8.5 Cancer Chemotherapy
Cancer chemotherapy targets rapidly dividing cells through various mechanisms including DNA damage, antimetabolite activity, and mitotic inhibition. Modern cancer therapy increasingly incorporates targeted agents and immunotherapies alongside traditional cytotoxic drugs.
Principles of Cancer Chemotherapy
Cell Cycle Specificity
Cell cycle-specific: Active only during specific phases (S, M)
Cell cycle-nonspecific: Active in all phases (more toxic)
Log-Kill Hypothesis
Each treatment kills a constant fraction of cells, not a constant number. Multiple cycles needed.
Combination Therapy
Use drugs with different mechanisms, toxicity profiles, and resistance patterns
Alkylating Agents
Mechanism of Action
Form covalent bonds (alkyl groups) with DNA bases (especially N7 of guanine), causing DNA cross-linking, strand breaks, and abnormal base pairing. Cell cycle-nonspecific.
Common Agents:
- Cyclophosphamide:
- • Broad spectrum; lymphomas, leukemias, solid tumors
- • Prodrug activated by CYP450 in liver
- • Hemorrhagic cystitis (acrolein metabolite); prevent with mesna + hydration
- • Also immunosuppressive (used in lupus, vasculitis)
- Ifosfamide:
- • Similar to cyclophosphamide but higher dose
- • Sarcomas, testicular cancer
- • Neurotoxicity, hemorrhagic cystitis (use mesna)
- Nitrosoureas (carmustine, lomustine):
- • Lipophilic; cross BBB (brain tumors)
- • Delayed bone marrow suppression (weeks)
Class Toxicities:
- • Bone marrow suppression: Dose-limiting (all blood cells)
- • Secondary malignancies: AML, myelodysplastic syndrome (years later)
- • Infertility (especially males)
- • Teratogenic
- • GI toxicity (nausea, vomiting)
Antimetabolites
Folate Antagonists: Methotrexate
Mechanism:
Inhibits dihydrofolate reductase (DHFR), preventing conversion of DHF → THF. Blocks purine and thymidine synthesis. S-phase specific.
Clinical Uses:
- • ALL (pediatric), lymphoma, osteosarcoma
- • Choriocarcinoma (highly curable)
- • Also: Rheumatoid arthritis, psoriasis, ectopic pregnancy
Leucovorin Rescue:
Give folinic acid (leucovorin) after high-dose MTX to "rescue" normal cells
Toxicities:
- • Myelosuppression, mucositis
- • Hepatotoxicity (chronic fibrosis)
- • Renal toxicity (high dose; hydration + urinary alkalinization)
- • Pulmonary fibrosis
Pyrimidine Analogs
5-Fluorouracil (5-FU)
- • Inhibits thymidylate synthase (dTMP synthesis)
- • Colorectal, breast, head/neck cancers
- • Given with leucovorin (enhances activity)
- ⚠️ Myelosuppression, hand-foot syndrome, coronary vasospasm
Cytarabine (Ara-C)
- • Inhibits DNA polymerase; chain terminator
- • AML (induction), ALL
- • S-phase specific
- ⚠️ Cerebellar toxicity (high dose), myelosuppression
Purine Analogs
6-Mercaptopurine (6-MP)
- • Inhibits purine synthesis (PRPP amidotransferase)
- • ALL maintenance therapy
- • Metabolized by xanthine oxidase
- ⚠️ Reduce dose 75% if on allopurinol
Fludarabine
- • Inhibits DNA polymerase, ribonucleotide reductase
- • CLL, low-grade lymphomas
- ⚠️ Immunosuppression (T-cells), tumor lysis syndrome
Microtubule Inhibitors
Vinca Alkaloids
Bind β-tubulin, inhibiting microtubule polymerization → mitotic arrest at metaphase. M-phase specific.
- Vincristine:
- • ALL, lymphomas (part of CHOP regimen)
- • Peripheral neuropathy (dose-limiting)
- • SIADH, constipation (paralytic ileus)
- ⚠️ Fatal if given intrathecally!
- Vinblastine:
- • Hodgkin lymphoma, testicular cancer
- • Myelosuppression (more than vincristine)
Taxanes
Stabilize polymerized microtubules, preventing depolymerization → mitotic arrest. M-phase specific.
- Paclitaxel:
- • Ovarian, breast, lung (non-small cell) cancers
- • Hypersensitivity reactions (premedicate with steroids, antihistamines)
- • Peripheral neuropathy, myelosuppression
- Docetaxel:
- • Breast, prostate, lung cancers
- • Fluid retention, myelosuppression
Topoisomerase Inhibitors
Topoisomerase II Inhibitors
- Etoposide:
- • Stabilizes DNA-topoisomerase II complex → DNA breaks
- • Testicular, small cell lung cancer, lymphomas
- • Myelosuppression, secondary AML (11q23 translocations)
- Doxorubicin (Adriamycin):
- • Anthracycline; intercalates DNA + topoisomerase II inhibition
- • Broad spectrum (breast, lymphomas, sarcomas)
- ⚠️ Cardiotoxicity (dilated cardiomyopathy; cumulative dose-dependent)
- • Monitor with echocardiogram; dexrazoxane cardioprotective
- • Red urine (harmless)
Topoisomerase I Inhibitors
- Irinotecan:
- • Camptothecin analog; stabilizes topoisomerase I-DNA complex
- • Colorectal cancer (with 5-FU/leucovorin)
- • Severe diarrhea (early: cholinergic, treat with atropine; late: damage to GI mucosa)
- • Myelosuppression worse in patients with UGT1A1 polymorphism
- Topotecan:
- • Ovarian, small cell lung cancer
- • Myelosuppression
Targeted Therapy & Biologics
Tyrosine Kinase Inhibitors (TKIs)
Imatinib (Gleevec)
- • Inhibits BCR-ABL tyrosine kinase
- • CML (Philadelphia chromosome t(9;22))
- • GIST (c-KIT mutations)
- • Well-tolerated; edema, GI upset
- ✓ Transformed CML from fatal to chronic disease
Gefitinib, Erlotinib
- • EGFR inhibitors
- • NSCLC with EGFR mutations
- • Rash, diarrhea
Sunitinib, Sorafenib
- • Multi-kinase inhibitors (VEGFR, PDGFR)
- • RCC, GIST, hepatocellular carcinoma
- • Hypertension, hand-foot syndrome
Vemurafenib
- • BRAF V600E inhibitor
- • Melanoma with BRAF mutations
- • Photosensitivity, SCC risk
Monoclonal Antibodies
Rituximab
- • Anti-CD20 (B-cell marker)
- • B-cell lymphomas, CLL
- • Infusion reactions, tumor lysis syndrome
- • Also: Rheumatoid arthritis
Trastuzumab (Herceptin)
- • Anti-HER2/neu
- • HER2+ breast cancer (20-25% of cases)
- ⚠️ Cardiotoxicity (reversible)
Bevacizumab (Avastin)
- • Anti-VEGF (angiogenesis inhibitor)
- • Colorectal, lung, renal cancers
- • Hypertension, proteinuria, impaired wound healing
Cetuximab
- • Anti-EGFR
- • Colorectal (wild-type KRAS), head/neck cancers
- • Acneiform rash (correlates with efficacy)
Immune Checkpoint Inhibitors
Pembrolizumab, Nivolumab
- • Anti-PD-1 (programmed death receptor)
- • Melanoma, NSCLC, RCC, others
- • Immune-related adverse events (pneumonitis, colitis, thyroiditis)
- ✓ Durable responses in some patients
Ipilimumab
- • Anti-CTLA-4
- • Melanoma
- • Severe immune-related toxicities (colitis, hypophysitis)
Supportive Care & Toxicity Management
Antiemetics
- • 5-HT3 antagonists: Ondansetron, granisetron
- • NK1 antagonist: Aprepitant
- • Steroids: Dexamethasone
- • Dopamine antagonists: Metoclopramide
Hematopoietic Growth Factors
- • G-CSF: Filgrastim (prevents neutropenia)
- • Erythropoietin: Epoetin alfa (anemia)
- • Thrombopoietin agonists: Romiplostim (thrombocytopenia)
Chemoprotectants
- • Mesna: Prevents hemorrhagic cystitis (cyclophosphamide, ifosfamide)
- • Leucovorin: Rescue from methotrexate
- • Dexrazoxane: Cardioprotection from doxorubicin
- • Amifostine: Protects from cisplatin nephrotoxicity
Tumor Lysis Syndrome Prevention
- • Allopurinol: Inhibits xanthine oxidase (↓ uric acid)
- • Rasburicase: Recombinant urate oxidase (converts uric acid → allantoin)
- • Aggressive hydration, urinary alkalinization