08a Major Organ Toxicities (Antimetabolites/Alkylators) Lee

Question 1

What are the common toxicities associated with Anti-Metabolites?

Answer 1

Myelosuppression, mucositis, alopecia, N/V, tumor lysis syndrome (TLS)

Question 2

What needs to be added to MTX IV treatment when using Intermediate or High-dose?

Answer 2

Leucovorin rescue

Question 3

What are some major toxicities associated with MTX?

Answer 3

Stomatitis/Mucositis. Myelosuppression (dose limiting). Neurologic. Renal

Question 4

What are the Purine Analogues used?

Answer 4

Mercaptopurine (6-MP, Purinethol). Thioguanine (6-TG, Tabloid)

Question 5

What are the toxicities associated with Purine Analogues (Mercaptopurine, Thioguanine)?

Answer 5

Cholestatic Liver Dysfunction! Myelosuppression, Mild N/V/D, stomatitis

Question 6

What is the issue with What are the toxicities associated with Purine Analogues (Mercaptopurine, Thioguanine) and Allopurinol?

Answer 6

6-MP metabolized by Xanthine Oxidase, which is inhibited by Allopurinol. Azathioprine, an immunosuppressant, a prodrug to 6-MP. Thus, REDUCE dose of Azathioprine and 6-MP by 75%

Question 7

What are the Pyrimidine Analogues used?

Answer 7

Fluorouracil (5-FU); Capecitabine (Xeloda; oral 5-FU); Cytarabine; Gemcitabine

Question 8

What are the toxicities like for the Pyrimidine Analogues (Fluorouracil; Capecitabine)?

Answer 8

Depends on route, dose, and schedule. Bolus: Myelosuppression. Continuous infusion: Mucositis, diarrhea, hand/foot syndrome

Question 9

What is Grade 1 Hand/Foot Syndrome?

Answer 9

Numbness, dysesthesia or paresthesia, tingling, painless swelling or erythema, and/or discomfort of hands or feet not disrupting normal activities

Question 10

What is Grade 2 Hand/Foot Syndrome?

Answer 10

Painful erythema and swelling of hands or feet and/or discomfort affecting ADLs

Question 11

What is Grade 3 Hand/Foot Syndrome?

Answer 11

Moist desquamation, ulceration, blistering or severe pain of hands or fee, or severe discomfort preventing work or performance of ADLs

Question 12

What is Hand/Foot Syndrome also known as?

Answer 12

Palmar-Plantar Erythrodyesthesia (PPE)

Question 13

What are the toxicities associated with Pyrimidine Analogue Cytarabine (Ara-C)?

Answer 13

Toxicities with high-dose: Conjuntivitis, Cerebellar dysfunction (coordination/balance)

Question 14

What are the toxicities associated with Pyrimidine Analogue Gemcitabine (Gemzar)?

Answer 14

Myelosuppression. Mild N/V, stomatitis, increased LFTs

Question 15

What are some toxicities with Efudex, Carax 0.5% cream (topical 5-FU)?

Answer 15

Application-site reaction, erythema, dryness, burning, pain, ulceration, allergic contact dermatitis. Cases of miscarriage/birth defect when applied to mucous membranes

Question 16

What are the common toxicities associated with Alkylators?

Answer 16

Sterility/infertility/teratogenicity. Second malignancies

Question 17

Which Alkylators unique toxicity is Nephrotoxicity?

Answer 17

Cisplatin

Question 18

What are the Platinum Alkylators used?

Answer 18

Cisplatin (Platinol); Carboplatin (Paraplatin); Oxaliplatin (Eloxatin)

Question 19

What are the toxicities associated with Platinum Alkylators?

Answer 19

Severe N/V (acute and delayed) w/ Cisplatin. Hypersensitivity with repeated use. Ototoxicity. Neurotoxicity (peripheral and loss of taste). Renal toxicity

Question 20

What is Renal Toxicity like with the Platinum Alkylators?

Answer 20

Cisplatin (Dose limiting toxicity (DLT)) > Carboplatin > Oxaliplatin. Dose-related toxicity of distal convoluted tubule and collecting duct

Question 21

What are the unique toxicities associated with Cyclophosphamide (Cytoxan, Neosar, oral and injectables)?

Answer 21

Highly emetogenic for doses > 1500 mg/m2. Hemorrhagic cystitis

Question 22

What are the more common toxicities associated with Busulfan?

Answer 22

Severe Synusoidal Obstruction Syndrome (SOS) of liver. Seizures. Hyperpigmentation of the skin (Busulfan Tan). Endocardial fibrosis (Busulfan Lung) < 1%

Question 23

What is some patient education for Alkylator: Procarbazine (Matulane)?

Answer 23

Ethanol causes Disulfiram-Like reactions. Safe handling. Alert dietitian, provide list of foods to avoid

Question 24

What are the different complications of the GI Tract?

Answer 24

Xerostomia/Dry mouth (radiation). Stomatitis/Mucositis/Esophagitis (MTX, 5-FU, High-dose). N/V (Cisplatin and others). Diarrhea (5-FU, Irinotecan). Constipation (Vincristine)

Question 25

How does Radiation (RT) to H/N cause Xerostomia?

Answer 25

Damage salivary glands. Loss of salivary buffering capacity, pH, IgA. Reversible w/in 6-12 months after end of treatment. Increase oral bacteria --> Infection

Question 26

What can be used to reduce Xerostomia?

Answer 26

Amifostine (Ethyol) 200mg/m2 or 500mg IV prior to RT. Pilocarpine (Salagen) 5-10mg PO TID, cholinergic

Question 27

What is Mucositis/Stomatitis?

Answer 27

Non-specific effect of chemotherapy and radiation on basal epithelium of mouth. Pain, may progress to ulceration; may extend esophagus, entire GI tract. Symptoms: Local pain, anorexia, N/D, thrush

Question 28

What are the main causes of Mucositis/Stomatitis?

Answer 28

Antimetabolites (MTX, FU, Cytarabine), Anthracyclines, High-dose Chemotherapy, Allogenic BMT

Question 29

How can Mucositis/Stomatitis be prevented?

Answer 29

Active rinses w/ mouthwashes. Sodium bicarbonate rinse, saline rinse, before eating and drinking. Cryotherapy (chew on ice before high dose melphalan - marginally effective). Paliformin

Question 30

What is the treatment for Mucositis/Stomatitis?

Answer 30

Palliative = symptom control. Topical anesthetics. Kaolin, Benadryl, Antacids. Mouthwashes

Question 31

What is the site of action of MTX?

Answer 31

Inhibits DHF Reductase

Question 32

What is the site of action of Leucovorin?

Answer 32

Increases the depleted N5, N10 Methylene THF

Question 33

What is the site of action of 5-FU?

Answer 33

Inhibits Thymidylate Synthetase, if given with Leucovorin it increases this inhibition

Question 34

What are the different Leucovorin options?

Answer 34

Leucovorin IV/PO. Levoleucovorin Injection (Fusilev) - dose 1/2 of LV

Question 35

What are the indications for Leucovorin?

Answer 35

Rescue after high-dose MTX. Reduces toxicity and counteracts effects of impaired elimination and inadvertent overdoses of MTX. In combo w/ 5-FU in palliative treatment of advanced metastatic colorectal cancer

Question 36

At what point is Leucovorin usually given with MTX?

Answer 36

When MTX > 500mg. Severe BM suppression and mucositis unless rescured by Leucovorin

Question 37

What is Calcium Leucovorin?

Answer 37

A reduced folate which can replenish the folate pool depleted by MTX. It allows DNA synthesis to begin again even in presence of MTX. Begin 24-36 hrs after initiation of MTX. Starting dose 10-15mg/m2 IV

Question 38

When can Calcium Leucovorin be stopped?

Answer 38

When MTX < 5x 10-8M (0.05 um) at 72 hrs

Question 39

When should precaution be used with Leucovorin?

Answer 39

If ascites or third space fluid collection --> Prolonged excretion and increased toxicity of MTX - may require Leucovorin dose increase as well as prolonged Leucovorin rescure

Question 40

When should MTX levels be obtained?

Answer 40

24, 48, 72 hrs after MTX started

Question 41

What should be done at 48 hrs if MTX level is less than 1x10^-6 M?

Answer 41

Continue Leucovorin 10-15mg/m2 Q6h x8 doses, IV

Question 42

What should be done at 48 hrs if MTX level is greater than 1x10^-6 M?

Answer 42

Increase Leucovorin to 50-100mg/m2 Q6h x8 doses IV until it falls below 1x10^-6, then follow other schedule

Question 43

How should MTX never be written?

Answer 43

QD!!! It is a weekly dose, not daily

Question 44

What is some patient education for MTX?

Answer 44

Inform MD if any signs of: Neutropenia (fever, chills, sore throat, cough). Bleeding, bruising. Mouth sores, SOB. Liver toxicity.

Question 45

How can nephrotoxicity from High-Dose MTX be prevented?

Answer 45

SCr < 1.5 or CrCl > 60. Intensive hydration. Alkalinization of urine to pH > 7 with Na Bicarbonate in IV fluids

Question 46

Which DDI with MTX causes a decreased elimination of MTX?

Answer 46

Probenecid and PPIs

Question 47

What is the MOA of Nephrotoxicity caused by Cisplatin?

Answer 47

Proximal tubular damage. Elevated BUN/SCr, chronic Mg wasting. SCr poorly coorelate w/ CrCl

Question 48

How can nephrotoxicity caused by Cisplatin be prevented?

Answer 48

Vigorous hydration with saline + Mg, K. Ensure diuresis w/ furosemide. Use analogue: Carboplatin. Uroprotectant: Amifostine

Question 49

What is Amifostine (Ethyol)?

Answer 49

Prodrug to free thiol that binds and detoxifies Cisplatin - "free radical scavenger". Used to prevent cumulative renal toxicity associated w/ repeated administration of Cisplatin. Reduction of moderate to severe Xerostomia (dry mouth) in radiation treatment for head and neck cancer

Question 50

What are the side effects associated with Amifostine (Ethyol)?

Answer 50

Hypotension, N/V

Question 51

What drugs cause Hemorrhagic Cystitis (bladder toxicity)?

Answer 51

Cyclophosphamide, Ifosfamide. Caused be metabolite, ACROLEIN

Question 52

What is used for prevention of Hemorrhagic Cystitis caused by Cyclophosphamide, Ifosfamide?

Answer 52

Mesna (binds to acrolein preventing its contact w/ bladder wall and subsequent damage). Suprahydration, patient should drink ~3L fluid/d x sever days and frequent voiding

Question 53

What are the ADRs with Mesna?

Answer 53

N/V (sulfur smell)

Question 54

What can be used for treatment of Hemorrhagic Cystitis is severe bleeding?

Answer 54

Bladder irrigation w/ saline, cytoscopy w/ fulguration. Bladder instillation w/ aminocaproic acid, formalin, or hydrocortisone

Question 55

What is the dosing of Mesna like for IFX bolus?

Answer 55

IFX bolus: Mesna = 20% of Ifosfamide dose given at 0, 4, 8hr after IFX

Question 56

What is the dosing of Mesna like for IFX continuous infusion?

Answer 56

Mesna continuous infusion at 60-100% IFX dose, then extra 12-24 hrs after end of IFX (till acrolein level falls to non-toxic level in the bladder)

Question 57

What are the signs/symptoms of Ifosfamide-induced Encephalopathy?

Answer 57

Decrease in arousability and disorientation leading to somnolence, drowsiness, lethargy, hallucination, encephalopathy, stupor, personality changes, paranoia, mutism, muscle twitching, incontinence, seizures, coma

Question 58

What are the risk factors for Ifosfamide-Induced Encephalopathy?

Answer 58

High dose, bolus dose, low albumin. Avoid concurrent benzos (also cause CNS effects) - difficult to diagnos

Question 59

What is used in the treatment of Ifosfamide-induced Encephalopathy?

Answer 59

Methylene blue; 50mg IV TID

Question 60

What is a caution with Busulfan?

Answer 60

Seizures d/t its good CNS penetration