studies of patients whose GISTs were unresectable suggest the potential for benefit. Based on the current experience with imatinib, at least two recommendations can be offered. The first is to ensure that patients treated with imatinib receive therapeutic doses: mg/day initially. Second, the experience of the patients in case 3 and case 6, in whom progressive disease developed rapidly during breaks in their imatinib therapy, is consistent with that reported in other patients and suggests that treatment be continued in responders to imatinib in the absence of documentation by a sensitive method that all viable disease has been eradicated. Further insight on issues of dosing, treatment duration, and the selection, timing, and monitoring of therapeutic interventions for GIST is awaited from clinical studies. Together with national guidelines for GIST treatment, clinical experience in the multidisciplinary setting will likely become the hallmark of optimal management. Acknowledgment These cases were originally presented at the symposium Glivec: First Successful Systemic Treatment for GIST, September 19, 2002, London, United Kingdom, sponsored by Novartis Oncology. Disclosure of Potential Conflicts of Interest All of the authors have spoken for, recieved honoraria from, and participated in advisory boards for Novartis. The Oncologist

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12 20 Case Studies in GIST Management Additional Reading Borden EC, Baker LH, Bell RS et al. Soft tissue sarcomas of adults: state of the translational science. Clin Cancer Res 2003;9: Duensing A, Heinrich MC, Fletcher CD et al. Biology of gastrointestinal stromal tumors: KIT mutations and beyond. Cancer Invest 2004;22: Eisenberg BL, Judson I. Surgery and imatinib in the management of GIST: emerging approaches to adjuvant and neoadjuvant therapy. Ann Surg Oncol 2004;11: Miettinen M, Sobin LH, Lasota J. Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up. Am J Surg Pathol 2005;29: Vlahovic G, Crawford J. Activation of tyrosine kinases in cancer. The Oncologist 2003;8: The Oncologist