What is the recommended adjuvant chemotherapy (chemo) regimen for patients with high-risk head and neck cancer?

Adjuvant Chemotherapy in Head and Neck Cancer

For patients with resected high-risk head and neck squamous cell carcinoma, adjuvant concurrent chemoradiotherapy with high-dose cisplatin (100 mg/m² every 3 weeks for 3 cycles) is the standard of care when extracapsular nodal spread and/or positive surgical margins (<5 mm) are present. 1

Defining High-Risk Disease Requiring Adjuvant Chemoradiotherapy

The two absolute indications for adjuvant chemoradiotherapy (not just radiotherapy alone) are:

• Extracapsular nodal spread from lymph nodes 1
• Positive or close surgical margins (defined as <5 mm) 1

These criteria are based on the landmark RTOG 9501 and EORTC 22931 trials, which demonstrated that only patients with these specific features benefited from the addition of cisplatin to postoperative radiotherapy in terms of survival outcomes. 1

Other High-Risk Features (Radiotherapy Alone May Be Sufficient)

The following features indicate high risk but do not automatically require chemoradiotherapy—postoperative radiotherapy alone is the established standard unless other factors are present: 1

• Multiple positive lymph nodes (≥2) without extracapsular spread 1
• Perineural or perivascular invasion 1
• pT3 or pT4 primary tumor 1
• Nodal involvement at levels 4 and 5 from oral cavity or oropharyngeal primary 1

However, the NCCN guidelines suggest clinicians "consider chemoradiation" for these other adverse features, as they were included in the EORTC 22931 trial which showed survival benefit. 1

Standard Adjuvant Chemoradiotherapy Regimen

The evidence-based regimen consists of: 1

• Cisplatin 100 mg/m² intravenously every 3 weeks for 3 cycles (total of 3 doses) 1
• Concurrent with conventional fractionation radiotherapy: 2.0 Gy per fraction to 70 Gy over 7 weeks 1
• Alternative dosing: Cisplatin 50 mg weekly has also shown survival benefit in randomized trials 1

This regimen improved locoregional control and disease-free survival in RTOG 9501, and improved overall survival in EORTC 22931. 1 The combined analysis of both trials confirmed survival benefit specifically for patients with extracapsular spread and/or positive margins. 1

Alternative Regimens for Cisplatin-Ineligible Patients

For patients who cannot tolerate cisplatin due to renal dysfunction, hearing loss, poor performance status, or advanced age, options are limited and evidence is weak: 1

• Docetaxel (15 mg/m² weekly) plus cetuximab (400 mg/m² loading, then 250 mg/m² weekly) plus radiotherapy is listed by NCCN as a category 2B option based on the phase 2 RTOG 0234 study 1
• Carboplatin-based regimens may be considered, though they lack the robust evidence base of cisplatin 2
• Radiotherapy alone remains an option but yields poor outcomes in high-risk patients 1

The 2023 Cancer Treatment Reviews emphasizes that cisplatin-ineligible patients represent a significant unmet need with no established standard of care. 1

What Does NOT Work: Adjuvant Chemotherapy Alone

Adjuvant chemotherapy without concurrent radiotherapy has no proven benefit and should not be used. 1 Multiple trials including the Head and Neck Contracts Program demonstrated that induction or maintenance chemotherapy alone (without concurrent radiotherapy) failed to improve survival. 3 The benefit comes specifically from the concurrent administration of chemotherapy with radiotherapy. 1

Critical Margin Considerations

A margin of <5 mm is considered "close" and warrants adjuvant chemoradiotherapy. 1 However, there is ongoing debate about whether margins of 1-4 mm carry the same risk as truly positive margins. 1 Some data suggest margins ≥1 mm may not significantly impact overall survival, but the conservative approach is to treat margins <5 mm with chemoradiotherapy when combined with other risk factors. 1

Important caveat: Tissue contraction during formalin fixation can reduce observed margins, and anatomical constraints may prevent achieving 5 mm clearance in certain locations. 1

Toxicity and Supportive Care

Concurrent chemoradiotherapy carries substantial toxicity: 1

• Grade 3-4 mucositis occurs in 17-35% of patients 1, 4
• Grade 3-4 lymphopenia, leukopenia, dysphagia, and neutropenia are common 1
• Weekly cisplatin regimens may improve tolerability compared to high-dose every-3-week dosing, with grade 3-4 mucositis rates of 35% and treatment completion rates of 81.5% 4

This treatment should only be administered by experienced multidisciplinary teams with robust supportive care infrastructure. 1

What About Neoadjuvant (Induction) Chemotherapy?

Neoadjuvant chemotherapy before surgery has demonstrated no effect on disease-free survival or overall survival and is not recommended in the adjuvant setting. 1 Its role is limited to organ preservation protocols in larynx and hypopharynx cancer. 1