Cancer Chemotherapy

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

• Chemotherapy targets dividing cells. The therapeutic index (the gap between a dose that works and a dose that is toxic) is narrow. This is because normal tissues that divide quickly (proliferating tissues) are also affected: bone marrow, the gut lining (epithelium) and hair follicles.
• The classical drug classes are alkylating agents (which chemically attach to DNA), platinum compounds (which cross-link DNA, meaning they form bonds within and between its strands), antimetabolites (which mimic the building blocks of DNA), anthracyclines (such as doxorubicin, which slide between the stacked DNA bases), topoisomerase inhibitors (which block enzymes that untangle DNA) and spindle poisons (which stop cells pulling their chromosomes apart). Antimetabolites, topoisomerase inhibitors and spindle poisons act mainly in a specific phase of the cell cycle. Alkylating agents and platinum compounds damage DNA in any phase.
• Targeted therapies (e.g. trastuzumab, imatinib, and inhibitors of the epidermal growth factor receptor, EGFR) 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 (sore, ulcerated mouth and gut), alopecia (hair loss), nausea and vomiting, and tumour lysis syndrome (tumour cells breaking down and releasing their contents into the blood).
• A few drug-specific toxicities are essential exam material:
  • doxorubicin and cardiotoxicity (heart damage)
  • cisplatin and nephrotoxicity (kidney damage)
  • bleomycin and pulmonary fibrosis (lung scarring)
  • vincristine and peripheral neuropathy (damage to nerves outside the brain and spinal cord, causing numbness or tingling)
  • cyclophosphamide and haemorrhagic cystitis (bladder inflammation with bleeding)

Introduction

Cancer is one of the leading causes of death in the UK. Chemotherapy (the use of cytotoxic drugs to kill cancer cells) remains the backbone of medical oncology (the medical treatment of cancer). It is often combined with surgery, radiotherapy (treatment with radiation), hormonal therapy (drugs that block or lower hormones that drive some cancers), 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 (what the body does to a drug) and Pharmacodynamics (what a drug does to the body) articles earlier in the series.

Principles of Chemotherapy

The Cell Cycle and Chemotherapy

The cell cycle has four active phases: G1 (growth), S (DNA synthesis), G2 (preparation for division) and M (mitosis, when the cell divides). Resting (quiescent) cells are in a G0 phase. Cytotoxic drugs are either cell-cycle-specific (they work only on cells that are actively dividing) or cell-cycle-non-specific (they act in any phase but still harm rapidly dividing tissue most).

• G0 (resting) cells are much less likely to be killed by chemotherapy. This is one reason "cancer stem cells" (cells that can regrow a tumour) can survive treatment and produce relapse.
• S-phase specific drugs (antimetabolites, which mimic the building blocks of DNA; examples are methotrexate, 5-fluorouracil (5-FU) and cytarabine) target DNA synthesis.
• M-phase specific drugs (vinca alkaloids and taxanes, which come from plants) target microtubule function during mitosis. Microtubules are the protein tubes that form the mitotic spindle.
• Phase-non-specific drugs (alkylating agents and platinum compounds) damage DNA at any point, although the lethal effect is greatest in dividing cells.
• Topoisomerase inhibitors (topoisomerases are enzymes that untangle DNA during replication) act mainly in particular phases: etoposide in late S and G2, and the camptothecins (irinotecan and topotecan) in S phase. Anthracyclines have both phase-specific and phase-non-specific effects.

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. The number of tumour cells therefore falls exponentially.

• A clinically detectable tumour contains around 10⁹ cells (about 1 g).
• Around 10¹² cells is generally fatal.
• Bone marrow usually recovers from a chemotherapy hit in 2-3 weeks. Surviving tumour cells also regrow between cycles, sometimes quickly (accelerated repopulation).
• 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 (some haematological cancers, such as Hodgkin lymphoma, and 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 (the cancer returning from tiny deposits too small to see on scans; e.g. breast cancer, colorectal cancer).
• Palliative: to control symptoms or prolong life without curative intent. Less toxicity is acceptable, because the aim is to improve quality of life.
• Salvage: chemotherapy for relapsed disease.

The Drug Classes

Alkylating Agents

Alkylating agents add an alkyl group (a small carbon-based chemical group) to DNA, principally at the N7 position of guanine (guanine is one of the four DNA bases). The resulting cross-links (bonds between DNA strands) and adducts (other chemical groups stuck onto the DNA) block DNA replication, triggering DNA damage responses and apoptosis.

• Cyclophosphamide: a pro-drug (inactive until the body converts it) activated by hepatic cytochrome P450 enzymes (CYP450, a family of liver enzymes that break down many drugs) to phosphoramide mustard (the alkylating species) and acrolein (the toxic urinary metabolite). Used in lymphomas, sarcomas, breast cancer, and as immunosuppression (damping down the immune system) in vasculitis (inflammation of blood vessel walls). Notable toxicity: haemorrhagic cystitis (bladder inflammation with bleeding) from acrolein. It is prevented by giving mesna, a sulfur-containing compound (a thiol donor) that binds acrolein and makes it harmless.
• Ifosfamide: similar, and also given with mesna to prevent haemorrhagic cystitis. It can also damage the kidneys and cause neurotoxicity (confusion, seizures and other changes in how the brain works).
• Chlorambucil: oral; chronic lymphocytic leukaemia (CLL) and some lymphomas. In CLL it can be given with obinutuzumab (an anti-CD20 monoclonal antibody: a laboratory-made antibody that binds CD20, a protein on the surface of B cells), and newer targeted drugs such as ibrutinib, acalabrutinib and venetoclax are also options.
• Busulfan: historically used in chronic myeloid leukaemia, but since superseded by tyrosine kinase inhibitors such as imatinib (drugs that block enzymes driving cell growth signals). Modern use is mainly as conditioning before haematopoietic stem-cell transplantation (a bone marrow or blood stem cell transplant). Conditioning means high-dose treatment given to clear the bone marrow before the transplant. Causes pulmonary fibrosis.

Cancer cells can become resistant (so that the drug stops working) in several ways. They can attach glutathione, a protective molecule, to the drug to inactivate it (glutathione conjugation). They can repair DNA damage faster. They can also pump the drug out of the cell (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 (damage to the proximal tubules of the kidney; cisplatin is given with vigorous IV hydration to protect the kidneys), ototoxicity (damage to hearing), peripheral neuropathy (damage to nerves outside the brain and spinal cord) and severe nausea and vomiting, which is often delayed. This needs aggressive antiemetic prophylaxis (anti-sickness drugs given in advance): ondansetron, dexamethasone, aprepitant (which blocks NK1 receptors) and olanzapine, which current international guidance adds.
• Carboplatin: less nephrotoxic, less neurotoxic, but more myelosuppressive (more likely to suppress the bone marrow). 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 (an enzyme that makes active folate), blocking the regeneration of tetrahydrofolate needed for thymidine and purine synthesis (two types of DNA building block). Used in leukaemia, lymphoma, and, at lower doses, for rheumatoid arthritis and psoriasis. For these conditions it is taken once a week, never daily: overdose from daily dosing is an NHS Never Event (a serious, preventable error). 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 (lookalikes of the pyrimidine DNA bases) that inhibit thymidylate synthase (an enzyme needed to make thymidine). Used in colorectal, breast and gastric cancers. DPD (dihydropyrimidine dehydrogenase) deficiency causes severe (sometimes fatal) toxicity. Since 2020 the Medicines and Healthcare products Regulatory Agency (MHRA) has advised testing all patients for DPD deficiency before treatment.
• 6-Mercaptopurine and azathioprine: purine analogues; activated by the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Inactivated by thiopurine methyltransferase (TPMT); testing before treatment is standard.
• Cytarabine (Ara-C): cytosine analogue (a lookalike of the DNA base cytosine); backbone of acute myeloid leukaemia treatment.
• Gemcitabine: pancreatic and lung cancers.

Anthracyclines

Doxorubicin, epirubicin, daunorubicin and idarubicin intercalate into DNA (slide between the stacked DNA bases) and inhibit topoisomerase II. They also generate free radicals (highly reactive molecules) that damage DNA and other cellular structures.

The notable toxicity is cardiotoxicity:

• Acute: arrhythmias (abnormal heart rhythms) and ECG changes.
• Chronic: dose-dependent dilated cardiomyopathy (a weak, enlarged heart muscle). Total cumulative dose is closely monitored (e.g. the usual doxorubicin lifetime dose limit is about 450-550 mg/m², meaning milligrams per square metre of body surface area). Heart failure can still occur at lower doses, so the limit is not a guarantee of safety.
• Dexrazoxane, an iron chelator (a drug that binds iron), is sometimes used to reduce cardiotoxicity (damage to the heart). In the UK it is licensed for this only in advanced or metastatic breast cancer, after a high cumulative dose of doxorubicin or epirubicin.

Other notable features: red urine (harmless, and not haematuria, meaning blood in the urine) and a severe vesicant action (the drug damages tissue if it leaks out of the vein, called extravasation).

Topoisomerase Inhibitors

• Etoposide: topoisomerase II inhibitor; lung, testicular and lymphoma chemotherapy. Risk of secondary acute myeloid leukaemia (a second cancer caused by the treatment).
• Irinotecan and topotecan: topoisomerase I inhibitors. Irinotecan is used in colorectal cancer. Its classic toxicity is diarrhoea, in two forms. The first is an acute cholinergic syndrome (sweating, salivation and abdominal cramps from excess acetylcholine) during or shortly after infusion, treated with atropine. The second is 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 (the structure of microtubules that pulls the chromosomes apart) and arrest cells in M phase.

• Vinca alkaloids (vincristine, vinblastine): inhibit microtubule polymerisation (the assembly of the tubules from their subunits). 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 (the breakdown of the tubules). Used in breast, ovarian and lung cancers. Notable toxicities: peripheral neuropathy, hypersensitivity (paclitaxel is dissolved in cremophor, a solvent that can trigger allergy), neutropenia (a low neutrophil count).

A vital safety point about vincristine: it is fatal if given intrathecally (into the fluid around the spinal cord) instead of intravenously. Deaths from this error in the UK led to national action. In 2008 the National Patient Safety Agency recommended that vinca alkaloids for adults and adolescents be diluted in 50 mL mini-bags.

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 (the ABVD regimen: doxorubicin, bleomycin, vinblastine and dacarbazine) and testicular germ-cell tumours (cancers of the sperm-forming cells of the testis; the BEP regimen: bleomycin, etoposide and cisplatin). The signature toxicity is pulmonary fibrosis (scarring of the lungs). The fibrosis is dose-dependent and can be progressive. High inspired oxygen has traditionally been thought to make the fibrosis worse, so patients are often given a card warning future anaesthetists to use the lowest acceptable inspired oxygen. However, studies of patients having surgery after bleomycin have not found that higher inspired oxygen increases lung injury, so the value of strict oxygen restriction is uncertain.

Targeted Therapies

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

• The "-mab" suffix denotes a monoclonal antibody (an antibody made in the laboratory to bind one target).
• The "-nib" suffix denotes a small-molecule kinase inhibitor (a drug that blocks an enzyme driving cell growth signals). Not every small-molecule targeted drug is a kinase inhibitor: olaparib, for example, is not.

High-yield examples:

• Imatinib: BCR-ABL tyrosine kinase inhibitor (BCR-ABL is the abnormal fusion enzyme that drives chronic myeloid leukaemia, CML); transformed prognosis for CML.
• Trastuzumab (Herceptin): anti-HER2 (human epidermal growth factor receptor 2) monoclonal antibody; HER2-positive breast cancer. Cardiotoxic, especially when combined with anthracyclines.
• Rituximab: anti-CD20 (a protein on the surface of B cells) monoclonal; B-cell lymphomas, also used in autoimmune disease.
• Cetuximab: anti-EGFR (epidermal growth factor receptor) monoclonal; metastatic colorectal cancer (only effective in RAS wild-type tumours, meaning no mutation in the KRAS or NRAS genes).
• Erlotinib, gefitinib, osimertinib: EGFR tyrosine kinase inhibitors; non-small-cell lung cancer with activating EGFR mutations.
• Bevacizumab: anti-VEGF (vascular endothelial growth factor, which drives the growth of new blood vessels); multiple solid tumours.
• Olaparib: PARP (poly ADP-ribose polymerase) inhibitor. PARP is a protein that helps damaged cells repair their DNA. Used in ovarian and breast cancers with BRCA mutations (changes in the BRCA genes that impair DNA repair).

Immunotherapy

Immune checkpoint inhibitors have revolutionised treatment in melanoma, lung cancer, kidney cancer (renal cell carcinoma), urothelial cancer (which mostly affects the bladder) and many others. The change began in 2010, when ipilimumab was shown to improve survival in melanoma. They block "checkpoint" molecules that tumours exploit to evade immune surveillance (the immune system's routine search for abnormal cells).

• Anti-PD-1 (programmed cell death protein 1) antibodies: pembrolizumab, nivolumab.
• Anti-PD-L1 (programmed death-ligand 1) antibodies: atezolizumab, durvalumab.
• Anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 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 involve the skin (rash, itching), the gut (diarrhoea and colitis, which is inflammation of the colon) and the endocrine glands (thyroid and pituitary). Hepatitis (inflammation of the liver) and pneumonitis (inflammation of the lungs) also occur. Treatment depends on the severity. Mild events may need only close monitoring. Severe events (grade 3, on a scale from 1, mild, to 5, fatal) usually mean pausing the checkpoint inhibitor and starting high-dose corticosteroids, with other immunosuppressive drugs if they do not respond. Hormone deficiencies, such as an underactive thyroid, are managed with hormone replacement.

Side Effects of Chemotherapy

General Toxicity

Most cytotoxic drugs cause:

• Bone marrow suppression: neutropenia (low neutrophils, the main infection-fighting white cells), anaemia (low red cells) and thrombocytopenia (low platelets). Neutropenic sepsis (infection in a patient with a very low neutrophil count) is an acute medical emergency and one of the most common complications of chemotherapy. G-CSF (granulocyte colony-stimulating factor, such as filgrastim or lenograstim) stimulates the bone marrow to make neutrophils. NICE advises against giving it routinely to prevent neutropenic sepsis. G-CSF is used only when it is an integral part of the chemotherapy regimen, or to maintain dose intensity (giving the full planned dose on time).
• Mucositis (inflammation and ulceration of the lining of the mouth and gut): sore mouth, ulceration, diarrhoea, gastrointestinal (gut) 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, with aprepitant and olanzapine added for highly emetogenic (strongly sickness-causing) schedules.
• Fatigue.
• Infertility: some drugs can affect fertility, so options such as storing sperm or eggs should be discussed before treatment starts.
• 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 (traditionally, use the lowest acceptable inspired O₂)
Vincristine → peripheral neuropathy; fatal if intrathecal
Cyclophosphamide / ifosfamide → haemorrhagic cystitis (mesna)
Methotrexate → mucositis, hepatotoxicity (liver damage), 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 (a fast-growing lymphoma). The biochemical hallmarks are:

• Hyperuricaemia (high uric acid in the blood, from released purines) → uric acid crystals in renal tubules → acute kidney injury.
• Hyperkalaemia (high potassium) → arrhythmias.
• Hyperphosphataemia (high phosphate) with secondary hypocalcaemia (low calcium) → tetany (muscle spasms), seizures.

Prevention is more effective than treatment. Give aggressive intravenous hydration plus allopurinol (a xanthine oxidase inhibitor, which prevents uric acid formation) or, in high-risk patients, rasburicase (a recombinant urate oxidase, a laboratory-made enzyme that breaks down existing uric acid into the soluble allantoin). Rasburicase is contraindicated in G6PD (glucose-6-phosphate dehydrogenase) deficiency, an inherited red cell enzyme deficiency, because it can cause haemolysis (breakdown of red cells), so G6PD status needs to be known before it is given.

Other oncological emergencies to recognise:

• Neutropenic sepsis: broad-spectrum IV antibiotics (e.g. piperacillin with tazobactam) immediately, and within 1 hour of recognition, in any unwell patient having anticancer treatment.
• Metastatic spinal cord compression (MSCC): contact the MSCC coordinator (the oncology service's point of contact) immediately. If there are neurological symptoms or signs, give dexamethasone 16 mg orally (or the equivalent parenteral dose, meaning by injection) as soon as possible. Arrange an MRI scan of the spine as soon as possible and always within 24 hours. Urgent radiotherapy or surgery follows, as decided by the MSCC service.
• Hypercalcaemia of malignancy (high blood calcium caused by cancer): IV fluid resuscitation, IV bisphosphonate (a drug that lowers blood calcium by blocking bone breakdown).
• Superior vena cava obstruction (blockage of the large vein that carries blood from the head, neck and arms to the heart): urgent oncology assessment. A stent (a mesh tube that holds the vein open) can relieve symptoms quickly. Chemotherapy or radiotherapy treats the underlying cancer. Steroids are sometimes used, but their benefit is uncertain.

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