Is induction chemotherapy with the TPF (Taxane, Platinum, Fluorouracil) regimen, consisting of docetaxel, cisplatin, and 5-fluorouracil, used for both chemoradiotherapy and surgery in patients with locally advanced head and neck cancer?

Induction Chemotherapy with TPF: Indications and Dosing

Induction chemotherapy with TPF is primarily used before chemoradiotherapy for organ preservation and disease control in locally advanced head and neck cancer, not routinely before surgery. 1, 2

Primary Indication: Organ Preservation with Chemoradiotherapy

The established role of TPF induction is for patients with locally advanced disease who will undergo definitive chemoradiotherapy, particularly in organ preservation strategies for hypopharyngeal and laryngeal cancers that would otherwise require total laryngectomy. 3, 4

• For hypopharyngeal cancers less than T4a requiring total laryngectomy, induction chemotherapy achieves the highest level of consensus (category 2A) as part of a larynx preservation strategy. 3
• TPF induction followed by chemoradiotherapy achieves organ preservation in 50-89% of cases at 2-5 years. 4
• The approach is also considered for patients with N2-3 disease at high risk for distant metastases (category 2B recommendation). 3

Limited Role Before Surgery

Induction chemotherapy is NOT a standard approach before primary surgical resection. 3

• Historical trials of induction chemotherapy followed by surgery (or radiotherapy) in the 1980s-1990s did not demonstrate overall survival improvements. 3
• The current paradigm uses induction TPF to select patients who respond well for organ-preserving chemoradiotherapy rather than as preoperative treatment. 4, 5
• Surgery remains an option after induction only for non-responders or as salvage for residual/recurrent disease. 3

Established TPF Regimen: Doses and Schedule

The standard TPF regimen consists of:

• Docetaxel: 75 mg/m² IV on day 1 1, 2, 6
• Cisplatin: 75-80 mg/m² IV on day 1 1, 2, 7
• 5-Fluorouracil: 750 mg/m²/day as continuous infusion for 5 days (days 1-5) 1, 2, 6
• Cycle frequency: Every 3 weeks 1, 2, 8
• Number of cycles: 3 cycles preferred, minimum 2 cycles acceptable 1, 2

Alternative dosing ranges include docetaxel 60-75 mg/m², cisplatin 60-80 mg/m², and 5-FU 600-750 mg/m²/day, though the higher doses are more commonly used. 1, 6

Subsequent Chemoradiotherapy

After completing TPF induction, patients must proceed to concurrent chemoradiotherapy within 21-28 days from the first day of the last induction cycle to minimize treatment failure risk. 1, 2

• Concurrent cisplatin options include:

  • High-dose cisplatin 100 mg/m² every 21 days × 3 cycles (standard but often not feasible after induction) 3, 2
  • Weekly cisplatin 40 mg/m² (more commonly used after induction, better tolerated) 2, 9
  • Target cumulative cisplatin dose of 160-200 mg/m² during concurrent phase 2

• Radiotherapy is typically delivered to 66-70 Gy using standard or hyperfractionated schedules. 3, 5

Evidence for TPF Superiority

Three phase III trials demonstrated that TPF significantly outperforms the older PF (cisplatin/5-FU) regimen:

• The TAX323 trial showed median overall survival of 18.8 months with TPF versus 14.5 months with PF (27% reduction in death risk, P=0.02). 8
• TPF improved progression-free survival (11.0 vs 8.2 months, P=0.007), response rates, and disease-free survival compared to PF. 3, 8
• A phase II randomized study showed radiologic complete response rates of 50% with TPF followed by chemoradiotherapy versus 21% with chemoradiotherapy alone (P=0.004). 7, 10

Toxicity Profile and Management

Grade 3-4 toxicities with TPF are substantial and require aggressive supportive care:

• Neutropenia: 35% 1, 2
• Leukopenia: 27% 1, 2
• Diarrhea: 8% 1, 2
• Treatment-related mortality: 2.3% 8

Critical management strategies include:

• Prophylactic antibiotics for all patients receiving TPF (used in TAX323 and TAX324 trials). 6
• Consider prophylactic G-CSF to mitigate hematologic toxicity. 6
• Premedication with dexamethasone to prevent hypersensitivity reactions. 6
• Antiemetics and hydration protocols for cisplatin administration. 6

Contraindications and Cautions

Do not administer TPF to patients with:

• Neutrophil counts <1500 cells/mm³ 6
• Bilirubin >upper limit of normal or AST/ALT >1.5× ULN with alkaline phosphatase >2.5× ULN 6
• History of severe hypersensitivity to docetaxel or polysorbate 80 6

Major pitfall: Approximately 24% of patients drop out before completing sequential induction followed by concurrent therapy due to cumulative toxicity. 4 Patient selection is critical—those with performance status 0-1 are most appropriate candidates. 3, 7

Unresolved Controversies

Despite proven efficacy of TPF over PF, adding induction to concurrent chemoradiotherapy remains controversial:

• For oropharyngeal T3-4a, N0-1 disease, induction has a category 3 designation (major disagreement among experts). 3
• No clear overall survival advantage has been demonstrated for induction TPF plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone. 3
• A three-arm study showed decreased time to treatment failure with induction but no survival difference, with 3× more patients excluded from efficacy assessments on induction arms due to toxicity. 3

The balance between proven survival benefits of TPF and substantial hematologic toxicity requires careful patient selection and aggressive supportive care. 1