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Management of Patients With Gastrointestinal Stromal Tumors Treated With Tyrosine Kinase Inhibitors Denise Reinke, MS, NP Sarcoma Nurse Practitioner, Multidisciplinary Sarcoma Clinic University of Michigan Comprehensive Cancer Center President, Sarcoma Alliance for Research Through Collaboration (SARC) Ann Arbor, Michigan

A supplement to Oncology Nursing News May/June 2009 © 2009 Haymarket Media Inc.

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astrointestinal stromal tumor (GIST), while rare, is the most common mesenchymal tumor of the gastrointestinal (GI) tract. GISTs are believed to originate in the interstitial cells of Cajal (ICCs), found in the wall of the GI tract, or in precursor cells that can develop into ICCs. ICCs, socalled “pacemaker cells,” are responsible for initiating and coordinating GI motility.1,2 Although the term “gastrointestinal stromal tumor” was first introduced in 1983, the discovery in 1998 that GISTs can contain mutations of a cell-surface protein, the tyrosine kinase receptor (KIT), marked the beginning of a new understanding and reclassification of sarcomas of the GI tract. GIST is, in fact, a soft-tissue sarcoma. Historically, patients with GIST were often misdiagnosed as having leiomyoma, leiomyosarcoma, or leiomyoblastoma.3 With improved understanding of the molecular characterization of GIST and therefore its correct classification, estimates of its incidence have increased accordingly.4 Previously, surgery was the only viable treatment option for GIST. Chemotherapy was largely ineffective, with poor

GISTs often initially appear as large, heterogeneous masses.

response rates.5 Radiation therapy was often impractical because of the extent and location of the disease. Improved understanding of the molecular mechanisms of GIST has led to a treatment approach employing two oral drugs—imatinib mesylate (Gleevec®) and sunitinib malate (Sutent®)—that has become a model of targeted therapy in oncology.6-8 Understanding the disease and its treatment is important in effectively caring for patients with GIST. To that end, this article discusses the clinical features of GIST, the molecular pathology related to KIT, and the use of imatinib and sunitinib in the treatment of patients with GIST, with a focus on practical nursing considerations in patient education and management.

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GISTs comprise 2.2% of all gastric malignancies, 13.9% of all small intestine malignancies, and 0.1% of all colonic malignancies. Symptoms of GIST are often nonspecific, such as vague gastrointestinal pain or discomfort, leading to the potential for misdiagnosis and under-diagnosis.10 Other symptoms may include anorexia, nausea, or anemia.10 Gastrointestinal hemorrhage occurs in up to 40% of patients.6 Endoscopic ultrasound-needle aspiration, with confirmation of cytologic diagnosis by immunohistochemistry, is now the most common procedure used to diagnose GIST.11 Many primary-care physicians, pathologists, and oncologists go through their entire careers without seeing a single case of GIST. With improved understanding, the appropriate classification of GIST is on the rise. But greater accuracy in diagnosis is far from universal. At present, physicians at major cancer referral treatment centers, especially those with sarcoma teams, 2 A Supplement to Oncology Nursing News

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Mucosa Submucosa Inner muscularis Myenteric plexus Outer muscularis



ISTs are the most common mesenchymal neoplasms of the GI tract.9 Mesenchyme is embryonic connective tissue. Mesenchymal stem cells can differentiate into a variety of cell types. Previously, GISTs were classified as leiomyomas, leiomyosarcomas, leiomyoblastomas, or schwannomas of the GI tract, because they were thought to originate in smooth muscle tissue.7 It is now widely accepted, however, that GISTs arise from mesenchymal stem cells programmed to differentiate into ICCs.9 While GISTs can develop anywhere in the GI tract, from the esophagus to the anus, they are found primarily in the stomach and small intestine.10 There is consensus that the word "benign" not be used to describe any GIST.4 Approximately 50% of primary localized GISTs relapse within the first 5 years.4 What distinguishes GIST as a unique clinical entity is the KIT proto-oncogene mutations in the tumor.9 Most GISTs (85%-90%) are KIT-positive.10

FIGURE 1. Gastrointestinal tract. The highest density of interstitial cells of Cajal (ICCs) is between the inner and outer layers of the muscularis propria, which is ultimately associated with nerves and ganglion cells of the myenteric plexus. Individual ICCs are also scattered throughout the muscle layers, transmitting signals from the nerves to the muscle cells to effect peristalsis.

are most likely to be familiar with GIST and its treatment.12 It is important that clinicians and nurses in private practice understand how to recognize the disease so that prompt, appropriate treatment can be initiated.

Incidence and Prevalence

While GISTs remain rare, with the advent of immunohistochemical staining techniques and ultrastructural evaluation that improve detection, the number of diagnoses for GIST is increasing.13 Adult population: There are over 50 subtypes of sarcomas, which represent about 1% of all adult cancers. In 2008, approximately 4,500 to 6,000 adults in the United States will be diagnosed with GISTs, about 1,500 of which will have metastasized at the time of initial diagnosis.2 Few large epidemiologic studies have been conducted to estimate the incidence and prevalence of GIST. One of the first US population-based studies to evaluate the incidence and survival of malignant GIST found an age-adjusted yearly incidence rate of 6.8 per million population, based on 1,458 cases diagnosed between 1992 and 2000.14 Risk factors for mortality included older age, African-American race, advanced stage at diagnosis, and no surgical intervention.14 Using modern histopathologic methods, Swedish investigators reevaluated a series of intra-abdominal sarcomas and estimated the incidence of GIST to be 14.5 cases per million population,15 equating to about 5,000 new cases annually in the US.4 The higher rates are linked to the inclusion of small, low-risk GISTs.

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Most GISTs occur in adults aged 50 years and older and are more common in men than in women.16 There is no conclusive evidence to associate GIST with any particular race or ethnic background. GISTs can arise anywhere along the GI tract but are most common in the stomach (50%) and small bowel (25%).17 Other sites include the large bowel, rectum, appendix, and esophagus, with rare occurrence in extra-intestinal sites such as the gallbladder, omentum, and mesentery.18 GISTs comprise 2.2% of all gastric malignancies, 13.9% of all small intestine malignancies, and 0.1% of all colonic malignancies.19 Gastric GIST has a better prognosis than extragastric GIST.20 The common metastatic sites for GIST include the liver and omentum, less frequently the lung, and rarely the regional lymph nodes and bone.17 Pediatric population: The genotype of most GIST in pediatric patients is “wild type,” which has no detectable KIT or platelet-derived growth factor-alpha (PDGFRα) mutations.21 Most cases of pediatric GIST occur in the stomach and these generally involve multiple tumor nodules. Compared with adults with GIST, pediatric patients with GIST are more likely to have lymph node involvement, are more likely to have tumors that recur in the original location, and are less likely to have metastatic disease; when metastasis does occur, the most frequent site is the liver. Disease course is more indolent among the pediatric population. Pediatric GIST is more common in females than in males.22,23

Pathogenesis of GIST

No known environmental or behavioral risk factors are believed to contribute to development of GIST; in fact, the only known risk factor for GIST is family history, which imparts a very small increase in risk of developing the disease.16 The apparent cause of GIST is random genetic mutations in one of the receptor protein tyrosine kinases (KIT, also called CD117).11 Approximately 85% to 95% of GISTs are KIT-positive. A mutation in exon 11, 9, 13, and 17 of the KIT gene is observed in 66%, 13%, 1%, and 0.6% of tumors, respectively.18 About 5% of GISTs have mutations in the PDGFRα genes and express little or no KIT.24 Within the PDGFRα gene, mutations of exon 18 or 12 are observed in 5% and 1.5% of cases.18 GISTs occurring during childhood have a lower incidence of KIT and PDGFRα gene mutations.25 Pediatric GISTs tested for gene mutations found wild-type for KIT22,23,26 and one case of a mutant exon 9.23 Those with inactivation of the neurofibromatosis 1 gene are more likely to develop GIST than the general

population and are more likely to be diagnosed at younger ages. Familial GIST also develops in younger or middle-aged adults.27 (See Inheritable Germ-Line Mutations below.)

Malignant Potential of Primary GIST

Malignant cells in GISTs are thought to arise from the ICCs (Figure 1) or from a cell in that lineage. Many factors have been evaluated in estimating the metastatic risk of primary GIST; the two most predictive appear to be the size of the tumor (greatest diameter) and the number of mitoses per high-power field, as measured by light microscopy.4 The true malignant activity of these tumors is unpredictable, however, as even small tumors (<1 cm) may recur 10 years or more after diagnosis.28

Diagnosis Of GIST


ymptoms of GIST are often vague and nonspecific. In patients with clinically significant GIST, symptoms may include early satiety, bloating, gastrointestinal bleeding, or fatigue related to anemia.10 GIST may also present as an abdominal mass, hemoperitoneum, anemia, perforation, or incidentally.25 The most common clinical manifestations of malignancy are liver metastases and/or dissemination within the abdominal cavity.10 Lymph node metastases are

INHERITABLE GERM-LINE MUTATIONS Hereditary gastrointestinal stromal tumor (GIST) is quite rare. Reports in the medical literature have identified only about 16 families of different ethnic origins worldwide with hereditary GIST.29 Each family with hereditary GIST may have its own unique germ-line mutation in a cancer susceptibility gene. Both the KIT and platelet-derived growth factor-alpha (PDGFRα) genes are involved in hereditary GIST. Not every family member with hereditary GIST will inherit the familial mutation. Other cancer susceptibility genes not yet discovered may also be associated with GISTs.16 There is currently no consensus on the most appropriate screening for individuals with a germ-line mutation in a GIST-susceptibility gene who have not developed a GIST. Surveillance should be tailored to the individual patient by the primary healthcare provider.

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n Management of Patients With GIST Treated With Tyrosine Kinase Inhibitors

TABLE 1. Rationale for Laboratory Studies for GIST



Complete blood count (CBC)

• Screen for anemia

Serum chemistries

• Determine organ function from GIST or another disease

Liver function tests: bilirubin, transaminase, alkaline phosphatase

•G  IST metastases commonly involve the liver

Electrolyte metabolism

•C  onduct follow-up testing 1-3 months while on therapy

Source: Mukherjee3; Berman et al.30

extremely rare, and metastases in the lungs and other extra-abdominal locations are observed only in advanced cases.10 The National Comprehensive Cancer Network (NCCN) recommends that all patients be managed by a multidisciplinary team with expertise in sarcoma. Patient workup should include history, physical examination, abdominopelvic computed tomography (CT) scan with contrast and/or magnetic resonance imaging (MRI), chest imaging, endoscopic ultrasound, endoscopy as indicated (if not previously done), and surgical assessment.10

Laboratory Testing

No known serum tumor markers exist for GIST.3 Baseline serum chemistries are useful to determine

whether a patient has organ involvement from GIST or another disease and as a benchmark prior to initiation of therapy. A complete blood count will detect anemia that may be a result of blood loss from intratumoral or transmucosal hemorrhage, anemia of chronic disease, or a combination of these mechanisms (Table 1).

Imaging Studies

Imaging techniques to evaluate GIST include endoscopy, endoscopic ultrasonography, CT, and MRI.25 Endoscopy: The local extent of a small tumor found incidentally during endoscopy should be evaluated using endoscopic ultrasonography.25 CT: Contrast-enhanced CT scan is currently the imaging modality of choice for patients with suspected abdominal mass or biopsy-proven GIST, both for staging and for surgical planning.25 (Figure 2). MRI: For rectal GIST, MRI provides better preoperative staging information than CT scan.25

Image courtesy of Jonathan C. Trent, MD, PhD


FIGURE 2. GISTs often initially appear as large, heterogeneous masses. 4 A Supplement to Oncology Nursing News

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Deciding whether to obtain a biopsy is based on the extent of disease and degree of suspicion of other malignancies. GISTs are soft and fragile; therefore, biopsy may cause the tumor to hemorrhage or possibly increase risk of tumor dissemination.10 Endoscopic ultrasound biopsy is preferred over percutaneous biopsy.10 A diagnosis of GIST relies on standard histological examination of the tumor material.25 The pathology report generally includes tumor size and mitotic rate; if available, molecular analysis can be conducted. A differential diagnosis of GIST is generally considered for any gastrointestinal or other intraabdominal sarcoma.10 Expert pathology evaluation of the biopsy or resected mass with staining of the pathologic specimen for the CD117 antigen (reflecting the KIT receptor tyrosine kinase) is recommended.10

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Treatment of GIST


Image courtesy of Denise Reinke, MS, NP

any patients with GIST may only have a localized disease at the time of diagnosis. Some patients however, will already have metastases. Initial treatment will depend on several factors, including whether the patient has metastases, the expected difficulty of the surgery, the size of the primary tumor, and the general health of the patient.2

Fluorine-18-fluorodeoxyglucose positron emission tomography

FIGURE 3A: Normal liver.

Image courtesy of Denise Reinke, MS, NP

Most metastases arise in the liver and peritoneal cavity, while pleural lung or lymph node metastases are rare (<10%) (Figure 3A and Figure 3B). Evaluation of fluorine-18-fluorodeoxyglucose (18FDG) uptake using positron emission tomography (PET) scan is recommended only when early detection of tumor response to imatinib treatment is required for purposes of planning surgery or response evaluation is equivocal (Figure 4A and Figure 4B).31,32


FIGURE 4A. Pre-imatinib: A PET scan revealed uptake of 18 FDG by the GIST. May/June 2009

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Image courtesy of Jonathan C. Trent, MD, PhD

FIGURE 3B: Liver with metastatic GIST.

Image courtesy of Jonathan C. Trent, MD, PhD

Surgery is the standard of care for localized or potentially resectable GIST. The goal is complete removal of the tumor.16 Surgery is recommended if bleeding and/or symptoms are present.10 Complete resection is possible in about 85% of patients with primary tumors; 50% of those individuals will develop recurrence or metastasis. Five-year survival rate is approximately 50%.33-35 For those who develop recurrence after resection of primary high-risk GIST, median time to recurrence is about 2 years.10 Neoadjuvant therapy: Preoperative treatment with imatinib may be considered if, by reducing the tumor size, surgical morbidity could be improved. Patients with marginally resectable or resectable GIST lesions with risk of significant morbidity may be treated with imatinib, with careful monitoring. Although PET scans allow rapid assessment of imatinib therapy, they are not a substitute for CT scans. Baseline CT scans with or without MRI followed by subsequent PET scans approximately 2 to 4 weeks following treatment with imatinib may be helpful to assess therapeutic effect. If GIST has not progressed, resection may be considered.10 Adjuvant therapy: Interim results of a large randomized trial in patients who had resection of primary GISTs found that postoperative adjuvant imatinib (400 mg/ day) improved recurrence-free survival (97%) compared

FIGURE 4B. 18FDG completely abrogated after only 3 days of therapy.

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n Management of Patients With GIST Treated With Tyrosine Kinase Inhibitors

Case Study 1 FOSTERING LONG-TERM COMPLIANCE WITH ORAL THERAPY for gist With an increasing number of therapeutic options for cancer patients available in oral formulation, nurses are faced with a challenge they did not face when administering infusion therapy: that of assisting patients to establish regimen routines that foster compliance, especially for daily oral therapy that is required to be taken long term.

INITIAL PRESENTATION A 76-year-old man presents with abdominal cramping, vomiting, and bloating strongly suggestive of small bowel obstruction. Diagnosis and Treatment The patient undergoes an exploratory laparotomy for surgical management of the small bowel obstruction at a local community hospital. A 10-cm mass is removed. Pathology reveals a gastrointestinal stromal tumor (GIST) of the proximal small bowel. While most of the pathology is benign, mixed elements are noted to be malignant. The sample is strongly positive for tyrosine kinase receptor (KIT) mutation. No additional therapy is advised at the time. The patient is thereafter regularly evaluated for recurrent/metastatic disease. He does well for nearly 2 years, until a computed tomography scan of the abdomen reveals small, lowattenuation hepatic lesions that are more conspicuous than they were at initial presentation and are suspicious for metastatic foci. Given the number and appearance of the lesions, metastatic GIST is determined to be the most likely cause and imatinib mesylate (Gleevec) therapy is initiated at a dose of 400 mg po daily. Follow-up The patient remains on 400 mg of imatinib for 5 years, with evaluations every 3 months that include a physical exam, laboratory studies (complete blood count and chemistry studies), and imaging of the abdomen and pelvis. Over the years, he experiences some side effects with imatinib therapy, which vary from intermittent loose stools (as many as 5 per day), to mild periorbital edema (grade 1), to moderate fatigue (grade 2). Overall, he is pleased that his disease is controlled with an oral agent; however, he periodically expresses frustration with the continued need for vigilance and therapy. On some days, the side effects are particularly disruptive. As a result, he contemplates discontinuing therapy for a few days, a week, or a month just to take a break and regain some semblance of his prior life. At a nurse’s suggestion, the patient becomes involved in an online support group. There, he encounters members whose disease eventually does progress, a reminder of his own need for continued therapy. But he feels conflicted and anxious. On one hand, he would like to be free of the medication and its side effects; on the other, he fears the potential for tumor growth and further spread of his disease. Discussion Explaining the rationale for dosing and timing of oral medication can help patients understand the importance of compliance to treatment efficacy. The patient must be enlisted as an active participant in his or her care in order to ensure proper dosing. While nurses fully control infusion dosing and timing, patients on oral therapy must establish a routine to ensure that dosing is performed according to the prescribed schedule without a nurse’s supervision. Nurses can provide patients with such tools as medication diaries, day/time-marked pill boxes, or electronic reminders (ie, watch alarms) to help them remember to take their medication as prescribed. Patients with computers can also use software schedulers for this purpose— or as reminder backups. Patients are often required to take the prescribed oral therapy for years. For some, needing to receive therapy for an extended period of time can be frustrating. They may grow weary of the constant reminder of their illness and long to be free of their disease and its treatment. The nurse who is aware of this possibility can provide an opportunity for patients to discuss such feelings. Simply having someone listen may have a therapeutic effect. Patients may also derive much-needed understanding and empathy by communicating with fellow patients with the same condition. Providing information on GIST support groups may give a patient the support necessary to continue with therapy. (See Resources for Patients With GIST on page 15.) Despite his nurses’ attempts to counsel him on the importance of his treatment, and despite joining a support group, the patient described above continues to express occasional frustration with being on daily long-term oral therapy. He acknowledges, however, that living more than 8 years with a disease that, until recently, had a poor prognosis, is a sufficiently compelling reason to take his medication when and as prescribed.

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Image courtesy of Jeffrey D. Wayne, MD

Image courtesy of Jeffrey D. Wayne, MD


FIGURE 5A: CT shows a 3.5 x 2.2 cm soft tissue mass of the duodenum. Endoscopic ultrasound-guided fine needle aspiration biopsy confirmed the mass to be a GIST.

FIGURE 5B: After 6 months of imatinib, the mass had decreased in size to 2.7 x 2.3 cm and was deemed resectable.

with placebo (83%).36 Based on these results, adjuvant treatment with imatinib is recommended as an alternative to observation after complete resection for primary GIST. Although optimum treatment duration has not yet been determined, patients with intermediate to high-risk GIST should receive imatinib for at least 12 months, with higher risk patients or those with persistent gross disease following resection receiving the drug for a longer period.10 There are ongoing studies to evaluate the optimal duration of adjuvant treatment. Continuous use of imatinib is recommended for metastatic GIST until disease progression. If imatinib therapy is interrupted, there may be an increase in the rate of progressive disease.37

ties, as it inhibits both the vascular endothelial growth factor receptor and the KIT receptor, respectively. Other agents: Other multitargeted tyrosine kinase inhibitors with high affinity for PDGFRα and KIT— eg, nilotinib, sorafenib, and dasatinib—are in early phase clinical trials. Such molecules were shown to be useful in imatinib-resistant mutant cell lines and the results of their activity in humans are being awaited.40

Targeted Therapy

GISTs have been shown to be resistant to conventional chemotherapies. Since KIT activation occurs in the majority of cases of GIST, KIT inhibition with tyrosine kinase inhibitors has emerged as an effective treatment for GIST.10 Imatinib: The US Food and Drug Administration (FDA) has approved imatinib for the treatment of patients with KIT-positive unresectable and/or metastatic malignant GIST, as well as for the adjuvant treatment of adult patients following resection of KIT-positive GIST38 (Figure 5A and Figure 5B). Sunitinib: The FDA has approved sunitinib for the treatment of GIST after disease progression on, or intolerance to, imatinib.39 Sunitinib potentially possesses both antiangiogenic and anti-oncogenic proper-

While GISTS are resistant to conventional chemotherapies, KIT inhibition with tyrosine kinase inhibitors has emerged as an effective treatment. Enrollment in Clinical Trials

Patients who have progression of GIST despite prior therapy or who have a recurrence should be considered candidates for enrollment in a clinical trial, if available.10 At the National Cancer Institute Web site (, educational material can be found on what clinical trials are, how they work, why they are useful, patient care costs, and more, as well as a searchable listing of more than 6,000 clinical trials of all types now accepting participants. May/June 2009

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n Management of Patients With GIST Treated With Tyrosine Kinase Inhibitors Prognostic Factors for Recurrence

The three major histologic subtypes characteristic of GIST are spindle cell (70%), epithelioid (20%), and a mixed subtype (10%).32 Prognostic factors for recurrence of GIST based on tumor site, mitoses per highpower field using light microscopy (mitotic index), and tumor size are summarized in Table 2.

Patient Education and Management


CCN has published evidence-based practice guidelines for the diagnosis, staging, treatment, and follow-up of patients with GIST as reviewed in this ar-

ticle ( PDF/sarcoma.pdf).10 Prior to initiation of therapy with an oral tyrosine kinase inhibitor, patients should be instructed in proper drug administration, side effects that can be expected, and how best to manage them.


Imatinib: For first-line treatment, imatinib 400 mg to 600 mg per day is currently recommended. A dose increase up to 800 mg/day (given as 400 mg twice daily) may be considered, as clinically indicated, in patients showing clear signs or symptoms of disease progression at a lower dose and in the absence of severe adverse drug reactions. For the adjuvant treatment of adult patients following complete gross resection of GIST, the recommended dose of imatinib is 400 mg/day.38 Adverse

TABLE 2. Risk of Recurrent GISTa

Mitotic Index (HPF)b ≤5/50


Tumor Size (cm)





≤2 >2 to ≤5 >5 to ≤10 >10 ≤2 >2 to ≤5 >5 to ≤10 >10

0% 1.9% 3.6% 10% Noned 16% 55% 86%

0% 4.3% 24% 52% Noned 73% 85% 90%

0% 8.3% NDc 34% NDc 50% NDc 86%

0% 8.5% NDc 57% 54% 52% NDc 71%

Data based on long-term follow-up of 1,055 gastric, 629 small intestinal, 144 duodenal, and 111 rectal GISTs. a Median follow-up (range: 1-175 months). b High-power field; ≤5/50 = ≤5 mitoses per 50 high-power field. c Not determined. d Denotes small number of cases. Source: Corless et al.41

TABLE 3. Management of Adverse Events With Imatinib

Adverse Event



• Take with food and at least 8 ounces of water 6 • Change the time of day imatinib is taken 6


• Do not repeat imatinib dose 6 • Take with food and at least 8 ounces of water 6 • Change the time of day imatinib is taken 6 • Antiemetic such as prochlorperazine (10 mg as needed every 6-8 hours) 6


• Take with food and at least 8 ounces of water 6

GI irritation38

• If history of esophagitis or hiatal hernia, take imatinib at least 2 hours before bedtime 6


• Take with food and at least 8 ounces of water 6 • Loperamide 4 mg initially, then 2 mg after each loose stool (total daily maximum dose: 16 mg) 6 • Metamucil taken 2-3 times daily if severe 6


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n TABLE 3. Management of Adverse Events With Imatinib (continued)

Adverse Event


DERMATOLOGICAL Skin discoloration38

• Proper counseling to prepare for possible occurrence 6 • Sun block to prevent further skin irritation 6

Cutaneous reactions38

• Skin should be well-moisturized at all times during course of imatinib treatment 6

Mild to moderate 38

• Antihistamines, topical preparations 6 • Topical or short-course oral glucocorticoids if inadequate response 6

Severe (eg, Stevens-Johnson syndrome) 38

• Stop imatinib 6 • May restart imatinib upon resolution of desquamative rashes if no alternative treatments for GIST available 6

HEMATOLOGICAL Myelosuppression (anemia, neutropenia, thrombocytopenia)38

• Rare 6 • Myeloid growth factors (eg, granulocyte-colony-stimulating factor, granulocytemacrophage-colony-stimulating factor) or erythropoietin may be considered 6 • Minimize invasive procedures, use of aspirin, and activities that increase risk of bleeding or infection , and avoid shaving6

Absolute neutrophil count (ANC) less than 1 x 109/L and/or platelets less than 50 x 109/L 38

• Stop imatinib until ANC at least 1.5 x 109/L and platelets at least 75 x 109/L 6,38 • Resume imatinib treatment with original starting dose 400 mg/d or 600 mg/d 6,38

Recurrence of ANC less than 1 x 109/L and/or platelets less than 50 x 109/L 38

• Stop imatinib until ANC at least 1.5 x 109/L and platelets at least 75 x 109/L 6,38 • Resume imatinib treatment at reduced dose (300 mg if starting dose of 400 mg, 400 mg if starting dose of 600 mg) 6,38

Hepatic Liver function abnormalities (transaminases, bilirubin, alkaline phosphatase) 38

• Dose reduction if severe 6 • Permanent cessation of imatinib therapy seldom necessary 6 • Monitor at baseline and monthly 38

Mild (total bilirubin greater than 1.0-1.5 x ULN) to moderate (total bilirubin greater than 1.5-3 x ULN) hepatic impairment 38

• No dose reduction necessary 38

Severe hepatic impairment (total bilirubin greater than 3-10 x ULN or transaminases greater than 5 x ULN) 38

• Withhold imatinib until total bilirubin less than 1.5 x ULN or transaminases less than 2.5 x ULN 38 • Continue at reduced daily dose 38 – Adults: 400 mg to 300 mg 600 mg to 400 mg 800 mg to 600 mg – Children: 3 40 mg/m2/d to 260 mg/m2/d 260 mg/m2/d to 200 mg/m2/d

Others • Have patient measure weight periodically and report weight gain of 5 pounds or more to nurses or physicians 6 • Limit salt intake 6 • Diuretic therapy if fluid retention is a concern 6



Muscle cramps 


• Increase fluid intake and daily exercise 6 • Daily multivitamin, calcium, magnesium supplements (eg, Tums), or quinine if muscle cramps still not relieved 6

Sources: Griffin et al 6; Gleevec.38

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IMATINIB: POTENTIAL DRUG INTERACTIONS • CYP3A4 Inhibitors (may increase plasma imatinib concentration)

Atazanavir, clarithromycin, grapefruit juice, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole

• CYP3A4 Inducers (may decrease plasma imatinib concentration)


• CYP3A4, 2C9 Substrates (imatinib may alter plasma concentration)

Alfentanil, cyclosporine, dihydroergotamine, dihydropyridine calcium channel blockers, ergotamine, fentanyl, pimozide, quinidine, simvastatin and certain other hydroxymethylglutaryl coenzyme A reductase inhibitors, sirolimus, tacrolimus, triazolo-benzodiazepines, warfarin (low-molecular weight or standard heparin should be used instead)

SUNITINIB: POTENTIAL DRUG INTERACTIONS • CYP3A4 Inhibitors (may increase plasma sunitinib concentration; therefore, dose should be decreased by 12.5 mg)

Atazanavir, cimetidine, clarithromycin, grapefruit juice, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole

• CYP3A4 Inducers (may decrease plasma sunitinib concentration; dose should be increased by 12.5 mg)

Carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, rifampin, St. John’s wort

Source: Sutent.39

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Drug Interactions

Any medications currently being taken by a patient, including prescription drugs, over-the-counter medications, herbal remedies such at St. John’s wort, and vitamins should be reviewed prior to starting treatment with a tyrosine kinase inhibitor to reduce the potential for drug-drug interactions.7 Imatinib and sunitinib are metabolized primarily by the cytochrome P450 enzyme, CYP3A4.38,39 (See Imatinib: Potential Drug Interactions, top left, and Sunitinib: Potential Drug Interactions, bottom left.) Exposure to acetaminophen is increased when administered with imatinib.38

Adverse Events

Source: Gleevec.38

effects can usually be managed. Caution is needed when administering with agents that may lead to subtherapeutic plasma concentrations of imatinib or increased exposure of the other agent.6 Sunitinib: Recommended dosage of oral sunitinib is 50 mg once daily for 4 weeks with or without food, with 2 weeks off.39 When co-administered with a strong CYP3A4 inhibitor (eg, ketoconazole), dose reduction should be considered; conversely, with a CYP3A4 inducer (eg, rifampin), the dose should be increased. Reductions or increases in 12.5 mg increments are recommended.7


Adverse events associated with imatinib and sunitinib are generally moderate and most often are tolerable in light of the significant improvement of the disease for most patients with GIST. Imatinib: Nausea, vomiting, dyspepsia, and diarrhea occasionally occur with imatinib treatment but can be minimized if the drug is taken with food and at least 8 ounces of water. Antiemetics such as prochlorperazine or loperamide for diarrhea may be recommended. Edema is a commonly reported side effect and is noted in the periorbital region. Most cutaneous reactions consist of a mild focal or generalized rash or dermatitis that is usually self-limiting and manageable. Skin may be dry and patients may bruise easily; therefore, skin should be well moisturized. Lightening of the skin tone is to be expected6 (Table 3). Sunitinib: Fatigue, diarrhea, nausea, vomiting, and stomatitis are common emergent adverse events associated with sunitinib. Dermatologic effects such as skin discoloration (yellow, perhaps from the drug’s color); dryness, thickness, and cracking; blisters; and rashes on the palms of the hand and soles of the feet (palmarplantar erythrodysesthesia or hand-foot syndrome) can also occur. Patients may be given a 5HT3 serotonin

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Case Study 2 ORAL THERAPY FOR GIST MAY BE DISCONTINUED DUE TO ADVERSE EVENTS After surgery for gastrointestinal stromal tumor (GIST), adjuvant imatinib mesylate (Gleevec) therapy is recommended because of its potential to reduce the risk of recurrence, including metastasis, which otherwise is high. However, when a patient experiences intolerable side effects, particularly when postoperatively the disease is asymptomatic, the patient may decide to discontinue the treatment regimen intermittently or altogether. This is when the role of the oncology nurse can be crucial.

Initial Presentation A 47-year-old woman presents with abdominal cramping and constipation. Diagnosis and Treatment The patient’s medical history suggests a possible pelvic mass, which is palpable on physical examination. As a result, she undergoes an exploratory laparotomy. During the procedure, the mass cannot be distinguished from the bowel or adnexal organs. An abdominal incision reveals a small bowel tumor that is large, hemorrhagic, and appears to be necrotic. The tumor is attached to and invading the bladder wall at the fundus. A small bowel resection with primary anastomosis and bladder wall resection is performed. On the patient’s postoperative visit, she learns that the tumor pathology is consistent with GIST. Referred to a regional sarcoma center for evaluation and treatment, an oncologist recommends adjuvant imatinib due to the high risk of recurrent disease without further intervention. An initial dosage of 400 mg po daily is prescribed. The patient lacks health insurance coverage for the drug. However, once the patient learns about such assistance from an oncology nurse, she is able to obtain the medication affordably. (See Where to Obtain Financial Assistance on page 15.) A repeat computed tomography (CT) scan of the abdomen and pelvis is recommended every 8 weeks. Follow-up Despite reminders from an oncology nurse, the patient is 2 weeks late for her next follow-up appointment. At that time, she complains of fatigue and diarrhea when taking imatinib. Use of loperamide HCl (Imodium) prn and dietary changes to minimize GI side effects are suggested, as are strategies to manage fatigue. Despite this, the patient elects to discontinue imatinib therapy, even though the risk of recurrent disease is reiterated by her doctor. Informed consent is obtained in writing. During the subsequent 18 months, her CT scans are normal. Her most recent CT scan, however, shows a lesion in her liver, and CT-guided biopsy reveals metastatic GIST. Imatinib 400 mg po daily is re-initiated. At her 4-week follow-up visit, the patient complains of intermittent abdominal discomfort and mild fatigue, but no nausea, vomiting, or diarrhea. Two years later, a CT scan of her abdomen and pelvis shows stable liver lesions that have undergone cystic degeneration when compared with her initial image. Discussion Intolerable side effects can lead to intermittent dosing of medication—or no dosing—depending on the severity of the side effects and the ability of the patient to manage them so that daily activities can be continued. Oncology nurses can help patients identify strategies for managing side effects so that potentially life-saving therapy is not abandoned. This is especially important when adjuvant imatinib is prescribed, because the patient may believe that the surgery has cured the disease and therefore additional treatment is excessive and unnecessary, particularly when it is discomfiting. The patient therefore needs to understand that the benefit of continuing therapy outweighs any discomfort. However, strategies for managing a side effect can often be tailored to individual needs. Nurse and patient can collaborate to select strategies that have the greatest potential to foster compliance. As nurses do not have the same time or venue for interacting with patients on oral therapies as they do when administering intravenous therapy, such interaction may now need to occur at the end of an office visit or via phone in order to educate the patient on side effect management. Limited time requires the nurse to have clear, direct information to offer, as well as the skill to assess the understanding, ability, and willingness to implement a particular strategy by patient and family. Once the patient described above was made to understand that successful surgery for GIST is not necessarily synonymous with being cured, and that continuing with imatinib therapy might prevent a disease with a high rate of recurrence from reappearing and metastasizing, she was able to summon the inner strength to work through any side effects and take her medication as prescribed.

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n Management of Patients With GIST Treated With Tyrosine Kinase Inhibitors

TABLE 4. Management of Adverse Events with Sunitinib

Adverse Event



• 5HT3 serotonin receptor antagonist7


• 5HT3 serotonin receptor antagonist7


• Loperamide7


• Brush, floss, and rinse with a saline or sodium bicarbonate solution after each meal and at bedtime



• Anti-hypertensive therapy when needed39 • Avoid non-dihydropyridine calcium channel blockers, such as verapamil and diltiazem, because of known inhibition of CYP3A442 • Temporary suspension of sunitinib if severe hypertension (greater than 200 mm Hg systolic or 110 mm Hg diastolic) until blood pressure is controlled39

Left ventricular dysfunction39

• Discontinue sunitinib if clinical manifestations of congestive heart failure39 • Discontinue sunitinib if ejection fraction is less than 50% and more than 20% below baseline39

QTC prolongation and torsade de pointes39

• Consider periodic monitoring with on-treatment electrocardiograms and electrolytes (magnesium, potassium)39

DERMATOLOGICAL Skin discoloration39

• Proper counseling that occurrence is possible7


• Moisturizing skin lotions or creams42 Papulopustular 43

• Topical clindamycin or corticosteroid43

Seborrheic-dermatitis-like 43

• Topical antifungals (ketoconazole 2% cream, ciclopirox 1% cream) or corticosteroid creams/ shampoos (fluocinonide 0.05% shampoo)43

Xerosis 43

• Use gentle soaps and topical creams or ointments43

Hand-foot syndrome39

• Apply moisturizing cream to affected areas liberally throughout the day7 • Apply multiple layers of sunscreen7 • Analgesics for further relief  7 • Apply ice packs or immerse hands and feet in cool water7 • Avoid pressure, friction, direct exposure to sunlight7 • F oot and hand-care products such as gel pad inserts, soft shoes, cotton gloves42,43 • Dose reduction if grade 3 or greater according to National Cancer Institute grading for hand-foot syndrome7

Other Bleeding39 (most commonly epistaxis7)

• Discontinue sunitinib for 2 weeks prior to any surgical procedure7

Sources: MacIntyre7; Sutent 39; Hutson42; Rosenbaum.43

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receptor antagonist for their nausea and vomiting and loperamide for diarrhea. An oral care protocol can be used to prevent or minimize effects of oral mucositisâ&#x20AC;&#x160;7 (Table 4).

Compliance With Oral Therapy

Oral formulations of treatment are increasingly used to treat patients with cancer,44 with patient preference for

Case Study 3 A COSMETIC ISSUE THREATENS COMPLIANCE WITH ORAL THERAPY FOR GIST Therapy with imatinib mesylate (Gleevec) can be associated with various adverse events, ranging from minor annoyances to more serious and disruptive side effects. One common side effect is fluid retention, including periorbital edema. For some patients, even those who stoically endure other side effects such as nausea, diarrhea, and fatigue, periorbital edema can be a make-orbreak issue in compliance with the medication regimen, because it can alter physical appearance in unpleasant ways.

oral chemotherapy one of the main drivers for its popularity.45 Oncology nurses have the opportunity to provide individualized patient support and patient and family education on their oral therapy, including managing adverse reactions.44 Potential advantages of oral therapy in cancer treatment include a sense of control, reduced interference with daily work and social activities, less travel time (and costs) associated with travel to an infusion

Initial Presentation A 61-year-old woman, who was initially diagnosed with a low-grade leiomyosarcoma 13 years earlier, presents with a peripancreatic mass biopsy-proven to be metastatic gastrointestinal stromal tumor (GIST). Diagnosis and Treatment Following her resection, the patient is enrolled in a clinical trial and randomized to receive imatinib 400 mg po bid. In the previous 8 years, she had one febrile episode, for which she was hospitalized; at this time, her liver enzymes were noted to be elevated. Repeat laboratory tests at 24 hours revealed normalization of the liver enzymes, and she became afebrile. She was discharged with a diagnosis of cholangitis. A 10-day episode of intractable diarrhea with greater than 6 stools per day spontaneously resolved. She has had no further problems. Her primary complaint during her treatment with imatinib is periorbital edema, a bothersome cosmetic issue. She believes it makes her look sad and tired, is noticed by friends and family, and is a constant reminder of her illness. Follow-Up A computed tomography scan of the abdomen and pelvis shows multiple welldefined hepatic lucencies. Follow-up visits are scheduled at 3-month intervals, and the patient is encouraged to call her doctor or nurse with any questions or problems. Discussion Treatment side effects that result in visible alteration in physical appearance can be distressing as patients attempt to continue their normal activities and interact with family, friends, and coworkers. Side effects are part of any chemotherapy. Imatinib therapy, for example, can result in varying degrees of periorbital edema, which can alter a personâ&#x20AC;&#x2122;s appearance. Mild edema can result in an individual appearing tired and haggard; severe edema can interfere with clear vision and cause unsightly swelling around the eyes. That can lead to noncompliance with oral therapy. The oncology nurse can lessen the impact of side effects by informing the patient that they may occur and by offering strategies to minimize them. Periorbital edema associated with imatinib therapy can be minimized by sleeping with the head of the bed raised, or by elevating the head with pillows to decrease dependent positioning. Most patients will eventually adjust to their changed appearance. Recognition of the life-saving potential of imatinib therapy usually helps to put cosmetic changes into perspective. Nonetheless, it can be a distressing and frustrating experience. Nurses should anticipate such negative reactions and permit patients to talk through their feelings and reaffirm treatment goals. Listening and empathizing can have a therapeutic effect. The patient discussed above is a case in point. She voiced a wish to discontinue imatinib on several occasions due to periorbital edema. At each contact, however, whether in person or by phone, a nurse took the time to listen to her complaints and to show compassion and empathy. The patient was also instructed to elevate her head in bed at night to minimize the swelling around her eyes. It is not a perfect solution. The patient still has some mild edema and still complains about it from time to time. But consider the big picture. To date, she has been on imatinib therapy for 8 years without interruption, and her disease has remained stable. Good nursing had a role in that.

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clinic, and reduced discomfort of an IV line insertion.44 A significant barrier to the effective use of oral agents is suboptimal compliance with oral therapy.45 This exists for two reasons: optimal compliance is dependent on patients self-administering the medication at the prescribed dose and schedule and patients knowing when to seek advice for the management of adverse effects. Therapeutic drug monitoring, or blood level testing, is critical for oral oncology drugs and will help determine if a patient

Factors Associated With Nonadherence to Oral Regimens • Misinterpretation of physician instructions • Denial • Forgetfulness or confusion • Polypharmacy syndrome • Distraction by competing priorities (eg, patients caring for ill spouse) • Cost of the medication • Dosing frequency • Adverse effects • Demands of employment • Insufficient family and friend support systems • Avocations, such as travel Source: Moore.44

Promoting Patient Adherence to Oral Medications • Provide an oral medication calendar • Provide patients with a diary to record dose and instruct them in its use • Provide pill boxes • Count pills at each patient visit • Request that patients return unused medication at the end of treatment • Ensure thorough patient teaching • Provide contact information regarding who and when to call • Keep an updated list of patient-assistance Web sites and phone numbers • Standardize printed prescription pads • Double check the height, weight, body surface area, diagnosis, and cycle number • Encourage patients to meet with an office pharmacist Source: Winkeljohn.48

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is nonadherent to therapy, is experiencing side effects that seem severe for the dose, or is experiencing a drugdrug interaction. In contrast with IV agents, oral agents are more susceptible to intrapatient and interpatient variability in absorption, bioavailability, and adherence.46,47 Several factors may contribute to noncompliance (See Factors Associated With Nonadherence to Oral Regimens, top left). Patient and family education should occur when the patient and family are calm and ready to hear new information—ideally, a day or two after the oncologist has discussed a new treatment plan with the patient. The goal is to discuss and reinforce key points and answer questions. A medication diary that includes written information individualized to the patient’s regimen, dose, and administration of medication is an effective tool to promote compliance and self-administration. Patients should be assessed for literacy level, physical limitations—especially in elderly patients, who may have limited sight and manual dexterity—and the ability to absorb oral medications.44 (See Promoting Patient Adherence to Oral Medications, bottom left.) The patient’s ability to pay for the medication should be discussed.48 (See Where to Obtain Financial Assistance, on page 15.) Compliance may also be increased if the oncology nurse meets with the patient at the beginning of each new treatment cycle, with time allotted to discuss side effects and to address any questions that may affect compliance. This would also allow for appropriate dose modifications. If possible, telephone encounters should be used to reinforce compliance and key education points.44 Validated tools for oral chemotherapy compliance and research-proven educational methods for patients and their families are needed.44



he discovery of tyrosine kinase inhibitors has changed the treatment and outlook of patients with GIST, especially those with unresectable or metastatic disease. Effective care of patients with GIST involves an understanding of the disease and its treatment. Treatment with imatinib and sunitinib requires oncology nurses to educate patients on how to manage potential adverse reactions. Patients should also be provided with tools to foster adherence to the prescribed dose and schedule, with the goal of optimizing treatment. n Editorial assistance and commercial support for this article provided by Novartis Pharmaceuticals Corporation.

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WHERE TO OBTAIN FINANCIAL ASSISTANCE The annual cost of medication to reduce the risk of or treat gastrointestinal stromal tumor (GIST) may be beyond the ability of some patients to afford, whether or not they have health insurance. There are, however, patient assistance programs available for both imatinib mesylate (Gleevec) and sunitinib malate (Sutent) offered by their manufacturers as well as by nonprofit organizations to help pay for medications. Novartis Oncology Reimbursement Hotline

HealthWell Foundation

For patients with health insurance coverage who still need financial assistance for imatinib.

Provides financial assistance to eligible patients for imatinib and sunitinib.

Phone: 800-282-7630 Web site:

Phone: 800-675-8416 Website:

Novartis Patient Assistance Foundation

Partnership for Prescription Assistance

For patients without health insurance coverage for imatinib.

Helps qualifying patients who lack prescription coverage obtain imatinib or sunitinib.

Phone: 800-277-2254 Web site:


Phone: 888-477-2669 Web site:

A financial assistance program from Pfizer for patients who are uninsured or underinsured and who lack coverage for sunitinib.

Patient Advocate Foundation Co-Pay Relief Program

Phone: 877-744-5675 Web site:

Phone: 866-512-3861 Web site:

Pfizer Pfriends

Patient Services Incorporated

Provides savings on sunitinib at the pharmacy for patients who lack health insurance coverage.

Helps qualifying patients subsidize the cost of prescriptions and co-payments for imatinib and sunitinib.

Phone: 866-776-3700 Web site:

Phone: 800-366-7741 Web site:

Provides co-payment assistance for imatinib and sunitinib to insured Americans who financially and medically qualify.

RESOURCES FOR PATIENTS WITH GIST Listed below are patient resources offered by two nonprofit groups devoted to patients with GIST, as well as the manufacturers of imatinib and sunitinib. Life Raft Group Among the Life Raft Group’s many offerings are newsletters, webcasts, videos, books, and other publications on GIST, available at no charge. There is also information about GIST, treatment options, clinical trials, obtaining financial and logistical support, coping with cancer, patient stories, and more. In addition to support groups in the United States, groups are available in more than 40 other countries. Phone: 973-837-9092 Web site:

GIST Support International In addition to offering patient education information on GIST, GIST Support International (GSI) administers an email-based support community consisting of more than 1,000 subscribers worldwide. In this open communication channel, members can ask questions, post information, share concerns, and interact with other members of the GSI community. Patients who lack computer access, or who would rather have a phone conversation with someone who knows firsthand about GIST, can speak directly with a volunteer staffer. Phone: 215-340-9374 Web site:

GIST Alliance™ Introduced by Novartis, GIST Alliance is designed to help optimize outcomes in patients with GIST. To that end, it offers patients information on what the disease is, understanding tests and treatment options, questions to ask the doctor, reimbursement issues, a glossary of terms, and links to other helpful Web sites. Phone: 888-669-6682 Web site:

Pfizer for Oncology Professionals In addition to professional resources, this Web site offers patient education materials on understanding GIST and treatment with sunitinib, as well as information on patient assistance programs and reimbursement. Phone: 800-438-1985 Web site: (Click on “Patient Education Materials,” then “GIST.”)

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24. Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003;299(5607):708-710. 25. European Society for Medical Oncology (ESMO). Gastrointestinal stromal tumors: ESMO Clinical Recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2007;18(suppl 2):ii27-ii29. 26. Li P, Wei J, Perle M, et al. Epithelioid gastrointestinal stromal tumor of the stomach with liver metastases in a 12-year-old girl: aspiration cytology and molecular study. Pediatr Dev Pathol. 2002;5(4):386-394. 27. GIST Support International (GSI). Genetic factors in gastrointestinal stromal tumor. http:// Accessed January 12, 2009. 28. Casali PG, Jost L, Reichardt P, et al. ESMO Guidelines Working Group. Gastrointestinal stromal tumors: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2008;19(suppl 2):ii35-ii38. 29. Kleinbaum EP, Chen LL, Lazar A, et al. Familial gastrointestinal stromal tumor with homo-/hemizygous kit exon 11 deletion: genotypic, histopathologic, radiography, and therapeutic findings. J Clin Oncol. 2006;24(18S)(June 20 Suppl):526s. Abstract 9527. 30. Berman E, Nicolaides M, Maki RG, et al. Altered bone and mineral metabolism in patients receiving imatinib mesylate. N Engl J Med. 2006;354(19):2006-2013. 31. Demetri GD, Benjamin R, Blanke CD. Optimal management of patients with gastrointestinal stromal tumors: expansion and update of NCCN Clinical Practice Guidelines. J Natl Compr Canc Netw. 2004;2(suppl 1):1-26. 32. Blay JY, Bonvalot S, Casali P, et al. Consensus meeting for the management of gastrointestinal stromal tumors: report of the GIST consensus conference 20-21 March 2004, under the auspices of ESMO. Ann Oncol. 2005;16(4):566-578. 33. DeMatteo RP, Lewis JJ, Leung D, et al. Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg. 2000;231(1):51-58. 34. Eisenberg BL, Judson I. Surgery and imatinib in the management of GIST: emerging approaches to adjuvant and neoadjuvant therapy. Ann Surg Oncol. 2004;11(5):465-475. 35. Gold JS, Dematteo RP. Combined surgical and molecular therapy: the gastrointestinal stromal tumor model. Ann Surg. 2006;244(2):176-184. 36. DeMatteo R, Owzar K, Maki R, et al. Adjuvant imatinib mesylate increases recurrence free survival (RFS) in patients with completely resected localized primary gastrointestinal stromal tumor (GIST): North American Intergroup Phase III trial ACOSOG Z9001. Presented at: 43rd Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2007; Chicago, IL. Abstract 10079. 37. Blay JY, Le Cesne A, Ray-Coquard I, et al. Prospective multicentric randomized phase III study of imatinib in patients with advanced gastrointestinal stromal tumors comparing interruption versus continuation of treatment beyond 1 year: the French Sarcoma Group. J Clin Oncol. 2007;25(9):1107-1113. 38. Gleevec [package insert]. East Hanover, NJ: Novartis Pharmaceuticals; 2008. 39. Sutent [package insert]. New York, NY: Pfizer Inc.; 2008. 40. Braconi C, Bracci R, Cellerino R. Molecular targets in gastrointestinal stromal tumors (GIST) therapy. Curr Cancer Drug Targets. 2008;8(5):359-366. 41. Corless CL, Heinrich MC. Molecular pathobiology of gastrointestinal stromal sarcomas. Annu Rev Pathol Mech Dis. 2008;3:557-586. 42. Hutson TE, Figlin RA, Kuhn JG, Motzer RJ. Targeted therapies for metastatic renal cell carcinoma: an overview of toxicity and dosing strategies. Oncologist. 2008;13(10):1084-1096. 43. Rosenbaum SE, Wu S, Newman MA, et al. Dermatological reactions to the multitargeted tyrosine kinase inhibitor sunitinib. Support Care Cancer. 2008;16(6):557-566. 44. Moore S. Facilitating oral chemotherapy treatment and compliance through patient/ family-focused education. Cancer Nurs. 2007;30(2):112-122. 45. Weingart SN, Brown E, Bach PB, et al. NCCN Task Force Report: Oral chemotherapy. J Natl Compr Canc Netw. 2008;6(suppl 3):S1-S4. 46. McLeod HL, Evans WE. Oral cancer chemotherapy: the promise and the pitfalls. Clin Cancer Res. 1999;5(10):2669-2671. 47. Kuppens IE, Breedveld P, Beijnen JH, Schellens JH. Modulation of oral drug bioavailability: from preclinical mechanism to therapeutic application. Cancer Invest. 2005;23(5): 443-464. 48. Winkeljohn DL. Oral chemotherapy medications: the need for a nurse’s touch. Clin J Oncol Nurs. 2007;11(6):793-796.

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Management of Patients With Gastrointestinal Stromal Tumors Treated With Tyrosine Kinase Inhibitors

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