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Traditional chemotherapy alkylators (1) Flashcards

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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

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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)

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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?

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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?

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

Ifosfamide neurotoxicity management

Study These Flashcards
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
What drug class is melphalan?
nitrogen mustard (alkylating agent)
26
Melphalan specific ADR
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
What is the dose limiting ADR for mustard alkylators?
Myelosuppression
28
Mustard Alkylator ADRs
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
Which 4 drugs are non-mustard and non platinum alkylating agents?
1. Dacarbazine 2. Carmustine (nitrosourea) 3. Lomustine (nitrosourea) 3. Temozolomide (TMZ)
30
Nitrosourea (carmustine and lomustine) and temozolomide (TMZ) properties and clinical use
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
Dacarbazine considerations
Alkylating agent IV only -very poor oral absorption and poor CNS penetration -so rarely used anymore Very highly emetogenic
32
High expression of which gene can lead to poor temozolomide response?
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
What is the dose limiting toxicity of temozolomide?
Myelosuppression (other than that it is pretty tolerable)
34
Temozolomide is often combined with _________________ ... because of this what should be done?
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
What is important to remember about the cycle duration for carmustine and lomustine?
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
Carmustine vs lomustine administration considerations
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
Carmustine/lomustine (nitrosourea) dose limiting toxicity
Myelosuppression (with prolonged nadir)
38
What delayed toxicity can carmustine and lomustine have?
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
Which 3 drugs are platinum derivative alkylators
Cisplatin Carboplatin Oxaliplatin
40
Platinum analog elimination considerations
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
Oxaliplatin is commonly used in combination with __________ for treatment of _____________
Oxaliplatin is commonly used in combination with 5-FU for treatment of colorectal cancer (and other GI cancers)
42
Which platinum derivative has more ADRs than the others?
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
What is the dose limiting toxicity of cisplatin?
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
Cisplatin ADRs (5)
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
Carboplatin dosing considerations
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
Carboplatin dose limiting toxicity
Myelosuppression -but particularly thrombocytopenia (more than neutropenia)
47
What can happen with carboplatin?
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
Oxaliplatin dose limiting toxicity
Neurotoxicity -progressive delayed peripheral neurotoxicity can occur - this can be irreversible (if dose is not reduced/medication is not changed)
49
Oxaliplatin specific ADR
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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