Incidence and management of ZIv-aflibercept related toxicities in colorectal cancer

Table 1 Selected grade 3/4 adverse events (%) with FOLFIRI/ziv-aflibercept in VELOUR study

Adverse event	Grade 3 %	Grade 4 %
Fatigue	11.9	0.7
Asthenia	4.9	0.2
Proteinuria	7.5	0.3
Urinary tract infections	0.8	0.0
Neutropenia	23.1	13.6

Table 2 General guidelines for Ziv-aflibercept dosing and schedule modification due to adverse events per CTCAE 4.0

Event	Action to be taken
Hypertension
Grade 3	If not controlled with medication, discontinue Ziv
Grade 4	Discontinue Ziv
Proteinuria
> 2 g protein/24 h	Hold Ziv until proteinuria improves to < 2 g of protein/ 24 h
	Discontinue Ziv in a patient with > 2 g proteinuria/24 h that does not resolve in 3 mo time after holding Ziv. Work-up for proteinuria such as renal biopsy should be considered
grade 4 proteinuria (nephrotic syndrome)	Discontinue Ziv treatment
Gastrointestinal perforation
Gastrointestinal perforation or dehiscence	Discontinue Ziv
Thromboembolic events
Grade 3 venous thromboembolic event or incidentally discovered pulmonary embolus first occurrence	Hold Ziv treatment
	If the planned duration of therapeutic-dose anticoagulant therapy is £ 2 wk, Ziv should be held until the period of therapeutic-dose anticoagulant therapy is over
	If the planned duration of therapeutic-dose anticoagulant therapy is > 2 wk, Ziv should be held for 2 wk and then may be resumed during the period of therapeutic-dose anticoagulant therapy as soon as all of the following criteria are met: The patient must be on a stable dose of anticoagulant and, if on warfarin, have an INR within the target range (usually between 2 and 3) prior to restarting study drug treatment The patient has no history of Grade 3 or 4 hemorrhagic events before starting Ziv The patient has no evidence of tumor invading or abutting major blood vessels on any prior CT scan
Any grade arterial thromboembolic event or symptomatic Grade 4 venous thromboembolic event first occurrence	Discontinue Ziv
Hemorrhage
Grade 1 and 2	No dose modification
Grade 3 or 4 (first occurrence)	Discontinue study treatment

Table 3 Recommendations for Dose Modification and Treatment Delay for Zaltrap

Discontinue ZALTRAP for:	Severe hemorrhage
	Gastrointestinal perforation
	Compromised wound healing
	Fistula formation
	Hypertensive crisis or hypertensive encephalopathy
	Arterial thromboembolic events
	Nephrotic syndrome or thrombotic microangiopathy (TMA)
	Reversible posterior leukoencephalopathy syndrome (RPLS)
Temporarily suspend ZALTRAP:	At least 4 wk prior to elective surgery
	For recurrent or severe hypertension, until controlled. Upon resumption, permanently reduce the ZALTRAP dose to 2 mg per kg
	For proteinuria of 2 grams per 24 h. Resume when proteinuria is less than 2 grams per 24 h. For recurrent proteinuria, suspend ZALTRAP until proteinuria is less than 2 grams per 24 h and then permanently reduce the ZALTRAP dose to 2 mg per kg (RULE OF 2)

Table 4 Special Situations about Toxicities of Zaltrap

Geriatric Use	The effect of ZALTRAP on overall survival was similar in patients < 65 yr old and ≥ 65 yr old who received ZALTRAP/FOLFIRI.
	No dose adjustment of ZALTRAP is recommended for patients ≥ 65 yr of age.
Paediatric Use	The safety in paediatric patients has not been established.
Hepatic Impairment	No dedicated clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of ziv-aflibercept.
Renal Impairment Contraception and Nursing Mothers	No dedicated clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of ziv-aflibercept.
	Females and males of reproductive potential should use highly effective contraception during and up to a minimum of 3 mo after the last dose of treatment.
Overdose	No information on the safety of aflibercept given at doses exceeding 7 mg/kg every 2 wk or 9 mg/kg every 3 wk is present.
	No specific antidote to ZALTRAP overdose exists.
	Patients of Zaltrap overdose should be managed with supportive measures.
Infections	The Velour study showed an increased incidence of infections in patients receiving ZALTRAP/FOLFIRI (46%, all grades; 12%, Grade 3-4) than in patients receiving placebo/FOLFIRI (33%, all grades; 7%, Grade 3-4), including urinary tract infection, nasopharyngitis, upper respiratory tract infection, pneumonia, catheter site infection, and tooth infection.
	Be vigilant about recognizing them.
	Treat them according to general guidelines.