Chemotherapy and Targeted Therapy

Chemo Basics - Drug Dueling Cancers

• Primary Goal: Cytotoxic (kill) or cytostatic (halt growth) effects on cancer cells.
• Drug Categories:
  • Cell Cycle Specific (CCS): Act on specific phases (e.g., S-phase: Antimetabolites; M-phase: Vincas, Taxanes).
  • Cell Cycle Non-Specific (CCNS): Effective in all phases, including G0 (e.g., Alkylating agents).
• Therapeutic Intent:
  • Adjuvant: Post-surgery/RT to eliminate micrometastases.
  • Neoadjuvant: Pre-surgery/RT to shrink tumor.
• Combination Regimens: Standard to maximize kill, minimize resistance.

⭐ Most chemotherapy drugs target rapidly dividing cells, leading to common side effects like myelosuppression, mucositis, and alopecia.

Key Chemo Drugs - H&N Hitmen

• Platinum Agents: Crucial for H&N cancers.
  • Cisplatin: Forms DNA cross-links. Toxicities: Severe Nausea/Vomiting, Nephrotoxicity (📌 Amifostine), Ototoxicity, Neuropathy.
  • Carboplatin: DNA cross-links. Toxicities: Myelosuppression (dose-limiting), less nephro/ototoxic. Calvert formula.
• Antimetabolites:
  • 5-Fluorouracil (5-FU): Inhibits thymidylate synthase $\rightarrow$ ↓DNA. Toxicities: Mucositis, Diarrhea, Myelosuppression.
  • Methotrexate (MTX): DHFR inhibitor. Toxicities: Mucositis, Myelosuppression, Hepatotoxicity. (📌 Leucovorin rescue).
• Taxanes (Paclitaxel, Docetaxel):
  • MOA: Stabilize microtubules $\rightarrow$ mitotic arrest.
  • Toxicities: Myelosuppression, Neuropathy, Hypersensitivity.
• Targeted Therapy:
  • Cetuximab: EGFR mAb. Toxicities: Acneiform rash, Hypomagnesemia, Infusion reactions.

    ⭐ Acneiform rash with Cetuximab often correlates with better treatment response.

Targeted Therapy Intro - Precision Payloads

• Drugs engineered to interfere with specific molecules ("targets") vital for cancer cell growth & survival.
• Deliver "precision payloads" by selectively targeting cancer cells, reducing harm to normal tissues.
• Major classes:
  • Monoclonal Antibodies (MAbs): Large proteins; bind extracellular targets (e.g., EGFR - Cetuximab). Suffix: "-mab".
  • Small Molecule Inhibitors (TKIs): Oral; enter cells, block intracellular targets (e.g., BCR-ABL - Imatinib). Suffix: "-nib".

⭐ Biomarker testing (companion diagnostics) is often mandatory to identify patients benefiting from specific targeted therapies.

Star Targeted Agents - EGFR & Immune Boosters

• EGFR Inhibitors:

  • Cetuximab: mAb vs EGFR.
    • Uses: LA HNSCC (w/ RT); R/M HNSCC (w/ chemo/alone).
    • SEs: Acneiform rash (predicts response; 📌 C-rash = C-benefit), hypomagnesemia, infusion rxns.
  • TKIs (Gefitinib, Erlotinib): Minor role HNSCC.

• Immune Checkpoint Inhibitors (ICIs) - "Immune Boosters":

  • PD-1 Inhibitors: Nivolumab, Pembrolizumab.
    • Mech: Blocks T-cell PD-1 → ↑anti-tumor activity.
    • Uses: R/M HNSCC (post-platinum, or 1st line [Pembrolizumab +/- chemo for PD-L1+]).
  • PD-L1 Inhibitors: Atezolizumab, Durvalumab.
  • SEs (irAEs): Skin, gut, liver, lung, endocrine toxicities.

⭐ Pembrolizumab: 1st-line for metastatic/unresectable recurrent HNSCC if PD-L1 CPS ≥ 1 (alone/with chemo).

Regimens & Resistance - Combo Combat & Defenses

• Key Regimens:
  • Induction (LA-SCCHN): TPF (Docetaxel, Cisplatin, 5-Fluorouracil) improves outcomes.
  • Concurrent (CCRT): High-dose Cisplatin (100 mg/m² every 3 weeks) is standard with RT.
• Resistance Mechanisms:
  • Drug efflux (e.g., MDR1/P-gp), target gene mutations, enhanced DNA repair, altered drug metabolism.
• Combat Strategies:
  • Combination chemotherapy, sequential therapies, novel targeted agents.

⭐ Acquired resistance to Cisplatin often involves increased cellular detoxification via glutathione conjugation or enhanced DNA repair pathways like NER.

High‑Yield Points - ⚡ Biggest Takeaways

• Cisplatin is a cornerstone for HNSCC chemoradiation; key toxicities include nephrotoxicity and ototoxicity.
• Induction chemotherapy (e.g., TPF regimen) is used for locally advanced HNSCC to improve outcomes.
• Cetuximab (EGFR inhibitor) is crucial for HNSCC, especially HPV-negative cases; characteristic acneiform rash.
• Immunotherapy (e.g., Pembrolizumab, Nivolumab) is vital for recurrent or metastatic HNSCC.
• 5-Fluorouracil (5-FU) is often combined with cisplatin for synergistic antitumour activity in HNSCC.