Chemotherapy Agents

• Alkylating agents (cyclophosphamide, nitrogen mustards, nitrosoureas) form covalent cross-links between DNA strands, preventing DNA separation during replication and transcription; these are cell-cycle phase-nonspecific and cause cumulative dose-dependent toxicity

• Platinum compounds (cisplatin, carboplatin, oxaliplatin) function similarly to alkylating agents by forming DNA adducts and interstrand crosslinks, triggering apoptosis; nephrotoxicity and ototoxicity are dose-limiting with cisplatin due to accumulation in proximal tubules and cochlea

• Antimetabolites (methotrexate, 5-FU, gemcitabine, mercaptopurine) are phase-specific agents that inhibit nucleotide synthesis (antifolates) or are incorporated into DNA/RNA, causing chain termination; methotrexate irreversibly inhibits dihydrofolate reductase, blocking thymidylate synthase

• Topoisomerase inhibitors (etoposide, doxorubicin, irinotecan, topotecan) prevent DNA religation by stabilizing the enzyme-DNA complex; they are phase-specific and cause double-strand breaks leading to apoptosis

• Antitumor antibiotics (doxorubicin, bleomycin, dactinomycin) intercalate into DNA and generate reactive oxygen species; cumulative cardiotoxicity with anthracyclines limits total lifetime dosing

• Microtubule inhibitors (vincristine, vinblastine, paclitaxel, docetaxel) disrupt mitotic spindle formation by binding tubulin; vinca alkaloids prevent microtubule assembly while taxanes stabilize assembled microtubules, both arresting cells in M phase

• Targeted/Molecular agents (tyrosine kinase inhibitors, monoclonal antibodies) exploit cancer cell-specific mutations or overexpressed receptors with greater selectivity; examples include imatinib (BCR-ABL), trastuzumab (HER2), and checkpoint inhibitors (anti-PD-1/PD-L1)

• General principle of toxicity: Most chemotherapy agents preferentially target rapidly dividing cells, which explains why bone marrow, GI epithelium, hair follicles, and germinal tissue are most affected; selectivity for cancer cells is relative, not absolute

• Acute infusion reactions and hypersensitivity manifesting as flushing, urticaria, bronchospasm, hypotension, and anaphylaxis (especially with taxanes, platinum compounds, and monoclonal antibodies); premedication and slow infusion rates reduce incidence

• Nausea and vomiting (especially with cisplatin, cyclophosphamide, doxorubicin) occurring within hours of administration; 5-HT3 antagonists and NK1 antagonists are standard prophylaxis

• Bone marrow suppression presenting with absolute neutropenia (increased infection risk, fever >38.5°C), thrombocytopenia (bleeding), and anemia (fatigue, dyspnea); nadir typically occurs 7-14 days post-chemotherapy

• Mucositis and diarrhea from GI epithelial damage, manifesting as painful mouth ulcers and severe watery diarrhea; risk increases with dose intensity and in combination regimens

• Alopecia from follicle destruction (reversible); occurs with many agents but is predictable and psychologically significant for patients

• Extravasation injury causing tissue necrosis when vesicant agents (doxorubicin, vinca alkaloids, cisplatin) leak from IV lines into surrounding tissue; presents as severe local pain, erythema, and blistering

• Tumor lysis syndrome presenting with hyperkalemia, hyperphosphatemia, hypocalcemia, and hyperuricemia when large tumor burdens rapidly die; causes cardiac arrhythmias, seizures, and acute kidney injury

• Hand-foot syndrome (palmar-plantar erythrodysesthesia) with 5-FU and capecitabine causing painful erythema and desquamation of palms and soles

• Baseline assessment before chemotherapy initiation: complete metabolic panel, CBC with differential, cardiac ejection fraction (ECHO or MUGA) for anthracycline-containing regimens, renal function, and hearing assessment if cisplatin planned

• Genetic and molecular testing to guide targeted therapy selection (EGFR mutation in lung cancer, BRAF mutation in melanoma, HER2 overexpression in breast cancer, microsatellite instability/TMB for checkpoint inhibitors)

• Tumor burden quantification using imaging (CT, MRI) to determine risk of tumor lysis syndrome and assess response; elevated uric acid, phosphate, and potassium in pre-treatment labs suggest high lysis risk

• CBC monitoring during treatment (often weekly during active chemotherapy) to identify nadir and guide dose modifications or growth factor support; absolute neutrophil count <500/μL requires intervention

• Renal function monitoring for agents with nephrotoxicity (cisplatin, methotrexate); baseline creatinine clearance and ongoing monitoring essential; dose adjustments required for estimated GFR <60 mL/min

• Cardiac monitoring for anthracycline-containing regimens via ECHO/MUGA at baseline, midway through therapy, and post-therapy; cumulative dose limits (doxorubicin ≤450 mg/m²) based on cardiac risk factors

• Selection of appropriate agent(s) based on cancer histology, stage, performance status, and comorbidities; combination chemotherapy (e.g., CHOP for lymphoma, FOLFOX for colorectal cancer) typically superior to monotherapy due to synergistic mechanisms and reduced resistance

• Premedication protocols: 5-HT3 antagonists (ondansetron 8 mg IV) ± dexamethasone ± NK1 antagonist (aprepitant) for highly emetogenic agents; antihistamines and acetaminophen for taxanes; prehydration (1-2 L normal saline) for cisplatin

• Supportive care during myelosuppression: G-CSF (filgrastim) for prevention of febrile neutropenia in high-risk patients (age >65, poor performance status, severe neutropenia expected); antimicrobial prophylaxis (fluoroquinolone or TMP-SMX) for prolonged neutropenia

• Tumor lysis syndrome prevention: aggressive IV hydration (200 mL/hr), allopurinol (300 mg daily, reduces uric acid production) or febuxostat, rasburicase (recombinant uricase, preferred in high-risk patients as it directly degrades uric acid), and potassium/phosphate restriction; monitor electrolytes q6-12h initially

• Cardiotoxicity mitigation with anthracyclines: limit cumulative dose, use liposomal formulations (reduced cardiotoxicity), consider dexrazoxane (cardioprotective agent, reduces anthracycline cardiomyopathy), and baseline/serial cardiac imaging

• Renal protection with cisplatin: aggressive saline hydration (1 L normal saline pre- and post-infusion) and magnesium supplementation; avoid loop diuretics unless fluid overloaded; monitor hearing and peripheral neuropathy

Second-line and special situations

• Dose modifications based on toxicity: reduce by 25% if Grade 2+ nonhematologic toxicity or Grade 3+ neutropenia/

Organ-specific toxicities and their mechanisms

• Cyclophosphamide/ifosfamide — hemorrhagic cystitis: the hepatic metabolite acrolein is urothelial-toxic. Mesna supplies free sulfhydryl groups that bind acrolein in urine; combine with aggressive hydration. Cyclophosphamide also causes SIADH; ifosfamide causes proximal tubulopathy (Fanconi syndrome) and encephalopathy from chloroacetaldehyde.
• Cisplatin — nephrotoxicity, ototoxicity, neuropathy: accumulation in proximal tubule and cochlear hair cells. Monitor creatinine, Mg²⁺ (renal wasting), and audiometry; amifostine is FDA-approved to reduce cumulative cisplatin nephrotoxicity but is not routinely used — saline hydration with magnesium repletion remains standard. Oxaliplatin gives cold-induced pharyngolaryngeal dysesthesia.
• Methotrexate: myelosuppression, mucositis, hepatotoxicity, and crystal nephropathy in acidic urine. Prevent with urinary alkalinization and hydration; rescue with leucovorin (bypasses DHFR blockade); glucarpidase cleaves methotrexate in delayed clearance. Absolutely contraindicated in pregnancy (abortifacient/teratogen).
• 5-FU/capecitabine: mucositis, diarrhea, hand-foot syndrome. DPYD loss-of-function variants cause life-threatening fluoropyrimidine toxicity; FDA labeling warns about DPD deficiency, and CPIC provides dosing guidance when a DPYD genotype is known (CPIC does not itself recommend whether to test; pre-emptive genotyping uptake in US practice varies). Uridine triacetate is the antidote for overdose.
• 6-Mercaptopurine: inactivated by xanthine oxidase — allopurinol requires substantial dose reduction. Low TPMT/NUDT15 activity predicts severe myelosuppression (CPIC dosing guidance).
• Anthracyclines: cumulative, largely irreversible dilated cardiomyopathy from ROS and topoisomerase IIβ inhibition; dexrazoxane is cardioprotective. Trastuzumab cardiotoxicity is typically reversible and not dose-dependent (ASCO cardiac dysfunction guidance).
• Bleomycin: pulmonary fibrosis; lung and skin lack bleomycin hydrolase. Follow DLCO; avoid high FiO₂ and prior lung disease. Busulfan also fibroses lung.
• Vincristine: peripheral/autonomic neuropathy and ileus, minimal myelosuppression; intrathecal administration is uniformly fatal — ASCO/ONS safety standards require dilution in a minibag.
• Irinotecan: early cholinergic diarrhea (atropine) and delayed diarrhea (loperamide); *UGT1A1*28* increases risk.
• Secondary malignancy: alkylators → MDS/AML with del(5q)/del(7q); etoposide → AML with 11q23 (MLL) translocation.
• Rasburicase: contraindicated in G6PD deficiency (hemolysis, methemoglobinemia).
• Checkpoint inhibitors: immune-related colitis, hypophysitis, thyroiditis, pneumonitis — treat with corticosteroids per ASCO/NCCN irAE guidance.

• Fever + ANC <500/μL is a medical emergency: the single best next step is blood cultures then immediate empiric antipseudomonal beta-lactam monotherapy (cefepime, piperacillin-tazobactam, or a carbapenem) per IDSA febrile neutropenia guidance — do not wait for imaging or the culture result, and do not add vancomycin reflexively unless there is a catheter infection, skin/soft tissue source, hemodynamic instability, or known MRSA colonization.
• "Hemorrhagic cystitis after cyclophosphamide" = acrolein; answer mesna plus hydration. The distractor is "stop the drug and give bladder irrigation" — prophylaxis is the tested point.
• Myelosuppression is the near-universal dose-limiting toxicity — except for three classic agents: vincristine (neurotoxic), bleomycin (pulmonary), and cisplatin (renal/otic). A stem describing wrist drop or constipation after CHOP points to vincristine, not the cyclophosphamide.
• Leucovorin does opposite things with two drugs: it rescues methotrexate toxicity (bypasses DHFR) but potentiates 5-FU (stabilizes the ternary complex with thymidylate synthase). Examiners love this reversal.
• Allopurinol + 6-mercaptopurine = toxic accumulation via xanthine oxidase inhibition; azathioprine behaves the same way. In tumor lysis prophylaxis, remember rasburicase is contraindicated in G6PD deficiency.
• Dyspnea with a dropping DLCO and basilar reticular changes on a testicular cancer or Hodgkin regimen = bleomycin pneumonitis; the associated point is to avoid high inspired oxygen perioperatively.
• Falling ejection fraction on ECHO — anthracycline injury is cumulative and often permanent (dexrazoxane is preventive), whereas trastuzumab injury is usually reversible after holding the drug (ASCO cardiac dysfunction guidance).
• Secondary leukemia has two signatures: alkylating agents → MDS/AML with chromosome 5/7 deletions after a several-year latency; topoisomerase II inhibitors → AML with 11q23 MLL rearrangement after a shorter latency.
• Vincristine given intrathecally is fatal — the correct answer is that it must never be dispensed in a syringe; methotrexate, cytarabine, and hydrocortisone are the agents routinely given intrathecally.