Chemotherapy Strategies in ENT (Head and Neck Cancer)

Introduction

1. Combination Chemotherapy

• Exposure to agents with different mechanisms of action and non-overlapping toxicities
• Reduction in drug resistance development
• Potential for synergistic activity

2. Adjuvant Chemotherapy

• Administered after curative surgery or radiotherapy in patients at high risk of relapse
• Intention: to eradicate micrometastatic disease
• However, randomized trials assessing adjuvant chemotherapy for head and neck squamous carcinoma do not demonstrate a significant survival benefit [Level 1 evidence]
• Therefore, adjuvant chemotherapy alone is not standard practice in HNSCC

3. Neoadjuvant (Induction) Chemotherapy

• Reduce tumour bulk before definitive treatment
• Improve local and distant disease control
• Achieve organ preservation
• Drug delivery is optimal in the previously untreated, non-debilitated patient with intact tumour vascularity

• VA Laryngeal Cancer Study (1991): Induction cisplatin/5-FU followed by RT vs. surgery + RT in stage III/IV laryngeal cancer. An 85% chemotherapy response rate was documented. No overall survival difference, but laryngeal preservation was achieved in responders - a landmark result for organ conservation.
• RTOG 91-11 trial: 547 patients randomized to: (i) induction cisplatin/5-FU → RT, (ii) concurrent cisplatin-based CRT, (iii) RT alone. Concurrent CRT was superior to induction chemotherapy or RT alone for organ preservation and locoregional control.
• TPF regimen (Docetaxel + Cisplatin + 5-FU): Improved response rates over PF alone in Phase III trials (TAX 324 trial), with improved overall survival and organ preservation rates.

4. Concurrent Chemoradiotherapy (CRT)

• Inhibits tumour repopulation between RT fractions
• Preferentially kills hypoxic cells (which are RT-resistant)
• Inhibits repair of sublethal radiation damage
• Sterilizes micrometastatic disease outside radiation fields
• Decreases tumour mass → improves blood supply and reoxygenation

• Inhibits repair of drug-induced damage
• Decreases tumour size → improved blood supply and enhanced drug delivery

• Positive lymph nodes, positive surgical margins, extracapsular spread (ECS) - the two strongest indications
• Perineural invasion, lymphovascular invasion

• RTOG 9501 and EORTC 22931 (two pivotal Phase III trials): Both demonstrated significantly improved locoregional control with the addition of chemotherapy (cisplatin) to postoperative RT in high-risk patients.
• Improved 5-year survival by 13% compared with RT alone in high-risk patients.
• Standard agent: cisplatin 100 mg/m² on days 1, 22, 43 (three cycles concurrent with RT).

5. Palliative Chemotherapy (Recurrent/Metastatic Disease)

• Patients with recurrent or metastatic HNSCC have a poor prognosis with median overall survival of under 1 year
• Objective response rates to commonly used therapies (methotrexate, docetaxel, paclitaxel) are well under 20%
• Median survival in Phase III trials is reproducibly reported at 5-6 months
• Cisplatin + 5-FU has been the standard first-line palliative regimen

6. Targeted Therapy and Biological Agents

EGFR-targeted therapy

• EGFR (Epidermal Growth Factor Receptor) is overexpressed in >80% of HNSCC and is associated with increased proliferative capacity, metastatic potential, and poor prognosis.
• Cetuximab (chimeric IgG monoclonal antibody against EGFR): binding affinity equal to natural ligand; blocks EGF and TGF-α; causes internalization of EGFR; activates cytotoxic immune mechanisms.
• Bonner trial: Cetuximab + RT significantly improved locoregional control and OS vs. RT alone in locally advanced HNSCC.
• EXTREME trial (ESMO 2008): Cetuximab + cisplatin/5-FU in recurrent/metastatic disease showed improved progression-free and overall survival vs. chemotherapy alone - the first regimen to improve OS in this setting.

Small molecule tyrosine kinase inhibitors (TKIs)

• Gefitinib, erlotinib: orally active EGFR-TKIs; results in HNSCC have been modest.

Anti-angiogenic agents

• VEGF pathway inhibitors are under investigation.

Immunotherapy

• Immune checkpoint inhibitors (anti-PD-1 antibodies: pembrolizumab, nivolumab) represent the newest strategy for recurrent/metastatic HNSCC, with improved survival in platinum-refractory disease.

Summary Table

Key Points for Exam

1. Cisplatin is the single most important drug in head and neck chemotherapy.
2. The RTOG 91-11 trial proved concurrent CRT is superior to induction chemo for laryngeal preservation.
3. ECS and positive margins are the strongest indications for postoperative CRT (from RTOG 9501 + EORTC 22931).
4. Adjuvant chemotherapy alone has no proven benefit in HNSCC.
5. The EXTREME trial established cetuximab + platinum + 5-FU as the first regimen to improve OS in recurrent/metastatic HNSCC.
6. TPF (docetaxel + cisplatin + 5-FU) is the preferred induction regimen over PF alone when induction is chosen.