Clinical Use of Antiangiogenic Agents: Dosing, Side Effects, and Management

Angiogenesis is a critical requirement for malignant growth, invasion, and metastases. Agents interfering with angiogenesis have shown efficacy in the treatment of a number of solid tumors, such as metastatic colorectal cancer, non–small-cell lung cancer, and renal cell cancer, and are being studied in many more. Each of the three agents currently approved by the US Food and Drug Administration-bevacizumab (Avastin), sunitinib (Sutent), and sorafenib (Nexavar)-offer challenges to nurses, in terms of assessment and management of toxicity, and to their patients as well: learning and integrating self-care strategies, such as self-assessment and self-administration (for sorafenib and sunitinib). This article reviews the recommended dosing, drug interactions, potential side effects, and management strategies for these three agents. Other agents that have antiangiogenesis properties, such as the epidermal growth factor inhibitors, the mTOR inhibitors, bortezomib, and thalidomide will not be addressed.

Oncology patients and their nurses are very excited about the effectiveness and availability of antiangiogenic agents; however, there are many challenges associated with their administration, and patient/family education is of paramount importance. This article will review the classification of agents, their indications, US Food and Drug Administration (FDA)-approved dosing, as well as class- and drug-specific side effects and their management.

As has been reviewed, tumors cannot grow beyond 1 to 2 mm without developing new blood vessels to deliver oxygen and nutrients, and to remove cellular waste products. These new blood vessels are stimulated by tumor-released vascular endothelial growth factor (VEGF), but other factors such as platelet-derived growth factor (PDGF) can also stimulate angiogenesis. When VEGF is released, it binds to the endothelial cell VEGF receptors on the nearby blood vessels: VEGFR1 (FLT1) and VEGFR2 (KDR or Flk-1). This initiates a signaling cascade (signal transduction) and messages are sent to the endothelial cell nucleus to stimulate endothelial cell proliferation and migration. Because the newly formed blood vessels are leaky and tortuous, pericytes are important to protect the fragile vessels, and act like shingles on a house. PDGF-b helps to recruit pericytes to the newly developing vessels.[1]

Antiangiogenesis Agents Available in 2007

Three antiangiogenesis agents that are VEGF-targeted agents have been FDA-approved in the treatment of solid tumors: bevacizumab (Avastin), sunitinib (Sutent), and sorafenib (Nexavar).

Anti-VEGF Agent

Bevacizumab is a humanized monoclonal antibody that targets VEGF, thus preventing the ligand VEGF from binding to the endothelial cell VEGFR1 and 2. Bevacizumab is indicated for first- and second-line treatment of patients with advanced colorectal cancer in combination with fluorouracil (5-FU)-based chemotherapy given every 2 weeks in combination with bolus IFL (irinotecan [Camptosar], 5-FU, leucovorin) for a bevacizumab dose of 5 mg/kg IV, and with FOLFOX (leucovorin, infusional 5-FU, and oxaliplatin [Eloxatin]) for a bevacizumab dose of 10 mg/kg IV. It is also approved for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non–small-cell lung cancer (NSCLC) in combination with paclitaxel and carboplatin at a dose of 15 mg/kg IV given every 3 weeks.

The drug is diluted in 100 mL of 0.9% sodium chloride injection USP, and given over 90 minutes initially, with the second dose given over 60 minutes, and if tolerated well, subsequent treatments given over 30 minutes.[2] A recent study by Reidy et al has shown that bevacizumab can be given safely over 10 mg for the 5-mg/kg dose.[3] The drug has a half-life of approximately 20 days, so it should be stopped at least several weeks before elective surgery and not resumed until at least 28 days after surgery and after the wound is healed. In addition, the drug is held if the patient experiences uncontrolled hypertension or moderate to severe proteinuria pending evaluation. The drug should be stopped if patients experience gastrointestinal (GI) perforation, fistula formation involving an internal organ, wound dehiscence requiring medical intervention, serious bleeding, a severe arterial thrombotic event, nephrotic syndrome, hypertensive crisis, or hypertensive encephalopathy (reversible posterior leucoencephalopathy syndrome, or RPLS).[2]

Drug interaction studies showed that the concentration of the irinotecan active metabolite SN-38 was 33% higher in patients receiving bevacizumab plus IFL compared to chemotherapy alone, perhaps explaining the higher incidence of grade 3/4 diarrhea and neutropenia in the combination arm.[2]

Anti-VEGF Receptor Agents

Sunitinib is a small-molecule signal transduction inhibitor that blocks multiple tyrosine kinases, some of which stimulate angiogenesis (PDGFa and PDGFb, VEGFR1, VEGFR2, and VEGFR3) and others which stimulate tumor proliferation (stem cell factor receptor [KIT], Fms-like tyrosine kinase-3 [FLT-3], colony-stimulating factor receptor type 1 [CSF-1R], and neurotrophic factor receptor [RET]).

It is indicated for the treatment of patients with advanced renal cell cancer or gastrointestinal stromal tumor after disease progression or intolerance to imatinib mesylate (Gleevec). The dose is 50 mg po daily, with or without food, for 4 weeks, followed by 2 weeks off, and then the cycle is repeated. The dose is modified in 12.5-mg increments if toxicity develops, or dose-increased if well tolerated and indicated. The drug is available in 12.5-, 25-, and 50-mg capsules. The drug is metabolized by the P450 microenzyme system, so the dose should be decreased (minimum of 37.5 mg po) if given with strong CYP3A4 inhibitors such as ketoconazole or the dose should be increased (maximum of 87.5 mg po) if given concomitantly with a CYP3A4 inhibitor such as rifampin[3,4] (see Table 1).

Sorafenib is also a small-molecule, multiple tyrosine kinase inhibitor that blocks signal transduction of angiogenesis (VEGFR2 and PDGFR) and tumor cell growth (RAF kinase pathway). It is indicated for the treatment of patients with advanced renal cell cancer, and those with unresectable hepatocellular carcinoma.

Sorafenib bioavailability is reduced by 29% when taken with a high-fat meal, so should be taken without food.[5] The recommended dose is 400 mg po twice daily 1 hour before or 2 hours after eating, and the drug is available in 200-mg tablets. The drug is continued for as long as there is clinical benefit or until unacceptable toxicity. If significant toxicity occurs, such as skin toxicity, the dose is reduced to 400 mg po daily; if additional dose reduction is needed, the drug is given at 400 mg po every other day. Sorafenib has not been studied in patients having significant hepatic or renal impairment.

Sorafenib is metabolized in the liver via the CYP3A4 and UGT1A9 pathways. The drug dose need not be modified if given concomitantly with CYP3A4 inhibitors such as ketoconazole. However, it is expected that CYP3A4 inducers, such as rifampin, phenytoin, dexamethasone, and St. John's wort will decrease sorafenib serum concentrations, so concomitant use should be avoided (see Table 1). Sorafenib is a competitive inhibitor of CYP2C9 substrates, with resulting uncommon bleeding events and elevated international normalized ratio (INR) in patients receiving warfarin; thus patients receiving sorafenib and warfarin should be monitored closely for bleeding, changes in prothrombin time, and INR, and their warfarin dose should be modified accordingly.

Caution should be used when combining sorafenib with chemotherapy. Irinotecan is eliminated by the UGT1A1 pathway, and coadministration resulted in a 67% to 120% increase in the area under the concentration-time curve (AUC) of the active metabolite SN-38 causing potentially severe irinotecan toxicity; combination with doxorubicin resulted in a 21% increase in the AUC of doxorubicin, potentially increasing doxorubicin toxicity; and lastly, combination with docetaxel also raises serum docetaxel concentrations. Finally, in Japanese patients, drug mean steady-state AUC was 45% lower, so drug dose may need to be increased.[5]

Potential Side Effects and Management

Potential side effects and their incidences are shown in Table 2, and are discussed as class effects or drug-specific effects.

Class Effects

The major side effects that are class effects of the blockade of normal angiogenesis are hypertension, bleeding, rare hemorrhage, rare gastrointestinal perforation, diarrhea, hypothyroidism, rare RPLS, teratogenicity, and fetotoxicity.

• Hypertension may arise because VEGF is necessary for the synthesis of the vasodilator nitric oxide. Normally, VEGF activates the endothelial cell to stimulate the production of nitric oxide synthase, which produces nitric oxide.[6,7] When VEGF is blocked, hypertension results from the inability of arteries to vasodilate which leads to vasoconstriction, increased peripheral resistance, and hypertension; in addition, low nitric oxide levels are associated with reduced renal excretion of sodium, with resulting sodium and water retention.[8]

The incidence of hypertension associated with bevacizumab is 23% with 12% grade 3/4; sunitinib is 30%, with10% grade 3/4; and sorafenib, 17% overall, and 3% grade 3/4. Hypertension emerges over time, so it is very important to assess blood pressure prior to treatment at least every 2 weeks with bevacizumab therapy, weekly for the first 6 weeks of sorafenib therapy, and every cycle (6 weeks) with sunitinib therapy.[2,4,5]

In addition, blood pressure should be monitored more frequently in patients with preexisting hypertension, or when patients are started on antihypertensive medications. Management is based on the JNC-7 Hypertension guidelines, with stage I hypertension defined as a systolic blood pressure 140 to 159 or a diastolic blood pressure of 90 to 99 and recommended single-agent therapy including thiazide diuretic, angiotensin-converting enzyme inhibitor (ACEI), angiotensin II-receptor blocker (ARB), beta-blocker, calcium channel blocker (CCB), or a combination.[9]

Stage 2 hypertension is a systolic blood pressure ≥ 160 or a diastolic blood pressure ≥ 100 and requires a two-drug combination for effective management. Thiazide diuretics are not used in patients with renal cell cancer because of potential renal toxicity, and ACEI/ARBs or CCBs are preferred to manage bevacizumab hypertension as these agents result in vasodilatation either by increasing circulating nitric oxide levels (ACEI/ARBs), or by direct vasodilation (CCB).[10] Fortunately for most patients, hypertension responds well to traditional management.

Rarely, hypertension may become severe and uncontrolled. Bevacizumab must be temporarily discontinued, and resumed when the blood pressure is under control. If hypertensive crisis occurs, the drug must be discontinued. Rarely, moderate to severe hypertension may cause RPLS characterized by headache, seizure, lethargy, confusion, blindness, and other visual/neurologic dysfunction.[2] Other causes may be changes in endothelial function resulting in blood-brain barrier dysfunction.[6] Onset is 16 hours to 1 year after treatment according to postmarketing reports. Definitive diagnosis is made with MRI. Incidence in bevacizumab clinical studies was < 0.1%; bevacizumab must be discontinued if RPLS occurs.[2] Sunitinib has been associated with less than 1% of seizures and RPLS[4]; occurrence is uncommon with sorafenib.[5,11]

Finally, hypertension may be related to proteinuria as VEGF is very important in normal renal function.[12] Proteinuria has occurred in patients receiving bevacizumab, and it has not been reported in patients receiving sunitinib or sorafenib. This is probably due to the short half-lives of these drugs compared to bevacizumab. Diagnosis and management will be discussed under bevacizumab.

• Bleeding may occur with each of the agents, and the etiology is unclear. It is thought that endothelial cell defects contribute to bleeding, but given the increased incidence of thrombosis as well, there are probably many effects of VEGF that are not well understood.[6] Fatal hemoptysis has occurred when bevacizumab was studied in patients with squamous cell histology of NSCLC. For this reason, the drug is not indicated for this patient population; in addition, bevacizumab is not indicated for patients with or having a history of hemoptysis of > one-half teaspoon of red blood.[2]

Most commonly when bleeding occurs, it is epistaxis. Rarely, patients receiving bevacizumab may develop a perforated nasal septum.[2] Bleeding is also common with sunitinib and sorafenib (see Table 2). Teach patients that nosebleeds may occur, to apply pressure and hold head down for up to 15 to 20 minutes until it resolves. If it does not resolve, a patient should call his/her provider and come to the emergency department for evaluation. If bleeding elsewhere occurs, such as hematuria, black tarry stools, or frank blood, the patient should call his or her provider and come to the emergency department to be evaluated right away. If hemorrhage occurs, the patient should call an ambulance immediately.

• GI perforation may occur rarely with each of the agents. The pathophysiology is unclear, but VEGF is necessary for functioning of the intestinal villous capillaries.[13] It is also hypothesized that for colorectal cancers, as the tumor shrinks and pulls away from the mucosa, it may thin the area resulting in increased risk of perforation.[14,15] Risk factors that appear to increase risk are tumor at the anastomotic site, abdominal carcinomatosis, bowel obstruction, intact colon or rectal tumor, history of pelvic/abdominal radiation, or recent colonoscopy.[14,15] In bevacizumab studies, it generally occurred during the first 60 days of treatment. In order to prevent GI perforation, bevacizumab should be held for at least the drug half-life (20 days) before elective surgery including colonoscopy. For major surgery, it may be prudent to wait up to 60 days for some surgical procedures such as hepatic metastatectomy as complications have occurred up to 56 days after the last bevacizumab dose.[15]

On patient assessment, the history is often significant for diffuse abdominal pain associated with fever, constipation, and/or vomiting; upon examination the patient will have tachycardia, rebound tenderness of the abdomen, and peripheral vasoconstriction with cool extremities.[2,15] It is important that patients are taught to come to the emergency department right away if they develop severe abdominal pain, with or without constipation, nausea, fever, and vomiting. If the patient develops GI perforation, including fistula formation and/or intra-abdominal abscess, bevacizumab should be discontinued.[2]

• Diarrhea as a class effect has not been fully elucidated.[16] VEGF is responsible for permeability, proliferation, migration, maintenance, and protection of endothelial cells. The GI gut mucosa is constantly injured by normal "wear and tear of digestion," and ongoing healing with angiogenesis is required for gut mucosal reconstitution.[17] Thus, blockade of VEGF in intestinal mucosa may result in decreased healing of mucosal injury, resulting in increased release of enzymes, inability to reabsorb water, and diarrhea.

Fortunately, patients are effectively managed with dietary modification, bulking and antidiarrheal medications, and adequate hydration.[18] Nursing assessment should focus on the patient's bowel elimination pattern baseline and with diarrhea noting stool consistency, frequency, whether it has mucus or blood, what makes it better or worse, and any associated symptoms that may further compromise the patient such as nausea, vomiting, inability to take oral fluids, dizziness, or safety issues. In addition, note the patient's medication profile for stool softeners, laxatives, or chemotherapy that may increase the risk of diarrhea such as irinotecan and 5-FU, or any potentially interacting medications that might increase toxicity. Assess the patient's and family's knowledge about how to assess diarrhea, when to call the provider (if diarrhea continues for more than 24 hours, patient has vomiting, fever, or is unable to take oral fluids), dietary modifications including increased oral fluid intake, and patient self-administration of loperamide or other recommended anti-diarrheal agent.

Dietary modifications include use of the BRAT (bananas, rice, apricots, tea) diet; avoidance of milk and dairy products as the mucosal injury may make the patient temporarily lactose intolerant; increase in soluble fiber; avoidance of foods with insoluble fiber; increase in oral fluids to at least 8 to 10 large glasses of clear liquids a day such as fat-free chicken broth and sports drinks; avoidance of caffeine, fried, spicy or fatty foods, alcohol, and other foods that can cause gas; and the taking of small, frequent meals. Some patients find that medicinal fiber helps to increase bulk in the stool and slow peristalsis.[18]

The goal of antidiarrheal medications is to reduce GI motility and secretion, and most patients have resolution of their diarrhea with loperamide.[18] As no evidence-based guidelines exist for the management of diarrhea associated with targeted therapies, the guidelines developed for chemotherapy-induced diarrhea are often very helpful.[19]

• Hypothyroidism may also be a class effect. The thyroid gland has many capillaries, and in animal models, VEGF inhibition results in regression of more than 50% of the thyroid capillaries in 3 weeks.[6] With all of the agents, it is important to assess baseline thyroid function tests and to monitor for signs and symptoms of hypothryroidism (increased sensitivity to cold, dry skin, hoarse voice, weight gain, myalgias and arthralgias, or depression), especially in patients receiving sunitinib. If hypothyroidism is confirmed, it is treated using standard medications.[4]

• Teratogenicity and fetoxicity result from inhibition, as angiogenesis is critical to the development of the embryo and fetus. These agents are either pregnancy class C (bevacizumab) or D (sorafenib and sunitinib). Teach female patients of childbearing age to use effective contraception so as to avoid pregnancy; also if currently breastfeeding an infant, not to breastfeed while receiving the drug. Effective birth control and avoidance of breastfeeding should continue for at least 2 weeks following cessation of sorafenib, and for at least 20 days after stopping bevacizumab.[2,5]

Drug-Specific Toxicity

Bevacizumab

• Wound-healing complications can occur with bevacizumab. Angiogenesis is very important in wound healing, and when inhibited, lack of angiogenesis can result in wound dehiscence and delayed wound healing, as well as fistula formation. In bevacizumab clinical trials, patients waited at least 28 days following surgery to begin the drug and the longest interval between the last dose of bevacizumab and wound dehiscence was 56 days. As bevacizumab has a long half-life of 20 days (range: 11–50 days) following surgery, bevacizumab should not be started until at least 28 days after major surgery, and the wound must be fully healed. Wound healing does not appear to be as significant a problem with sorafenib and sunitinib, probably because the drugs have such a short half-life compared to bevacizumab; this allows a more rapid recovery of normal wound healing processes.[6] Patients should be taught the rationale for stopping the drug before surgery and not resuming it until the wound is fully healed. In addition, teach the patient to call the provider right away if a previous wound begins to drain or open.

• Proteinuria may occur. The glomeruli are made up of capillaries, and it appears that VEGF is necessary for glomerular endothelial repair; thus one hypothesis is that blocking VEGF may compromise the glomeruli endothelial cell integrity. The incidence is not actually known as most patients are asymptomatic, but in pivotal studies almost a third of patients had proteinuria. Assess urine for protein baseline, and regularly during treatment. If the urine dipstick is ≥ 2+, a 24-hour urine for protein should be collected prior to the next cycle, and if urine protein is ≥ 2g, delay bevacizumab dose until urine protein has fallen to < 2 g. In this case, repeat the 24-hour urine for protein prior to each cycle. If the 24-hour urinary protein falls to < 1 g, resume monitoring with urine dipstick.[20]

• Arterial thromboembolism occurs in about 4.5% of patients, and complications include MI, CVA, and unstable angina. Risk factors include age > 65, pre-existing cardiac disease and previous history of thromboembolic events. Patients should be evaluated closely, and monitored during therapy. In some instances low dose aspirin may be indicated.[21]

Sunitinib

• Cardiac abnormalities may be experienced. Left ventricular dysfunction may occur in approximately 11% of patients.[4,22] Assess baseline left ventricular ejection fraction (LVEF) for all patients, and continue to monitor during therapy if the patient has had a cardiac event within the preceding 12 months, such as myocardial angina or artery bypass graft, or has congestive heart failure.[4] Interrupt or reduce dose in patients who have an LVEF < 50% and > 20% below baseline. QT prolongation may occur which increases the risk for ventricular arrythmias (eg, torsade de pointes), especially if the serum magnesium and potassium are low. Assess patient's history of QT prolongation, drug profile for drugs which may prolong the QT interval or antiarrythmic drugs, as well as serum electrolytes. If the patient is at risk, close monitoring with ECG and frequent electrolyte monitoring and repletion should be done.

• Laboratory abnormalities are a possibility. Assess complete blood count and platelet count and serum chemistries including phosphate at the beginning of each treatment cycle.

• Adrenal insufficiency has been found in lab animals. Monitor patient for adrenal insufficiency (muscle weakness, fatigue, weight loss, anorexia, hypotension, hypoglycemia, irritability, depression, salt craving) if the patient experiences surgery, trauma, or severe infection.

• Stomatitis may be encountered. Assess oral mucosa baseline and prior to each cycle. Teach patient oral hygiene regimen, and to report pain or difficulty chewing or swallowing. Management is similar to that for chemotherapy-induced oral stomatitis, and the drug dose may need to be interrupted or reduced.

• Skin alterations may occur. The skin may become yellow in 30% of patients. Depigmentation of the hair may occur when the patient is on therapy, becoming normal during the 2-week break, and then becoming depigmented again. This resembles a zebra-like hair color and will stop when the drug is stopped. Acral erythema, blistering, and desquamation may occur on the palms of the hands and soles of the feet. Teach patient to avoid repetitive pressure such as jogging, and to keep the surfaces of hands and feet moist with creams such as Eucerin or Udderly Smooth. Teach patient to report pain or interference with activities of daily living. Assess the impact on the patient's activities of daily living and comfort, and the need for drug interruption or dose reduction. Subungual splinter hemorrhage can occur under the fingernails. Dry skin can be managed with hydrating creams, and pruritis managed with anti-itch creams, or those that contain aloe vera. Scalp itch can be managed with antidandruff shampoos or tea tree oil.[18]

Sorafenib

• Hand-foot syndrome occurs in over a third of patients, and is usually grade 1/2; it appears during the first 6 weeks of treatment. Teach patients that this may occur, and to keep the skin of the hands and feet, as well as areas of friction, hydrated with skin emollients such as Eucerin cream, and to avoid repetitive movements such as jogging. Teach patients to assess skin areas, and to report skin erythema or edema that interferes with activities of daily living as this constitutes grade 2. Topical agents are used for up to 7 days but if there is no relief, the drug should be interrupted until it resolves to a grade 1, and then resumed at a reduced dose.

If grade 3 toxicity occurs, such as moist desquamation or ulceration so that the patient is unable to work or carry out activities of daily living, the drug should be interrupted until it resolves to grade 1/2.[4] In addition, hyperkeratosis with callus formation may occur on the soles of the feet. Kerasal (over-the-counter) may reduce the callus formation, and wearing shock absorbers or gel shoe inserts may reduce discomfort.[18]

• Cardiac ischemia or myocardial infarction occurs rarely,[22] and the drug should be stopped or discontinued. Although rare, teach patients to report chest pain or shortness of breath right away.

• Laboratory abnormalities include hypophosphatemia, increased lipase and amylase, and less commonly, lymphopenia and thrombocytopenia. Teach patient that blood tests will be done frequently, and elevated lipase and amylase may require treatment.

• Sensory neuropathy may occur in 13% of patients compared to 6% in the control arm.[5] Teach patients to report this if it occurs, and assess comfort and impact on activities of daily living.

Summary

This decade has seen the FDA approval of three antiangiogenic drugs. Although the drugs are in general well tolerated, significant and severe side effects are possible. The pathophysiology is still being determined for many of these, as well as optimal management. There are no prospective studies providing evidence for best practices, and so anecdotal and expert nursing experience guide us at this time. This is a perfect opportunity for oncology nurses to work together to conduct research and establish the evidence for best practice.

References:

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19. Benson AB, Ajani JA, Catalano RB, et al: Recommended guidelines for the treatment of cancer treatment-induced diarrhea. J Clin Oncol 22:2918-2926, 2004.

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21. Scappaticci FA, Skillings JR, Holden SN, et al: Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst 99(16):1232-1239, 2007.

22. Force T, Krause DS, Van Etten RA: Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer 7:332-344, 2007.