oncology nursing news gist supplement

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

Denise Reinke, MS, NPSarcoma Nurse Practitioner, Multidisciplinary Sarcoma Clinic

University of Michigan Comprehensive Cancer Center

President, Sarcoma Alliance for Research Through Collaboration (SARC) Ann Arbor, Michigan

introduction

Gastrointestinal 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, so-called “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 sar-comas 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 charac-terization of GIST and therefore its correct classification, estimates of its in-cidence have increased accordingly.4

Previously, surgery was the only viable treatment option for GIST. Chemo-therapy was largely ineffective, with poor

response rates.5 Radiation therapy was often impractical because of the extent and location of the disease. Improved un-derstanding 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 car-ing 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 educa-tion and management.

A supplement to Oncology Nursing News May/June 2009

© 2009 Haymarket Media Inc.

GISTs often initially appear as large, heterogeneous masses.

ONN_GIST_supp v20.indd 1 4/17/09 9:52:42 AM

overview

GISTs are the most common mesenchymal neo-plasms 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 mus-cle 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 primar-ily 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

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 ane-mia.10 Gastrointestinal hemorrhage occurs in up to 40% of patients.6 Endoscopic ultrasound-needle aspiration, with confirmation of cytologic diagnosis by immuno-histochemistry, 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 under-standing, 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,

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

Incidence and PrevalenceWhile GISTs remain rare, with the advent of immuno-histochemical staining techniques and ultrastructural evaluation that improve detection, the number of diag-noses for GIST is increasing.13 Adult population: There are over 50 subtypes of sarco-mas, 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.

2 A Supplement to Oncology Nursing News n May/June 2009

n Management of Patients With GIST Treated With Tyrosine Kinase Inhibitors

GISTs comprise 2.2% of all gastric malignancies, 13.9% of all small intestine malignancies, and 0.1% of all colonic malignancies.

Mucosa

Submucosa

Inner muscularis

Myenteric plexus

Outer muscularis

FIGURE 1. Gastrointestinal tract. The highest density of inter-stitial 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.

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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 extra- gastric 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 meta-static 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 GISTNo 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 inci-dence 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 GISTMalignant 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

Symptoms of GIST are often vague and nonspecific. In patients with clinically significant GIST,

symptoms may include early satiety, bloating, gastroin-testinal bleeding, or fatigue related to anemia.10 GIST may also present as an abdominal mass, hemoperito-neum, anemia, perforation, or incidentally.25

The most common clinical manifestations of malig-nancy are liver metastases and/or dissemination within the abdominal cavity.10 Lymph node metastases are

May/June 2009 n A Supplement to Oncology Nursing News 3

n

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.

INHERITABLE GERM-LINE MUTATIONS




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 StudiesImaging techniques to evaluate GIST include endos-copy, 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 imag-ing 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 preopera-tive staging information than CT scan.25

BiopsyDeciding 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 con-ducted. A differential diagnosis of GIST is generally considered for any gastrointestinal or other intra- abdominal 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

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 exami-nation, abdominopelvic computed tomography (CT) scan with contrast and/or magnetic resonance imaging (MRI), chest imaging, endoscopic ultrasound, endos-copy as indicated (if not previously done), and surgical assessment.10

Laboratory TestingNo known serum tumor markers exist for GIST.3 Baseline serum chemistries are useful to determine

TEsT RaTIonalE

Complete blood count (CBC) • Screen for anemia

Serum chemistries • Determine organ function from GIST or another disease

Liver function tests: bilirubin, transaminase, alkaline phosphatase • GIST metastases commonly involve the liver

Electrolyte metabolism • Conduct follow-up testing 1-3 months while on therapy

Source: Mukherjee3; Berman et al.30

TaBlE 1. Rationale for Laboratory Studies for GIST

FIGURE 2. GISTs often initially appear as large, heterogeneous masses.

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treatment of gist

Many 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 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 recom-mended 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

SurgerySurgery is the standard of care for localized or poten-tially 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 ima-tinib 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 ap-proximately 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

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FIGURE 3a: Normal liver.

FIGURE 3B: Liver with metastatic GIST.

FIGURE 4a. Pre-imatinib: A PET scan revealed uptake of 18FDG by the GIST.

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

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Case Study 1FOSTERING 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, low- attenuation 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 dis-ruptive. 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 dis-ease 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 super-vision. 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 medica-tion 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.



ties, as it inhibits both the vascular endothelial growth factor receptor and the KIT receptor, respectively.Other agents: Other multitargeted tyrosine kinase in-hibitors 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

Enrollment in Clinical TrialsPatients 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 (www.cancer.gov/clinicaltrials), 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.

with placebo (83%).36 Based on these results, adjuvant treatment with imatinib is recommended as an alterna-tive 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 per-sistent 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 met-astatic GIST until disease progression. If imatinib therapy is interrupted, there may be an increase in the rate of progressive disease.37

Targeted TherapyGISTs 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 treat-ment of GIST after disease progression on, or intolerance to, imatinib.39 Sunitinib potentially pos-sesses both antiangiogenic and anti-oncogenic proper-

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.

While GISTS are resistant toconventional chemotherapies,KIT inhibition with tyrosinekinase inhibitors has emergedas an effective treatment.

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ticle (http://www.nccn.org/professionals/physician_gls/PDF/sarcoma.pdf).10 Prior to initiation of therapy with an oral tyrosine kinase inhibitor, patients should be in-structed in proper drug administration, side effects that can be expected, and how best to manage them.

DosagesImatinib: For first-line treatment, imatinib 400 mg to 600 mg per day is currently recommended. A dose in-crease 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 recom-mended dose of imatinib is 400 mg/day.38 Adverse

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

Patient education and management

NCCN has published evidence-based practice guide-lines for the diagnosis, staging, treatment, and

follow-up of patients with GIST as reviewed in this ar-

MIToTIc IndEx (HPF)b

TUMoR sIzE (cM) GasTRIc dUodEnUM JEJUnUM/IlEUM REcTUM

≤5/50 ≤2>2 to ≤5

>5 to ≤10>10

0%1.9%3.6%10%

0%4.3%24%52%

0%8.3%NDc

34%

0%8.5%NDc

57%>5/50 ≤2

>2 to ≤5>5 to ≤10

>10

Noned

16%55%86%

Noned

73%85%90%

NDc

50%NDc

86%

54%52%NDc

71%Data based on long-term follow-up of 1,055 gastric, 629 small intestinal, 144 duodenal, and 111 rectal GISTs.aMedian follow-up (range: 1-175 months).bHigh-power field; ≤5/50 = ≤5 mitoses per 50 high-power field.cNot determined.dDenotes small number of cases.

Source: Corless et al.41

TaBlE 2. Risk of Recurrent GISTa

advERsE EvEnT ManaGEMEnT

GASTROINTESTINAL

Nausea38 • Take with food and at least 8 ounces of water 6• Change the time of day imatinib is taken 6

Vomiting38

• 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

Dyspepsia38 • 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

Diarrhea38• 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

TaBlE 3. Management of Adverse Events With Imatinib




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, granulocyte- macrophage-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: 340 mg/m2/d to 260 mg/m2/d 260 mg/m2/d to 200 mg/m2/d

OTHERS

Edema 38

• 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 38• 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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MIToTIc IndEx (HPF)b

TUMoR sIzE (cM) GasTRIc dUodEnUM JEJUnUM/IlEUM REcTUM

≤5/50 ≤2>2 to ≤5

>5 to ≤10>10

0%1.9%3.6%10%

0%4.3%24%52%

0%8.3%NDc

34%

0%8.5%NDc

57%>5/50 ≤2

>2 to ≤5>5 to ≤10

>10

Noned

16%55%86%

Noned

73%85%90%

NDc

50%NDc

86%

54%52%NDc

71%Data based on long-term follow-up of 1,055 gastric, 629 small intestinal, 144 duodenal, and 111 rectal GISTs.aMedian follow-up (range: 1-175 months).bHigh-power field; ≤5/50 = ≤5 mitoses per 50 high-power field.cNot determined.dDenotes small number of cases.

Source: Corless et al.41

TaBlE 3. Management of Adverse Events With Imatinib (continued)


effects can usually be managed. Caution is needed when administering with agents that may lead to subthera-peutic 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

Drug InteractionsAny medications currently being taken by a patient, including prescription drugs, over-the-counter medica-tions, 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 EventsAdverse 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 con-sist 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 associ-ated 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 (palmar-plantar erythrodysesthesia or hand-foot syndrome) can also occur. Patients may be given a 5HT3 serotonin


• CYP3A4Inhibitors (may increase plasma imatinib concentration)

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

• CYP3A4Inducers (may decrease plasma imatinib concentration)

Rifampin

• CYP3A4,2C9Substrates (imatinib may alter plasma concentration)

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

Source: Gleevec.38

IMATINIB: POTENTIAL DRUG INTERACTIONS

• CYP3A4Inhibitors (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

• CYP3A4Inducers (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

SUNITINIB: POTENTIAL DRUG INTERACTIONS




n

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 laparoto-my. 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 recom-mended 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 discon-tinue 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 strate-gies 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 unneces-sary, 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 compli-ance. 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. Lim-ited 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.

Case Study 2ORAL THERAPY FOR GIST MAY BE DISCONTINuED DuE TO ADVERSE EVENTS

After surgery for gastro-intestinal 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.





GASTROINTESTINAL

Nausea39 • 5HT3 serotonin receptor antagonist7

Vomiting39 • 5HT3 serotonin receptor antagonist7

Diarrhea39 • Loperamide7

Mucositis/stomatitis39 • Brush, floss, and rinse with a saline or sodium bicarbonate solution after each meal and at bedtime

CARDIAC

Hypertension39

• 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

Rash39 • 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 • Foot 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

TaBlE 4. Management of Adverse Events with Sunitinib



n

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 meta-static 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 diar-rhea 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 well-defined 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 person’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.

Case Study 3A 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-or-break issue in compliance with the medication regimen, because it can alter physical appearance in unpleasant ways.

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 mucositis 7 (Table 4).

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

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


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 pa-tients 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


• Misinterpretationofphysicianinstructions• Denial• Forgetfulnessorconfusion• Polypharmacysyndrome• Distractionbycompetingpriorities

(eg, patients caring for ill spouse)• Costofthemedication• Dosingfrequency• Adverseeffects• Demandsofemployment• Insufficientfamilyandfriendsupportsystems• Avocations,suchastravel

Source: Moore.44

FACTORS ASSOCIATED WITH NONADHERENCE TO ORAL REGIMENS

• Provideanoralmedicationcalendar• Providepatientswithadiarytorecorddose

and instruct them in its use• Providepillboxes• Countpillsateachpatientvisit• Requestthatpatientsreturnunused

medication at the end of treatment• Ensurethoroughpatientteaching• Providecontactinformationregardingwho

and when to call• Keepanupdatedlistofpatient-assistance

Web sites and phone numbers• Standardizeprintedprescriptionpads• Doublechecktheheight,weight,body

surface area, diagnosis, and cycle number• Encouragepatientstomeetwithanoffice

pharmacist

Source: Winkeljohn.48

PROMOTING PATIENT ADHERENCE TO ORAL MEDICATIONS

is nonadherent to therapy, is experiencing side effects that seem severe for the dose, or is experiencing a drug-drug interaction. In contrast with IV agents, oral agents are more susceptible to intrapatient and interpatient variability in absorption, bioavailability, and adher-ence.46,47 Several factors may contribute to noncompli-ance (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 infor-mation—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 in-formation 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 limita-tions—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 chemother-apy compliance and research-proven educational meth-ods for patients and their families are needed.44

concLusion

The 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 under-standing 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.



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.

WHERE TO OBTAIN FINANCIAL ASSISTANCE


n

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: www.liferaftgroup.org

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: www.gistsupport.org

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: www.gistalliance.com

PfizerforOncologyProfessionalsIn 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: www.pfizeroncology.com (Click on “Patient Education Materials,” then “GIST.”)

RESOURCES FOR PATIENTS WITH GIST

Novartis Oncology Reimbursement Hotline For patients with health insurance coverage who still need financial assistance for imatinib.

Phone: 800-282-7630 Web site: www.gistalliance.com

Novartis Patient Assistance Foundation For patients without health insurance coverage for imatinib.

Phone: 800-277-2254 Web site: www.pap.novartis.com

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

Phone: 877-744-5675 Web site: www.pfizerhelpfulanswers.com

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

Phone: 866-776-3700 Web site: www.pfizerhelpfulanswers.com

HealthWell Foundation Provides financial assistance to eligible patients for imatinib and sunitinib.

Phone: 800-675-8416 Website: www.healthwellfoundation.com

Partnership for Prescription AssistanceHelps qualifying patients who lack prescription coverage obtain imatinib or sunitinib.

Phone: 888-477-2669 Web site: www.pparx.org

Patient Advocate Foundation Co-Pay Relief ProgramProvides co-payment assistance for imatinib and sunitinib to insured Americans who financially and medically qualify.

Phone: 866-512-3861 Web site: http://www.copays.org/about_cpr.php

Patient Services IncorporatedHelps qualifying patients subsidize the cost of prescriptions and co-payments for imatinib and sunitinib.

Phone: 800-366-7741 Web site: www.uneedpsi.org


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