What are the NCCN (National Comprehensive Cancer Network) 2025 guidelines for treating oral cavity cancer?

NCCN 2025 Guidelines for Oral Cavity Cancer

The NCCN 2025 guidelines prioritize surgery as the primary treatment for oral cavity cancer, with adjuvant therapy determined by pathologic risk factors, though the specific 2025 NCCN guidelines are not directly available in the provided evidence.

Initial Workup and Staging

All patients require comprehensive staging evaluation before treatment planning:

• Clinical examination with rigid head and neck endoscopy under general anesthesia is mandatory 1
• Contrast-enhanced CT and/or MRI of the head and neck to assess primary tumor extent and depth of invasion (DOI) 1
• Chest imaging with CT and/or FDG-PET to evaluate for distant metastases 1
• Pathological confirmation via biopsy is required before initiating treatment 1
• Endoscopic ultrasound if early-stage disease is suspected 1

Pre-treatment assessment must include:

• Nutritional status with weight assessment 1
• Dental examination with rehabilitation planning if radiotherapy is anticipated 1
• Cardiopulmonary and renal function evaluation 1
• Performance status and comorbidity assessment 1
• Speech and swallowing function baseline 1

Critical caveat: If weight loss exceeds 10% in the 6 months before diagnosis, enteral nutrition via percutaneous gastrostomy should be initiated before starting treatment 1.

Primary Treatment by Stage

Early Stage Disease (T1-2 N0)

Surgery is the primary treatment modality for early-stage oral cavity cancer:

• Wide local excision with 1 cm clinical margins (vital structures permitting) 1, 2
• Pathologic margins must achieve ≥5 mm clearance when possible 3
• Depth of invasion (DOI) determines neck management:
  • DOI <5 mm and cT1N0: active surveillance of the neck is acceptable 1
  • DOI <10 mm: sentinel lymph node biopsy is a valid option 1
  • DOI ≥10 mm: elective neck dissection recommended 1, 2

For well-lateralized tongue tumors, ipsilateral selective neck dissection (levels I-IV) is appropriate 3.

Alternative to surgery: External beam radiotherapy or brachytherapy for selected stage I subsites provides similar locoregional control, though this is based on retrospective data only 1.

Locally Advanced Disease (T3-4a N0-3)

Surgery followed by risk-adapted adjuvant therapy is the standard approach:

Primary surgical resection with neck dissection, followed by:

• Observation only if all of the following are present:

  • pT1-2 tumors
  • Negative margins (R0 resection)
  • ≤1 involved lymph node
  • No extracapsular extension
  • No perineural or lymphatic invasion 1

• Adjuvant radiotherapy (56-60 Gy) for intermediate-risk features 1, 3:

  • pT3-4 tumors
  • Close or microscopically positive margins (R1)
  • Perineural invasion 3
  • Lymphatic invasion

  • 1 involved lymph node 1

• Adjuvant chemoradiotherapy with cisplatin for high-risk features 1:

  • Macroscopically positive margins (R2)
  • Extracapsular extension 1

Timing is critical: Postoperative radiotherapy or chemoradiotherapy must begin within 6-7 weeks of surgery, with the entire treatment sequence (surgery + adjuvant therapy) completed within 11 weeks 1.

Unresectable Disease (T4b or Unresectable Nodes)

Concurrent chemoradiotherapy is the primary treatment:

• Cisplatin-based chemoradiotherapy reduces the risk of death by more than 20% compared to radiotherapy alone 1, 4
• Standard regimen: High-dose cisplatin (100 mg/m²) every 3 weeks during radiotherapy 1
• Alternative: Weekly cisplatin (40 mg/m²) is non-inferior for postoperative settings 1

Induction chemotherapy options (though evidence for survival benefit is insufficient):

• Cisplatin plus 5-fluorouracil prior to radiotherapy or chemoradiotherapy 1, 4
• Docetaxel/cisplatin/5-fluorouracil (TPF) regimen 1, 4

Important limitation: Induction chemotherapy does not show clear survival benefit and should not delay definitive locoregional treatment 4.

Pathologic Assessment Requirements

Surgical specimens must be evaluated for:

• Tumor size and growth pattern 1
• Depth of invasion (DOI) - critical for oral cavity staging 1
• Total number of lymph nodes removed and number involved 1
• Presence of extracapsular extension 1
• Perineural and lymphatic infiltration 1
• Surgical margin status (R0, R1, or R2) 1

Recurrent and Metastatic Disease

Treatment depends on prior therapy and PD-L1 status:

First-Line Therapy (No Platinum in Last 6 Months)

For PD-L1-positive tumors (CPS ≥1):

• Pembrolizumab monotherapy (median OS 12.3-14.9 months) 1
• Alternative: Pembrolizumab plus platinum/5-FU if rapid tumor shrinkage needed 1

For PD-L1-negative tumors:

• Pembrolizumab plus platinum/5-FU (median OS 13 months) 1
• Alternative: Platinum/5-FU/cetuximab (EXTREME regimen) 1

Second-Line Therapy (Platinum Within Last 6 Months)

For immunotherapy-naïve patients:

• Nivolumab or pembrolizumab 1

For prior immunotherapy:

• Taxane, methotrexate, or cetuximab 1

Locoregional recurrence: Refer to tertiary center for multidisciplinary evaluation of salvage surgery or re-irradiation 1.

Surveillance Protocol

Follow-up schedule:

• Months 0-24: Clinical examination with flexible endoscopy every 2-3 months 1
• Years 3-5: Every 6 months 1
• After year 5: Annually 1

Imaging:

• Baseline post-treatment imaging at 3 months for locally advanced disease 1
• FDG-PET/CT at 3 months post-chemoradiotherapy for node-positive disease to assess need for neck dissection 1
• Additional imaging only if clinically indicated 1

Ancillary monitoring:

• TSH levels every 6-12 months following neck irradiation (hypothyroidism occurs in 20-25% of patients) 3
• Dental evaluation every 6 months for patients who received radiotherapy 1
• Tobacco and alcohol cessation counseling 1

Key Clinical Pitfalls

Avoid treatment delays: Any delay in radiotherapy initiation or prolongation of overall treatment time significantly reduces local control rates 1.

Do not perform transpleural biopsy if thymoma is in the differential diagnosis 1.

Neck dissection after chemoradiotherapy: Only perform if FDG-PET shows persistent disease or lymph nodes remain abnormal at 12 weeks post-treatment 1.

Nutritional support: Do not delay treatment for nutritional optimization unless weight loss exceeds 10% - use percutaneous gastrostomy for long-term support 1.