Chemotherapy agents: mechanisms and toxicities

Cell cycle & mechanism overview

• Cell cycle phases: G1 → S (DNA synthesis) → G2 → M (mitosis). G0 is quiescent.
• Cell-cycle-specific agents: antimetabolites (S phase), taxanes/vinca alkaloids (M phase).
• Cell-cycle-non-specific: alkylators, anthracyclines, platinum.
• Fractional cell kill: each cycle kills a constant proportion (not a constant number) of cells; basis for multiple cycles at highest tolerable dose using non-cross-resistant agents with non-overlapping toxicities.
• Goldie-Coldman hypothesis: tumors acquire spontaneous mutations conferring drug resistance; supports early combination therapy. Principles apply best to rapidly growing cancers (leukemias, lymphomas).

General principles

• ASCO rule: give white-cell-stimulating factors (G-CSF) as primary prophylaxis when the regimen carries a ≥ 20% risk of febrile neutropenia.
• Do NOT offer G-CSF primary prophylaxis when risk is < 20% and the patient has no risk factors.
• Intermediate risk (10 to 20%) plus ≥ 1 risk factor: consider G-CSF primary prophylaxis. Risk factors: prior chemo or radiation, persistent neutropenia, marrow involvement by tumor, recent surgery or open wounds, liver dysfunction (bilirubin ≥ 2), renal dysfunction (CrCl < 50), age > 65 receiving full dose intensity.
• Regimens with > 20% febrile neutropenia risk (need prophylaxis): BEACOPP and brentuximab vedotin + AVD (Hodgkin), docetaxel/cisplatin/fluorouracil (gastric), MVAC (bladder), R-ICE and hyperCVAD (NHL), MAID and cisplatin/doxorubicin (sarcoma/osteosarcoma), FOLFOXIRI (colorectal), docetaxel or topotecan (ovarian), FOLFIRINOX (pancreatic), TIP or VIP (testicular). Dose-dense MVAC therefore needs prophylactic G-CSF.

• Several oral agents need an acidic environment for complete absorption: bosutinib, dasatinib, erlotinib, gefitinib, neratinib, pazopanib.
• PPIs should be avoided or dose-separated with dasatinib, erlotinib, gefitinib, neratinib, bosutinib (reduced exposure). Pazopanib: avoid PPIs and H2 blockers; prefer short-acting antacids separated by several hours; if a PPI is unavoidable, take pazopanib once daily in the evening together with the PPI (dose separation does not help). Nilotinib: PPIs not recommended; H2 blockers (10 h before, 2 h after) and antacids (2 h apart) can be used with dosing separation. Dabrafenib absorption is not meaningfully affected by acid suppression.

• Use full weight-based dosing of cytotoxic chemo regardless of obesity; underdosing is linked to higher mortality in obese patients.
• Limit fixed dosing to selected agents (e.g., bleomycin). Use FDA prescribing information for ICIs and targeted therapies regardless of obesity.
• Apply the same dose-reduction rules for high-grade toxicity in all patients. Any standard BSA formula is acceptable (no formula proven superior).

Extravasation: vesicants, irritants, and antidotes

• Hyaluronidase: degrades hyaluronic acid, breaking subcutaneous tissue bonds to promote drug diffusion and absorption. Give 1 mL as five 0.2 mL injections into the site (25 gauge or smaller, new needle each time).
• Sodium thiosulfate: creates an alkaline site to which alkylators bind (drug binds thiosulfate rather than tissue; excreted in urine). 1/6 molar solution = 4 mL of 10% sodium thiosulfate + 6 mL sterile water.
• DMSO: solvent that penetrates tissue, neutralizes free radicals, enhances systemic absorption; vasodilatory, analgesic, anti-inflammatory. Apply topically over twice the infiltration area, let dry (do not cover), repeat every 6 to 8 h for 7 to 14 days.
• Dexrazoxane: only agent with EU and FDA approval for anthracycline extravasation; binds iron and prevents free-radical formation. IV in a vein away from the site: 1,000 mg/m² within 6 h on day 1, 1,000 mg/m² day 2, 500 mg/m² day 3 (max 2,000 mg on days 1 and 2; max 1,000 mg on day 3).

Hepatic dose adjustment

• Agents mainly cleared/metabolized by the liver (adjust for hepatic dysfunction): doxorubicin, irinotecan, actinomycin (dactinomycin), fluorouracil, mitoxantrone, taxanes (docetaxel, paclitaxel), vinca alkaloids.

Renal dose adjustment

• Agents mainly cleared/metabolized by the kidney (adjust for renal impairment): fludarabine, cladribine, capecitabine, methotrexate, 6-mercaptopurine, pemetrexed, bleomycin, streptozocin, etoposide, topotecan, cyclophosphamide, cisplatin, ifosfamide, mitomycin C, bendamustine.
• Agents marked as needing both renal and hepatic adjustment include methotrexate, etoposide, ifosfamide, and bendamustine.
• Assess renal function before starting (NCCN, SIOG). Cockcroft-Gault is common; no single equation is consensus-preferred.

Alopecia risk by agent

Leukoencephalopathy

• Progressive structural damage to cerebral white matter, primarily from myelin damage. Chemo-induced leukoencephalopathy is reversible if the offending agent is withdrawn before irreversible damage. Suspect it when acute neurologic symptoms arise during chemo.
• Culprit agents: methotrexate, 5-FU, vincristine, cyclosporine, ifosfamide, fludarabine, cisplatin. Methotrexate and 5-FU are the most commonly reported. 5-FU (a fluorine-substituted uracil analogue that blocks DNA synthesis) readily crosses the blood-brain barrier.
• Presentation: headache, dizziness, depression, confusion, seizures; acute, subacute, or chronic ischemic attacks; posterior reversible encephalopathy syndrome; cerebellar dysfunction; myopathy.
• Imaging: CT shows bilateral, relatively symmetric hypodense white-matter areas. MRI shows diffuse T2/FLAIR hyperintensity in deep periventricular white matter and corpus callosum, sparing basal ganglia, thalamus, and subcortical U fibers; post-gadolinium enhancement variable.
• Management: no definitive treatment. Stop the offending agent immediately; supportive care with corticosteroids and antioxidants (coenzyme Q, vitamin E, vitamin C) may improve outcomes. Continuing 5-FU may be risky.

Antimetabolites (S phase)

• Antifolates: mimic folate; entry via reduced folate carrier (RFC) and folate receptor protein, polyglutamated by FPGS. Resistance from ↓ RFC/FRP or ↑ DHFR.
  • Methotrexate: inhibits DHFR (affinity ~1000× that of folate), blocking dihydrofolate → tetrahydrofolate. Renally eliminated; excretion inhibited by ASA, NSAIDs, penicillins, cephalosporins, probenecid, PPIs, Bactrim (avoid around treatment). Half-life prolonged by third-space fluid (tap effusions/ascites first). HDMTX (≥ 500 mg/m²): aggressive hydration, alkalinize urine pH > 7, check levels q24h, leucovorin rescue 24 h after dose. Glucarpidase for delayed clearance with AKI (works extracellularly, ↓ MTX ≥ 97% within 15 min). Tox: myelosuppression, mucositis, nephrotoxic (crystal precipitation), hepatotoxic, pneumonitis, neurotoxicity.
  • Pemetrexed: inhibits thymidylate synthase. Supplement folate + B12 (↓ folate and homocysteine > 10 predict worse toxicity); premedicate with dexamethasone for rash. Hold if CrCl < 45.
  • Pralatrexate: high affinity for RFC-1 and FPGS; used in T-cell lymphoma; give folate and B12.
• Fluoropyrimidines:
  • 5-FU: FdUMP inhibits thymidylate synthase (leucovorin stabilizes the ternary complex and enhances activity); metabolites also impair DNA/RNA. Metabolized ~80% hepatically by DPD. Tox: myelosuppression (worse with bolus), hand-foot syndrome and mucositis/diarrhea (worse with infusion), coronary vasospasm (uncommon, roughly 1 to 5%; large cohort 2.16%; chest pain often during the first cycle, not limited to 12 h), tear-duct stenosis. DPD deficiency (3 to 5%) → severe toxicity; rescue with uridine triacetate.
  • Capecitabine: oral 5-FU prodrug activated in 3 steps (final step by tumor thymidine phosphorylase). Similar to infusional 5-FU: more hand-foot syndrome and diarrhea, less myelosuppression. Reduce 25% if CrCl 30 to 50, avoid if < 30; interacts with warfarin (↑ INR) and phenytoin.
  • TAS-102 (trifluridine + tipiracil): tipiracil blocks trifluridine degradation. Active in 5-FU-resistant CRC regardless of KRAS (RECOURSE). Main tox: myelosuppression.
• Cytidine analogs:
  • Cytarabine (ara-C): ara-CTP inhibits DNA polymerase, incorporates into DNA. Very short half-life (continuous infusion). Tox: myelosuppression, cholestasis/pancreatitis, ara-C syndrome (fever, myalgia, rash, conjunctivitis), and with high-dose (HIDAC) cerebellar/cerebral toxicity (days 3 to 8); give steroid eye drops for conjunctivitis.
  • Gemcitabine: like cytarabine plus RNA incorporation; clearance ↓ ~30% in women and elderly. Tox: myelosuppression, flu-like symptoms, rare pneumonitis/ARDS/HUS.
• Thiopurines: 6-MP (azathioprine is its prodrug): inhibits purine synthesis, incorporates into DNA/RNA. Broken down by xanthine oxidase, so allopurinol ↑ 6-MP toxicity; TPMT deficiency also ↑ toxicity.
• Purine analogs: fludarabine (immunosuppressive, PJP risk, TLS; renal dose adjust) and cladribine (adenosine-deaminase-resistant; three black-box warnings: renal, neuro, prolonged myelosuppression; used in hairy cell leukemia).
• Hypomethylating agents: azacitidine and decitabine (↓ DNA methyltransferase). Azacitidine: reduce or hold for renal toxicity (low bicarbonate, rising BUN/creatinine); caution in liver disease. Decitabine: not studied in organ impairment but hold for creatinine at least 2 mg/dL or ALT/bilirubin at least 2x ULN.

Alkylating agents (cell-cycle non-specific)

• Mechanism: covalent DNA cross-links (interstrand and intrastrand) → ↓ DNA synthesis.
• Nitrogen mustards:
  • Cyclophosphamide: hepatic P450 activation; acrolein metabolite → hemorrhagic cystitis (5 to 10%), prevented by mesna (detoxifies acrolein; does not prevent other toxicities). Also SIADH, nephrotoxicity, AML risk, cardiotoxicity, interacts with warfarin.
  • Ifosfamide: like cyclophosphamide plus neurotoxicity from chloroacetaldehyde (confusion → seizures/coma); treat grade III to IV with methylene blue or thiamine. CYP2B6 variation drives toxic metabolite formation.
  • Melphalan: DNA cross-links; delayed myelosuppression, mucositis (melphalan = mucositis), pulmonary fibrosis, secondary malignancy; renal dose reduction.
  • Bendamustine: primarily inactivated by hydrolysis (minor CYP1A2); little unchanged renal excretion; avoid in moderate to severe hepatic or renal impairment per label; delayed myelosuppression (3 to 4 wk), infusion reactions.
• Nitrosoureas (carmustine/lomustine): lipophilic, cross the BBB (CNS tumors); delayed myelosuppression (dose q6wk), pulmonary toxicity (baseline PFTs), interstitial nephritis.
• Methylating/triazenes: temozolomide (DNA methylation; give TMP-SMX with concurrent RT for PJP), dacarbazine (activated to MTIC; highly emetogenic), procarbazine (MAO-inhibitor effect, avoid tyramine foods; disulfiram-like effect).
• Platinum analogs: bind guanine N-7 → cross-links; excreted in urine (minimal hepatic clearance). Given before taxanes, platinums ↑ taxane levels (give paclitaxel first).
  • Cisplatin: nephrotoxic (avoid if Cr > 1.5; hydrate), ototoxic (irreversible high-frequency loss), peripheral neuropathy, highly emetogenic, ↓ Mg/Ca/K. Cisplatin-ineligibility (urothelial): ECOG PS ≥ 2, CrCl < 60, neuropathy ≥ grade 2, NYHA ≥ III, hearing loss ≥ grade 2.
  • Carboplatin: dosed by AUC (Calvert). Dose-limiting thrombocytopenia; highly emetogenic at AUC ≥ 4; hypersensitivity around the 7th to 8th dose (desensitize).
  • Oxaliplatin: acute cold-induced dysesthesia and cumulative chronic neuropathy; active in MMR-deficient tumors; fewer interactions than cisplatin.
• Miscellaneous: busulfan (HSCT conditioning; hepatic VOD/SOS, seizure prophylaxis, pulmonary fibrosis), trabectedin and lurbinectedin (minor-groove binders; myelosuppression, hepatotoxicity, trabectedin causes rhabdomyolysis).

Antitumor antibiotics

• Anthracyclines (doxorubicin, daunorubicin, epirubicin, idarubicin): iron-dependent free radicals, topo II inhibition, DNA intercalation; cell-cycle independent, ~50% hepatic metabolism. Vesicant; red/orange urine; RT recall.
  • Cumulative cardiotoxicity: heart is iron-rich, detox-poor. Baseline echo. Acute (days, dose-independent arrhythmia/pericarditis) vs chronic (dose-dependent dilated cardiomyopathy). Lifetime caps: doxorubicin 450 to 550 mg/m² (400 with prior mediastinal RT), daunorubicin 550 mg/m², epirubicin 900 mg/m², idarubicin ~150 mg/m² (no label-defined cap; CHF incidence ↑ above 90 mg/m²). Risk ↑ with age, CAD, HTN, mediastinal RT, and combination with cyclophosphamide, mitomycin-C, trastuzumab, taxanes, bevacizumab.
  • Dexrazoxane (iron chelator) for cardioprotection, e.g., start when doxorubicin cumulative > 300 mg/m² (no established agent-specific dexrazoxane initiation thresholds for daunorubicin, epirubicin, or idarubicin); ~10:1 ratio.
  • Liposomal doxorubicin: ↓ cardiotoxicity, N/V, and myelosuppression, but hand-foot syndrome and acute infusion reactions.
• Bleomycin: single/double-strand DNA breaks; minimal myelosuppression. Key tox: pulmonary fibrosis (↑ with growth-factor use, prior lung disease, chest RT, age > 65, cumulative > 400 units); hyperpigmentation.
• Mitomycin-C: DNA cross-links; delayed prolonged myelosuppression, HUS, pneumonitis; vesicant.
• Dactinomycin: DNA intercalation inhibiting DNA-dependent RNA synthesis; myelosuppression, VOD (children), radiation recall; vesicant.

Antimicrotubular agents (M phase)

• Taxanes (paclitaxel, docetaxel, nab-paclitaxel, cabazitaxel): bind microtubules and stabilize/↑ polymerization → mitotic arrest. Hepatic P450 metabolism. Give paclitaxel before platinum. All cause alopecia, low emetogenicity.
  • Paclitaxel: hypersensitivity from the cremophor vehicle (premedicate steroids + H1/H2); bradycardia/arrhythmia; dose-dependent sensory neuropathy.
  • Docetaxel: polysorbate-80 vehicle (premedicate dexamethasone); characteristic fluid retention (steroid premedication reduces it); less neuropathy than paclitaxel.
  • Nab-paclitaxel: albumin-bound; less hypersensitivity but more neuropathy. Cabazitaxel: resistant to P-glycoprotein efflux.
• Vinca alkaloids (vincristine, vinblastine, vinorelbine): prevent tubulin polymerization → mitotic arrest. All cause SIADH; vesicants. Vincristine: dose-limiting neuropathy (sensory, autonomic, cranial palsies, ileus); NEVER intrathecal (fatal).
• Others: ixabepilone (epothilone, active despite taxane resistance), eribulin (halichondrin analog; QTc prolongation, neuropathy). MMAE (vedotin) is the antimitotic payload in ADCs (brentuximab, polatuzumab, enfortumab).

Topoisomerase inhibitors

• Topoisomerase I inhibitors:
  • Irinotecan: activated by carboxylesterase to SN-38, detoxified by UGT1A1 (↓ in Gilbert syndrome). Homozygous UGT1A1*28/*28 needs ~30% dose reduction. Diarrhea has two phases: acute (< 24 h, cholinergic, treat with atropine) and delayed (> 24 h, treat with loperamide, octreotide, antibiotics). Also myelosuppression.
  • Topotecan: renally eliminated (unlike irinotecan); myelosuppression (mainly neutropenia). Liposomal irinotecan (NAPOLI) gives longer SN-38 exposure.
• Topoisomerase II inhibitors: etoposide (VP-16): PO:IV = 2:1; hepatic glucuronidation with renal excretion (adjust for renal and hepatic impairment); infusion hypotension (slow rate); polysorbate-80 vehicle (etoposide phosphate for hypersensitivity). Causes therapy-related AML with 11q23 (KMT2A/MLL) rearrangements, ~2 to 3 years after treatment.

Targeted therapy overview

• Small molecules vs monoclonal antibodies: small molecules are oral, cross membranes to hit intracellular kinases, are usually CYP3A4-metabolized (many food and pH interactions), and have short half-lives; antibodies are large, long half-lived (slow toxicity reversal), and block cell-surface targets or deliver payloads. Detailed agent-level content is kept in the dedicated class notes; the classes below are an orientation only.
• Anti-angiogenic / VEGF pathway: bevacizumab (anti-VEGF-A), ramucirumab (anti-VEGFR-2), ziv-aflibercept (VEGF trap), and multikinase VEGFR TKIs (sunitinib, sorafenib, pazopanib, cabozantinib, axitinib, lenvatinib, regorafenib). Class effects: HTN, proteinuria, arterial and venous thrombosis, bleeding, GI perforation, impaired wound healing (hold around surgery), RPLS/PRES.
• BCR-ABL TKIs: imatinib (1st gen) → dasatinib/nilotinib/bosutinib (2nd gen) → ponatinib (T315I); asciminib (allosteric STAMP inhibitor; T315I, later lines, and newly diagnosed CML-CP, FDA Oct 2024). Watch pH-dependent absorption and CYP3A4 interactions; dasatinib causes pleural effusions and pulmonary HTN; ponatinib carries vascular occlusion warnings.
• Anti-HER2 (ErbB): trastuzumab (reversible cardiotoxicity, monitor LVEF), pertuzumab, ado-trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd; ILD), lapatinib (oral EGFR/HER2 TKI).
• Anti-EGFR (ErbB-1): TKIs erlotinib, gefitinib, afatinib, dacomitinib, osimertinib (covers T790M); antibodies cetuximab and panitumumab (in CRC, RAS wild-type only, except with a KRAS G12C inhibitor; cetuximab plus encorafenib for BRAF V600E CRC). Class effects: acneiform rash (marker of activity), ILD; cetuximab/panitumumab also cause hypomagnesemia.
• BRAF/MEK: dabrafenib+trametinib, encorafenib+binimetinib, vemurafenib+cobimetinib for BRAF V600E. Toxicities: cutaneous SCC/keratoacanthoma, pyrexia (BRAF), cardiomyopathy and ocular/retinal effects (MEK).
• ALK: alectinib, brigatinib, or lorlatinib first line (crizotinib and ceritinib no longer preferred). ROS1 (separate): crizotinib, entrectinib, or repotrectinib first line; lorlatinib or repotrectinib for resistance. Class effect: ILD/pneumonitis.
• NTRK: larotrectinib, entrectinib (tumor-agnostic for NTRK fusions).
• PARP inhibitors: olaparib, niraparib, rucaparib (BRCA/HRD contexts); watch myelosuppression and secondary MDS/AML.
• B-cell / BTK inhibitors: ibrutinib, acalabrutinib, zanubrutinib (covalent), pirtobrutinib (non-covalent, active in C481 resistance). Class effects: bleeding (hold around surgery), atrial fibrillation (less with newer agents), infection.
• PI3K inhibitors: idelalisib (CLL with rituximab; FL/SLL indications withdrawn 2022), duvelisib (R/R CLL/SLL after ≥2 lines; FL withdrawn 2021), alpelisib, inavolisib (PIK3CA-mutated HR+ breast, FDA Oct 2024); umbralisib (2022) and copanlisib (2023) withdrawn from the US market. Boxed warnings: idelalisib hepatotoxicity, diarrhea/colitis, pneumonitis, infection, intestinal perforation; duvelisib treatment-related mortality, infection, diarrhea/colitis, cutaneous reactions, pneumonitis. Alpelisib and inavolisib cause hyperglycemia.
• CDK4/6 inhibitors: palbociclib, ribociclib, abemaciclib (HR+ breast cancer with endocrine therapy). Neutropenia (palbo/ribo), diarrhea (abema), QTc (ribo).
• Immune checkpoint inhibitors: ipilimumab (anti-CTLA-4); pembrolizumab, nivolumab, cemiplimab, dostarlimab (anti-PD-1); atezolizumab, durvalumab, avelumab (anti-PD-L1). Biomarkers: PD-L1, MSI-high/dMMR, tumor mutational burden. Immune-related adverse events can affect any organ.
• Antibody-drug conjugates and bispecific T-cell engagers: covered in detail in the dedicated notes and in the 2026 update below.

Hormonal therapy

• Tamoxifen: SERM. Breast cancer. ↑ endometrial cancer and DVT.
• Aromatase inhibitors (anastrozole, letrozole, exemestane): postmenopausal breast cancer. Bone loss, joint pain; no increased endometrial cancer or thromboembolism unlike tamoxifen.
• Fulvestrant: SERD; degrades the estrogen receptor.
• Oral SERDs for ER+/HER2− ESR1-mutated advanced breast cancer: elacestrant (FDA Jan 2023) and imlunestrant (FDA Sep 2025; with abemaciclib Sep 2026) after endocrine therapy; camizestrant plus CDK4/6 inhibitor on emergent ESR1 mutation (SERENA-6, FDA Sep 2026).
• LHRH agonists (leuprolide, goserelin): chemical castration (initial flare, block with anti-androgen).
• LHRH antagonists (degarelix, relugolix): no flare, faster onset.
• AR pathway inhibitors (enzalutamide, apalutamide, darolutamide, abiraterone). Enzalutamide has the highest seizure risk (CNS penetration); abiraterone causes mineralocorticoid excess (HTN, hypokalemia), so give with corticosteroid.

Biologics / monoclonal antibodies

• Trastuzumab (anti-HER2), pertuzumab, T-DM1, T-DXd.
• Cetuximab, panitumumab (anti-EGFR): rash, hypomagnesemia. Do NOT give in RAS-mutant CRC as monotherapy or with chemo; exception: cetuximab + adagrasib or panitumumab + sotorasib in previously treated KRAS G12C mCRC.
• Bevacizumab (anti-VEGF): HTN, proteinuria, bleeding, GI perforation, wound healing.
• Rituximab (anti-CD20): infusion reaction (first dose), HBV reactivation, PML (JC virus).

Toxicity highlights to know

• Cardiotoxicity:
  • Anthracyclines (cumulative dose).
  • Trastuzumab (reversible LV dysfunction; check LVEF q3 mo).
  • 5-FU/capecitabine (coronary spasm).
  • VEGF/TKIs (HTN, LV dysfunction).
• Pneumonitis: bleomycin, mTOR-i, IO, T-DXd, cetuximab, methotrexate, gefitinib.
• Hemorrhagic cystitis: cyclophosphamide/ifosfamide (mesna prophylaxis).
• Nephrotoxicity: cisplatin, methotrexate, ifosfamide.
• Ototoxicity: cisplatin (high-frequency hearing loss).
• Peripheral neuropathy: platinums, taxanes, vincristine, bortezomib, brentuximab vedotin, polatuzumab.
• Hepatotoxicity: busulfan (VOD/SOS), high-dose MTX, MEK-i, IO.
• Secondary malignancies: alkylators (AML, MDS-pattern), etoposide (AML 11q23), RT (sarcomas).

Pharmacogenomics relevant to chemo

• DPD (DPYD) deficiency: severe 5-FU/cape toxicity. Test before treatment.
• UGT1A1*28: ↑ irinotecan toxicity (Gilbert syndrome).
• TPMT/NUDT15: severe 6-MP/azathioprine myelosuppression.
• CYP2D6: tamoxifen metabolism (controversial clinical impact).

Practical principles

• Dose by BSA (Mosteller, DuBois). ASCO recommends full weight-based dosing in obese patients (no routine BSA 2.0 m² cap).
• Carboplatin Calvert formula: dose = AUC × (GFR + 25). Cap GFR at ~125.
• Renal/hepatic dose adjustments: required for cisplatin, methotrexate, anthracyclines, taxanes (hepatic).
• Drug interactions: CYP3A4 (azoles, macrolides, grapefruit) affects taxanes, TKIs, vincristine. Warfarin/INR.
• Cumulative dose tracking: anthracyclines (lifetime).

High-yield chemo pearls

• Mesna routinely with ifosfamide; with cyclophosphamide only for high-dose/transplant regimens (not routine with standard-dose AC or R-CHOP).
• Folate + B12 with pemetrexed.
• Leucovorin rescues high-dose MTX.
• Atropine for cholinergic syndrome from irinotecan.
• Dexrazoxane for anthracycline cardioprotection or extravasation.
• Glucarpidase: for HD-MTX delayed clearance.
• Methylene blue for ifosfamide encephalopathy; uridine triacetate for 5-FU/capecitabine overdose or early severe toxicity.
• Vincristine is NEVER intrathecal.
• DPYD test before any 5-FU/cape unless treatment is urgent (FDA boxed warning; labels revised late 2025, announced Feb 2026).
• Ototox screening (audiometry) for cisplatin if young or musician.
• Anthracycline lifetime cap: doxorubicin 450 to 550 mg/m² (400 with prior mediastinal RT).

2026 update: new therapy classes / practice-changing evidence

• T-DXd: HER2-low (DESTINY-Breast04); HER2-ultralow (DESTINY-Breast06, FDA Jan 2025); tumor-agnostic HER2 IHC 3+ (DESTINY-PanTumor02, FDA Apr 2024).
• Datopotamab deruxtecan: TROP2-ADC; HR+/HER2− MBC (FDA Jan 2025); EGFR-mut NSCLC (FDA Jun 2025).
• Enfortumab vedotin + pembro 1L urothelial (EV-302, FDA Dec 2023): new CT-free SOC.
• Mirvetuximab soravtansine full approval FRα+ platinum-resistant ovarian (MIRASOL, FDA Mar 2024).
• Tisotumab vedotin full approval recurrent/metastatic cervical (innovaTV 301, FDA Apr 2024).
• Telisotuzumab vedotin c-Met+ NSCLC (LUMINOSITY, FDA May 2025): first c-Met ADC.
• Zanidatamab (HER2 biparatopic bispecific antibody, not an ADC) HER2+ BTC (HERIZON-BTC-01, FDA Nov 2024); 1L HER2+ gastroesophageal adenocarcinoma with chemo ± tislelizumab (HERIZON-GEA-01, FDA 2026).
• Deruxtecan class-effect ILD: baseline CT, hold G≥1, d/c G≥2.

• Tarlatamab (Imdelltra) DLL3×CD3 for 2L+ ES-SCLC (DeLLphi-301, FDA May 2024).
• Talquetamab (GPRC5D×CD3): R/R MM ≥4 lines (MonumenTAL-1, FDA Aug 2023).
• Elranatamab (BCMA×CD3): R/R MM (MagnetisMM-3, FDA Aug 2023).
• Epcoritamab (CD3×CD20) SC for R/R DLBCL (EPCORE NHL-1, FDA May 2023) and R/R FL (FDA Jun 2024).
• Glofitamab (CD3×CD20) IV fixed-duration for R/R DLBCL (Dickinson NEJM 2022, FDA Jun 2023).
• Class toxicity: CRS (usually low-grade, tocilizumab), ICANS, hypogammaglobulinemia + infection.

• Lifileucel (Amtagvi) TIL: melanoma post-PD-1 (FDA Feb 2024). First FDA-approved TIL therapy (sipuleucel-T, 2010, was the first cellular immunotherapy for a solid tumor).
• Afami-cel (Tecelra): MAGE-A4 TCR-T for synovial sarcoma (FDA Aug 2024). First engineered TCR-T for solid tumor.
• Obe-cel (Aucatzyl): CD19 CAR-T for R/R adult B-ALL (FDA Nov 2024). First CAR-T approved without a REMS (FDA removed REMS for all autologous CD19/BCMA CAR-Ts, Jun 2025).
• CAR-T black box (Jan 2024): secondary T-cell malignancies, class effect.

• Trilaciclib (Cosela): transient CDK4/6-i given IV before chemo; arrests HSPC in G0/G1 → ↓ chemo-induced myelosuppression. FDA Feb 2021 for ES-SCLC on platinum/etoposide (+ IO) or topotecan; SCLC approval was based on 3 randomized phase 2 trials; PRESERVE-1 (mCRC, FOLFOXIRI/bev) reduced severe neutropenia but ORR and PFS were worse with trilaciclib.

• 177Lu-PSMA-617 (Pluvicto): VISION mature; PSMAfore (FDA Mar 2025) expanded to pre-taxane mCRPC post-ARPI.
• 177Lu-DOTATATE (Lutathera): NETTER-2 (Singh Lancet 2024) 1L well-differentiated grade 2 to 3 GEP-NET (PFS benefit); the FDA Apr 23, 2024 action was a pediatric expansion (age ≥ 12, NETTER-P), not a NETTER-2 label change.

Pharmacogenomics update

• DPYD pretest: SOC in UK NHS (Apr 2020) and most EU; US FDA boxed warning (labels revised late 2025; FDA announced Feb 2026): test for DPYD variants before 5-FU/capecitabine unless treatment is urgent. Genotype 4 variants (*2A, *13, D949V, HapB3); reduce starting dose about 50% for intermediate metabolizers (activity score 1 or 1.5); avoid in poor metabolizers.