Alkylators

Question 1

Dose limiting toxicity:

Answer 1

Dose limiting toxicity:
= myelosuppression
Usually, neutropenia and thrombocytopenia

Question 2

They form potent electrophilic cations, and exert cytotoxic activity by:

Answer 2

They form potent electrophilic cations, and exert cytotoxic activity by:

1. Inhibition of DNA replication and transcription 2.Mispairing of DNA
2. Strand breakage

Question 3

toxicities common to most agents

Answer 3

Other toxicities common to most agents 
•Nausea and vomiting
•Alopecia
•Infertility
•Secondary leukemias

Question 4

Cyclophosphamide

Answer 4

• A prodrug–must be activated in the liver to the active metabolites
• Typical doses (600-750 mg/m2) are used for treatment of lymphomas and breast cancer
• High doses (2 g/m2) are used in bone marrow transplants

Question 5

Cyclophosphamide toxicities

Answer 5

Toxicities:
Nausea and vomiting,
SIADH,
hemorrhagic cystitis (rare, mostly when high doses are given)

Question 6

Ifosfamide

Answer 6

• Analogue of cyclophosphamide

Administration Issues
o MUST ADMINISTER MESNA!!
o Vigorous hydration with 1.5-2 liters of Normal Saline pre-and post-hydration.
o Encourage patients to increase oral fluid intake

Question 7

ifosfamide active form

Answer 7

Ifosfamide mustard cytotoxic

Question 8

ifosfamide toxic form for bladder

Answer 8

Acrolein

Question 9

MESNA MOA and for which ADR and drug

Answer 9

Mesna is an antidote for bladder toxicity (can result in bleeding in urine) when used with ifosfamide.

MOA:
Autooxidation in vivo to a dimer and enter kidney. in the bladder it form complex with acrolein rendering it inactive. need lots of hydration to flush them out.

Question 10

ifosfamide toxicity

Answer 10

Nausea and Vomiting
Dose-limiting - hemorrhagic cystitis-use MESNA!
CNS Toxicity (neurotoxicity)
Nephrotoxicity

CNS toxicity (neurotoxicity) –>transient; just wait it out.

• Halluinations
• Confusion
• Somnolence
• Symptoms usually begin 2-5 days after start of ifosfamide

Question 11

Neurotoxicity of ifosfamide is due to

Answer 11

•Accumulation of chloroacetaldehyde

Question 12

Prevention / Management: Neurotoxicity due to ifosfamide

Answer 12

• Use with caution in elderly patients
• Caution with renal dysfunction
• Increase infusion time
• Avoid concurrent administration of CNS active drugs
• Decrease dose or discontinue treatment with onset of symptoms

•Methylene blue (case reports)
–Inhibits monoamine oxidase metabolism to chloroacetaldehyde

Question 13

Platinum analogues and MOA

Answer 13

Cisplatin
Carboplatin
Oxaliplatin

Alkylating-like agents which form a reactive electrophile that covalently binds to DNA

Question 14

Cisplatin ADR

Answer 14

1) Cisplatin-induced Nephrotoxicity.
- Deterioration of renal function and electrolyte wasting

2) Ototoxicity (may be irreversible)
•Related to high peak doses
•Unable to hear high pitch sounds

3) Peripheral neuropathy (may be reversible)

4) Irritant to veins
5) Nausea vomiting

Question 15

Preventive strategies for cisplatin-induced nephrotoxicity.

Answer 15

Deterioration of renal function and electrolyte wasting

Preventive Strategies:

• Avoid in patient with renal dysfunction
• Hydration w/ at least 1-2 L 0.9% NaCl IV pre-and concurrent with cisplatin, with potassium & magnesium supplementation
• Maintain urine output >100 ml/h
• Provide mannitol and/or furosemide to flush out cisplatin.
• Prolong infusion time (e.g. 24 hour infusion)
• Amifostine  Antidote for nephrotoxicity by binding to free ROS.  Might affect tx effectiveness. Therefore not useful.

Question 16

Tx for Cisplatin induced peripheral neuropathy.

inc
symptoms present in ______% of patients after _____________mg/m2 cumulative dose

Answer 16

symptoms present in 50% of patients after 300-500 mg/m2 cumulative dose
•Limit cumulative doses
•Decrease dose or discontinue treatment
•Substitute with carboplatin (but may compromise the treatment of some cancers)
•Medications to reduce neuropathic pain

Question 17

Unique dosing method –based on Calvert equation

give eqn

Answer 17

Carboplatin

•Dose = AUC X (GFR + 25)
– Use AUC = 2 for weekly dosing and AUC=5 or 6 for every 3 weeks

Question 18

Dose limiting toxicity for carboplatin

Answer 18

Dose limiting myelosuppression(especially thrombocytopenia)

Question 19

Carboplatin ADR

Answer 19

Comparing to cisplatin, much lower incidence of nephrotoxicity, ototoxicity and delayed nausea and vomiting
Hypersensitivity –can occur after 6-7 doses of carboplatin
myelosuppression

Question 20

Oxaliplatin ADR

Answer 20

• Cumulative peripheral neuropathy
• Acute: usually within the first 2 days, reversible and primarily peripheral symptoms that are often exacerbated by cold air
• Persistent(>14 days) that often interferes with daily activities such as writing, buttoning and swallowing; symptoms may improve upon treatment discontinuation
• Other toxicities: myelosuppression, nephrotoxicity (much less than cisplatin), hypersensitivity