Contents

1. Introduction
2. Principles of Chemotherapy
   • The Cell Cycle and Chemotherapy
   • Fractional Cell Kill
   • Aims of Treatment
3. The Drug Classes
   • Alkylating Agents
   • Platinum Compounds
   • Antimetabolites
   • Anthracyclines
   • Topoisomerase Inhibitors
   • Spindle Poisons (Microtubule-Targeting Agents)
   • Bleomycin
   • Targeted Therapies
   • Immunotherapy
4. Side Effects of Chemotherapy
   • General Toxicity
   • Drug-Specific Toxicities
   • Tumour Lysis Syndrome
5. Administration
6. Summary
7. Drug Summary Table
8. Quiz

Abstract

• Chemotherapy targets dividing cells. The therapeutic index is narrow because normal proliferating tissues (bone marrow, gut epithelium, hair follicles) are also affected.
• The classical drug classes are alkylating agents, platinum compounds, antimetabolites, anthracyclines, topoisomerase inhibitors and spindle poisons. Each acts at a specific point in DNA synthesis or mitosis.
• Targeted therapies (e.g. trastuzumab, imatinib, EGFR inhibitors) and immune checkpoint inhibitors (pembrolizumab, ipilimumab, nivolumab) have transformed prognosis for several cancers in the last 20 years.
• Common toxicities include bone marrow suppression, mucositis, alopecia, nausea and vomiting, and tumour lysis syndrome. A few drug-specific toxicities are essential exam material: doxorubicin and cardiotoxicity, cisplatin and nephrotoxicity, bleomycin and pulmonary fibrosis, vincristine and peripheral neuropathy, and cyclophosphamide and haemorrhagic cystitis.

Core

Introduction

Cancer is the leading cause of death in the UK. Chemotherapy; the use of cytotoxic drugs to kill cancer cells; remains the backbone of medical oncology, often combined with surgery, radiotherapy, hormonal therapy, targeted therapy, and immunotherapy. This article focuses on the cytotoxic and targeted drug classes at pre-clinical level. The prescribing principles are informed by the Pharmacokinetics and Pharmacodynamics articles earlier in the series.

Principles of Chemotherapy

The Cell Cycle and Chemotherapy

The cell cycle has four active phases (G1, S, G2, M) plus a quiescent G0 phase. Most cytotoxic drugs are cell-cycle-specific: effective only against actively dividing cells, or cell-cycle-non-specific, where they act regardless of phase but still preferentially harm rapidly dividing tissue.

• G0 quiescent cells are not killed by most chemotherapy. This is one reason "cancer stem cells" can survive treatment and produce relapse.
• S-phase specific drugs (antimetabolites such as methotrexate, 5-FU, cytarabine) target DNA synthesis.
• M-phase specific drugs (vinca alkaloids, taxanes) target microtubule function during mitosis.
• Phase-non-specific drugs (alkylating agents, platinum compounds, anthracyclines, topoisomerase inhibitors) damage DNA at any point and often even in non-dividing cells, although the lethal effect is greatest in dividing cells.

Fractional Cell Kill

The fractional cell kill hypothesis is the central conceptual model: each round of chemotherapy kills a constant fraction of tumour cells, not a constant number. So a regimen that kills 99% of cells in cycle 1 will kill 99% of the remaining cells in cycle 2, and so on; producing exponential decline.

• A clinically detectable tumour contains around 10⁹ cells (about 1 g).
• Around 10¹² cells is generally fatal.
• Bone marrow recovers from a chemotherapy hit in 2-3 weeks; tumour cells recover more slowly.
• Treatment is therefore given in cycles spaced to allow normal tissue recovery while keeping tumour kill ahead of regrowth.

Aims of Treatment

Five distinct intentions, each affecting the choice of drug, dose and tolerance for toxicity:

• Primary (curative): first-line treatment with intent to cure (most haematological cancers, some solid tumours).
• Neoadjuvant: given before surgery or radiotherapy to shrink the primary tumour and improve operability.
• Adjuvant: given after curative surgery to reduce the risk of micrometastatic relapse (e.g. breast cancer, colorectal cancer).
• Palliative: to control symptoms or prolong life without curative intent. Tolerated toxicity is lower.
• Salvage: chemotherapy for relapsed disease.

The Drug Classes

Alkylating Agents

Alkylating agents add an alkyl group to DNA, principally at the N7 position of guanine. The resulting cross-links and adducts cannot be replicated past, triggering DNA damage responses and apoptosis.

• Cyclophosphamide: a pro-drug activated by hepatic CYP450 to phosphoramide mustard (the alkylating species) and acrolein (the toxic urinary metabolite). Used in lymphomas, sarcomas, breast cancer, and as immunosuppression in vasculitis. Notable toxicity: haemorrhagic cystitis from acrolein, prevented or treated with the thiol donor mesna.
• Ifosfamide: similar; same haemorrhagic cystitis prophylaxis.
• Chlorambucil: oral; chronic lymphocytic leukaemia and some lymphomas.
• Busulfan: historically used in chronic myeloid leukaemia (since superseded by tyrosine kinase inhibitors such as imatinib); modern use is mainly as conditioning before haematopoietic stem-cell transplantation. Causes pulmonary fibrosis.

Resistance mechanisms include enhanced glutathione conjugation, increased DNA repair, and drug efflux.

Platinum Compounds

Platinum compounds form intra- and inter-strand DNA cross-links, behaving functionally as alkylating agents. They are cell-cycle-non-specific.

• Cisplatin: testicular, ovarian, lung, head and neck, bladder cancers. Toxicities are the high-yield exam material: nephrotoxicity (proximal tubular damage; given with vigorous IV hydration), ototoxicity, peripheral neuropathy, severe nausea and vomiting (often delayed; needs aggressive antiemetic prophylaxis with ondansetron, dexamethasone and aprepitant).
• Carboplatin: less nephrotoxic, less neurotoxic, but more myelosuppressive. Often used as a first-line alternative to cisplatin.
• Oxaliplatin: colorectal cancer; produces a distinctive cold-induced peripheral neuropathy.

Antimetabolites

Antimetabolites resemble the natural building blocks of DNA synthesis and inhibit the enzymes that make or use them. They are S-phase specific.

• Methotrexate: an inhibitor of dihydrofolate reductase, blocking the regeneration of tetrahydrofolate needed for thymidine and purine synthesis. Used in leukaemia, lymphoma, and at lower doses for rheumatoid arthritis and psoriasis. Folinic acid (calcium folinate) "rescue" is given after high-dose methotrexate to bypass the block in normal tissue.
• 5-Fluorouracil (5-FU) and capecitabine (an oral pro-drug of 5-FU): pyrimidine analogues that inhibit thymidylate synthase. Used in colorectal, breast and gastric cancers. DPD deficiency causes severe (sometimes fatal) toxicity; the MHRA now requires DPD testing before treatment.
• 6-Mercaptopurine and azathioprine: purine analogues; activated by HGPRT. Inactivated by thiopurine methyltransferase (TPMT); testing before treatment is standard.
• Cytarabine (Ara-C): cytosine analogue; backbone of acute myeloid leukaemia treatment.
• Gemcitabine: pancreatic and lung cancers.

Anthracyclines

Doxorubicin, epirubicin, daunorubicin and idarubicin intercalate into DNA and inhibit topoisomerase II. They also generate free radicals that damage DNA and other cellular structures.

The notable toxicity is cardiotoxicity:

• Acute: arrhythmias and ECG changes.
• Chronic: dose-dependent dilated cardiomyopathy. Total cumulative dose is closely monitored (e.g. doxorubicin lifetime dose limit ~450-550 mg/m²).
• Dexrazoxane, an iron chelator, is sometimes used to reduce cardiotoxicity.

Other notable features: red urine (cosmetic, not haematuria), severe vesicant action on extravasation.

Topoisomerase Inhibitors

• Etoposide: topoisomerase II inhibitor; lung, testicular and lymphoma chemotherapy. Risk of secondary acute myeloid leukaemia.
• Irinotecan and topotecan: topoisomerase I inhibitors. Irinotecan is used in colorectal cancer; the classic toxicity is diarrhoea in two forms: an acute cholinergic syndrome during or shortly after infusion (treated with atropine), and delayed-onset diarrhoea 24 hours or more later (treated with loperamide, with hospital admission if severe).

Spindle Poisons (Microtubule-Targeting Agents)

These drugs disrupt the mitotic spindle and arrest cells in M phase.

• Vinca alkaloids (vincristine, vinblastine): inhibit microtubule polymerisation. Used in lymphomas, leukaemias, and many combination regimens. The signature toxicity of vincristine is peripheral neuropathy; vinblastine is more myelosuppressive.
• Taxanes (paclitaxel, docetaxel): stabilise microtubules and prevent depolymerisation. Used in breast, ovarian and lung cancers. Notable toxicities: peripheral neuropathy, hypersensitivity (paclitaxel is dissolved in cremophor), neutropenia.

A vital safety point about vincristine: it is fatal if given intrathecally instead of intravenously, and a small number of UK deaths from this error led to mandatory dedicated mini-bag preparation.

Bleomycin

Bleomycin deserves a separate note because of its distinctive toxicity profile. It generates free radicals that produce single- and double-strand DNA breaks, and is used as a key component of regimens for Hodgkin lymphoma (ABVD) and testicular germ-cell tumours (BEP). The signature toxicity is pulmonary fibrosis, which is dose-dependent, can be progressive, and is exacerbated by high-flow oxygen; patients carry a card warning future anaesthetists to use the lowest acceptable inspired oxygen.

Targeted Therapies

Targeted therapies exploit molecular features specific to the cancer. Two suffix conventions are worth knowing:

• The "-mab" suffix denotes a monoclonal antibody.
• The "-nib" suffix denotes a small-molecule kinase inhibitor.

High-yield examples:

• Imatinib: BCR-ABL tyrosine kinase inhibitor; transformed prognosis for chronic myeloid leukaemia (CML).
• Trastuzumab (Herceptin): anti-HER2 monoclonal antibody; HER2-positive breast cancer. Cardiotoxic, especially when combined with anthracyclines.
• Rituximab: anti-CD20 monoclonal; B-cell lymphomas, also used in autoimmune disease.
• Cetuximab: anti-EGFR monoclonal; metastatic colorectal cancer (only effective in KRAS wild-type).
• Erlotinib, gefitinib, osimertinib: EGFR tyrosine kinase inhibitors; non-small-cell lung cancer with activating EGFR mutations.
• Bevacizumab: anti-VEGF; multiple solid tumours.
• Olaparib: PARP inhibitor; BRCA-mutated ovarian and breast cancer.

Immunotherapy

Immune checkpoint inhibitors have revolutionised treatment in melanoma, lung cancer, renal cell carcinoma, urothelial carcinoma and many others over the last decade. They block "checkpoint" molecules that tumours exploit to evade immune surveillance.

• Anti-PD-1 antibodies: pembrolizumab, nivolumab.
• Anti-PD-L1 antibodies: atezolizumab, durvalumab.
• Anti-CTLA-4 antibody: ipilimumab.

The toxicity profile is distinctive: rather than the classical chemotherapy adverse effects, checkpoint inhibitors cause immune-related adverse events: autoimmune-style attacks on any organ. The most common are dermatitis, colitis, hepatitis, pneumonitis, thyroiditis, hypophysitis and adrenalitis. Treatment is high-dose steroids and, in severe cases, additional immunosuppression.

Side Effects of Chemotherapy

General Toxicity

Most cytotoxic drugs cause:

• Bone marrow suppression: neutropenia, anaemia, thrombocytopenia. Neutropenic sepsis is the most important medical emergency in oncology and a leading cause of treatment-related death. Prophylactic G-CSF (filgrastim, lenograstim) is given for high-risk regimens.
• Mucositis: sore mouth, ulceration, diarrhoea, GI bleeding.
• Alopecia, usually starts at 2-3 weeks; almost universal with anthracyclines and taxanes; minimal with platinums. Scalp cooling reduces incidence.
• Nausea and vomiting: acute and delayed. Treated with the regimens covered in Antiemetics and Laxatives: ondansetron + dexamethasone ± aprepitant for highly emetogenic schedules.
• Fatigue.
• Infertility.
• Secondary malignancy, particularly leukaemias after alkylating agents and topoisomerase II inhibitors.

Drug-Specific Toxicities

The drug-toxicity pairings worth committing to memory:

Doxorubicin / anthracyclines → cardiotoxicity (cumulative dose limited)
Cisplatin → nephrotoxicity, ototoxicity, peripheral neuropathy
Bleomycin → pulmonary fibrosis (avoid high-flow O₂)
Vincristine → peripheral neuropathy; fatal if intrathecal
Cyclophosphamide / ifosfamide → haemorrhagic cystitis (mesna)
Methotrexate → mucositis, hepatotoxicity, pneumonitis (folinic acid rescue)
5-Fluorouracil → severe toxicity in DPD deficiency
Trastuzumab → cardiotoxicity
Irinotecan → severe diarrhoea

Tumour Lysis Syndrome

Tumour lysis syndrome (TLS) is a medical emergency that follows the rapid breakdown of tumour cells, particularly in acute leukaemia and high-grade lymphoma. The biochemical hallmarks are:

• Hyperuricaemia (released purines) → uric acid crystals in renal tubules → acute kidney injury.
• Hyperkalaemia → arrhythmias.
• Hyperphosphataemia with secondary hypocalcaemia → tetany, seizures.

Prevention is more effective than treatment: aggressive intravenous hydration plus allopurinol (xanthine oxidase inhibitor, prevents uric acid formation) or, in high-risk patients, rasburicase (a recombinant urate oxidase that breaks down existing uric acid into the soluble allantoin).

Other oncological emergencies to recognise:

• Neutropenic sepsis: same-day broad-spectrum antibiotics (e.g. piperacillin-tazobactam) within 1 hour of arrival in any unwell neutropenic patient.
• Spinal cord compression: high-dose dexamethasone, urgent imaging, urgent oncology / radiotherapy.
• Hypercalcaemia of malignancy: IV fluid resuscitation, IV bisphosphonate.
• Superior vena cava obstruction: high-dose steroids and urgent oncology.

Administration

Most cytotoxic drugs are given intravenously, usually via a central venous access device:

• Hickman line: tunnelled central venous catheter; can stay in for months.
• PICC line: peripherally inserted central catheter; suitable for outpatient infusion pumps.
• Implantable port: subcutaneous reservoir accessed by needle.

Extravasation: leakage of a vesicant cytotoxic outside the vein: can cause severe tissue necrosis. Anthracyclines and vinca alkaloids are the highest-risk agents; specific extravasation kits and antidotes (e.g. dexrazoxane for anthracyclines, hyaluronidase for vinca alkaloids) are part of every chemotherapy unit's standard equipment.

Other routes used for specific situations: oral (capecitabine, several targeted therapies), subcutaneous (some monoclonals), intrathecal (CNS prophylaxis with methotrexate, cytarabine), intravesical (BCG and mitomycin C for non-muscle-invasive bladder cancer), and intracavitary infusion.

Summary

• Chemotherapy targets dividing cells; G0 cells are spared. The fractional cell kill hypothesis explains why treatment is given in cycles.
• Five intentions of chemotherapy: primary, neoadjuvant, adjuvant, palliative, salvage.
• Drug classes by mechanism: alkylating agents (cyclophosphamide), platinum (cisplatin), antimetabolites (methotrexate, 5-FU), anthracyclines (doxorubicin), topoisomerase inhibitors (etoposide, irinotecan), spindle poisons (vincristine, paclitaxel).
• Targeted therapies (-mab antibodies, -nib kinase inhibitors) and checkpoint inhibitors (pembrolizumab, nivolumab, ipilimumab) are increasingly the dominant agents.
• General side effects: bone marrow suppression, mucositis, alopecia, nausea/vomiting. Drug-specific toxicities to remember: doxorubicin (cardiomyopathy), cisplatin (kidney/ear/nerve), bleomycin (lung), vincristine (nerve, fatal if intrathecal), cyclophosphamide (cystitis; mesna).
• Tumour lysis syndrome: hyperuricaemia, hyperkalaemia, hyperphosphataemia, hypocalcaemia. Prevent with hydration plus allopurinol or rasburicase.
• Neutropenic sepsis: broad-spectrum antibiotics within 1 hour of presentation.

Drug Summary Table

The drug-toxicity pairings here are amongst the highest-yield exam material in oncology.

Class	Examples	Mechanism	Signature toxicity
Alkylating agents	Cyclophosphamide, ifosfamide, chlorambucil, busulfan	Alkylate DNA → cross-links	Cyclophosphamide / ifosfamide: haemorrhagic cystitis (mesna). Busulfan: pulmonary fibrosis. Late: secondary malignancy
Platinum compounds	Cisplatin, carboplatin, oxaliplatin	DNA cross-links	Cisplatin: nephrotoxicity, ototoxicity, peripheral neuropathy, severe N&V. Oxaliplatin: cold-induced neuropathy
Antimetabolites	Methotrexate, 5-FU / capecitabine, 6-MP, cytarabine, gemcitabine	Inhibit DNA synthesis (folate / pyrimidine / purine analogues)	Methotrexate: mucositis, marrow, hepatitis, pneumonitis (folinic acid rescue). 5-FU: severe toxicity in DPD deficiency. 6-MP: TPMT screen
Anthracyclines	Doxorubicin, epirubicin, daunorubicin, idarubicin	DNA intercalation, topo II inhibition, free radicals	Cardiotoxicity (cumulative dose-limited; dexrazoxane); red urine; vesicant
Topoisomerase inhibitors	Etoposide (topo II); irinotecan, topotecan (topo I)	Topoisomerase inhibition	Etoposide: 2° AML. Irinotecan: severe diarrhoea (acute: atropine; delayed: loperamide)
Vinca alkaloids	Vincristine, vinblastine	Inhibit microtubule polymerisation	Vincristine: peripheral neuropathy; FATAL if intrathecal. Vinblastine: myelosuppression
Taxanes	Paclitaxel, docetaxel	Stabilise microtubules	Peripheral neuropathy, hypersensitivity, neutropenia
Bleomycin	Bleomycin (in ABVD, BEP)	Free-radical DNA breaks	Pulmonary fibrosis: avoid high-flow O2
Targeted: monoclonal antibodies (-mab)	Trastuzumab (HER2), rituximab (CD20), cetuximab (EGFR), bevacizumab (VEGF)	Block specific tumour molecules	Trastuzumab: cardiotoxicity. Rituximab: infusion reactions, HBV reactivation. Cetuximab: KRAS wild-type only
Targeted: small-molecule kinase inhibitors (-nib)	Imatinib (BCR-ABL), erlotinib / gefitinib / osimertinib (EGFR), olaparib (PARP)	Inhibit specific kinases / pathways	Drug-specific (imatinib transformed CML prognosis)
Immune checkpoint inhibitors	Pembrolizumab, nivolumab (anti-PD-1); ipilimumab (anti-CTLA-4); atezolizumab (anti-PD-L1)	Release T-cell brake on tumour	Immune-related adverse events: colitis, pneumonitis, hepatitis, thyroiditis, hypophysitis: treat with steroids

Reviewed by: Dr. Marcus Judge

Quiz

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