Chemotherapy in gynaecology
Chemotherapy in gynaecological cancer and trophoblastic disease: methotrexate, actinomycin D and platinum drugs
Trophoblast and many gynaecological cancers divide rapidly, so drugs that block DNA synthesis or damage DNA kill them; the same action harms marrow, gut lining and hair. CPSP asks each drug's mechanism, cell-cycle phase, typical toxicity and its antidote, and the uses of methotrexate in ectopic pregnancy and trophoblastic disease.
One of the most tested topics in past papers
Cell cycle and how chemotherapy kills
- Cytotoxic drugs mainly trigger apoptosis, which is why tumours regress after treatment.
| Phase | Drugs | Action |
|---|---|---|
| S phase | Methotrexate, 5-fluorouracil, cytarabine | Antimetabolites block DNA synthesis |
| G2 | Bleomycin, etoposide | DNA strand breaks; topoisomerase II block |
| M phase | Paclitaxel (stabilises microtubules), vincristine (prevents assembly) | Mitotic arrest |
| Not phase specific | Cyclophosphamide, cisplatin, carboplatin, actinomycin D | DNA cross-linking or intercalation |
Methotrexate
- A folate analogue and competitive inhibitor of dihydrofolate reductase (DHFR), so tetrahydrofolate is not regenerated and thymidine and purines cannot be made; cells die in S phase.
- Folinic acid (leucovorin) is already reduced and needs no DHFR, so it bypasses the block and rescues normal cells in high-dose and multi-day regimens; folic acid cannot. Folinic acid enhances 5-FU instead (it stabilises thymidylate synthase inhibition).
- Uses: unruptured ectopic pregnancy (single IM dose, low hCG, no heartbeat), low-risk gestational trophoblastic neoplasia (FIGO score 6 or less), medical abortion historically, and outside gynaecology rheumatoid arthritis and psoriasis (once weekly).
- Toxicity: mucositis, marrow suppression, liver fibrosis, pneumonitis, teratogenicity.
- It is excreted unchanged by the kidney. NSAIDs reduce renal excretion and trimethoprim (also a DHFR inhibitor) adds toxicity; both cause pancytopenia and mucositis. Stop folic acid supplements during ectopic treatment.
- Tissue polyglutamates persist, so conception is delayed for at least 3 months after the last dose.
Actinomycin D (dactinomycin)
- Intercalates DNA and blocks RNA polymerase, stopping mRNA synthesis.
- Second line for low-risk GTN, or first line when methotrexate cannot be used (liver disease); part of EMA-CO for high-risk disease (FIGO score 7 or more).
- A vesicant: extravasation causes severe local necrosis. Also mucositis, alopecia and marrow suppression.
Platinum drugs
- Cisplatin loses chloride inside cells, becomes reactive and binds guanine N7, forming intrastrand DNA cross-links; it is not phase specific. Saline keeps it inactive in the bag.
| Toxicity | Cisplatin | Carboplatin |
|---|---|---|
| Kidney | Proximal tubular damage; saline hydration essential | Little |
| Magnesium | Renal magnesium wasting, causing low PTH, hypocalcaemia and hypokalaemia; replace magnesium first | Little |
| Ear | High-frequency hearing loss | Little |
| Nerve | Dorsal root ganglion damage: sensory loss, lost position sense, may worsen after stopping | Little |
| Vomiting | Most emetogenic drug | Moderate |
| Marrow | Moderate | Dose-limiting thrombocytopenia |
- Carboplatin is cleared by glomerular filtration, so its dose uses the Calvert formula: target AUC × (GFR + 25).
- Carboplatin with paclitaxel is standard for advanced epithelial ovarian cancer. Weekly low-dose cisplatin with radiotherapy for cervical cancer acts as a radiosensitiser, blocking repair of radiation damage.
- Acute chemotherapy vomiting comes from 5-HT released by gut enterochromaffin cells acting on vagal 5-HT3 receptors; ondansetron blocks it.
Other drugs in gynaecological oncology
| Drug | Mechanism | Signature toxicity |
|---|---|---|
| Paclitaxel | Stabilises microtubules, M phase | Hypersensitivity in the first minutes from its castor oil solvent (premedicate with dexamethasone, H1 and H2 blockers); glove-and-stocking neuropathy from blocked axonal transport |
| Cyclophosphamide | Prodrug activated by liver CYP450; phosphoramide mustard cross-links DNA | Acrolein causes haemorrhagic cystitis and later bladder cancer: give mesna |
| Etoposide | Topoisomerase II inhibitor | Secondary AML with 11q23 (MLL) rearrangement after 1–3 years |
| Bleomycin | Oxygen-radical DNA breaks | Pulmonary fibrosis and skin changes; little marrow effect because lung and skin lack bleomycin hydrolase |
| Doxorubicin | Intercalates, topoisomerase II, oxygen radicals | Dose-related cardiomyopathy (dexrazoxane); liposomal form causes hand–foot syndrome |
| Vincristine | Prevents microtubule assembly | Peripheral and autonomic neuropathy; fatal if given intrathecally |
| Bevacizumab | Antibody against VEGF | Hypertension, bowel perforation |
- BEP (bleomycin, etoposide, cisplatin) treats malignant ovarian germ cell tumours.
- Tamoxifen is a prodrug activated by CYP2D6 to endoxifen; paroxetine and fluoxetine block this. It is oestrogenic in the endometrium. A levonorgestrel IUS treats atypical hyperplasia in women wanting fertility by opposing oestrogen-driven growth.
Gestational trophoblastic neoplasia and hCG
- All trophoblast makes hCG, whose level reflects tumour volume. After evacuation of a mole, serial hCG is followed; a plateau or rise, persistent hCG, choriocarcinoma on histology or metastases mean chemotherapy.
- Low risk: methotrexate (actinomycin D second line). High risk: EMA-CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine). Choriocarcinoma is highly chemosensitive even when metastatic.
- Reliable contraception during follow-up prevents a new pregnancy confusing the hCG.
Remember Rescue methotrexate with folinic acid, protect the bladder from cyclophosphamide with mesna, and hydrate for cisplatin.
Exam trap Folinic acid rescues methotrexate but enhances 5-FU; folic acid rescues neither.
Exam trap Cisplatin damages kidney, ear and nerve; carboplatin damages marrow, especially platelets.
Test yourself on this topic
5 of the 46 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
During an infusion of actinomycin D for methotrexate-resistant trophoblastic disease, the cannula is found to have leaked into the forearm. Which complication is the main concern?
Answer: Severe local tissue necrosis
Actinomycin D (dactinomycin) intercalates into DNA and blocks RNA polymerase. It is a vesicant: if it leaks outside the vein it causes severe pain, ulceration and necrosis of the soft tissues, which may need surgical debridement. Infusions must stop at once if extravasation is suspected. It also causes mucositis, marrow suppression and radiation recall. Haemorrhagic cystitis is caused by cyclophosphamide, pulmonary fibrosis by bleomycin and neuropathy by vinca alkaloids and taxanes.
Actinomycin D
- Intercalates DNA, blocks RNA polymerase
- Vesicant: necrosis if extravasated
- Mucositis, marrow suppression
- Second line in low-risk GTN
Remember Actinomycin leaks: the skin dies.
Exam trap Stop the infusion and aspirate the cannula before removing it.
Why the other options are wrong
- Haemorrhagic cystitis Caused by cyclophosphamide and ifosfamide.
- Acute pulmonary fibrosis Caused by bleomycin; not related to extravasation.
- Peripheral sensory neuropathy Caused by vincristine, taxanes and cisplatin.
- Acute cardiomyopathy Caused by anthracyclines.
Cyclophosphamide, part of the EMA-CO regimen, has no cytotoxic activity when tested on tumour cells in a culture dish. Why is it effective in patients?
Answer: It is activated by hepatic cytochrome P450
Cyclophosphamide is a prodrug. Hepatic cytochrome P450 enzymes hydroxylate it to 4-hydroxycyclophosphamide, which breaks down into phosphoramide mustard, the alkylating species that cross-links DNA, and acrolein, which damages the bladder. Without liver metabolism it is inactive, so it does not work in cell culture. Enzyme inducers and inhibitors can alter its activation.
Cyclophosphamide
- Prodrug
- Activated by liver CYP450
- Phosphoramide mustard: DNA cross-links
- Acrolein: bladder damage
Remember Cyclophosphamide needs the liver to work.
Exam trap Mesna protects the bladder from acrolein, not from phosphoramide mustard.
Why the other options are wrong
- It is activated by tumour cell phosphatases Not the activating pathway.
- It is activated by stomach acid It is given IV in EMA-CO; acid plays no role.
- It is activated by renal tubular enzymes The kidney excretes, not activates, it.
- It is activated by binding plasma albumin Albumin binding does not activate drugs.
A woman receiving her fourth cycle of cisplatin for ovarian cancer has muscle cramps and a positive Trousseau sign. Calcium is 1.9 mmol/L (7.6 mg/dL), magnesium 0.4 mmol/L (1.0 mg/dL) and potassium 3.0 mmol/L, with urine magnesium inappropriately high. What is the primary disturbance?
Answer: Renal tubular magnesium wasting
Cisplatin is concentrated in and damages proximal and distal renal tubular cells, causing a persistent renal magnesium leak in a large proportion of patients. Low magnesium reduces PTH secretion and causes end-organ resistance to PTH, producing hypocalcaemia, and also promotes renal potassium loss, so all three fall. Calcium and potassium do not correct until magnesium is replaced. Magnesium is routinely added to cisplatin hydration fluids.
Cisplatin hypomagnesaemia
- Tubular damage: Mg²⁺ wasting
- Low Mg²⁺: low PTH and PTH resistance
- Leads to low Ca²⁺ and K⁺
- Replace magnesium first
Remember Cisplatin cramps: check the magnesium.
Exam trap Giving calcium alone will not correct hypocalcaemia caused by low magnesium.
Why the other options are wrong
- Vitamin D deficiency Would not explain the high urine magnesium.
- Primary hypoparathyroidism Magnesium would be normal.
- Tumour lysis syndrome Causes high potassium and phosphate.
- Malabsorption from vomiting Urine magnesium would be low.
Three years after EMA-CO chemotherapy for high-risk choriocarcinoma, a woman develops acute myeloid leukaemia with a rearrangement of the MLL gene at 11q23. Which action of a drug in her regimen is most responsible?
Answer: Inhibition of topoisomerase II
Etoposide, a component of EMA-CO, stabilises the complex between topoisomerase II and DNA, preventing re-joining of the double-strand breaks the enzyme makes. Unrepaired breaks lead to chromosomal translocations, classically involving the MLL gene at 11q23, and therapy-related AML that appears 1–3 years after treatment without a preceding myelodysplastic phase. Alkylating agents such as cyclophosphamide cause a later AML with chromosome 5 and 7 losses.
Etoposide
- Inhibits topoisomerase II
- Double-strand DNA breaks
- Secondary AML with 11q23 (MLL)
- Appears 1–3 years after treatment
Remember Topoisomerase II inhibitors: early AML with 11q23.
Exam trap Do not confuse topoisomerase II (etoposide) with topoisomerase I (irinotecan, topotecan).
Why the other options are wrong
- Inhibition of dihydrofolate reductase Methotrexate does not typically cause secondary leukaemia.
- Blockade of microtubule assembly Vincristine is not leukaemogenic.
- Inhibition of RNA polymerase Actinomycin D is not linked to 11q23 AML.
- Inhibition of thymidylate synthase This is 5-fluorouracil.
Within 5 minutes of starting her first paclitaxel infusion for ovarian cancer, a woman becomes flushed, wheezy and hypotensive. She had been premedicated only with ondansetron. Which component of the drug is chiefly responsible?
Answer: Its polyoxyl castor oil solvent
Paclitaxel is very poorly water-soluble and is formulated in polyoxyl 35 castor oil (Cremophor EL) with ethanol. This vehicle activates complement and triggers mast cell histamine release, causing hypersensitivity reactions, usually within minutes of the first or second infusion. Premedication with dexamethasone and H1 and H2 antihistamines reduces the risk greatly. Albumin-bound paclitaxel avoids this solvent.
Paclitaxel reactions
- Solvent: Cremophor EL (castor oil)
- Complement and histamine release
- Within minutes of first infusions
- Premedicate: dexamethasone, H1, H2
Remember Paclitaxel reactions come from its castor oil vehicle.
Exam trap Carboplatin reactions, by contrast, usually appear after many cycles.
Why the other options are wrong
- The taxane ring of paclitaxel The reaction is mainly due to the vehicle.
- Contaminating platinum salts Paclitaxel contains no platinum.
- Its albumin carrier protein Albumin-bound paclitaxel avoids Cremophor reactions.
- Preservative benzyl alcohol Not the main cause.
Where this sits in the CPSP syllabus
- Obstetrics & Gynaecology, Paper 2: Drugs in obstetrics and gynaecology, Chemotherapy in gynaecological cancer and trophoblastic disease: methotrexate, actinomycin, platinum
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