Clinical Pharmacology of Anti-Cancer Agents (Part 1)

Question 1

How can anti-cancer medications be classfied?

Answer 1

Biochemically or based on their effect on the cell-cycle

Question 2

Biochemical classification of anti-cancer agents

Answer 2

1. Alkylating agents
2. Enzyme inhibitors
3. Antimetabolites
4. Antimicrotubules
5. Endocrine therapies
6. Immunotherapies
7. Targeted therapies
8. Miscellaneous

Question 3

Cell-cycle classification of cancer agents

Answer 3

Cell-cycle phase specific agents

• most toxic to cancer cells based on the part of the cell cycle that it is active
• especially toxic to the S phase of the cell cycle
• continuous infusion will increase exposure to cancer cells

Cell-cycle phase non-specific agents

• kills normal and cancer cells to the same extent
• attacks cancer cells at any phase of the cell cycle, including the resting phase.
• cell kill is proportional to dose.
• applies to: alkylating agents, anthracycline antibiotics, anti-tumour antibiotics, nitrosoureas

Question 4

Differences between acute and delayed toxicities

Answer 4

Acute toxicities:

• inhibit host cell division
• occurs most in rapidly renewing cell populations such as GI mucosal cells, skin/hair cells and bone marrow cells

Delayed toxicities:

• occurs months to years after initiation of cancer treatment.
• infertility, secondary malignancies

Question 5

Alkylating agents

1. MOA
2. Toxicity

Answer 5

1. MOA:
   - Major cytotoxic effect: formation of an electrophilic carbonium ion that binds to the nucleophilic sites (amines, hydroxyl, phosphates) of the reactive molecules in the DNA.
   - N7 atom of guanine is highly susceptible.
   - Cytotoxic effects result from the inhibition of transcription and replication of DNA, DNA strand mispairing and breakage.
2. Toxicity
   - Dose-limiting toxicity for alkylating agents is myelosuppression.
   - Acute toxicites include: alopecia, neurotoxicity, mucositis, CINV
   - Long-term toxicities include: infertility, secondary leukemias, pulmonary fibrosis.

Question 6

Cyclophosphamide:

1. MOA
2. Side effects
3. Dose precautions
4. Dose

Answer 6

1. Cyclophosphamide is converted to 4-hydroxyphosphamide, which is then converted into acrolein (active metabolite in the liver) and subsequently phosphoramide mustard.
2. Myelosupression, emetogenic potential, nausea and vomiting, cardiac dysfunction at high doses, dose-limiting hemorrhagic cystitis.
3. Absorption is usually done on an empty stomach, but medication can be taken with food in the event of a GI upset.
   Need to dose adjust for people with renal dysfunction
4. 600-750mg/m2 for those with lymphomas and breast cancer. 2g/m2 for those with bone marrow transplant.

Question 7

Ifosfamide:

1. MOA
2. Side effects
3. Dose precautions
4. Indications

Answer 7

1. Analogue of cyclophosphamide that is activated in the liver by CYP3A4. Alkylation of iphosphoramide mustard at guanine N7 positions, forming DNA crosslinks that result in cell death.
2. Side effects include CNS toxicity, nephrotoxicity, dose-limiting hemorrhagic cystitis, nausea and vomiting.
3. Dose precautions:
   - administer with MESNA, vigorous hydration 1-2L before and after administration of drug.
4. testicular and diffuse, large B-cell lymphoma

Question 8

Symptoms of ifosfamide neurotoxicity, how to prevent/manage it?

Answer 8

Symptoms (due to an accumulation of chloroacetaldehyde):

• confusion
• hallucinations
• somnolence

Prevention/management of ifosfamide:

1. beware of using in elderly and people with renal dysfunction
2. increase infusion time
3. avoid concurrent administration of CNS active drugs 4. decrease or discontinue treatment with onset of symptoms
4. administer methylene blue to prevent the accumulation of chloroacetaldehyde.

Question 9

Cisplatin:
1. Indication
2. Dose and administration
Toxicities

Answer 9

1. Wide range of solid tumours
2. Dose and administration precautions:
   - verify dose if it is above 100mg/m2/cycle
   - pre-hydrate and ensure urine output of >100mL/h before initiation of treatment
   - administer 1-2L of 0.9% NaCI IV alongside potassium and magnesium supplements.
   - use not recommended for renally impaired patients, with SCr <1.5mg/dL
   - administer furosemide, mannitol, amifostine
3. Toxicities:
   - nephrotoxicity
   - ototoxicity
   - cumulative peripheral neuropathy
   - delayed CINV
   - irritant to veins

Question 10

Carboplatin

1. Indication
2. Dose
3. Toxicities

Answer 10

1. Indicated for a wide range of solid tumours
2. Use BSA to calculate dose: AUC x (GFR + 25), where AUC = 2 for daily dosing, AUC = 5 or 6 for every 3 weeks
3. Toxicities:
   - Dose-limiting myelosuppression
   - Compared to cisplatin, much lower incidence of nephrotoxicity, ototoxicity and delayed CINV
   - Hypersensitivity

Question 11

Oxaliplatin

1. Indication
2. Dose
3. Toxicities

Answer 11

1. Indicated for a wide range of solid tumours
2. Dose based on indication and regimen. Stable only in D5W.
3. Toxicities:
   - cumulative peripheral neuropathy
   - myelosuppression
   - nephrotoxicity (much less than cisplatin)
   - hypersensitivity

Question 12

Difference between topoisomerase I and II inhibitors

Answer 12

Topo I inhibitor : single-stranded DNA break
- irinotecan, topotecan

Topo II inhibitor: forms a complex, resulting in double-stranded breaks
- etoposide, teniposide, anthracyclines

Question 13

Irinotecan:

1. MOA
2. Indication
3. Toxicities

Answer 13

1. MOA:
   - semi-synthetic, water-soluble derivative derived from alkaloid extracted plants.
   - Irinotecan and its active metabolite, SN-38, inhibit the action of topoisomerase I, preventing the religation of the DNA strand, resulting in cell breakage and death.
   - cell-cycle specific (S-phase).
2. Indication
   - indicated for metastatic colorectal cancer
3. Toxicities
   - Dose-limiting diarrhoea
   » Diarrhoea: administer with 4g of loperamide initially, then 2g of loperamide every 2 hours until diarrhoea free for 12 hours.
   - Cholinergic syndrome (SC or IV atropine 0.25-1mg)
   - UGT1A1 deficiency (reduction of starting dose by at least one should be made).

Question 14

Anthracyclines:

1. Drug class
2. MOA
3. Toxicities

Answer 14

1. • rubicins + mitoxantrone
2. Induce the formation of topoisomerase II DNA complexes, thus preventing the religation of DNA, resulting in double-stranded DNA breaks. Intercalations between DNA base pairs, metabolised in liver to form oxygen-free radicals, which can add to cytotoxicity.
3. cardiotoxicity, dose-limiting myelosuppression, alopecia, acute nausea and vomiting, can cause red discolouration of urine, requires patient education.

Question 15

Anthracycline induced cardiotoxicity

1. Pathophysiology
2. Risk factors
3. Prevention methods

Answer 15

1. Pathophysiology:
   - Acute (few hours): pericarditis, arrhythmias
   - Subacute (weeks to months): tachycardia
   - Late (> 5 years): cardiomyopathy
2. Risk factors
   - cumulative doses
   - age
   - administration schedule (administration peaks)
   - mediastinal radiation
   - known cardiac disease
3. Prevention methods
   - limit cumulative dose
   - administration schedule
   » fractionate doses
   » prolonged infusion
   - administer a less cardiotoxic anthracycline /analogue: liposomal doxorubicin (caelyx) or mitoxantrone, and dexrazoxane (cardiac protectant)
   - take baseline MUGA to evaluate LVEF before starting on anthracyclines.

Question 16

Different MOA of antimetabolites

Answer 16

1. compete for binding sites on enzymes (antifolate agents: methotrexate)
2. Incorporate directly into DNA or RNA (analogues: purine and pyrimidine)

Question 17

Methotrexate:

1. MOA
2. Indication
3. Main toxicities
4. Drug interactions
5. Drug precautions
6. Summary

Answer 17

1. Methotrexate irreversibly binds to DHFR to inhibit the production of tetrahydrofolate that is used for purine and thymidylate synthesis.
   » inhibition of DHFR results in prevention of cellular replication, DNA transcription and translation.
2. Indication: for all cancers
3. Dose-limiting myelosuppression, nephrotoxicity
4. NSAIDs, probenecids/sulfonamides, vitamin C, salicylates, omeprazole, penicillins
5. Don’t take with food: food delays absorption and reduces peak concentration
6. Summary
   - methotrexate can be administered at high doses across a variety of adminstration routes.
   - At high doses (> 1g/m2), it should undergo therapeutic drug monitoring and folinic rescue therapy, until its levels drop to 0.1uM.
   - Methotrexate is unsuitable for those with pleural effusions or ascites as it can escape into third spaces.