Joleen M. Hubbard
GASTROINTESTINAL STROMAL TUMOR
Gastrointestinal stromal tumors (GISTs), a type of sarcoma, are the most common nonepithelial tumors of the gastrointestinal (GI) tract that arise from precursors of connective tissue cells. 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. Approximately 80% to 85% of GIST tumors have a mutation in the proto-oncogene KIT, and 5% to 8% harbor a mutation in the platelet-derived growth factor receptor alpha (PDGFRa) gene (5% to 10%), both of which lead to ligand-independent signal transduction resulting in increased cell proliferation and inhibition of apoptosis. The development of targeted therapies, which inhibit KIT and PDGFRa, has revolutionized the treatment of GIST in both the adjuvant and advanced settings.
Epidemiology
The incidence of GIST is estimated to be approximately 10 to 15 cases per 1,000,000 persons in the United States; the median age at diagnosis is 55 to 65 years. There are no established risk factors for the development of GIST.
Pathology
GISTs are believed to originate from interstitial cells of Cajal. The majority of cases can be classified into two categories: spindle cell type (70%) and epitheliod type (20%). The spindle cell type has uniform eosinophilic spindle cells organized in short fascicles or in a short storiform growth pattern. The epitheliod cell type has round-shaped cells exhibiting eosinophilic or clear cytoplasm that tend to exhibit a nested growth pattern.
GISTs most commonly occur in the stomach (60%) or duodenum, followed by the small intestine (25%), rectum (5%), and esophagus (2%); 5% are found in the colon, mesentery, and retroperitoneum. Early-stage GIST typically manifests as a localized tumor (i.e., in the stomach). Approximately 10% to 20% of patients present with metastatic disease, predominantly in the liver or peritoneum.
Diagnosis
Approximately 85% of GISTs express KIT, a type 3 transmembrane receptor tyrosine kinase. It is the single most common tumor marker for GIST and is identified with anti-CD117 antibodies on immunohistochemistry. PDGFRA mutations are homologous to those responsible for KIT- and Flt-3L-independent kinase activation in other malignancies, including acute myeloid leukemia, mast cell disorders, and seminomas. KIT and PDGFRA mutations and overexpression are usually mutually exclusive in GIST. Thirty-five percent of KIT wild-type GISTs have PDGFRA mutations. Mutations in both KIT and PDGFRA lead to dysregulation of downstream intracellular signaling processes involving protein kinases and transcription factors such as AKT, MAPK, and STATs (STAT1 and STAT3), which play a critical role in the development and progression of cancer.
Computerized tomography (CT) scans remain the standard for initial staging workup and evaluation of response to therapy. Positron emission tomography (PET) scans are reserved for early response assessment or to further characterize inconclusive results on morphologic imaging, such as when results of a CT are ambiguous or inconsistent with clinical findings.
Clinical Presentation
The clinical presentation of GIST depends on the location of the tumor and may include the following:
■Abdominal discomfort or pain
■Sense of abdominal fullness
■Nausea
■Vomiting
■GI bleeding
■Fatigue related to anemia
Prognostic Factors
The risk stratification for recurrence after resection is based on size, mitotic index, and location of the tumor. Gastric GISTs are associated with a better outcome than GISTs located in the small bowel or rectum. Tumors with >5 mitoses per 50 high power field (HPF) are also at higher risk for recurrence.
Mutations are a prognostic factor in GISTs. Patients with KIT mutations have a higher rate of relapse than patients with “wild-type” GIST. In addition, PDGFRA exon 18 mutations, typically found in the stomach, are associated with improved outcomes after resection.
Treatment
Surgery
Surgery is the primary treatment of choice for localized or potentially resectable GIST. Since GIST tumors rarely give rise to lymph node metastases, extensive lymph node dissection is not routinely required. Neoadjuvant therapy with imatinib may be considered if significant morbidity would result after an en bloc resection of a large tumor.
Approximately 60% of patients with operable GIST will be cured with surgery alone. Median time to recurrence after resection of primary high-risk GIST is about 2 years. Metastases can develop 10 to 15 or more years after primary surgery, necessitating long-term clinical follow-up. Metastases into the abdominal cavity or liver are more common than in lymph nodes and extremely rare in the lungs and other extra-abdominal locations.
Adjuvant Therapy
The need for adjuvant therapy is determined by risk stratification tools. The NIH risk stratification criteria (Table 11.1) categorizes risk into very low, low, intermediate, and highly based on size and mitotic rate per 50 HPF. Based on the degree of risk of GIST recurrence, the current management after surgical resection is observation, 1 year of imatinib or 3 years of imatinib.
Imatinib mesylate (Gleevec) is a tyrosine kinase inhibitor that targets the c-KIT and PDGFa receptors. Imatinib became the standard of care after the resection of GISTs based on the results of the American College of Surgeons Oncology Group (ACOSOG) Intergroup Adjuvant GIST Study Z9001 study. In this phase III clinical trial, 708 patients were randomized in a double-blind fashion to 1 year of imatinib 400 mg daily or placebo following complete gross resection of a primary GIST measuring at least 3 centimeters and expressing KIT. Upon recurrence, treatment assignment was unblinded and patients were allowed to cross over to imatinib if they had been on placebo or increase the daily dose of imatanib to 800 mg if they were already receiving the drug. Recurrence-free survival (RFS) at 1 year, the primary endpoint of the trial, was 98% in the imatinib arm versus 83% in the placebo arm (P < 0.0001). Overall survival (OS) was not statistically significant between the two arms, likely due to short-term follow-up and the ability to crossover from the placebo arm to the imatinib arm.
In the Z9001, approximately 50% of patients with tumors >10 cm had recurrences in the first 3 years. This finding prompted a European study randomizing patients with high-risk of recurrence to 12 versus 36 months of adjuvant imatinib. The 5-year RFS was 65.6% in the 3-year arm compared to 47.9% in the 1-year arm (P < 0.0001). OS at 5 years was 92.0% and 81.7% in the 3-year and 1-year arms respectively (P = 0.02).
Neoadjuvant Therapy
RTOG 0132/ACRIN 6665, a prospective phase 2 study, evaluated safety and efficacy of neoadjuvant imatinib mesylate (600 mg per day) for patients with primary GIST or the preoperative use of imatinib mesylate in patients with operable metastatic GIST. The trial continued post-op imatinib mesylate for 2 years. Early results among 63 patients, of whom 52 were analyzable, 30 patients with primary GIST (group A) and 22 with recurrent metastatic GIST (group B) showed response (RECIST) as follows: group A, 7% partial, 83% stable, 10% unknown; group B, 4.5% partial, 91% stable, 4.5% progression. Two-year PFS was 83% for group A and 77% for group B. Estimated OS was 93% for group A and 91% for group B. Complications of surgery and imatinib mesylate toxicity were minimal. This trial represents the first prospective report of pre-op imatinib mesylate in GIST. This approach is feasible, requires multidisciplinary consultations, and is not associated with notable postoperative complications.
Therapy for Unresectable Disease
Prior to the development of targeted therapy, the treatment options for metastatic GIST were extremely limited. GIST does not respond to conventional cytotoxic agents, with reported response rates to doxorubicin lower than 5%. Other commonly used chemotherapeutic agents yielded similarly poor responses in GIST. Kinase inhibitors have dramatically increased survival in GIST, with the median survival approaching 5 years.
Imatinib
Imatinib 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, which results in fast relief of symptoms.
Imatinib is approved at a dose of 400 to 600 mg daily for GIST. Investigators have attempted to determine the most effective dose of imatinib in GIST patients. Two large international randomized phase 3 trials compared the efficacy of two different doses of imatinib in GIST patients. The studies were designed similarly to be combined in a meta-analysis (MetaGIST). Patients were randomized 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). Response rates (mostly partial response or stable disease) were similar between doses in both trials. In the individual trials and the meta-analysis, PFS was prolonged with the 800 mg dose, but OS was not different between dosages.
Among KIT mutations, 70% are found on exon 11, 10% on exon 9; exons 13 and 17 are rarely involved. In a subgroup analysis of the MetaGIST analysis, the higher dose of imatinib was associated with better PFS for patients with KIT exon 9 mutations, but again, the higher dose was not associated with improved OS. In addition, approximately 80% of patients eventually develop secondary mutations in KIT exons resulting in progressive disease. Therefore, the current recommendations are to initiate therapy at 400 mg daily, and to increase to 800 mg daily for nonresponders.
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.
Sunitinib
Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activities. Sunitinib is approved for the treatment of patients with GIST after disease progression or intolerance to imatinib mesylate therapy. A double-blind placebo-controlled, multicenter, randomized phase 3 trial confirmed the efficacy and safety of sunitinib as second-line therapy in 312 patients with GIST showing disease progression or intolerance under imatinib mesylate therapy. Patients were randomized in a 2:1 ratio to receive sunitinib 50 mg daily for 4 weeks, with 2 weeks off (n = 207) or placebo (n= 105). Objective response rates in the sunitinib arm and in the placebo arm were 8% and 0%, respectively. Median time to progression was significantly longer in the sunitinib arm (6.3 vs. 1.5 months). Fifty-nine patients in the placebo group crossed over to sunitinib therapy due to disease progression. Ten percent had subsequent partial responses, suggesting that the optimal therapeutic effect of sunitinib may be observed when it is administered in the early disease phase. Hypertension and asthenia are the most common side effects with sunitinib.
Regorafenib
Regorafenib, a novel multikinase inhibitor that targets several protein kinases involved in tumor angiogenesis (VEGFR1–3 and TEK), oncogenesis (KIT, RET, RAF1, BRAF, and BRAFV600E), and the tumor micro environment (PDGFR and FGFR), was tested in a randomized phase III trial for patients with metastatic GIST who had progressed on imatinib and sunitinib. Median PFS was 4.8 months for regorafenib and 0.9 months for placebo (HR 0.27; 95% CI 0.19 to 0.39; P < 0.0001). OS was not significantly improved with regorafenib; however, crossover was allowed on the study. Common adverse events were hypertension, hand–foot skin reaction, and diarrhea.
Radiotherapy
The effectiveness of radiation therapy in treating GIST also has not been proven, and is typically reserved in rare circumstances for palliation of symptoms.
SMALL BOWEL ADENOCARCINOMA
Despite the fact the small intestine comprises over 90% of the intestinal surface area, small bowel adenocarcinoma (SBA) is actually a rare entity, accounting for <2% of all GI tumors. SBA accounts for approximately one-third of small bowel malignancies with the remaining histologies being neuroendocrine cancers (carcinoid), lymphoma, and GIST. The rarity of SBAs has limited research into the natural history, prognosis, and management of patients with this disease. Recent studies suggest SBA is more closely related to colorectal carcinoma than gastroesophageal cancers. Given the lack of clinical trial data to support treatment recommendations, SBAs are often managed similarly to colorectal cancers.
Epidemiology
Approximately 6,110 new cases of SBA and 1,100 deaths from the disease are reported annually in the United States. The incidence of adenocarcinoma is estimated to be 5.7 to 7.3 per million in the United States. Some studies have suggested the incidence of SBA is increasing, particularly in the duodenal region, which may be explained by the increased use of upper endoscopies. Although SBAs are only one-fiftieth as common as large bowel adenocarcinomas, they share a similar geographic distribution, with predominance in Western countries. In addition, they tend to co-occur in the same individuals, with an increased risk of SBA in survivors of colorectal cancer and vice versa.
Risk Factors
Genetic Predisposition
■Familial adenomatous polyposis: Patients with this condition develop multiple adenomas throughout the small bowel and colon, which may lead to adenocarcinomas. After the colon, the duodenum is the most common site of adenocarcinoma. A 1993 study from Johns Hopkins by Offerhaus et al. found that patients with familial adenomatous polyposis have a relative risk of more than 300 for duodenal adenocarcinoma but no elevated risk of gastric or nonduodenal small bowel cancer.
■Hereditary nonpolyposis colorectal cancer: Aside from colorectal carcinoma, patients with this genetic syndrome also develop endometrial, gastric, small bowel, upper urinary tract, and ovarian carcinomas. The lifetime risk of SBA in patients with hereditary nonpolyposis colorectal cancer is 1% to 4%, which is more than 100 times the risk in the general population. SBAs in persons with hereditary nonpolyposis colorectal cancer are distributed evenly throughout the small bowel. They occur at younger age and appear to have a better prognosis than sporadic small bowel cancers.
Predisposing Medical Conditions
■Crohn’s disease: The relative risk of SBA is estimated to be between 15 and more than 100 in patients with Crohn’s disease. Unlike most SBAs, Crohn-related tumors generally occur in the ileum, reflecting the distribution of Crohn’s disease. The risk of adenocarcinoma does not begin until at least 10 years after the onset of Crohn’s disease, and the adenocarcinoma typically occurs more than 20 years afterward.
■Celiac disease (nontropical sprue): Patients with celiac disease appear to be at increased risk of small bowel lymphoma and adenocarcinoma. A 2001 survey of adult celiac disease patients in the United States performed by Green et al. found a relative risk of 300 for the development of lymphoma and 67 for the development of adenocarcinoma. SBAs associated with celiac disease appear to have an increased incidence of defective DNA mismatch repair compared with those not associated with celiac disease, and are associated with an earlier stage at diagnosis and a better prognosis.
■Peutz-Jeghers syndrome: Hemminki has reported an approximately 18-fold increase in the incidence compared to that in the general population.
Pathology
Approximately 50% of SBAs arise in the duodenum, 30% in the jejunum, and 20% in the ileum. Similar to adenocarcinomas in the colon, those in the small bowel arise from premalignant adenomas. This occurs both sporadically and in the context of familial adenomatous polyposis.
Genetic analyses of sporadic SBAs suggest similarities and differences from the pathogenesis from colorectal carcinomas. Although K-ras mutation and p53 overexpression appear to be as common in SBA as in colorectal carcinoma, mutation of the APC tumor suppressor gene, which is characteristic of colorectal carcinoma, does not commonly occur in SBA. The SMAD4/DPC4 gene, which is often mutated in pancreatic and colorectal carcinomas, also appears to be inactivated in SBAs.
Most SBAs are solitary, sessile lesions, often appearing in association with adenomas. They are usually moderately well differentiated and are almost always positive for acid mucin. SBAs 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. SBAs arising from the ileum may show staining with neuroendocrine markers.
Clinical Presentation
The clinical presentation of SBA 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 tumors. Because of a vague presentation of SBA, 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.
Diagnosis
Lab Studies
■Complete blood count (CBC) may show mild anemia related to chronic blood loss.
■Liver function tests may reveal hyperbilirubinemia, which may be related to biliary obstruction from periampullary tumors. Elevated transaminase levels also may be found in the presence of liver metastases.
■CEA levels may be elevated. Although cases with elevation of CA 19-9, or CA 125 levels have been reported, no clear role for such tumor markers has been established for diagnosis.
Imaging Studies
■Plain abdominal x-ray films may reveal partial or complete small bowel obstruction.
■Upper GI series with small bowel follow through show abnormalities in 53% to 83% of patients with small bowel cancer.
■Small bowel enteroclysis studies are done with double-contrast barium enema, which has a sensitivity of 95%. However, it is difficult to perform as it requires a long tube to be inserted in the small bowel to instill air and contrast.
■Abdominal CT scan may elucidate the site and extent of local disease and the presence of liver metastases.
Other Tests
In those rare cases of bleeding due to a small bowel tumor, the diagnostic approach is the same for all cases of lower GI bleeding. In the case of negative upper and lower endoscopy, tagged red blood cell scan and angiography can be helpful in localizing the disease process. Capsule endoscopy has a better sensitivity and specificity and may identify an SBA during the workup for occult GI bleeding.
Procedures
■Upper GI endoscopy with small bowel enteroscopy (push enteroscopy) may identify and allow biopsy of lesions in the duodenum and jejunum. Push enteroscopy is difficult to perform. The endoscopes are long and difficult to manipulate. The procedure is lengthy.
■Colonoscopy with retrograde ileoscopy may be useful in identifying ileal tumors.
■Capsule endoscopy: This test is done with a capsule with dimensions of 11 × 26 mm that weighs 4 g. The capsule contains a small video camera, batteries, and a radiofrequency transmitter. The batteries last 8 hours. The capsule takes about 50,000 pictures as it passes through the GI system. The pictures are captured in a device that is strapped to the waist. The test was FDA approved for small bowel use in 2001. Cobrin et al. reported that 9% of cases of occult GI bleeding were caused by small bowel tumors.
Staging
SBAs 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. In a recent SEER database study evaluating the incidence of SBAs, 11.8% presented with stage I, 30.1% with stage II, 26.0% with stage III, and 32.2% with stage IV disease.
Prognosis
Resectability is the key prognostic factor. Historically, the median survival of patients with localized, locally advanced, and metastatic disease is 50.1, 22.2, and 8.6 months, respectively. Factors associated with poor prognosis after surgical resection of SBAs included age greater than 55 years, duodenal location, T4 tumors, nodal or distant metastases, poorly differentiated tumor, and involved surgical margins. Despite the resemblance to colorectal cancer, the stage-adjusted prognoses for SBAs are inferior to colorectal cancer.
Treatment of Localized Disease
Surgery
Surgical resection provides the only hope of cure for patients with SBAs. This is possible in approximately two-thirds of patients. The remaining have unresectable disease as a result of extensive local disease or metastases to regional lymph nodes, the liver, or the peritoneum. Wide local excision is recommended on lesions in the distal duodenum, jejunum, or ileum. Patients with lesions in the proximal duodenum, including those in the periampullary region, should undergo pancreaticoduodenectomy, which now has an operative mortality rate of less than 5%. Ileal tumors are more likely to develop intestinal obstruction than jejunal tumors. Emergency surgery for these patients relieves the obstruction but precludes a complete and negative margin resection.
Adequate lymph node dissection appears to play an important role in the survival outcomes of patients with SBAs. In a large, retrospective study, Overman et al. found among all patients as much as a 28.8% decrease in 5-year cancer-specific survival for resected SBAs compared to large bowel cancers. However, if more complete nodal dissection is performed with surgical resection of SBA, survival rates are not as discrepant with those of colorectal cancer. Among patients with at least 8 lymph nodes examined, the cancer-specific survival for SBA was 80.3% for stage I, 69.9% for stage II, and 45.1% for stage III disease compared to 93.3%, 85.8%, and 63.6% for large bowel cancers respectively.
Adjuvant Therapy
There is not a clear survival benefit to adjuvant chemotherapy in SBA, but no prospective phase 2 or 3 trials have investigated this issue. In addition, retrospective studies regarding the use of adjuvant therapy in SBA have yielded mixed results. Regardless, the use of adjuvant chemotherapy utilization for patients with SBA has increased from 8.1% in 1985 to 23.8% in 2005, which may be a reflection of clinicians applying the adjuvant data from large bowel cancers to SBAs. Patients are often treated similarly to colon cancer adjuvant therapy recommendations with a fluoropyrimidine combined with oxaliplatin.
In a large, retrospective study, 75 patients who received either adjuvant chemotherapy (n = 34) or chemoradiation therapy (n = 41) were compared to patients with no adjuvant therapy. Patients who underwent adjuvant therapy, chemotherapy, or chemoradiation therapy had a median OS of 35.7 months and a 5-year OS of 39% versus 29.3 months and 36% for patients without adjuvant therapy, respectively (P = 0.44). Although these results were not statistically significant, they do warrant further study of adjuvant therapy for SBA.
Treatment of Metastatic Disease
Surgery
The role of surgical resection is limited to either palliative measures or prevention of bowel obstruction or bleeding in patients with metastatic SBA.
Chemotherapy
There is no clearly established front-line systemic treatment regimen for metastatic disease due to the difficulty of conducting a randomized clinical trial on such a rare disease. Patients with metastatic disease do gain a survival benefit with the use systemic chemotherapy. Retrospective studies have demonstrated patients with stage IV SBA have median OS of 12 to 15.5 months with the receipt of chemotherapy compared to 2 to 7.7 months without treatment.
Metastatic SBA is commonly treated with regimens used in colorectal cancer given their similarities in histology and clinical behavior. Two prospective phase II studies have shown that combination of a fluoropyrimidine with oxaliplatin is both effective and well tolerated. In the study reported by Overman et al. of patients with metastatic or unresectable SBAs, the use of capecitabine and oxaliplatin (CAPOX) showed a median time to progression (TTP) of 11.3 months and a median OS of 20.4 months. Among the patients with metastatic disease only the median TTP was 9.4 months and median OS was 15.5 months.
The use of an oxaliplatin-based regimen for metastatic SBA is also supported by several retrospective studies. The largest of these studies from Japan included 132 patients with unresectable or recurrent SBA who received systemic chemotherapy with either fluoropyrimidine monotherapy, fluoropyrimidine plus cisplatin, fluoropyrimidine plus oxaliplatin, fluoropyrimidine plus irinotecan, or another regimen. Median OS was 13.9 months, 12.6 months, 22.2 months, 9.4 months, and 8.1 months respectively. This study suggests using a fluoropyrimidine combined with oxaliplatin may be associated with survival rates expected in metastatic colorectal cancer. A similar trend was seen in a retrospective study of 93 patients reported by the AGEO group, which reported median OS times of 13.5 months, 17.8 months, 10.6 months, and 9.3 months with the use of fluoropyrimidine monotherapy, fluoropyrimidine plus oxaliplatin, fluoropyrimidine plus irinotecan, and fluoropyrimidine plus cisplatin respectively.
Fluoropyrimidine plus irinotecan is another systemic therapy option for metastatic colorectal cancer and it has also been evaluated for used in SBAs. A small, retrospective study evaluated 28 patients who were treated with FOLFIRI after first-line therapy with a fluoropyrimidine plus a platinum agent. The response rate was 20%, and 52% of patients had disease control 52%. The median PFS was 3.2 months and OS was 10.5 months.
Follow-Up
Patients who have undergone surgical resection for localized disease should have a follow-up visit in the outpatient setting every 3 months to assess for symptoms or signs suggestive of recurrent disease.
■CBC and liver function test results may be checked periodically to identify anemia related to blood loss or abnormal liver enzymes related to hepatic metastases or biliary obstruction, respectively.
■Abdominal CT scan images should be obtained every 6 months to identify subclinical recurrent disease early, which may be amenable to repeat surgical resection.
■Patients with SBA should also undergo colorectal cancer screening (i.e., colonoscopy) because of the high risk of secondary malignancies.
■Patients with advanced metastatic disease may be treated with chemotherapy in an outpatient setting. They should also be observed for hematologic and other toxicity related to chemotherapy.
Complications
■Partial or complete small bowel obstruction may occur because of an obstructing intraluminal tumor. This may be treated either conservatively (i.e., nasogastric tube decompression and parenteral nutrition) or with surgery (i.e., small bowel resection or bypass).
■Intestinal bleeding is common with small bowel sarcomas and may require transfusion support and surgical intervention.
■Biliary obstruction may result from compression of the extrahepatic common bile duct by a periampullary or proximal duodenal tumor. Biliary stenting via endoscopic retrograde cholangiopancreatography or transhepatic biliary drainage may be performed if feasible.
REVIEW QUESTIONS
1.A 54-year-old male underwent surgical resection of a gastric mass found on upper endoscopy as part of a workup for anemia. Pathology revealed a 5.8 cm gastrointestinal stromal tumor with > 10 mitoses per 50 HPF. The next best step in management is
A.Observation
B.Adjuvant radiation therapy
C.Adjuvant chemotherapy with doxorubicin
D.Adjuvant imatinib for 1 year
E.Adjuvant imatinib for 3 years
2.A 67-year-old female presents with progressively worsening diffuse abdominal pain. CT scan reveals a lesion in the ileum as well as multiple peritoneal nodules. Biopsy of one of the peritoneal nodules is consistent with GIST carrying a mutation in exon 9. She was initiated on systemic therapy with imatinib at 400 mg daily and after 3-month repeat imaging showed progression of her disease. What is the next best step in management?
A.Increase the dose of imatinib to 400 mg twice daily
B.Discontinue imatinib and initiate therapy with regorafenib.
C.Discontinue imatinib and initiate therapy with sunitinib.
D.Discontinue imatinib and initiate therapy with doxorubicin plus ifosfamide
3.A 62-year-old male underwent emergent surgery for small bowel obstruction. Pathology reveals a moderately differentiated adenocarcinoma originating in the jejunum. Staging CT scan of the abdomen and pelvis reveals multiple lesions in the liver throughout both lobes of the liver. Biopsy of a liver lesion is also consistent with adenocarcinoma. On surgical consultation he is felt not to be a candidate for resection of the liver lesions. The patient is asymptomatic of the liver disease. What is the next best step in management?
A.Referral to hospice
B.Systemic therapy with 5-fluoruracil
C.Radiation therapy to the liver lesions
D.Systemic therapy with gemcitabine
E.Systemic therapy with a fluoropyrimidine and oxaliplatin
Suggested Readings
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