Wake Chemotherapy 1

Front 1

Which drugs classes interfere with mitosis?

Back 1

vinca alkaloids
taxanes

Front 2

Which drug classes are cycle nonspecific?

Back 2

Alkylating Agents
Anthracyclines

Front 3

Which drug classes interfere with DNA synthesis?

Back 3

Anti-metabolites
Epipodophyllotoxins
Camptothecins

Front 4

Since ther are cells growing quickly and growing slowly, what type up of chemotherapy should you use?

Back 4

Synergistic chemotherapy... try to kill the cell at various points in the life cycle

Front 5

What does a topoisomerase do? (difference between 1 and 2?)

Back 5

a topoisomerase unwinds DNA
1- only cuts one strand to uncoil/recoil
2 - cuts both strands to uncoil/recoil

Front 6

List the alkylating Drugs

Back 6

Cyclophosphamide
Ifosfamide
Platinums
Nitrosureas
Mechlorethamine
Melphalan
Chlorambucil
Busulfan
Thiotepa
Procarbazine
Dacarbazine
Temozolamide

Front 7

Nitrosureas

Back 7

(type of alkylating agent)
Lomustine
Carmustine

Front 8

Platinums

Back 8

(type of alkylating agent)
Cisplatin
Carboplatin
Oxaliplatin

Front 9

Potential Outcomes of Alkylating Agents

Back 9

1. Template being replicated is misread or mispaired during DNA synthesis
2. Cross-linking prevents DNA strands from unwinding
3. Single or double-strand breaks in DNA occur

Front 10

Cyclophosphamide
Metabolism

Back 10

- Parent drug (it is a prodrug) is converted by hepatic microsomal enzymes to 4-hydroxycyclophosphamide (4-HCP)
- 4-HCP is converted to acrolein and phosphoramide mustard
- Phosphoramide mustard alkylates DNA
- Acrolein is responsible for causing hemorrhagic cystitis

Front 11

Ifosfamide
Metabolism

Back 11

- Parent drug (it is a prodrug) is converted to acrolein and ifosforamic mustard by the liver
- There is more acrolein formed with ifosfamide
- Acrolein is responsible for causing hemorrhagic cystitis

Front 12

Which causes more hemorrhagic cystitis cyclophosphamide or ifosfamide?

Back 12

Ifosfamide b/c more acrolein is made with its metabolism by the liver

Front 13

Cyclophosphamide
Toxicities

Back 13

* Myelo suppression (LIMITING TOXICITY)
- Hemorrhagic cystitis
- Nausea & vomiting
- Alopecia
- Syndrome of inappropriate anti-diuretic hormone (SIADH)

Front 14

Ifosfamide
Toxicities

Back 14

* Hemorrhagic cystitis (LIMITING TOXICITY)
- Myelosuppression
- CNS toxicity
- Nausea & vomiting
- Alopecia
- Pulmonary & cardiac toxicity

Front 15

What happens to your electrolytes with Syndrome of inappropriate anti-diuretic hormone

Back 15

low sodium

Front 16

Can you use Ifosfamide with drugs metabolized in the liver?

Back 16

No because they are both metabolized by the liver, so there will be an increase in Ifosfamide toxicity

Front 17

Hemorrhagic Cystitis

Back 17

- Caused by accumulation of acrolein
- Binds to thiol in bladder wall
- this is not always acute, most often it occurs with days, but it can happen 3-4 months later
* problem with ifosfamide and cyclophosphamide
- Hematuria, urinary frequency & irritation

Front 18

How do you prevent Hemorrhagic Cystitis?

Back 18

Prevent with vigorous hydration (≥2 L/day) & MESNA

Front 19

How do you treat Hemorrhagic Cystitis?

Back 19

- Treat with bladder irrigation, alum irrigation, and other therapies
- Heme test urine while on therapy

Front 20

MESNA

Back 20

(a.k.a. mercaptoethane sodium)
- Uroprotectant containing sulfhydryl group
- Binds to acrolein in the bladder to form a nontoxic compound
- Not systemically absorbed so does not interfere with cytotoxic activity
- Use with cyclophosphamide >2 g/m2/dose, ifosfamide ALWAYS
- Effective in prevention only .: must give prior to alkylating agent

Front 21

Cisplatin

Back 21

(alkylating agent - platinum)
- Filtered by glomerulus & concentrated in renal tubules; incompletely cleared
- Nephrotoxicity – ↓ GFR, electrolyte losses (Mg, K), and renal failure
- Prevent with aggressive hydration (NaCl)

Front 22

Carboplatin

Back 22

(alkylating agent - platinum)
- Not concentrated in the renal tubules; more efficiently cleared
- Dosing based on area under the curve (AUC) and renal function
- Dose = AUC ( GFR + 25 )

Front 23

Cisplatin
Toxicities

Back 23

* Vomiting (LIMITING TOXICITY)

* Nephrotoxicity (LIMITING TOXICITY)
- Peripheral neuropathy
- Neurotoxicity
- Ototoxicity

Front 24

Carboplatin
Toxicities

Back 24

* Myelosuppression (LIMITING TOXICITY)
- Neurotoxicity
- Vomiting

Front 25

Oxaliplatin
Toxicities

Back 25

* Peripheral neuropathy induced by cold (LIMITING TOXICITY)
- Myelosuppression

Front 26

What baseline should you obtain before starting cisplatin or carboplatin?

Back 26

an audiogram with continued hearing monitoring because of ototoxicity

Front 27

Amifostine

Back 27

(Ethyol)
- chemoprotectant agent that is metabolized to an active free thiol which binds to cisplatin and prevents damage to normal tissue (against nephrotoxicity and nuerotoxicity)
- free radical scavenger
- side effects include hypotension and nausea and vomiting
- also used to prevent radiation-associated xerostomia

Front 28

Should you give amifostine with cisplatin?

Back 28

If you can give carboplatin instead, then do it.
Why? because both cisplatin and amifostine cause nausea and vomiting.

Front 29

What allows amifostine to only rescue non-cancer cells?

Back 29

Tumor cells have lower levels of alkaline phosphatase, which amifosting needs to be active. Tumor cells cannot activate amisfostine, so cispltin can cause cytotoxicity

Front 30

What are the oral alkylating agents?

Back 30

- Chlorambucil
- Busulfan
- Melphalan
- Temozolomide

Front 31

Temozolomide (Temodar)

Back 31

- Used for treatment of brain tumors and multiple myeloma
- 150 mg/m2 PO daily days 1-5 a cycle repeat cycle every 28 days

Front 32

Melphalan (Alkeran)

Back 32

- Used for the treatment of multiple myeloma
- 8 mg/m2 PO daily day 1-4 repeat every 28 days

Front 33

Busulfan (Myleran)

Back 33

- Used for treatment of leukemia and transplant
- Also available IV form (used more for transplant)
- toxicity is decreasing seizure threshold
- must give seizure prophylactic drug at high doses

Front 34

Chlorambucil (Leukeran)

Back 34

Used for the treatment of chronic lymphocytic leukemia

Front 35

List the Anthracyclines

Back 35

think "rubi" - make secretions orange/red
- Doxorubicin
- Daunorubicin
- Idarubicin
- Epirubicin
- Mitoxantrone (makes secretions blue)
- Bleomycin
- Mitomycin C

Front 36

Anthracyclines
Mechanism of Action

Back 36

1. Inhibition of topoisomerase II
2. Intercalation between DNA base pairs, interfering with DNA synthesis
3. Formation of free radicals that damage DNA and cell membranes

Front 37

Anthracyclines
Toxicities

Back 37

TOXICITY LIMITING:
* Myelosuppression
* Cardiotoxicity
* Extravasation injury
- Nausea and vomiting
- Mucositis
- red/orange urine discoloration

Front 38

How is Mitoxantrone different from the "rubi"s

Back 38

Mitoxantrone has less free radical formation; therefore, less risk of cardiotoxicity, extravasation injury, N/V, mucositis

Front 39

Extravasation injury

Back 39

fluid leaks out of the vein and into the surrounding tissues
This can cause cell death… must make sure that drug is infused into high flow area or pull back on the line to make flow is present in periphery

Front 40

Extravasation injury
Treatment

Back 40

wydase and cold

Front 41

Anthracyclines
Cardiotoxicity

Back 41

Acute
- arrhythmias
- within 24 hours of administration
- Related more to peak concentrations
Chronic
- cardiomyopathy
- secondary to free radical formation
- cumulative doses > 550 mg/m2

...if you have a low baseline EF, use another therapy...beware of CHF as a result of anthracyclines

Front 42

Dexrazoxane (Zinecard®)

Back 42

- Cardioprotectant
- Disrupts iron-ANTHRACYCLINE complex
- Prevents free radical formation without interfering with cytotoxic activity
- Used in leukemia with patients who have underlying heart dysfunction

Front 43

Liposomal doxorubicin (Doxil®)

Back 43

- cardio-friendly drug
- Liposomal delivery system not as readily taken up by cardiac tissue --> decrease risk of cardiotoxicity
- Used in breast, ovarian cancer

Front 44

Mitoxantrone

Back 44

- Similar ring structure to anthracyclines
- Similar mechanism of action, with decreased tendency for free radical formation
- Decreased cardiotoxicity and extravasation (b/c of less free radical potential)
- Decreased nausea and vomiting
- Blue-green urine discoloration

Front 45

Bleomycin

Back 45

- Used in testicular cancer, Hodgkin’s Disease
- Test dose needed only for Hodgkin’s disease
- Watch for PULMONARY TOXICITY and N/V

Front 46

Mitomycin C

Back 46

- used in gastrointestinal tumors
- used intravesicularly in bladder cancer
- Sent to OR for shake and bake (local effect instead of systemic effects)

Front 47

Types of Antimetabolites

Back 47

Antifolates
Purine Analogs
Pyrimidine antagonists

Front 48

Antifolates

Back 48

Methotrexate* (MTX)
Pemetrexed (Alimta)

Front 49

Purine Analogs

Back 49

Mercaptopurine* (6-MP)
Thioguanine* (6-TG)
Fludarabine
Cladribine

Front 50

Pyrimidine antagonists

Back 50

Cytarabine (Ara-C)
Gemcitabine (Gemzar®)
Fluorouracil (5-FU)
Capecitabine* (Xeloda®)
Nelarabine (Arranon)
Clofarabine (Clolar)

Front 51

Methotrexate
Mechanism of Action

Back 51

- Taken up intracellularly by cancer & healthy cells
- Inhibits dihydrofolate reductase --> decrease tetrahydrofolate --> decrease purine & thymidylate
Lack of purines & thymidylate prevents DNA synthesis

Front 52

Leucovorin rescue

Back 52

(cytoprotective number 4)
- Reduced folate that bypass MTX inhibition of tetrahydrofolate synthesis
- this is giving FH4
- Uptake healthy cells > cancer cells

Front 53

Why does Leucovorin rescue work?

Back 53

because methotrexate is absorbed faster by Cancer cells

Front 54

Toxicities of Methotrexate

Back 54

(LIMITING TOXICITY)
* Myelosuppression and mucositis
* Nephrotoxicity (crystallization of MTX)
- Neurotoxicity (with Interthecal therapy)
- Photosensitivity, eye discomfort
- Pneumonitis
- Hepatotoxicity

Front 55

What drugs should you avoid while on methotrexate?

Back 55

- Avoid nephrotoxic meds (NSAIDs, sulfa)

Front 56

Safety considerations regarding Methotrexate administration

Back 56

- PREVENT RENAL DAMAGE BY ALKALINIZING THE URINE WITH SODIUM BICARBONATE SOLUTIONS
- avoid drugs that can interfere with excretion of methotrexate: Bactrim, NSAIDS, etc.
- leucovorin rescue with high doses
- can accumulate in fluid and leach out over time causing serious toxicity – ensure patient has no fluid collections (ascitis, pleural effusions, etc.)
- Make sure CXR is obtained prior to dose

Front 57

When should you use leucovorin rescue?

Back 57

- needed when administering high-doses of methotrexate > 100-500 mg/m2
- directly converted into tetrahydrofolate without the need for dihydrofolate reductase
- begin 24 hours after methotrexate given
- should be given until methotrexate level is < 0.05 micromolar (5 x 10-8M)

Front 58

Pemetrexed (Alimta)
MOA

Back 58

inhibits multiple enzymes involved in folate metabolism and DNA synthesis
- does not inhibit dihydrofolate reductase

Front 59

Pemetrexed (Alimta)
Uses

Back 59

used for malignant pleural mesothelioma, non-small cell lung cancer

Front 60

Pemetrexed (Alimta)
toxicity

Back 60

cutaneous reactions – prevent with dexamethasone 4 mg bid day -1, 0, +1

Front 61

What should you administer before you start a patient on pemetrexed?

Back 61

give folic acid 350-1000 mcg daily and vitamin B12 1000 mcg IM q 9 weeks starting week before initiation and for 21 days after therapy to prevent hematologic and gastrointestinal toxicity

Front 62

Cytarabine (Ara-C)

Back 62

- Arabinose analog of cytosine
- Phosphorylated to active component within cancer cells
- Inhibits DNA polymerase

Front 63

What is the standard of care in leukemia?

Back 63

Cytarabine (Ara-C)
b/c it does not enter tissues very well; Ara-C stays in blood

Front 64

Ara-C
Toxicities at 100 mg/m2/day

Back 64

LIMITING TOXICITY
* Myelosuppression (100 mg/M2/day)
- Alopecia
- Gastrointestinal
- Rash—plantar-palmer syndrome (can treat with steroids)

Front 65

Ara-C
Toxicities at 3 g/m2/q 12 hrs

Back 65

LIMITING TOXICITY
* High dose toxicities
- nausea
- CNS toxicity
- chemical conjunctivitis, acral erythema (must give eye drops q 2 hrs to prevent ara-C accumulation in eyes)

Front 66

What must a patient do to receive Ara-C?

Back 66

pt must write there name and do the finger-to-nose test to show cns intact and cerebellum functioning
- CROSSES BLOOD BRAIN BARRIER
- cns toxicity is reversible if you stop the drug

Front 67

Gemcitabine (Gemzar®)

Back 67

MOA & structure similar to cytarabine
Intermittent dosing more effective than continuous dosing
Effective for solid tumors (b/c stays in tissues well)
- Pancreatic cancer
- NSCLC
Achieves intracellular concentrations 20x greater than cytarabine

Front 68

When would you give Ara-C over gemcitabine, and vice versa?

Back 68

Ara-C when you want drug to stay in circulation
Gemcitabine when you want drug to enter tissues

Front 69

Gemcitabine (Gemzar®)
Toxicities

Back 69

- Myelosuppression
- Generalized rashes
- Fever and flu-like symptoms
- Peripheral edema
- Nausea and vomiting-mild
- NOT Neurotoxic

Front 70

Clofarabine (Clolar)

Back 70

- Relapsed pediatric ALL
- Peds 52 mg/m2 IV daily x 5 days
- Adults 30-40 mg/m2 IV daily x 5 days
- AE-skin toxicity-rash to desquamation = main toxicity (drug concentrates in calloused hand tissues)
- not frontline tx b/c expensive

Front 71

Nelarabine (Arranon)

Back 71

- Tcell ALL or Tcell lymphoblastic lymphoma
- Peds 650 mg/m2 IV daily for 5 days
- Adults 1500 mg/m2 IV Day 1,3,5
- AE-neurotoxicity = main toxicity

Front 72

MOA for Nelarabine and Clofarabine

Back 72

inhibit DNA polymerase

Front 73

Which pyrimidine antagonists can be used in peds?

Back 73

Nelarabine and Clofarabine

Front 74

Fluorouracil
Mechanism of Action

Back 74

- fluorinated analog of uracil
- prodrug that is metabolized to FdUMP in order to be active
- FdUMP binds to thymidylate synthase (TS)
- prevents conversion of uracil (RNA) to thymidine (DNA)
- stabilizes TS & FdUMP in the presence of leucovorin (given with leucovorin to treat colon cancer)

Front 75

What are the uses of leucovorin?

Back 75

- Augment FU tx (not necessary)
- Rescue methotrexate pts (required)

Front 76

Fluorouracil
Toxicity

Back 76

* Myelosuppression (bolus)
* Bloody diarrhea (CI)
* Mucositis (CI)
- Dermatologic
- Ocular
- Nausea and vomiting (mild)
- Cardiotoxicity (rare)

Front 77

Capecitabine (Xeloda®)
Toxicity

Back 77

- Diarrhea
- palmar-plantar rash

Front 78

Capecitabine (Xeloda®)

Back 78

- Oral prodrug of fluorouracil
- Metabolized to active component in tumor tissue
- Use in metastatic colorectal & breast cancer
- Take BID with food (↓ N/V)

Front 79

Purine Analogs

Back 79

Inhibit de novo purine synthesis
- given a lot in pediatric patients on ALL maintenance treatment

Front 80

Mercaptopurine (6-MP)

Back 80

(Purine analog)
- Metabolized by xanthine oxidase
- ↓ dose x 75% if used with allopurinol

Front 81

Thioguanine (6-TG)

Back 81

(Purine analog)
- No dose reduction required with allopurinol

Front 82

Fludarabine & cladribine

Back 82

(Purine analogs)
- Immunosuppressive → risk of opportunistic infections (PCP, CMV)
- Consider prophylactic antibiotics

Front 83

List the Vinca alkaloids

Back 83

Vincristine (Oncovin®)
Vinblastine (Velban®)
Vinorelbine (Navelbine®)

Front 84

List the Taxanes

Back 84

Paclitaxel (Taxol®)
Docetaxel (Taxotere®)

Front 85

Vinca alkaloids
Mechanism of Action

Back 85

- Inhibit microtubule assembly
- Interfere with formation of mitotic spindle
- Cells accumulate in mitosis
- “Spindle poisons” which bind to tubulin

Front 86

Taxanes
Mechanism of Action

Back 86

- Promote microtubule assembly
- Interfere with microtubule disassembly
- “Spindle poisons” which bind to tubulin

Front 87

Why do you need to be careful with vincristine?

Back 87

there is nothing you can do to stop it's action, so never give more than 2 mg... and it paralyzes your smooth muscle until you die

Front 88

Vincristine
Toxicities

Back 88

* Neurotoxicity (LIMITING TOXICITY)
- Constipation
- Vesicant
- Extravasation
- SIADH
* Do not give Intrathecally

Front 89

Vinblastine
Toxicities

Back 89

- Myelosuppression (LIMITING TOXICITY)
- Vesicant
- Extravasation

Front 90

How do you treat extravasation of vinca alkaloids

Back 90

Use warm compresses & hyaluronidase

Front 91

Vinorelbine
Toxicities

Back 91

* myelosuppression (LIMITING TOXICITY)
- neuropathy
- nausea and vomiting
- extravasation
- alopecia

Front 92

Vinorelbine (Navelbine)

Back 92

- semi-synthetic vinca alkaloid
- used for lung, breast, ovarian, lymphoma

Front 93

Taxanes
Toxicities

Back 93

* Myelosuppression (LIMITING TOXICITY)
* Mucositis (LIMITING TOXICITY)
- Peripheral neuropathy (cumulative)
Alopecia
- Hypersensitivity reactions
- Nausea and vomiting (rare)

Front 94

Why do taxanes have hypersensitivity reactions and what can we do about it?

Back 94

- becase the drug is oil based and put into blood
- premedicate with dexamethasome, H1 and H2 antagonist

Front 95

Paclitaxel
Toxicities

Back 95

- Myalgia
- Bradycardia
- Cremaphor EL - oil in solution that causes hypersensitivity

Front 96

Docetaxel
Toxicities

Back 96

- Fluid retention
- Palmar-plantar rash
- Polysorbate-80 - oil in solution that causes hypersensitivity

Front 97

Ixabepilone
Adverse Events

Back 97

- Neurotoxicity about 65% overall in studies
- Neutropenia incidence 65% but febrile neutropenia incidence only 3-4%

Front 98

What premeds are given with Ixabepilone?

Back 98

H1 blocker – diphenhydramine 50 mg
H2 blocker – ranitidine 50 mg IV

Front 99

Ixabepilone (ix-a-BEP-i-lone)Ixempra® (ix-EM-pra)

Back 99

- Semi-synthetic analog of epothilone B
- Binds directly to ß-tubulin on microtubules, leading to suppression of microtubule dynamics
- Some binding sites overlap with paclitaxel
- accounts for its activity in taxane resistant patients