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Hematology/Oncology > Traditional chemotherapy alkylators (1) > Flashcards

Traditional chemotherapy alkylators (1) Flashcards

1
Q

3 types of radiation

A
  1. External beam radiation
  2. Brachytherapy
  3. Proton therapy
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2
Q

External beam radiation

A

-x ray delivered from outside (source is outside of body)

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3
Q

Brachytherapy

A

-radiation source is inside the patient’s body (radioactive seeds implanted into the patients tumor)

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4
Q

Proton therapy

A

-proton is more powerful and targeted radiation

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5
Q

T cell therapy

A

T cells are extracted from patients
Engineered to express receptor that can target tumor antigen
Then injected back into patient to kill cancer cells

This is a one time injection, and these engineered t cells last in the patient’s body forever - can be curative

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6
Q

What is the main difference between traditional and current targeted chemotherapy?

A

Traditional chemotherapy targets DNA
-cause DNA damage and induce cell death

Current targeted therapy - target a variety of proteins
-oncoproteins specific to different cancers

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7
Q

Primary vs neoadjuvant vs adjuvant chemotherapy

A

Primary chemotherapy
-the chemo is the main agent

Neoadjuvant
-chemo is not the primary agent, the primary agent is surgery or radiation
-chemo is done BEFORE the primary agent

Adjuvant
-chemo is not the primary agent, the primary agent is surgery or radiation
-chemo is done AFTER the primary agent

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8
Q

Chemotherapy is ___________ for most cancers, it is curative for which cancers?

A

Chemotherapy is palliative for most cancers
-chemo can NOT cure most cancers

It can be curative in a few cases…
-leukemia in children
-testicular cancer
-Hodgkin’s lymphoma
(note - Hodgkin’s lymphoma is not as common, tends to occur in younger patients, non-Hodgkin’s is more common, tends to occur in older patients and can not be cured)

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9
Q

Log 1st order kill hypothesis

A

The main point of this is that chemotherapy can only cure a portion of cancer cells, and it kills in first order (not a fixed number)

So the idea is we need to give higher doses and more frequent doses to kill as much and as fast as possible

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10
Q

Cell division cycle phases

A

G1 phase - protein synthesis phase
S phase - DNA replication (genome is duplicated)
G2 phase - protein synthesis
M phase - mitosis (cell division, newly formed DNA is separated into 2 daughter cells)

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11
Q

Why do bone marrow, skin, and GI cells have more side effects due to chemotherapy?

A

Because these cells have faster turnover rate
And chemotherapy is better at targeting cells that are proliferating (rather than resting cells) - cells that are proliferating more are more sensitive to chemotherapy

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12
Q

Resistance to chemotherapy (3 methods)

A

Cells can change/adapt to avoid the toxic agents being thrown at them…
-they can increase DNA repair (repair damage being done by the drug)
-Form thio trapping agents - most chemo drugs are pro drugs, these trapping agents form a complex with the pro drugs, preventing them from being metabolized into active drug
-Increase efflux - express more efflux pumps to remove toxin from cell

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13
Q

Why is combination therapy used for chemo?

A

Combination therapy is more effective (increased killing of cancer cells) and also helps minimize adverse effects (of high dose single agent)
- note you don’t want to use 2 drugs that target the exact same thing (phase)
- you don’t want to use 2 drugs that have the same toxicities

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14
Q

How do alkylating agents work?

A

They generate DNA adducts by alkylating themselves to DNA (bind covalently)
They are particularly sensitive for the guanine base … by binding to it it interferes with DNA paring, causes DNA breakage, and effects DNA replication

When there is DNA damage beyond repair, the cell will undergo apoptosis

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15
Q

Are alkylating agents cell cycle specific or non-specific?

A

These are cell cycle NON specific agents
(bind to DNA)

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16
Q

What are the 4 categories of drugs that are alkylating agents?

A
  1. Nitrogen mustards
  2. Nitrosoureas
  3. Alkyl sulfonates
  4. Platinum analogs
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17
Q

Does changing the route of administration effect the n/v that occurs with chemotherapeutic agents?

A

NO
it will occur even if given IV
why? - these are toxins - so they will trigger the n/v reaction in the chemoreceptor zone in the brain

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18
Q

Which 3 agents are mustard alkylators (nitrogen mustards)?

A

Cyclophosphamide
Ifosfamide
Melphalan

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19
Q

Cyclophosphamide metabolism considerations

A

Cyclophosphamide (mustard alkylator) is a pro-drug it is metabolized by enzymes to active cytotoxic metabolites - phosphoramide mustard and acrolein … these are the substances that damage DNA

Since this process is enzyme dependent - patients who are deficient in these enzymes may have diminished effect

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20
Q

Acrolein metabolite effects

A

Cyclophosphamide and ifosfamide produce the toxic metabolite - acrolein
-this is very irritating to the bladder and can cause hemorrhagic cystitis (inflammation and bleeding of bladder)

21
Q

Acrolein induced hemorrhagic cystitis prevention (3)

A
  1. Aggressive oral and IV hydration
    -this is done before the infusion of cyclophosphamide or ifosfamide
    -wait until patient is voiding enough (reached certain urine output) - only then can we start infusion
  2. MESNA
    -this is given IV or PO, and is reuptaken by the kidney into the bladder where it detoxifies acrolein (limited ADRs, just works in the bladder
    -must be given with high doses of cyclophosphamide and any doses of ifosfamide (produces 4x as much acrolein)
  3. Continuous bladder irrigation
    -pump fluid into the bladder
    -not comfortable for the patient, but better than having hemorrhagic cystitis
22
Q

Ifosfamide also undergoes a different metabolism pathway producing another metabolite that causes what kind of toxicity?

A

Ifosfamide is also metabolized to chloroactaldehyde which causes neurotoxicity (this metabolite crosses the BBB, which is why these symptoms occur)
-symptoms include: sedation, confusion, cerebellar symptoms
-this is usually reversible once infusion is stopped

23
Q

What are 3 risk factors for neurotoxicity associated with ifosfamide?

A
  1. Elderly (65 or older)
  2. Female
  3. Frail
24
Q

Ifosfamide neurotoxicity management

A

It is caused by the build up of the metabolite chloroacetaldehyde (from ifosfamide) - and it is usually reversible

Symptoms will usually go away within 24-48 hours after stopping the ifosfamide infusion - if no improvement by then, then we can give treatment

Or, if symptoms are very severe - coma/seizure , can give treatment before then

Pre treatment is NOT recommended (even if patient is high risk)

Treatment: methylene blue and thiamine

25
Q

What drug class is melphalan?

A

nitrogen mustard (alkylating agent)

26
Q

Melphalan specific ADR

A

Feeling very HOT
-very uncomfortable - ice chips, cooling blankets recommended

But no hemorrhagic cystitis or neurotoxicity like with the other nitrogen mustard agents
(But not commonly used for solid tumors)

27
Q

What is the dose limiting ADR for mustard alkylators?

A

Myelosuppression

28
Q

Mustard Alkylator ADRs

A

Dose limiting: myelosuppression

Mild/moderate emetogenic

Alopecia & mucositis

Electrolyte wasting
-potassium, magnesium, and phosphate wasting
-IV fluid with electrolytes to give these back
-check BMP before infusions, make sure electrolytes are normal before starting - if not give bolus of electrolytes

29
Q

Which 4 drugs are non-mustard and non platinum alkylating agents?

A
  1. Dacarbazine
  2. Carmustine (nitrosourea)
  3. Lomustine (nitrosourea)
  4. Temozolomide (TMZ)
30
Q

Nitrosourea (carmustine and lomustine) and temozolomide (TMZ) properties and clinical use

A

These are highly lipophilic agents - readily cross the BBB
-nitrosoureas are IV, TMZ can be taken orally (very high oral bioavailability)

So, these drugs are effective for treatment of brain tumors (gliomas)
-specifically temozolomide (TMZ) which is the standard drug for treatment of high grade gliomas

(these are all alkylating agents - will bind to the DNA specifically guanine)

31
Q

Dacarbazine considerations

A

Alkylating agent
IV only
-very poor oral absorption and poor CNS penetration
-so rarely used anymore

Very highly emetogenic

32
Q

High expression of which gene can lead to poor temozolomide response?

A

High expression of MGMT - this is a repair gene that can be expressed by glioblastoma cells (remember TMZ is used to treat brain tumors)

We don’t want the cells to express this MGMT repair gene a lot - this will decrease the effect of TMZ

So we look to see how much MGMT is expressed by cells before starting treatment with TMZ

33
Q

What is the dose limiting toxicity of temozolomide?

A

Myelosuppression
(other than that it is pretty tolerable)

34
Q

Temozolomide is often combined with _________________ … because of this what should be done?

A

Temozolomide is often combined with radiation therapy

TMZ causes myelosuppression, which can be worsened by the radiation therapy - patients may be neutropenic for a while … so if combined with radiation, patients MUST be started on PCP prophylaxis
-first line agent for that is Bactrim
(alternatives are dapsone and atovaquone)

35
Q

What is important to remember about the cycle duration for carmustine and lomustine?

A

These are the 2 drugs that are the exception to the ~7 day nadir rule…
they have a prolonged nadir … so there are 42 days between cycles

36
Q

Carmustine vs lomustine administration considerations

A

Both are very lipophilic (cross BBB)

Carmustine is given IV
-important to note that it is given in can only be given in an ethanol vehicle- resulting in side effects similar to alcohol toxicity

Whereas lomustine is given PO (avoids that ethanol toxicity effect)
-note other side effects are just as dangerous with PO version though

37
Q

Carmustine/lomustine (nitrosourea) dose limiting toxicity

A

Myelosuppression
(with prolonged nadir)

38
Q

What delayed toxicity can carmustine and lomustine have?

A

Pulmonary toxicity
-it is pretty common for patients to have some capacity of lung damage
-typically occurs 6-8 weeks after completion of therapy

39
Q

Which 3 drugs are platinum derivative alkylators

A

Cisplatin
Carboplatin
Oxaliplatin

40
Q

Platinum analog elimination considerations

A

These drugs have platinum in them, they are excreted unchanged through the kidney
-renal problems can effect elimination
-and these drugs can cause renal toxicities

41
Q

Oxaliplatin is commonly used in combination with __________ for treatment of _____________

A

Oxaliplatin is commonly used in combination with 5-FU for treatment of colorectal cancer (and other GI cancers)

42
Q

Which platinum derivative has more ADRs than the others?

A

Cisplatin
-this is the oldest one, has a LOT of toxicity (so the other 2 - carboplatin and oxaliplatin are used more commonly), but it is effective so it is still used

43
Q

What is the dose limiting toxicity of cisplatin?

A

Nephrotoxicity
(it is the most nephrotoxic chemo agent)
Because of this there is a max dose of 100 mg/m2 per dose (or per cycle)

44
Q

Cisplatin ADRs (5)

A
  1. Highly emetogenic
    -can be acute (within 24 hours) or delayed - several days after
    -patients can get dehydrated and lose weight
  2. Nephrotoxicity
    -dose limiting toxicity
  3. Electrolyte wasting
    -MUST hydrate patients with Mg and KCl pre and post infusions (they should be on the upper end of the normal electrolyte level before starting infusion)
  4. Ototoxicity
    -high frequency hearing loss (doesn’t interfere much with daily living)
    -patients get hearing test before each infusion
  5. Neuropathy
    -due to max dose - the higher the dose, the greater the neuropathy - and this can be reversible damage

Note - there is less myelosuppression than with other drugs though

45
Q

Carboplatin dosing considerations

A

Dosed using Calvert formula
(using AUC target)
Note - CrCl should be capped at 125 ml/min when using this formula (even if the patient’s is higher, do not use higher than that)

46
Q

Carboplatin dose limiting toxicity

A

Myelosuppression
-but particularly thrombocytopenia (more than neutropenia)

47
Q

What can happen with carboplatin?

A

Anaphylaxis
-unclear of how it occurs - type 1 (IgE) for some patients, type 4 (t cell mediated) for others
-risk increases with exposure, particularly after 6 cycles
-if anaphylaxis does happen - desensitization protocols should be followed (these agents are effective, we want to continue to use them)

48
Q

Oxaliplatin dose limiting toxicity

A

Neurotoxicity
-progressive delayed peripheral neurotoxicity can occur - this can be irreversible (if dose is not reduced/medication is not changed)

49
Q

Oxaliplatin specific ADR

A

Neurotoxicity…
Sensitivity to COLD temperatures
-avoid cold for 4 days post infusion (can be painful)

Numbness/tingling
Paresthesia

Hematology/Oncology (17 decks)

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