What other landmark postoperative chemoradiotherapy trial follows the Bernier (EORTC 22931) and Cooper (RTOG 9501) studies in head and neck squamous cell carcinoma?

Landmark Postoperative Chemoradiotherapy Trials Beyond Bernier and Cooper

The JCOG1008 trial (2024) represents the next major landmark study after Bernier (EORTC 22931) and Cooper (RTOG 9501), demonstrating non-inferiority of weekly cisplatin 40 mg/m² compared to the standard 3-weekly 100 mg/m² regimen for postoperative chemoradiotherapy in high-risk head and neck squamous cell carcinoma. 1

Historical Context: The Foundation Trials

The Bernier (EORTC 22931) and Cooper (RTOG 9501) trials, both published in 2004, established the standard of postoperative chemoradiotherapy with cisplatin 100 mg/m² every 3 weeks for 3 doses concurrent with radiotherapy 2. These trials demonstrated:

• Improved locoregional control in both studies 3, 2
• Improved disease-free survival in both trials 3, 2
• Overall survival benefit in the EORTC trial but not in RTOG 9501 3

The combined analysis of these trials identified that patients with extracapsular nodal spread and/or positive surgical margins derived the clearest benefit from adding cisplatin to postoperative radiotherapy 3, 4. This analysis became the foundation for current treatment recommendations 3, 5, 6.

The JCOG1008 Trial: Addressing Cisplatin Delivery Challenges

The Clinical Problem

The high-dose cisplatin regimen (100 mg/m² every 3 weeks) established by Bernier and Cooper has been plagued by insufficient cisplatin delivery due to high-dose-related toxicity 1. The Cooper trial reported:

• 77% of patients experienced grade 3 or greater acute adverse effects with combined therapy versus 34% with radiotherapy alone 2
• Four treatment-related deaths occurred in the combined therapy arm 2

The JCOG1008 Solution

JCOG1008 proved the non-inferiority of weekly cisplatin 40 mg/m² compared to 3-weekly cisplatin 100 mg/m² in terms of overall survival 1. This represents a paradigm shift because:

• Weekly dosing improves cisplatin delivery rates by reducing acute toxicity 1
• The regimen maintains efficacy while being better tolerated 1
• This addresses the long-standing debate over insufficient cisplatin delivery with the traditional high-dose approach 1

Other Notable Postoperative Trials

RTOG 88-24 (1997): The Precursor Study

This phase II trial preceded the landmark randomized trials and provided the preliminary evidence that postoperative radiotherapy with concurrent cisplatin 100 mg/m² on days 1,23, and 43 may improve locoregional control rates 7. The study showed:

• 81% locoregional control at 3 years by actuarial analysis 7
• This led directly to the design of RTOG 9501 7

TROG 05.01 (2018): The Negative Trial for Cutaneous SCC

This trial specifically addressed high-risk cutaneous squamous cell carcinoma of the head and neck, testing whether adding weekly carboplatin (AUC 2) to postoperative radiotherapy improved outcomes 8. Key findings:

• No benefit was observed with the addition of carboplatin to radiotherapy 8
• 5-year freedom from locoregional relapse was 83% for RT alone versus 87% for CRT (hazard ratio 0.84, P=0.58) 8
• This trial is important because it demonstrates that carboplatin-based regimens lack robust evidence in the postoperative setting 6, 8

Current Standard of Care Based on These Trials

Absolute Indications for Postoperative Chemoradiotherapy

Extracapsular nodal extension and/or positive surgical margins (<5 mm) are the only absolute indications for adding cisplatin to postoperative radiotherapy 3, 5, 6, 4. The NCCN recommends:

• Cisplatin 100 mg/m² every 3 weeks for 3 doses as the traditional standard 3, 5, 6
• Weekly cisplatin 40 mg/m² is now an evidence-based alternative based on JCOG1008 1
• Radiotherapy dose of 60-66 Gy in 2.0 Gy fractions over 6-6.6 weeks 9, 2

Relative Indications

For patients with multiple positive nodes without extracapsular spread, perineural invasion, vascular invasion, or pT4 primary tumors, the NCCN recommends to "consider chemoradiotherapy" rather than making it an absolute recommendation 3. This is because:

• The combined analysis showed no survival advantage for patients with multiple nodes without extracapsular spread as their only risk factor 3, 4
• These patients were included in EORTC 22931 which showed survival benefit, creating some equipoise 3

Critical Implementation Considerations

Timing

The time from surgery to completion of radiotherapy should be kept as short as possible, ideally less than 6 weeks 5, 9. This is crucial for maintaining treatment efficacy.

Supportive Care Requirements

Chemoradiation requires an experienced multidisciplinary team with substantial supportive care infrastructure 5, 6. Common pitfalls include:

• Inadequate antiemetic prophylaxis for high-dose cisplatin 5
• Insufficient hydration protocols leading to nephrotoxicity 5
• Poor nutritional support during treatment 5
• Lack of close monitoring for hematologic toxicity 6

Patient Selection

Not all patients can tolerate concurrent therapy 5. Careful assessment of performance status and comorbidities is essential before committing to combined modality treatment 5.