Chemotherapy: classes and toxicities

• Chemotherapy in this topic means classical cytotoxic anti-cancer drugs: drugs that kill or block division by harming DNA or the machinery of cell division, rather than the newer targeted or immune therapies.
• Classes are taught by biological target, not by chemical family alone. The six core classes are alkylating agents, antimetabolites, anthracyclines, platinum agents, taxanes and vinca alkaloids.
• Cancer cells are affected most because they divide rapidly, but so are many normal tissues with a high turnover rate: bone marrow, gut lining, hair follicles and germ cells. That is why the toxicities repeat across classes.
• Each class damages a different step in the chain from DNA to division, so its dose-limiting toxicity and its long-term risks follow from its mechanism. Knowing the mechanism lets you predict the bedside picture and what must be monitored.
• Treatment is protocol-driven: combinations, doses and cycles are chosen for the tumour type, stage and the patient's organs. The page below gives the reasoning and the warning signs, not a substitute recipe.

By the end of this page you should be able to:

1. Name the six core cytotoxic classes and give a representative drug for each.
2. Explain how each class disturbs DNA or mitosis, and why that produces its characteristic toxicities.
3. Recognise the dose-limiting toxicities of alkylating agents, antimetabolites, anthracyclines, platinums, taxanes and vinca alkaloids, and the organs at risk.
4. Use cumulative dose thresholds to judge anthracycline cardiotoxicity risk, and state the renal and hepatic precautions for methotrexate and taxanes.
5. Outline a monitoring plan for blood counts, renal function, cardiac function and infection during cytotoxic treatment.
6. Recognise the drug-specific rescue and protective strategies for high-dose methotrexate, cyclophosphamide and cisplatin.

Cytotoxic chemotherapy is the branch of cancer treatment that uses drugs designed to kill rapidly dividing cells. The goal is to remove or control dividing cancer cells while keeping the damage to normal tissue recoverable. The ideal drug would target only cancer cells, but most older agents are toxic to normal cells as well, so advances have moved toward more selective therapy even as the classical drugs remain essential. ^[1]

Cytotoxic drugs damage DNA and kill many normal cells as well as cancer cells. ^[1] A review of chemotherapy side-effects describes the group as classical, mostly DNA-damaging agents that also harm healthy tissue, and divides them into agents that do or do not lead to DNA damage. ^[2]

Classes are taught by biological target. Merck's professional manual lists them as alkylating agents, which damage DNA; antimetabolites, which block DNA; antitumour antibiotics, including anthracyclines, which interfere with DNA; mitotic inhibitors, which disrupt cell division; topoisomerase inhibitors; and other agents such as asparaginase that do not fit these categories. ^[1] This page covers the first six core classes only: alkylating agents, antimetabolites, anthracyclines, platinum agents, taxanes and vinca alkaloids.

The reason toxicities occur is direct. The normal tissues most commonly affected are those with the highest intrinsic turnover rate: bone marrow, hair follicles and the gastrointestinal epithelium. ^[1] Because cancer and these tissues share the property of rapid division, most cytotoxic side-effects are predictable from the mechanism and worsen with dose and cumulative exposure.

Cytotoxic chemotherapy is usually given in combinations rather than as a single agent. Regimens bring together drugs with different mechanisms and, where possible, different toxicities, so that efficacy rises while any one organ receives less drug. ^[1] Agents can be cell-cycle specific, with a nonlinear dose-response relationship, or not cell-cycle specific, with a linear relationship. Merck notes that antimetabolites such as fluorouracil and methotrexate are cell-cycle specific, whereas alkylating agents, also called DNA cross-linkers, have a linear dose-response relationship and kill more cancer cells at higher doses. ^[1]

One of the best characterised resistance mechanisms is overexpression of MDR1, a cell membrane transporter that pumps out vinca alkaloids, taxanes and anthracyclines, among other drugs. ^[1] That is why a tumour may become resistant to one of these classes while still responding to an alkylating agent.

The sections below follow the order in which a student usually meets them: first the agents that damage DNA template, then those that disturb the spindle.

Alkylating agents carry an alkyl group that bonds covalently to DNA bases, especially guanine, and forms cross-links between and within DNA strands. They are not phase-specific: they damage DNA in any phase of the cycle, so they kill resting as well as dividing cells. Cyclophosphamide and ifosfamide are nitrogen mustards; busulfan is an alkyl sulfonate; chlorambucil, melphalan and bendamustine are related nitrogen mustards; dacarbazine, procarbazine and temozolomide are triazenes. Many are prodrugs that need hepatic activation.

At high doses, alkylating agents damage the bone marrow. ^[1] Myelosuppression is the class dose-limiting toxicity. The granulocyte count falls to a nadir during treatment, with platelets and haemoglobin affected too. The platinum agents, discussed with the alkylating group in some texts, follow a related pattern but are treated separately below because their clinical behaviour differs.

The cytotoxicity is wide. Alkylating agents also commonly cause mucositis, nausea and vomiting, alopecia and delayed gonadal failure. Less common but serious long-term risks include infertility and secondary malignancies, and prolonged busulfan use can injure liver sinusoids.

Nephrotoxicity occurs with some members. The comparison below is supported by a review of nephrotoxicity management: with cyclophosphamide, the metabolite acrolein damages the urothelium and causes haemorrhagic cystitis, while with ifosfamide the metabolite chloroacetaldehyde injures renal tubules. ^[6] Ifosfamide carries the higher renal risk and can cause Fanconi-type proximal tubular dysfunction and irreversible chronic kidney injury; cyclophosphamide is more often responsible for hyponatraemia through SIADH, which can appear even with low doses. ^[6] Mesna, which binds the toxic metabolites, is the standard preventive treatment for cyclophosphamide-induced cystitis. ^[6]

Antimetabolites are small molecules that resemble natural purines, pyrimidines or folate and interrupt synthesis of DNA or its precursors. They are mostly S-phase specific: they work only when the cell is copying DNA, so they hit rapidly dividing tumours hard and spare some resting cells. Merck classes methotrexate and fluorouracil as examples of antimetabolites that block DNA. ^[1]

They fall into broad groups:

• Folate antagonists, such as methotrexate and pemetrexed: they inhibit dihydrofolate reductase or other folate-dependent enzymes and starve the cell of thymidine and purines.
• Pyrimidine analogues, such as 5-fluorouracil, capecitabine, cytarabine and gemcitabine: they substitute for normal pyrimidines and block thymidylate synthase or chain elongation.
• Purine analogues, such as 6-mercaptopurine, 6-thioguanine and fludarabine: they disrupt purine synthesis and DNA repair.
• Ribonucleotide reductase inhibitor, hydroxyurea: it depletes deoxyribonucleotides.

The class dose-limiting toxicity is usually myelosuppression or mucositis, sometimes both. Mucositis is the price of injuring a rapidly dividing epithelium: sore mouth, diarrhoea and, with fluoropyrimidines, nausea. Important drug-specific points follow from where the drug acts.

Methotrexate can crystallise in renal tubules at high dose. High-dose methotrexate can lead to acute kidney injury from crystal precipitation in the distal tubular lumen, after impaired clearance prolongs exposure. ^[6] Leucovorin rescue 24 to 36 hours later counters the folate blockade, and glucarpidase (carboxypeptidase G2) can cleave methotrexate to inactive metabolites when renal clearance fails. ^[6] Methotrexate is also hepatotoxic with prolonged use and can cause pulmonary fibrosis and an acute cerebellar syndrome after intrathecal dosing.

5-Fluorouracil has a surprising toxicity that is easy to miss: it can cause coronary vasospasm and myocardial ischaemia with angina-like chest pain, sometimes with arrhythmia. ^[2] Capecitabine, an oral prodrug of 5-fluorouracil, and cytarabine are also associated with cardiac ischaemia. ^[2] Intravenous hydration and dose reduction are the response.

Pemetrexed, a folate antagonist used in mesothelioma and non-small cell lung cancer, causes myelosuppression and can produce reversible acute kidney injury with interstitial fibrosis reported in some cases. ^[6]

Anthracyclines are antitumour antibiotics that intercalate into DNA and poison topoisomerase II, an enzyme needed to relieve torsion during DNA replication. They also generate free radicals. Doxorubicin, daunorubicin, epirubicin and idarubicin are the four classic agents; mitoxantrone is related and behaves similarly.

Their dose-limiting toxicity is cardiomyopathy, and the detailed cumulative-dose thresholds, protective measures and monitoring are given in the Adverse effects section below.

Anthracyclines also carry the ordinary cytotoxic burden of myelosuppression, mucositis and alopecia, and long-term risks including secondary malignancy. ^[2]

Cisplatin, carboplatin and oxaliplatin are heavy metal complexes that bind DNA and form intra- and inter-strand cross-links. They act like alkylating agents in outcome but differ in pharmacology and toxicity. They are not phase-specific. Cisplatin is one of the most widely used and most nephrotoxic drugs in oncology. ^[5]

Cisplatin's adverse effects include bone marrow suppression, peripheral neuropathy, ototoxicity, anaphylaxis and nephrotoxicity. ^[5] After a single dose of cisplatin of 50 to 100 mg per m2, approximately one-third of patients develop nephrotoxicity. ^[5] The injury is cumulative and dose-dependent, and it is the main reason cisplatin is replaced by carboplatin or oxaliplatin in many protocols. ^{[5] [4]}

Mechanistically, cisplatin accumulates in the proximal tubule at a concentration around five times that in serum, causes apoptosis and necrosis of tubular cells, and activates inflammatory and oxidative stress pathways. ^{[5] [6]} Prevention is therefore built on hydration, electrolyte replacement and avoidance of other nephrotoxins: saline hydration before and for at least three days after dosing, magnesium replacement, and avoiding simultaneous NSAIDs, aminoglycosides and contrast media. ^{[5] [6]} Amifostine, a free radical scavenger, may be considered for patients at high risk of kidney injury. ^{[5] [6]}

Ototoxicity is especially important in children, where cisplatin can cause permanent high-frequency hearing loss. Peripheral neuropathy is dose-limiting for cisplatin and oxaliplatin, with oxaliplatin producing an acute cold-sensitive neuropathy in addition to chronic cumulative numbness. Carboplatin is less nephrotoxic and less neurotoxic than cisplatin, but it causes more thrombocytopenia.

The alkylating comparison is useful for students: cyclophosphamide and ifosfamide share a nitrogen mustard origin, while platinum is a separate class whose end result on DNA is similar but whose organs at risk are different. ^[6]

Taxanes stabilise microtubules by binding their interior surface, preventing the dynamic assembly and disassembly needed for the mitotic spindle. They are M-phase specific and act during G2 and M. Classic members are paclitaxel, docetaxel and cabazitaxel; nab-paclitaxel is an albumin-bound formulation.

The dose-limiting toxicities are peripheral neuropathy and neutropenia. Neurotoxicity is sensory and distal: numbness and paraesthesia in the feet and hands, and sometimes myalgia and myopathy. ^[2] Taxanes also commonly cause alopecia, nail changes, mucositis and arthralgia. Infusion hypersensitivity was a major early problem with paclitaxel and required premedication; modern preparations have reduced but not removed this risk.

Cardiac effects are classically described: taxanes can produce arrhythmia, sinus bradycardia and atrioventricular block. ^[2] Hepatic impairment is a caution for the group, and dose modification or exclusion of taxanes is advised in liver dysfunction. ^[1]

Vinca alkaloids are plant alkaloids that bind tubulin and prevent microtubule polymerisation, the opposite of the taxane mechanism. They arrest mitosis in metaphase. Vincristine, vinblastine, vinorelbine and vindesine are the main members. They are also M-phase specific.

They are classed as vesicants and are irritant to soft tissue if they leak from the vein. The dose-limiting toxicity is neurotoxicity: sensory impairment, distal motor weakness, ataxia, autonomic neuropathy causing constipation and urinary retention, muscle cramps, jaw pain and, in severe cases, encephalopathy and seizures. ^{[2] [6]} The neurological picture is often early and reversible with dose reduction, but severe neuropathy can persist.

Vincristine differs importantly from vinblastine. Vincristine causes little myelosuppression but much neuropathy. Vinblastine causes prominent neutropenia and thrombocytopenia and less neuropathy. Vinorelbine is intermediate and more marrow-suppressive than vincristine.

Hyponatraemia from SIADH is a recognised problem with vinca alkaloids, attributed to a hypothalamic and antidiuretic effect. ^[6] Cardiac ischaemia and myocardial infarction have been reported with the class. ^[2] Nephrotoxicity from hyponatraemia and SIADH is managed with hypertonic saline and fluid restriction rather than stopping chemotherapy alone. ^[6]

All cytotoxic agents disrupt the chain from DNA to cell division by one or more routes. Cancer cells are more likely to be caught during division, but normal tissues with high turnover are hit too. ^[1]

• Alkylating agents and platinum agents create cross-links that block replication and transcription; they are not confined to any one phase.
• Antimetabolites are false substrates or enzyme blockers that stop DNA synthesis in S phase.
• Anthracyclines intercalate and trap topoisomerase II, creating double-strand breaks; their free radical chemistry also injures mitochondria in heart muscle.
• Taxanes and vinca alkaloids do not attack DNA directly. They freeze or destroy the mitotic spindle, which triggers cell-cycle arrest in M phase and apoptosis.

Combination chemotherapy uses drugs with different mechanisms and different toxicities to increase cell kill, lower dose-related toxicity and reduce the chance of drug resistance. ^[1] Resistance can also arise from pumps such as MDR1 that expel vinca alkaloids, taxanes and anthracyclines from the cell. ^[1]

Most classical cytotoxic drugs are given intravenously or subcutaneously, and some are oral. Frequent or prolonged dosing may need a central venous access device. ^[1] Hepatic impairment and renal impairment matter because the two organs clear most agents: taxanes are an example where liver dysfunction necessitates dose modification, and methotrexate where kidney failure does. ^[1]

Distribution is by body surface area, which explains the milligrams per square metre dosing. Protein binding, hepatic metabolism and renal excretion vary widely between drugs. Half-lives range from minutes to days, so schedules are designed around recovery of bone marrow rather than simple drug clearance.

Classical cytotoxic chemotherapy is used across haematological cancers and solid tumours, sometimes with curative intent and sometimes to control disease or prolong survival. It is often given in the adjuvant setting after surgery, as neoadjuvant treatment before surgery, as concurrent chemoradiotherapy, or as palliative treatment for advanced disease. Single agents cure a few cancers, such as choriocarcinoma and hairy cell leukaemia, whereas most cancers require multidrug regimens. ^[1]

Endocrine therapy, targeted therapy and immunotherapy are separate families and are not covered here. The numeral lists of indications in oncology protocols are based on trial evidence rather than on this page; the page focuses on the class behaviour and toxicities that any regimen using these drugs shares.

Dose is not a single number that can be looked up for a drug. It depends on the tumour protocol, body surface area, renal function, hepatic function, haematological recovery and comorbidity. Adjustments for renal and hepatic impairment are not optional; they are part of the prescription.

The following thresholds from a review of chemotherapy nephrotoxicity are widely used as precaution points during cytotoxic treatment: a glomerular filtration rate below 60 ml per minute per 1.73 m2, which indicates moderate chronic kidney disease, or a creatinine clearance below 30 ml per minute, which indicates severe disease, both require caution and often dose adjustment. ^[6] Cisplatin at 50 to 100 mg per m2 in a single dose produces nephrotoxicity in roughly one-third of patients, which is the reason its renal clearance and dose density are monitored so closely. ^[5]

Children need special mention. They clear many drugs faster and have larger volumes of distribution than adults, so they often tolerate higher milligram-per-m2 doses; their protocols are therefore not simply adult doses scaled down. Drug accumulation in renal tubules, infection risk and late effects matter more over the long time a child has after cure.

The normal tissues hit hardest are those that turn over quickly: bone marrow, gut mucosa and hair follicles. ^[1] Myelosuppression produces anaemia, neutropenia and thrombocytopenia. Mucositis, diarrhoea, nausea and vomiting, fatigue and alopecia are frequent. The depth and timing of the neutrophil and platelet fall, often called the nadir, varies by drug and by schedule. The exact timing is protocol information and is not repeated here.

The red flag is fever during neutropenia, which requires prompt assessment and treatment according to neutropenic sepsis pathways. Myelosuppression is the reason combinations of drugs with different organs at risk are chosen, rather than stacking two bone-marrow-toxic agents.

A review of dose-limiting toxicities reminds that for most anticancer drugs the dose-limiting toxicity is defined by the activation of inflammatory, apoptotic, ion imbalance and tissue-specific pathways. ^[2] It also notes that the dose-limiting toxicity of most anticancer drugs is managed mainly by discontinuation or dose reduction, because specific antidotes are rare. ^[2]

• Alkylating agents: myelosuppression, mucositis, nausea and vomiting, alopecia, infertility and an increased risk of secondary malignancy in the long term.
• Ifosfamide: Fanconi-type proximal tubular dysfunction, salt and phosphate wasting, hyponatraemia, haemorrhagic cystitis and occasionally central nervous system toxicity. ^[6]
• Cyclophosphamide: haemorrhagic cystitis prevented with mesna, hyponatraemia via SIADH even at low dose, and cardiomyopathy at high doses. ^[6]
• Busulfan: hepatotoxicity, veno-occlusive disease and pulmonary fibrosis.
• Platinum agents: nephrotoxicity with cisplatin; thrombocytopenia with carboplatin; acute cold-sensitive neuropathy and chronic numbness with oxaliplatin; ototoxicity; nausea and vomiting; mild haematological suppression.

The review of nephrotoxicity shows how these agents differ even within a family: cyclophosphamide's metabolite acrolein mainly damages the bladder, whereas ifosfamide's metabolite chloroacetaldehyde damages the kidney. ^[6] It also lists vinca alkaloids among the causes of SIADH, with cyclophosphamide and methotrexate. ^[6]

Ototoxicity from platinum agents is especially important in children and in patients with pre-existing hearing loss. Peripheral neuropathy tends to appear after a cumulative dose and may be partly reversible once treatment stops.

• Methotrexate: myelosuppression, mucositis, hepatotoxicity, pulmonary fibrosis, and acute kidney injury from crystal precipitation at high dose. ^[6] Leucovorin rescue 24 to 36 hours after high-dose methotrexate is an effective counter to crystallisation damage. ^[6]
• 5-Fluorouracil and capecitabine: mucositis, diarrhoea, hand-foot syndrome and, importantly, coronary ischaemia with angina-like chest pain. ^[2]
• Cytarabine: myelosuppression and cerebellar syndrome at high dose; gemcitabine can cause thrombotic microangiopathy and haemolytic uraemic syndrome.
• Pemetrexed: myelosuppression and neutropenia, with reversible or sometimes interstitial renal injury. ^[6]

High-dose methotrexate can lead to acute kidney injury from crystal precipitation, and renal dysfunction in cancer patients is common, so renal function is monitored before and during treatment. ^[6]

Anthracyclines carry a cardiovascular risk unlike any other class here. Their cardiac toxicity is cumulative, partly irreversible, and often delayed. The occurrence of congestive heart failure associated with anthracyclines is 2 to 4 per cent, sub-clinical structural changes occur in approximately 10 per cent, arrhythmias in 12 per cent, and cardiac-related biomarker positivity in 30 to 35 per cent of patients. ^[4] Cardiotoxicity is tracked clinically and by serial measurement of left ventricular function rather than by a single universal ejection fraction cut-off.

Clinical prediction by cumulative dose is essential:

• The 2022 ESC Guidelines on cardio-oncology consider doxorubicin or an equivalent anthracycline dose of 250 mg per m2 or more to be high risk. ^[4]
• A pooled analysis of three doxorubicin trials estimated 5 per cent heart failure at a cumulative dose of 400 mg per m2, 26 per cent at 550 mg per m2, and 48 per cent at 700 mg per m2. ^[3]
• Once anthracycline cardiomyopathy progresses to congestive heart failure, about half of patients die within two years. ^[3]
• The recommended maximum lifetime cumulative doxorubicin exposure is 400 to 450 mg per m2 in patients without prior chest radiotherapy, so that doses do not exceed 550 mg per m2 of doxorubicin-equivalent drug and 900 mg per m2 of epirubicin. ^{[4] [3]}

Protective measures are evidence based. Dexrazoxane is the only FDA-approved cardioprotective drug for anthracycline toxicity, approved for adult patients with advanced or metastatic breast cancer who have received doxorubicin or an equivalent with a minimum cumulative dose of 300 mg per m2. ^[4] Slower continuous infusions reduce risk, with a meta-analysis showing a relative risk of 0.27 for heart failure with infusion intervals of six hours or more (95 per cent confidence interval 0.09 to 0.81) and 0.35 for subclinical cardiotoxicity (95 per cent confidence interval 0.15 to 0.9). ^[4] Liposomal preparations reduce cardiotoxicity compared with conventional doxorubicin, with a relative risk of 3.75 in favour of the liposomal form. ^[4] Once cardiotoxicity occurs, the 2022 ESC guideline advocates beta-blockers, ACE inhibitors and angiotensin receptor blockers for secondary prevention. ^[4]

Anthracyclines also bring the ordinary cytotoxic burden of myelosuppression, mucositis and alopecia, and long-term risks including secondary malignancy. ^[2]

Taxanes carry the peripheral nervous system as their main liability. The typical picture is a distal, length-dependent sensory neuropathy with numbness and paraesthesia, sometimes motor weakness, myalgia and myopathy. ^[2] Neutropenia is the other dose-limiting problem. Other effects include alopecia, nail changes, mucositis and arthralgia. Hypersensitivity on first infusion was common with paclitaxel and remains a concern, so premedication and infusion settings follow local protocol. Cardiac effects include arrhythmia, sinus bradycardia and atrioventricular block. ^[2] The group should be used with caution in liver dysfunction. ^[1]

Vinca alkaloids are neurotoxic, vesicant and, for vincristine, surprisingly free of marrow suppression. The neurological syndrome is the dose-limiting toxicity: distal sensory and motor loss, ataxia, muscle cramps, jaw pain, autonomic neuropathy causing constipation and urinary retention, and in severe cases encephalopathy and seizures. ^{[2] [6]} The picture is often early and partly reversible on dose reduction, but severe neuropathy can persist.

The members differ in marrow toxicity. Vincristine gives little myelosuppression but much neuropathy. Vinblastine gives prominent neutropenia and thrombocytopenia. Vinorelbine is intermediate. Cardiac ischaemia and myocardial infarction are reported with the class. ^[2]

SIADH with hyponatraemia is a well-recognised effect of vinca alkaloids, attributed to a hypothalamic and antidiuretic mechanism, and it is managed with hypertonic saline and fluid restriction alongside cancer treatment. ^[6]

• Pregnancy is a general contraindication for cytotoxic chemotherapy in the first trimester because of teratogenic risk, although treatment may be considered later in pregnancy for aggressive cancers after specialist discussion.
• Severe renal impairment is a caution or contraindication for methotrexate, cisplatin and ifosfamide; severe liver impairment for taxanes and 6-mercaptopurine; severe cardiac failure for anthracyclines and cyclophosphamide. ^[1]
• Concomitant nephrotoxins, including NSAIDs, aminoglycosides and radiographic contrast, should be avoided during cisplatin therapy, since the risk adds. ^{[5] [6]}
• Combinations should allow recovery of tissues. Adding two agents with the same dose-limiting toxicity removes the rationale for combining them.
• Extravasation of a vesicant such as a vinca alkaloid requires stopping the infusion immediately and following local management; these drugs damage soft tissue outside the vein.

Interactions are usually pharmacodynamic rather than pharmacokinetic: additive myelosuppression, overlapping neuropathy, or combined cardiac and renal injury. Merck describes MDR1 overexpression as a resistance mechanism for vinca alkaloids, taxanes and anthracyclines, so agents that affect MDR1 can alter exposure. ^[1] Drugs that share renal excretion, such as methotrexate and NSAIDs or proton pump inhibitors, can produce unexpected accumulation. In practice, every new drug is checked against the oncology protocol before it is added to a patient on chemotherapy.

A sensible monitoring plan follows the organ at risk for each class:

• Before and during treatment: full blood count, renal function, liver function and, in women of childbearing age, pregnancy testing.
• With anthracyclines and some alkylating agents: baseline echocardiography or multigated acquisition scanning, electrocardiogram and serial cardiac imaging when cumulative risk rises. ^[4]
• With cisplatin: creatinine, electrolytes including magnesium, before each cycle. ^{[5] [6]}
• With methotrexate: plasma methotrexate levels after high dosing, plus renal function, to decide on leucovorin rescue or glucarpidase. ^[6]
• With taxanes and vinca alkaloids: neurological examination each cycle, bowel function, and liver enzymes.
• With all classes: surveillance for infection during the expected nadir, especially fever.

There is no universal antidote for cytotoxic chemotherapy. Management is specific and supportive: drug-specific rescue where it exists, otherwise stop the drug, support the failing organs and prevent infection.

• High-dose methotrexate: leucovorin rescue 24 to 36 hours later; carboxypeptidase-G2 (glucarpidase) when methotrexate levels indicate high systemic risk or renal clearance fails. ^[6]
• Cyclophosphamide: mesna prevents urothelial damage from acrolein. ^[6]
• Cisplatin: amifostine and forced diuresis are used for prevention; there is no reliable rescue once tubular injury is established, so hydration and avoidance of other nephrotoxins are the mainstay. ^{[5] [6]}
• Anthracyclines: stop further dosing and treat heart failure; dexrazoxane is approved for prevention, not rescue. ^[4]
• Taxanes and vinca alkaloids: there is no antidote for neuropathy beyond dose reduction or substitution.

Most cytotoxic agents are teratogenic and are avoided in the first trimester. For cancers diagnosed during pregnancy, treatment is individualised by the oncology, obstetric and paediatric teams; some agents and later-gestation treatment can be used when benefit outweighs risk. Breastfeeding is usually not advised during and for a variable interval after cytotoxic chemotherapy. Local protocol and drug label information guide the exact interval, because clearance differs between drugs.

• Children tolerate higher milligram-per-m2 doses than adults because of better clearance, but late effects including hearing loss from platinums, cardiomyopathy from anthracyclines and second cancers are lifelong concerns. Protocols are not simply adult doses scaled down.
• Older adults clear many drugs more slowly, have more renal and cardiac disease and are at greater risk of neutropenic sepsis; dose intensity is sometimes reduced.
• Pregnancy and breastfeeding are discussed above; standard advice is that the decision belongs to the multidisciplinary team.
• Patients with renal impairment: methotrexate, cisplatin and ifosfamide are the main agents needing dose adjustment or substitution; creatinine clearance should be reassessed before each cycle. ^[6]

• Hydration before and after cisplatin and careful electrolyte replacement can be delivered even where drugs are limited. ^{[5] [6]}
• A full blood count and basic renal and liver function are more important than advanced biomarkers. Check before each cycle.
• Anthracycline cardiotoxicity can be suspected from symptoms and a clinical examination; echocardiography adds information but is not a prerequisite for avoiding overdose of the drug.
• Where oncology drugs are intermittent, use the same class-level principles to avoid the most dangerous errors: do not give cisplatin without hydration, and do not give high-dose methotrexate without leucovorin rescue.
• Refer early when specialist input and cardiopulmonary bypass are unavailable locally.

• Classical cytotoxic classes are alkylating agents, antimetabolites, anthracyclines, platinum agents, taxanes and vinca alkaloids.
• Most kill rapidly dividing cells by damaging DNA or freezing the mitotic spindle, so their toxicities target marrow, gut, hair follicles and germ cells.
• Alkylating agents are non-specific and have a linear dose-response; they are usually limited by myelosuppression.
• Antimetabolites are S-phase specific. Methotrexate can crystallise in the kidney and is rescued with leucovorin or glucarpidase.
• Anthracyclines cause cumulative, often irreversible cardiomyopathy. Congestive heart failure occurs in 2 to 4 per cent overall ^[4], with risk rising to 26 per cent at a cumulative doxorubicin dose of 550 mg per m2 ^[3].
• The 2022 ESC Guidelines on cardio-oncology classify doxorubicin-equivalent doses of 250 mg per m2 or more as high risk ^[4], and the lifetime maximum is 400 to 450 mg per m2 without prior chest radiotherapy ^[3].
• Platinum agents are DNA cross-linkers limited by nephrotoxicity. A single cisplatin dose of 50 to 100 mg per m2 produces nephrotoxicity in about one-third of patients ^[5], so hydration and magnesium are mandatory.
• Taxanes produce distal sensory neuropathy and neutropenia and are cautious in liver disease.
• Vinca alkaloids are vesicant, strongly neurotoxic and prone to SIADH with hyponatraemia; vincristine has little marrow toxicity, while vinblastine has much.
• There is no universal antidote. Drug-specific rescue, monitoring and dose reduction are the practical tools.

Atrial myxoma and tumour plop on physical examination. Heart failure and left ventricular dysfunction. Acute kidney injury and electrolyte disorders. Neutropenic sepsis and antimicrobial prophylaxis. Peripheral neuropathy and its grading. Pregnancy and drug safety. Low-resource oncology care. Cardiac imaging and left ventricular ejection fraction measurement.