Pharmacology · Short notes

Chemotherapy of Neoplasms: Short Notes & Cheat Sheet

Cell-cycle specificity, alkylating agents, antimetabolites, natural products, targeted and hormonal therapy, and supportive care.

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Short notes

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Cell cycle specificity of anticancer drugs

Phase-specific drugs work best against rapidly dividing tumours. Cell-cycle non-specific drugs also kill resting (G0) cells.

Principles

Cell-cycle specific drugs: antimetabolites act in S phase, vinca alkaloids and taxanes in M phase, and bleomycin in G2.
Cell-cycle non-specific drugs: alkylating agents, platinum compounds and anthracyclines.
Bone marrow suppression is the usual dose-limiting toxicity, with its lowest point (nadir) at about 7–14 days.
Drugs that largely spare the bone marrow: vincristine, bleomycin and L-asparaginase.
Combination regimens use drugs with different mechanisms and non-overlapping toxicities to prevent resistance.

Alkylating agents and platinum

Cyclophosphamide is a prodrug activated by CYP enzymes. Its metabolite acrolein causes haemorrhagic cystitis, prevented with mesna and hydration. Ifosfamide does the same and is also neurotoxic.
Nitrosoureas (carmustine, lomustine) cross the blood–brain barrier and are used for brain tumours. Temozolomide is used for glioblastoma.
Busulfan causes pulmonary fibrosis and hyperpigmentation. Melphalan is used for myeloma, and chlorambucil for CLL.
Cisplatin is the most emetogenic drug. It is nephrotoxic (give aggressive hydration), ototoxic and causes neuropathy and low magnesium.
Carboplatin's dose-limiting toxicity is myelosuppression; it is dosed by AUC using the Calvert formula. Oxaliplatin causes neuropathy triggered by cold.

Antimetabolites

Methotrexate inhibits dihydrofolate reductase (DHFR). After high doses, leucovorin (folinic acid) rescues normal cells and the urine is alkalinised. NSAIDs, penicillins and PPIs reduce its clearance.
5-Fluorouracil inhibits thymidylate synthase, and leucovorin enhances it. DPD deficiency causes severe toxicity. It causes hand-foot syndrome. Capecitabine is an oral prodrug of 5-FU.
6-Mercaptopurine and azathioprine are broken down by TPMT and xanthine oxidase, so with allopurinol their dose must be cut by about 75%.
Cytarabine is used for AML and causes cerebellar toxicity at high doses. Gemcitabine is used for pancreatic cancer.
Hydroxyurea inhibits ribonucleotide reductase and is used in sickle cell disease (it raises HbF), CML and polycythaemia vera.

Natural products

Vinca alkaloids stop microtubules forming. Vincristine causes neuropathy and constipation but little marrow suppression, and is fatal if given intrathecally. Vinblastine suppresses the bone marrow.
Taxanes (paclitaxel, docetaxel) stabilise microtubules. They cause hypersensitivity reactions, so patients are premedicated with dexamethasone and antihistamines. They also cause neuropathy.
Etoposide inhibits topoisomerase II. Irinotecan and topotecan inhibit topoisomerase I. Irinotecan causes severe diarrhoea: early diarrhoea is treated with atropine, late diarrhoea with loperamide.
Anthracyclines (doxorubicin, daunorubicin) cause cumulative, dose-dependent cardiomyopathy, prevented with dexrazoxane. They turn the urine red.
Bleomycin causes pulmonary fibrosis and skin pigmentation but little marrow suppression.
L-asparaginase is used for ALL. It causes pancreatitis, thrombosis and hypersensitivity.

Targeted and hormonal therapy

Imatinib inhibits the BCR-ABL tyrosine kinase in CML and c-KIT in GIST.
Trastuzumab targets HER2. Its cardiotoxicity is reversible and not cumulative.
Rituximab targets CD20 and can reactivate hepatitis B.
Bevacizumab targets VEGF and can cause bleeding, GI perforation, hypertension and poor wound healing.
Cetuximab targets EGFR (used only in RAS wild-type tumours) and causes an acne-like rash. Erlotinib and gefitinib are EGFR tyrosine kinase inhibitors used in lung cancer.
ATRA and arsenic trioxide treat acute promyelocytic leukaemia (APL); both can cause differentiation syndrome.
Checkpoint inhibitors (pembrolizumab and nivolumab against PD-1, ipilimumab against CTLA-4) cause immune-related adverse effects.
Hormonal: tamoxifen; anastrozole and letrozole (in postmenopausal women); leuprolide (causes an initial flare, so start an antiandrogen first); bicalutamide; abiraterone (CYP17 inhibitor, given with prednisone).

Cheat sheet

High-yield facts in one place. Cover the right-hand column and test yourself.

Toxicity → protector

Drug · toxicity	Prevent / rescue with
Cyclophosphamide, ifosfamide · haemorrhagic cystitis	Mesna + hydration
Methotrexate · myelosuppression, mucositis	Leucovorin (folinic acid)
Doxorubicin · cardiomyopathy	Dexrazoxane
Cisplatin · nephrotoxicity	Hydration, amifostine
Tumour lysis syndrome	Hydration + allopurinol / rasburicase
Neutropenia	G-CSF (filgrastim)
Chemotherapy-induced vomiting	Ondansetron + dexamethasone + aprepitant

Signature toxicities

Drug	Remember
Bleomycin, busulfan, carmustine	Pulmonary fibrosis
Doxorubicin	Cumulative cardiotoxicity, red urine
Trastuzumab	Reversible cardiotoxicity
Vincristine	Peripheral neuropathy, ileus
Cisplatin	Nephro-, ototoxicity, severe emesis
5-FU / capecitabine	Hand-foot syndrome, DPD deficiency
Irinotecan	Severe diarrhoea
L-asparaginase	Pancreatitis, thrombosis
Cetuximab	Acneiform rash
Bevacizumab	Bleeding, perforation, hypertension

Classic regimens

Regimen	Components · cancer
ABVD	Doxorubicin, bleomycin, vinblastine, dacarbazine · Hodgkin
R-CHOP	Rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone · NHL
BEP	Bleomycin, etoposide, cisplatin · testicular
FOLFOX	Folinic acid, 5-FU, oxaliplatin · colorectal

Memory aids

vinBLASTine BLASTS the marrow; vinCRISTine is neuro-CRISTal: Vinblastine is myelosuppressive; vincristine is neurotoxic and marrow-sparing.
Bleomycin — Breathless: Pulmonary fibrosis is bleomycin's dose-limiting toxicity.

Exam traps

Vincristine given intrathecally is fatal; it is for IV use only.
Leucovorin rescues normal cells from methotrexate but enhances 5-FU; it is the same drug with opposite roles.
Carboplatin causes more myelosuppression than cisplatin; cisplatin is more nephrotoxic.
Taxanes stabilise microtubules, while vinca alkaloids stop them forming. Both act in M phase.
When a GnRH agonist is started for prostate cancer, give an antiandrogen first to cover the testosterone flare.

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