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Managing Adverse Events Associated With Anti- angiogenic Biologic Agents for Metastatic Colorectal Cancer: A Nursing Perspective of Ziv-Aflibercept

TON - May 2013, Vol 6, No 4 published on May 28, 2013 in Colorectal Cancer
Julie A. Koch, RN, BSN, OCN, CCRP

The US Food and Drug Administration (FDA) approved ziv-aflibercept injection (Zaltrap, Sanofi US, Inc.) for use in combination with 5-fluorouracil/leucovorin/irinotecan (FOLFIRI) for the treatment of patients with metastatic colorectal cancer that is resistant to or has progressed following an oxaliplatin-containing regimen. This approval was granted on August 3, 2012. For more information about the FDA approval, see

Survival outcomes for colorectal cancer (CRC) are poor, particularly for patients whose metastatic disease has progressed despite previous treatment.1,2 The vascular endothelial growth factor (VEGF) family of growth factor ligands is thought to play several roles in tumor angiogenesis, including metastatic colorectal cancer (mCRC). Ziv-aflibercept (formerly known as aflibercept in the United States), an agent that inhibits the VEGF pathway, was approved by the US Food and Drug Administration (FDA) in August 2012 in combination with 5-fluorouracil (5-FU), leucovorin (LV), and irinotecan (FOLFIRI) for patients with mCRC that is resistant to or has progressed following an oxaliplatin-containing regimen.3 For the past several years, bevacizumab (Avastin; Genentech, Inc.)—a monoclonal antibody that binds with VEGF-A to inhibit the VEGF pathway—has been approved by the FDA to treat mCRC in combination with cytotoxic therapy, including fluoropyrimidine-containing chemotherapy such as IFL (irinotecan/bolus 5-FU/LV) or FOLFOX4 (5-FU/LV/oxaliplatin).4-7 Unlike bevacizu- mab, ziv-aflibercept is a multiple angiogenic factor trap that binds to and prevents not only VEGF-A but also VEGF-B and placental growth factor from activating their native receptors; it targets multiple pathways to inhibit tumor angiogenesis, tumor growth, endothelial cell proliferation, and recruitment of bone marrow–derived myeloid progenitors.8,9

This review summarizes clinical trial data on the efficacy of ziv-aflibercept plus chemotherapy along with the incidence of treatment-related toxicities and strategies for their management based on clinical practice guidelines. Because bevaciz- umab’s adverse events (AEs) profile is well characterized and similar to that of ziv-aflibercept, this will also be discussed. It should be noted that experience with bevaciz-umab in combination with FOLFIRI in mCRC is limited to phase 2 trials. Oncology nurses need to understand and manage the AEs associated with antiangiogenic therapies; this review will present the nurse’s role in managing toxicities.



The VELOUR Trial
The efficacy and safety of ziv-aflibercept in patients with mCRC previously treated with oxaliplatin were demonstrated in the VELOUR (Aflibercept Versus Placebo in Combination With 5-FU in the Treatment of Patients With Metastatic Colorectal Cancer After Failure of an Oxiplatin-Based Regimen) trial. Patients who progressed during or after completing a single oxaliplatin-containing regimen, including those who relapsed within 6 months of completing adjuvant oxaliplatin-based therapy, were enrolled. Patients were randomized to receive ziv-aflibercept 4 mg/kg + FOLFIRI or placebo + FOLFIRI, administered every 2 weeks until disease progression or unacceptable toxicity. Ziv-aflibercept was administered as a 1-hour infusion prior to any component of the FOLFIRI regimen on the day of treatment. Median overall survival improved significantly with ziv-aflibercept + FOLFIRI versus placebo + FOLFIRI (13.50 vs 12.06 months, respectively; P = .0032) (Figure). Median progression-free survival with ziv-aflibercept versus placebo (6.90 vs 4.67 months, respectively; P <.0001) and response rate (complete + partial response; 19.8% vs 11.1%, respectively; P = .0001) also significantly improved (Table 1).10

Combination ziv-aflibercept + FOLFIRI demonstrated generally the same safety profile as placebo + FOLFIRI. Chemotherapy-associated AEs included nausea, vomiting, diarrhea, constipation, fatigue, and myelosuppression.10 Some AEs (all grades), however, occurred more frequently in patients receiving ziv-aflibercept compared with placebo (Table 2).3 The differences in incidence of AEs between the ziv-aflibercept + FOLFIRI versus placebo + FOLFIRI groups are similar to those observed with bevacizumab + IFL versus placebo + IFL.4 AEs (grade ≥3) that occurred more frequently with the ziv-aflibercept + FOLFIRI versus placebo + FOLFIRI (≥5% incidence and ≥2% higher in the ziv-aflibercept arm), in order of decreasing frequency, were neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue, proteinuria, and asthenia.3 AEs leading to treatment discontinuation occurred in 26.6% of patients treated with ziv-aflibercept and 12.1% of those who received placebo10; these AEs most frequently included asthenia/fatigue, infections, diarrhea, dehydration, hypertension, stomatitis, venous thromboembolic events, neutropenia, and proteinuria.3

As with bevacizumab, some AEs observed with ziv-aflibercept treatment—hypertension, proteinuria, neutropenia, leukopenia, wound healing complications, bleeding/hemorrhage, thromboembolic events, and gastrointestinal perforation—arise from its anti-VEGF properties. In other trials of anti-VEGF therapy (ie, bevacizumab + chemotherapy), the most common grade 3/4 toxicities were neutropenia (16%–64%), leukopenia (4%–37%), diarrhea (2%–32.4%), arterial/venous thromboembolic events (0%–22%), hypertension (2%–19%), venous thromboembolic events (5%–19%), fatigue (3%–14%), and anorexia (1%–8%).7,11-16

Management of Anti-VEGF Adverse Events

Management of AEs in patients treated with ziv-aflibercept must address those that are anti-VEGF as well as those from chemotherapy (ie, FOLFIRI). As observed in the VELOUR trial, chemotherapy-related AEs included nausea, vomiting, diarrhea, constipation, fatigue, and myelosuppression. These and less frequently observed AEs are often managed by using institutional protocols. Alternatively, guidelines are available from the National Cancer Institute,17 the American Society of Clinical Oncology,18 and the National Comprehensive Cancer Network.19 Several strategies can help to manage anti-VEGF AEs, such as identifying patients at increased risk or providing supportive care before or during treatment.

Strategies to Minimize Anti-VEGF Adverse Events

Screening patients to determine if they have a history of or are at increased risk for vascular-related AEs (ie, hypertension, proteinuria, hemorrhage, thrombosis) is important because of the possibility of end-organ damage and death. If blood pressure is elevated, secondary causes such as uncontrolled pain should be investigated.20 A morning urine spot for urinary protein:creatinine ratio (UPCR) should be used to detect proteinuria; ziv-aflibercept should not be initiated in a patient with severe hemorrhage.3

Once bevacizumab or ziv-aflibercept therapy is initiated, regular monitoring is necessary. Blood pressure should be monitored every 2 to 3 weeks, or more frequently if clinically indicated. A 24-hour urine collection is recommended for a urine dipstick reading ≥2 prior to the bevacizumab dose or a UPCR >1 for ziv-aflibercept, if proteinuria is suspected.3,4 However, this approach has been questioned because of its high cost and low impact on treatment decisions.21 Monitor the complete blood count and differential at baseline and before initiation of each cycle of ziv-aflibercept.3

Table 2

Supportive Care

Supportive care includes premedication, palliative therapy, or dose modification, interruption, or discontinuation. Premedication for emesis may not be necessary because the emetic risk with ziv-aflibercept is low3,10; however, antiemetic prophylaxis is common with FOLFIRI.22 Grade ≥3 neutropenia occurs in about one-third of patients treated with bevacizumab or ziv-aflibercept combined with cytotoxic chemotherapy.3,4 Consequently, prophylactic use of colony-stimulating factors (CSFs; ie, filgrastim or pegfilgrastim) is recommended for patients at high risk (>20%) for febrile neutropenia. For patients at intermediate risk (10%–20%) of febrile neutropenia, prophylactic CSF therapy can be considered. Should febrile neutropenia occur, filgrastim can also be used for treatment.23


Antihypertensive therapy should be optimized or initiated, based on patient characteristics, to achieve blood pressure <140/90 mm Hg (<130/80 mm Hg for those with chronic kidney disease or diabetes).20,24 For most patients, a thiazide, angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, beta-blocker, or calcium channel blocker is appropriate, based on comorbidities.25 A thiazide is not recommended if diarrhea is present (author’s opinion). For older persons, a calcium channel blocker (preferably with vasodilatory properties, such as nifedipine or amlodipine) may be preferred.20,25


Management of diarrhea is based on severity and its classification as uncomplicated (grade 1/2 with no other signs or symptoms) or complicated. There is no clearly superior approach for uncomplicated diarrhea. Therefore, management is often empiric and nonspecific. Bulk laxatives and
promotility agents such as metoclopramide should be discontinued, and clear fluid intake increased to ≥3 liters per day. Various dietary approaches have been investigated, but few have been shown to be effective. Broths, soups, sports drinks, canned fruits, and bananas may help to replenish electrolytes. Opioids (notably loperamide because it is the least likely to impair cognition) may be used, as they reduce transit time within the gastrointestinal tract. The initial dose of loperamide is typically 4 mg followed by 2 mg after each unformed stool, to a maximum of 12 mg daily. Probiotics—nutritional supplements containing a specified amount of viable microorganisms such as Lactobacillus or Bifidobacterium—have also been investigated for the management of diarrhea.17 While some benefit with probiotic therapy has been reported, further investigation is needed.26

Dose Reduction, Interruption, or Discontinuation

Several situations exist where the dose of bevacizumab or ziv-aflibercept should be modified. Although there are no recommended dose reductions for bevacizumab, the ziv-aflibercept dose should be reduced to 2 mg/kg on resuming treatment after recurrent or severe hypertension or proteinuria ≥2 g/24 hours.3,4 At least 4 weeks before elective surgery, interrupt bevacizumab if a patient has uncontrolled severe hypertension, moderate to severe proteinuria, or a severe infusion reaction.4 Ziv-aflibercept therapy should be interrupted 4 weeks before and after major surgery (longer if the wound has not healed) if a patient has moderate proteinuria, recurrent or severe hypertension, or a neutrophil count <1.5 x 109/L.3 Discontinuation is appropriate in cases of severe hemorrhage, gastrointestinal perforation, compromised wound healing, fistula formation, hypertensive crisis or hypertensive encephalopathy, arterial thromboembolic events, nephrotic syndrome or thrombotic microangiopathy, or reversible posterior leukoencephalopathy syndrome.3,4

Implications for Oncology Nurses

Since its approval in 2004, bevacizumab has been associated with improved response rates and survival in mCRC, yet in 2013, the 5-year survival rate for patients with mCRC is only 20%.2 As demonstrated in the VELOUR trial, combining ziv-aflibercept with FOLFIRI provides opportunities for improved outcomes in these patients.

It is critically important to manage AEs caused by pharmacologic agents used to treat malignancies. Patients receiving bevacizumab or ziv-aflibercept should be educated about the occurrence and management of chemotherapy- and anti-VEGF–related AEs, as treatment decisions are made and again at each visit. Good communication and a collaborative relationship will enable individualized patient education. Providing information to patients and family members—preferably in writing—as to how to report distressing symptoms and other concerns they may have between office visits is key. Educational resources for patients who wish to manage treatment-related AEs are available from the National Cancer Institute,27 the American Society of Clinical Oncology,28 and the National Comprehensive Cancer Network29; another excellent resource is the Oncology Nursing Society’s Putting Evidence Into Practice.30


Medical editorial assistance was provided by Susan DePetris, PhD, of Phase Five Communications Inc, and supported by Sanofi-Aventis US LLC, in collaboration with Regeneron Pharmaceuticals.

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12. Horita Y, Yamada Y, Kato K, et al. Phase II clinical trial of second-line FOLFIRI plus bevacizumab for patients with metastatic colorectal cancer: AVASIRI trial. Int J Clin Oncol. 2012;17(6):604-609.
13. Kopetz S, Hoff PM, Morris JS, et al. Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J Clin Oncol. 2010;28(3):453-459.
14. Sobrero A, Ackland S, Clarke S, et al. Phase IV study of bevacizumab in combination with infusional fluorouracil, leucovorin and irinotecan (FOLFIRI) in first-line metastatic colorectal cancer. Oncology. 2009;77(2):113-119.
15. Fuchs CS, Marshall J, Mitchell E, et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007;25(30):4779-4786.
16. Souglakos J, Ziras N, Kakolyris S, et al. Randomised phase-II trial of CAPIRI (capecitabine, irinotecan) plus bevacizumab vs FOLFIRI (folinic acid, 5-fluorouracil, irinotecan) plus bevacizumab as first-line treatment of patients with unresectable/metastatic colorectal cancer (mCRC). Br J Cancer. 2012;106(3):453-459.
17. National Cancer Institute Web site. Gastro-intestinal complications (PDQ). Diarrhea. 2012. care/gastrointestinalcomplications/HealthProfessional/AllPages#5. Accessed March 28, 2013.
18. American Society of Clinical Oncology Web site. Supportive Care and Quality of Life Guidelines. 2013. Accessed March 28, 2013.
19. National Comprehensive Cancer Network Web site. NCCN Guidelines for Supportive Care. lines.asp#supportive. Accessed March 28, 2013.
20. Maitland ML, Bakris GL, Black HR, et al. Initial assessment, surveillance, and management of blood pressure in patients receiving vascular endothelial growth factor signaling pathway inhibitors. J Natl Cancer Inst. 2010;102(9):596-604.
21. Yeh J, Frieze D, Martins R, Carr L. Clinical utility of routine proteinuria evaluation in treatment decisions of patients receiving bevacizumab for metastatic solid tumors. Ann Pharmacother. 2010;44(6):1010-1015.
22. Ettinger DS, Amstrong DK, Barbour S, et al. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology. Antiemesis. Version 1.2013. Accessed March 28, 2013.
23. Crawford J, Armitage J, Balducci L, et al. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology. Myeloid growth factors. Version 1.2013. Accessed March 28, 2013.
24. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289(19):2560-2572.
25. Copur MS, Obermiller A. An algorithm for the management of hypertension in the setting of vascular endothelial growth factor signaling inhibition. Clin Colorectal Cancer. 2011;10(3):151-156.
26. Reid G, Gaudier E, Guarner F, et al. Responders and non-responders to probiotic interventions: how can we improve the odds? Gut Microbes. 2010; 1(3):200-204.
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28. American Society of Clinical Oncology Web site. Managing Side Effects. Accessed March 28, 2013.
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30. Mitchell SA, Friese CR. ONS PEP (Putting Evidence into Practice). Weight of Evidence Classification Schema: Decision Rules for Summative Evaluation of a Body of Evidence.
evidence-table.pdf. Accessed March 28, 2013.

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Last modified: April 27, 2020