Medical oncology

Question 1

Name the anthracyclines and a little about them

Answer 1

Doxorubicin and idarubacin. There are other niche ones. These are part a wider group known as the cancer antbiotics or anti-tumour antibiotics. They are microbiologically derived chemicals that naturally inhibit mammalian cell replication.

The other anti-tumour antibiotics are dactinomycin, which intercalates with DNA and interferes with RNA polymerase activity preventing transcription, and may also interfere with topoisomerase II inhibitor (like the anthracyclines), bleomycin, which is an iron chelating aminoglycoside ab with destroys DNA through liberation of iron causing free radical formation in the cell nuclei, and lastly mitomycin that works like an alkylating agent in that it causes inappropriate base pair cross linking.

Question 2

How do anthracyclines work?

Answer 2

They inhibit topoisomerase 2 alpha preferentially in cancer cells. This inhibits the S phase of the cell cycle by interfering with DNA replication and syntehsis.

Question 3

What are the different phases of the cell cycle?

Answer 3

Go - not replicatin
With the introduction of growth singals
–>G1. Enhanced protein synthesis of the component required for synthesis. This process is driving by cyclin-dependent cyclase 4 and 6 (not CDK4/6 inhibitors in hormone +ve HER2 -ve breast cancer work here).
–>Restriction/checkpoint 1 (Rb and p53 dependednet). Progression only if limited DNA errors on detected.
–>S phase - DNA replication phase with chromosome duplication.
–> G2 checkpoint - checks for successful error free replication. If passed, then onto mitosis
–> G2 - prepartion for mitosis (synthesis of the mitosis machinery)
–> M phase / mitosis. Tubule dependent. Note that vinca alkaloids work here - they prevent tubulin from forming the polymors needed to form mitotic spindles.
–>fin

Question 4

Which cell cycle phase to bleomycin impact most?

Answer 4

G2 - it’s an iron chelator that when bound to iron is able to intercalate with open DNA and create free radicals that cleave DNA into small components. It is thoerised that chromatin may open into its most bleomycin susceptible shape during G2.

Question 5

With regards to DNA, what are the pyrimidines?

Answer 5

Cytosine, thymine and uracil.

Question 6

With regards to DNA, what are the purines?

Answer 6

Guanine and adenine

Question 7

How do alkylating agents work?

Answer 7

The cause intrastrand cross linking of nucleosides leading to errors during replication (S phase) and cell death after failure to pass through the G2 checkpoint.

Question 8

Name the subgroups of alkylating agents

Answer 8

Nitrogen mustards, nitrosoureas, platinum compounds.

Question 9

Name some nitrogen mustards (alkylating agents)

Answer 9

Cyclophosphamide, ifosfamide, melphalan, chlorambucil, estramustin, bendamustine.

Question 10

Name some nitrosoureas? (subgroup of alkylating agents)

Answer 10

Lomustine and armustine. These are lipid soluble and cross the blood/brain barrier.

Question 11

What are the classic side effects of cyclophosphamide and ifosfamide?

Answer 11

Myelosuppression, nausea and vomiting, haemorrhagic cystitis, increased risk of bladder TCC. Mesna or NAC can be used to reduced the risks of harmorrhagic cystitis.

Question 12

What cyclophosphomide/ifosfamide toxic metabolite is responsible for haemorrhagic cystitis?

Answer 12

acrolein. It is neutrolised by mesna or NAC

Question 13

What are the major side effects of the nitrosoureas? (lomustine, carmustine)

Answer 13

Dose accumulation (3-6 weeks of treatment) related myelosuppression. If continued can lead to bone marrow failure.

Question 14

What are the ungrouped alkylating agents?

Answer 14

Dacarbazine (highly emetegenic), temozolomide (just used for glioma), procarbazine (used in Hodgkin’s lymphoma), thiotepa, bisulfan (specific bone marrow activity - granulocytes and platelets at low concentrations, red cells as well at high concentrations - used in CML) and tresulfan.

Question 15

What are the platinum alylating agents?

Answer 15

Cisplatin, carboplatin, and oxaliplatin.

Question 16

What are the major side effects of cisplatin?

Answer 16

Highly nephrotoxic, ototoxic and emetagenic. Causes myelosuppression, but less than other drugs. Also causes peripheral neuropathies.

Question 17

What’s the key difference between cisplatin and carboplatin?

Answer 17

Carboplatin was developed to have fewer side effects than cisplatin. It is less emetegenic, nephrotoxic, neurotoxic, and less ototoxic than cisplatin. It is, however more myelotoxic than cisplatin!

Question 18

What are the subgroups of antimetabolite drugs?

Answer 18

Folate antagonists, pyrimidine analogs, purine analogs

Question 19

What are the folate antagonists?

Answer 19

Methotrexate, ralitrexed, and pemetrexed.

Question 20

What are the main side effects of folate antagnosist? (e.g. methotrexate)

Answer 20

Myelosuppression, GI epithelium damage, pneumonitis. In very high doses - nephrotoxicity (thus the high dose methotrexate protocols requiring lots of fluid and rescue folinic acid).

Question 21

Name the pyrimadine analogues

Answer 21

Fluorocuracil (uracil analog), capecitabine (tpet flurouracil pro-drug), cytrarbine (cytosine analog), gemcitabine (cytarabine/cytosine analog with fewere adverse effects).

Question 22

What are the key side effects of the pyrimadine analogs?

Answer 22

5-FU is renowned for coronary artery vasospasm. All of them can cause hand foot syndrome (palmoplanter erythrodysaethesia). These agents are also renowned for causing severe diarhoea (chemotherapy enduced colitis). Myelosuppression remains and issue.

Question 23

Name the purine analogs

Answer 23

Fludarabine, claridbine, pentostatin, clofarabrine, nelarabrine, mercaptopurine, and tioguanine.

Question 24

What are the most emetogenic anti cancer drugs?

Answer 24

Alkylating agents are hands down the worst. However recently the antibody bound radioactive agents have joined them. Cisplatin (platinum) and carmustine (nitrogen mustard) are alkylating agents renouned for this. There is a new drug sacituzumab (a anti trophoblast 2 ab that binds breast cancer) that is bound to govitecan (a campthecins that causes topo isomerase I inhibition) that is very emetigenic. When cyclophosphamide is given with an anthracycline it’s particularly bad too.

Question 25

What are the plant derived cytotoxic cancer drugs?

Answer 25

Vinca alkaloids, taxanes, camptothecins, etoposide (in a group of its own).

Question 26

What are the vinca alkaloids and how do they work?

Answer 26

Vincristine, vinblastine, vindesine - all derived from the Madagascar periwinkle. Work by inhibting the ability of tubulin to polymerase to form microtubules in mammalian cells - critical for forming the spindles used during mitosis.

Question 27

What are the taxanes, and how do they work?

Answer 27

Also plant derived, paclitaxel and docetaxel are derived from the the bark of the yew tree. They also act on microtubules, but unlike the vinca alkaloids that prevent microtubule formation, the taxanes stabilise them - effectivley freezing them. This makes them inflexible and unable to participate in mitosis, nor be deconstructed.

Question 28

What are the camptothecins and how do they work?

Answer 28

Inrinotecan and topotecan are the most commonly used. They are plant derived chemo, and come from the camptotheca tree. They are topoisomerase I inhibitors - so they impair chromatin relaxation that would otherwise allow DNA replication in the S phase of the cell cycle. Irinotecan can cause life threatening diarrheoa.

Question 29

What is etoposide? How does it work?

Answer 29

Etoposide is derived from mandrake root (plant derived chemo). It’s a topoisomerase II inhibitor like the anti-tumour antiobiotics: the anthracyclines (doxorubicin etc). Topoisomerase II is required for the manipulation of the hinge region of DNA strands that are unzipping for DNA replication. Without it, unintended crosslinking causes errors during replication and the cell fails at the G2 chekpoint.

Question 30

What time range after cytotoxic chemotherapy is usual for the nadir of cell counts?

Answer 30

7-14 days

Question 31

What is netupitant?

Answer 31

It’s an antiemetic used in high emetegenic chemotherapy regimens in a fixed forumlation with palonosetron. It works by inhibiting binding of substance P to the receptor neurokinin-1. Substance P is rich in the vagus nerve and the NK-1 receptor rich in the brain stem near the vagal afferent projections. It’s though that NK-1 activation (G-coupled receptor) plays an important role in both acute and delayed chemo induced vomiting. Further NK-1 inhibition increases tge dyration of activity of the 5-HT3 antagonists like ondansetron/palonsetron.

Question 32

What cancer treatment classically causes planter-palmer hyperkeratosis?

Answer 32

The BRAF inhibitors (recall the importance of BRAF mutations in melanoma, and the use of BRAF tyrosine kinase inhibitors - dabrafenib, vemurafenib etc.) Rash onset is usually about 8 weeks after commencing treatment.

Question 33

What cancer treatments classically cause an actineform rash?

Answer 33

Classically, the EGFR receptors will do this - e.g. erlotinib, gefitinib, cetuximab, and panitumumab. Used in lung and GI malignancies.

Question 34

Which cancer treatment classes classically cause peripheral neuropathy?

Answer 34

Taxanes (paclataxel/docetaxel - microtubule freezing plant derived anticancer drugs), vinca alkaloids (plant derived tubulin polymerisation inhibitors), platinum-based alkylating agents (e.g. cisplatin/carboplatin/oxalipatin) all cause peripheral neuropathy.

Question 35

How is the management of acute and delayed chemotherapy induced emesis different?

Answer 35

Acute nausea and vomiting is managed with long acting 5HT3 receptor antagnosist (like palonosetron), olanzipine, dexamethasone and NK-1 receptor antagonists (e.g. netupitant). In high emetorgenic risk regimes, all 4 are used up front as prophylaxis. For delayed emesis - 5HT3 anatagnoists are not very useful.o Instead, the focus is on dexamethasone and olanzapine use. An important exception is dexamethasone is not used for delayed emesis in doxorubicin/cyclophosphamide (breast cancer AC) regime beyond day 1 due to lack of evidence of benefit. Instead NK1 receptor antagonists may need to be re-introduced.