University of Alabama at Birmingham, Birmingham, Alabama
GASTROINTESTINAL STROMAL TUMOR
Gastrointestinal stromal tumors (GISTs), a type of sarcoma, are the most common non-epithelial tumors of the digestive tract that arise from precursors of connective tissue cells located in the gastrointestinal (GI) tract. Most GI soft tissue neoplasms, previously classified as leiomyomas, schwannomas, leiomyoblastomas, or leiomyosarcomas, are presently classified as GIST on the basis of molecular and immunohistologic features. GISTs are strongly and uniformly positive for CD117 (c-kit), a type III receptor tyrosine kinase. c-kit mutations, mostly in exon 11, leading to ligand-independent constitutive activation, are supposed to play a major role in the pathogenesis of GIST.
The incidence of GIST is estimated to be approximately 10 to 20 cases per 1,000,000 population; the median age at diagnosis has been reported to be 55 to 65 years. GISTs most commonly occur in the stomach (70%) or duodenum, followed by the small intestine (20% to 30%), and 10% are found elsewhere in the GI tract. Early stage GIST typically manifests as a localized tumor (i.e., in the stomach). Approximately 50% of patients present with metastatic disease at first diagnosis, predominantly in the liver or peritoneum.
GIST cells express c-kit, a growth factor receptor with tyrosine kinase activity derived from the protooncogene c-kit. In fact, the most specific criterion for the diagnosis of GIST is immunohistochemical staining of CD117, which allows the expression of c-kit to be detected. Mutations in the protooncogene that activate the tyrosine kinase function of c-kit are observed in most GISTs and are considered to be a central part of pathogenesis of the disease.
The positron emission tomography (PET) and computerized tomography (CT) scans are sensitive and reliable indicators of tumor response to therapy, particularly with imatinib. 2-fluoro-2-deoxy-d-glucose (FDG). PET improves staging, accurately separates responders from nonresponders in an early phase, and is helpful during follow-up of patients.
Prognostic factors have recently been identified for GIST and include tumor size, mitotic rate, and other minor factors (Table 11.1).
TABLE 11.1. The prognostic factors that define different risk groups for gastrointestinal stromal tumors (GISTs)
At present, surgery is the standard treatment for primary resectable GIST. However, often, surgical removal of GISTs either is not feasible or is palliative in nature. Overall 5-year survival after surgical resection of GIST is approximately 60%.
Recurrent or malignant GIST does not respond to conventional cytotoxic agents; the response rate of this fatal disease to doxorubicin has been reported to be less than 5%. Other commonly used chemotherapeutic agents yield similarly poor responses in GIST.
The effectiveness of radiation therapy, another typical component of cancer treatment, in treating GIST also has not been proven.
The development of a tyrosine kinase inhibitor has changed the management of unresectable GIST. Imatinib mesylate (STI571, Glivec), a tyrosine kinase inhibitor, which inhibits the c-kit receptor, has been proven to be highly effective against GIST and has improved survival in metastatic GIST.
Early results from clinical trials confirm the high activity of this novel treatment, with response rates of approximately 60% and arrest of tumor progression seen in more than 80% of patients, resulting in fast relief of symptoms (see Table 11.2).
TABLE 11.2. Responses to Imatinib Mesylate in a Phase II Trial of Patients with Advanced Gastrointestinal Stromal Tumors (GISTs)
Imatinib is approved at a dose of 400 to 600 mg daily for GIST. Some investigators have attempted to determine the most effective dose of imatinib in GIST patients. A large international randomized phase III trial compared the efficacy of two different doses of imatinib in GIST patients. The study randomized 946 patients to receive either 400 mg of imatinib once daily (with crossover to 800 mg per day with disease progression) or 400 mg twice daily (for a daily dose of 800 mg). The interim analysis presented at American Society of Clinical Oncology (ASCO) meeting showed that patients responded well to both doses of imatinib, with an objective response of 43% observed in each arm of the trial. Complete response was similar between the two arms—5.6% and 3.9%, respectively, for the 400-mg and 800-mg groups. Most patients, however, showed either partial response (44.7% and 47.2%, respectively) or stable disease (32.7% and 33.3%, respectively). Data also showed that progression-free survival (PFS), the primary end point of the study, was significantly higher in patients who received the 800-mg dose of imatinib (p = 0.0216; see Fig. 11.1).
FIG. 11.1. Progression-free survival curve from a phase III study of gastrointestinal stromal tumors (GISTs); patients treated with 400 or 800 mg of imatinib mesylate. [From Verweij J, Casali PG, Zalcberg J, et al. Progression-free survival in gastrointestinal stromal tumors with high-dose lmatinib: randomized trial. Lancet 2004; 364(9440):1127–1134, with permission.]
Treatment with imatinib is generally well tolerated, although most common toxicities include grade 1 or 2 adverse events—most commonly nausea, diarrhea, periorbital edema, muscle cramps, fatigue, headache, and dermatitis.
The role of adjuvant treatment after potentially curative resection of GIST is being evaluated in ongoing clinical trials. An investigational agent, SU11248, has also shown promising results against imatinib-resistant GIST in early trials. Other novel agents that are being tested include RAD001 and PKC412.
SMALL BOWEL ADENOCARCINOMA
Cancer of the small bowel is a relatively rare malignancy, accounting for approximately 2% of GI tumors. Approximately 5,300 new cases of small bowel adenocarcinoma and 1,100 deaths from the disease are reported annually in the United States. An estimated 40% of small bowel cancers are adenocarcinomas, 40% are carcinoids, 15% are sarcomas (GIST), and less than 5% are lymphomas. Limited information is available on the incidence, prognosis, and role of chemotherapy in the treatment of this disease.
An increased risk of developing small bowel adenocarcinoma has been described in patients with:
Familial clustering of small bowel adenocarcinomas with multicentric colorectal cancer and gastric cancer has been identified (4).
An estimated 40% of small bowel cancers are adenocarcinomas, 40% are carcinoids, 15% are sarcomas (GISTs), and less than 5% are lymphomas.
Small bowel adenocarcinoma includes adenocarcinomas arising in the duodenum, jejunum, and ileum. Whereas adenocarcinomas arising from the ampulla of Vater and the periampullary region are typically included in the category of small bowel adenocarcinomas, those arising from the ileocecal valve, appendix, and Meckel diverticulum are excluded.
Small bowel adenocarcinomas are similar to their colonic counterparts in the adenoma–carcinoma sequence and demonstrate similar pathologic features, with slight differences in frequency of histologic types and immunohistochemical markers.
Most small bowel adenocarcinomas are solitary, sessile lesions, often appearing in association with adenomas. They are usually moderately well differentiated and are almost always positive for acid mucin.
Small bowel adenocarcinomas can be positive for carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), and p53. Expression of c-erbB-2, Ki-67, and tenascin has also been described. Small bowel adenocarcinomas arising from the ileum may show staining with neuroendocrine markers.
The clinical presentation of small bowel adenocarcinoma depends on the location of the primary tumor, its growth pattern, and the extent of metastatic spread. In general, symptoms are initially nonspecific and include anemia, bleeding, abdominal pain, nausea and vomiting, or obstruction and/or perforation in cases of locally advanced tumor. Because of a vague presentation of small bowel adenocarcinoma, the time between initial development of symptoms and diagnosis is often relatively long, approximately 6 to 8 months, and contributes to the higher percentage of advanced cases at the time of diagnosis (in contrast to colorectal cancer). Common sites of metastases include locoregional lymph nodes, liver, lung, and the peritoneum.
The staging workup of small bowel adenocarcinoma includes the following:
Small bowel adenocarcinomas are staged according to the tumor–node–metastasis (TNM) criteria, as used for colon cancer. Staging is based on the extent to which the tumor is present in the bowel wall, the regional nodal status, and the presence or absence of distant metastasis.
Resectability is the key prognostic factor. Other factors include age older than 75 years, performance status, well-differentiated and moderately differentiated versus undifferentiated small bowel adenocarcinomas, tumor location (arising in the duodenum), and presence of distant metastasis. The prognostic significance of lymph node status for survival is controversial.
The median survival of patients with localized, locally advanced, and metastatic disease is 50.1, 22.2, and 8.6 months, respectively.
Treatment of Localized Disease
Surgical resection is the mainstay of treatment for small bowel adenocarcinomas because it offers a potential cure. A large review of the Department of Defense database from 1970 to 1996 found that 47% of 144 small bowel malignancies were small bowel adenocarcinomas; 91% of these patients underwent surgical resection, 45% with curative surgery. During a median follow-up of 38.9 months (range 1 to 405 months), the median survival was 182 months versus 33 months and the 5-year survival rate was 81% versus 42% after curative surgery and incomplete resection, respectively. In patients not amenable to surgery, the median survival was 10 months with a 5-year survival of 39%. Rose et al. found that among 79 patients with primary duodenal small bowel adenocarcinomas, the patients with completely resected disease (node-negative) had a median survival of 86 months and a 5-year survival of 60%, whereas patients with completely resected disease (node-positive) had a median survival of 41 months and a 5-year survival of 43% (5). Patients who either had palliative surgery or who did not undergo surgery had a median survival of 9 months, and no patient was alive at 5 years. This study, although small, suggested that resection of the primary tumor, even with known locoregional involvement, may provide survival benefit.
Data for adjuvant therapy involving agents such as 5-fluorouracil (5-FU), obtained from the experience gained in the treatment of colorectal cancer and the information obtained from patients with metastatic small bowel disease are scarce. No prospective phase II or randomized phase III data are currently available. A review of the National Cancer Data Base from 1985 to 1995 was published by Howe et al. in Cancerin 1999, which revealed an increasing use of adjuvant chemotherapy for regionally advanced disease—from 28% from 1985 to 1990 to more than 40% from 1990 to 1995—a practice based on the current treatment standards for colorectal cancer. It is estimated that 14% of patients in the United States with only localized small bowel adenocarcinoma receive some form of adjuvant chemotherapy. An intensified adjuvant therapy—protracted intravenous infusion of 5-FU modulated with leucovorin with an intense-dose external-beam radiotherapy to liver, regional lymph nodes, and tumor bed—was evaluated in patients with pancreatic or periampullary adenocarcinoma. The regimen was found to be very toxic, with no survival benefit when compared to the historical data from patients who were receiving more conventional doses of chemotherapy or radiation. Median disease-free survival was approximately 8 months, with earlier recurrences suggesting that the disease may promptly develop resistance to chemotherapy and radiation.
Coia L et al. treated four patients with resectable duodenal cancer at Fox Chase Cancer Center as part of a clinical study for pancreatic cancer with neoadjuvant or preoperative chemoradiation (6). The regimen consisted of two cycles of 5-FU at a dosage of 1 g/m2/day for 4 days on days 2 to 5 and days 29 to 32 and mitomycin C at a dosage of 10 mg per m2 on day 2 given with concurrent radiation administered at a dose of 1.8 Gy per day to a total dose of 50.4 Gy. Surgical resection was performed 4 to 6 weeks after completion of chemoradiation. All four patients underwent surgical resection and achieved complete pathologic response. At a median follow-up of 4.5 years, all patients were alive without recurrence, with actual survival durations of 12, 23, 35, and 90 months, respectively.
Treatment of Metastatic Disease
The role of surgical resection is limited to either palliative measures or prevention of bowel obstruction or bleeding in patients with metastatic small bowel adenocarcinoma.
The choice of chemotherapeutic agents and the actual efficacy of such treatment in metastatic disease are less defined. This is partly because of the lack of well-controlled clinical trials and partly because this disease is not very common. The National Cancer Data Base indicates that 37% of all patients with advanced disease received some form of chemotherapy, 12% received external-beam radiation with or without surgery, and 25% received no cancer-related therapy. Historically, the most commonly used chemotherapy includes 5-FU alone or 5-FU–based regimens. Other chemotherapy regimens include tegafur, thiotepa, mitomycin C, and cisplatin, anthracyclines, or alkylating agents. Regimens such as ECF (epirubicin, cisplatin, and 5-FU) have been tested in a small group of patients with advanced small bowel cancer at the Royal Marsden Hospital (7). Patients received epirubicin at 50 mg per m2, cisplatin at 60 mg per m2, each given every 3 weeks, and protracted venous infusion (PVI) of 5-FU at a dose of 200 mg per m2. The overall response rate was 37%. The median progression-free survival was 7.8 months, with a median overall survival of 13 months. The authors concluded that small bowel
adenocarcinoma is sensitive to infusional 5-FU and that chemotherapy appears to have clinical benefit over palliative surgery alone. In summary, lack of prospective, randomized trials; the minimal benefit, if any, reported in clinical series; and the associated toxicity should be taken into account. The decision to treat should be individualized, and the risks and benefits should be carefully explained to the patient.
Abrams RA, Grochow LB, Chakravarthy A, et al. Intensified adjuvant therapy for pancreatic and periampullary adenocarcinoma: survival results and observations regarding patterns of failure, radiotherapy dose and CA 19-9 levels. Int J Radiat Oncol Biol Phys 1999;44:1039–1046.
Buemming P, Meis-Kindblom JM, Kindblom LG, et al. Is there an indication for adjuvant treatment with imatinib mesylate in patients with aggressive gastrointestinal stromal tumors (GISTs)?. Presented at: 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31, June 3, 2003, Abstract 3289.
Casali G, Verweij J, Zalcberg J, et al. Imatinib (Gleevec) 400 and 800 mg daily in patients with gastrointestinal stromal tumors (GIST): a randomized phase III trial from EORTC Soft Tissue and Bone Sarcomas Group, the Italian Sarcoma Group (ISG), and the Australasian Gastro-intestinal Trials Group (AGITG). A toxicity report. Presented at: 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 1824, 2002, Abstract 1650.
Choi H, Charnsangavej C, Macapinlac HA, et al. Correlation of computerized tomography (CT) and proton emission tomography (PET) in patients with metastatic GIST treated at a single institution with imatinib mesylate. Presented at: 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31, June 3, 2003, Abstract 3290.
Crawley C, Ross P, Norman A, et al. The Royal Marsden Experience of small bowel adenocarcinoma treated with protracted venous infusion 5-fluorouracil. Br J Cancer 1998;78:508–510.
Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002;347:472–480.
Howe JR, Karnell LH, Menck HR, et al. Adenocarcinoma of the small bowel, review of the National Cancer Data Base, 1985–1995. Cancer1999;86:2693–2696.
Joensuu H, Roberts PJ, Sarlomo-Rikala M, et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 2001;344:1052–1056.
Veyrieres M, Baillet P, Hay JM, et al. Factors influencing long-term survival in 100 cases of small intestine primary adenocarcinoma. Am J Surg 1997;173:237–239.