Table 3.

Frequency of CTCAE Grade 3/4 Nonhematological Toxicity by Drug in Primary Brain Tumor Trials^a

	Toxicity (%)	%	References	Management and Consequences for Tumor-Specific Treatment
Temozolomide	Fatigue	13	Stupp et al.76	Dose reduction
	Skin	3		Pause until resolution, reexpose
	Nausea, vomiting	2		Enforce antiemetic treatment
	Infection	7		Antibiotics
	Hepatotoxicity	Rare		Stop treatment and assess relatedness with hepatologist
Procarbazine	Nausea and vomiting	3	Yung et al.82	Dose reduction or stop
	Fatigue	2		Dose reduction
	Rash	25		Stop treatment
Lomustine	Nausea	23	Wick et al.83	Enforce antiemetic treatment
	Infection	4		Dose reduction
	Hepatotoxicity	Not reported		Dose reduction or discontinue
Vincristine	Polyneuropathy			Stop in case of signs of polyneuropathy
PCV	Nausea (mostly lomustine related)		Van den Bent et al.84 and Wick et al.149	Prevent with 5-HT3 antagonists
	Rash (grades 2/3)	1–10		Stop procarbazine, regardless of grade
	Polyneuropathy (grades 2/3)	2–7		Stop vincristine once signs appear
	Hepatotoxicity (grades 2/3)	10		Dose reduction of procarbazine first, then lomustine
	Asthenia, lack of appetite, weight loss	5		Mild cases: metoclopramide, if severe: dose reduction or stop procarbazine
Bevacizumab	Hypertension grade 3 or 4	4.2	Gilbert et al.150	Treat with antihypertensive medication and continue. Dose reduction recommended depending on severity of antihypertensive medication. Consider extension of treatment intervals up to 4–6 weeks between infusions
		11.3	Chinot et al.44
	Proteinuria	5.4	Chinot et al.44	Treatment interruption up to normalization. Consider dose reduction or extension of treatment intervals, eg, 4–6 weeks between infusions
	Fatigue	5–13.1	Gilbert et al.150	Consider specific physical activity
	Venous thromboembolic events	4.6	Gilbert et al.150	Anticoagulation and continuation of therapy without dose reduction
		7.6	Chinot et al.44
	Arterial thromboembolic events	5	Chinot et al.44	Evaluation of stroke etiology, reevaluation of treatment continuation
	Hemorrhage, not further specified	1.6	Gilbert et al.150	Treatment discontinuation
	Cerebral hemorrhage grade 4	2	Chinot et al.44	Treatment discontinuation
	Bleeding outside the CNS	1.3	Chinot et al.44	Treatment interruption. Evaluation of bleeding severity and available clinical strategies. Evaluate dose adaptation or treatment discontinuation
	Wound dehiscence	1.3–1.6	Gilbert et al.150	Treatment interruption. Continue without dose reduction after complete wound healing
		3.3	Chinot et al.44
	Nausea and vomiting	1–4.2	Gilbert et al.150	5-HT3 antagonists, no treatment interruption or dose reduction
	Visceral perforation	1.2	Gilbert et al.150	Treatment discontinuation
		1.1	Chinot et al.44
Vemurafenib	Skin	5–15	Larkin et al.148	Dose interruption and dose reduction
	Arthralgia	3
	Liver function	5
	Fatigue	3
Larotrectinib (n = 33, including 7 adults)	Dysphagia	6	Doz et al.88	Dose interruption and dose reduction
	Pneumonia	6
	Vomiting	3
	Headache	3
	Pyrexia	3
	Urinary tract infection	3

CNS, central nervous system; CTCAE, Common Terminology Criteria for Adverse Events.

^aAlternative causes of toxicity should always be explored.