Standard of Care for Recurrent Sinonasal Squamous Cell Carcinoma
For recurrent sinonasal squamous cell carcinoma, the treatment approach depends critically on whether the recurrence is amenable to salvage surgery or re-irradiation versus requiring systemic palliative therapy, with surgical resection plus adjuvant therapy offering the best survival outcomes when feasible. 1, 2
Initial Assessment and Treatment Stratification
The first critical decision point is determining resectability of the recurrent disease through multidisciplinary tumor board evaluation 1. This assessment should include:
- Imaging with CT and/or MRI to define extent of local recurrence and rule out distant metastases 1
- Endoscopic evaluation to assess mucosal involvement and obtain tissue confirmation 3
- Assessment of prior radiation dose and interval since initial treatment to determine feasibility of re-irradiation 4
- Performance status evaluation (ECOG 0-1 preferred for aggressive therapy) 1
Locoregionally Recurrent Disease (No Distant Metastases)
If Surgically Resectable
Salvage surgery followed by adjuvant radiation or chemoradiation represents the optimal approach for resectable locoregional recurrence 1, 2. Patients undergoing surgical intervention ± adjuvant therapy demonstrate significantly lower mortality risk compared to definitive radiation/chemoradiation alone (HR ≥ 1.97; p < 0.001) 2.
- Postoperative radiotherapy is indicated for pT3-4 tumors, positive margins (R1/R2), perineural invasion, lymphatic invasion, >1 positive lymph node, or extracapsular extension 1
- Postoperative chemoradiation with cisplatin is indicated specifically for R1 resection margins and extracapsular rupture 1
- Treatment should begin within 6-7 weeks of surgery 1
If Unresectable but Locoregionally Confined
Re-irradiation with concurrent chemotherapy should be considered for patients with good performance status (ECOG 0-1) who have not received prior radiation or have sufficient interval since initial radiation 1, 4.
- Concurrent cisplatin-based chemoradiation is superior to radiation alone for locoregional control and overall survival 1
- Standard cisplatin dosing is 100 mg/m² on days 1,22, and 43 concurrent with radiation (70 Gy) 1
- IMRT or VMAT techniques should be utilized to minimize toxicity 1
Role of Induction Chemotherapy
Induction chemotherapy followed by surgery may be considered for locally advanced recurrent disease, particularly when orbital preservation is desired 5, 2.
- Platinum-taxane combinations (with or without 5-FU) achieve partial response or better in approximately 58% of patients 5
- Patients achieving at least partial response to induction chemotherapy have significantly better overall and disease-free survival (p = 0.028 and p = 0.021) 5
- Orbital preservation rate of 81.5% can be achieved with this approach 5
- Induction chemotherapy followed by surgery demonstrates similar survival to primary surgery ± adjuvant therapy (p ≥ 0.672) 2
Recurrent/Metastatic Disease Not Amenable to Locoregional Therapy
First-Line Systemic Therapy
The choice of first-line systemic therapy depends on PD-L1 expression status (Combined Positive Score, CPS):
For PD-L1 CPS ≥1 Tumors
Two validated first-line options exist 1:
Pembrolizumab monotherapy (200 mg IV every 3 weeks) - preferred when rapid tumor shrinkage is not urgently needed 1, 6
Pembrolizumab plus platinum/5-FU (cisplatin or carboplatin) - preferred for symptomatic patients requiring rapid tumor shrinkage 1
For PD-L1 Negative Tumors (CPS <1)
The EXTREME regimen remains standard of care 1:
- Platinum (cisplatin or carboplatin) + 5-FU + cetuximab 1
- Median OS: 10.1 months vs 7.4 months with platinum/5-FU alone 1
- Alternative: TPeX regimen (cisplatin/docetaxel/cetuximab) shows comparable results and may be considered for patients with DPD deficiency 1
Important caveat: Current evidence does not demonstrate whether pembrolizumab plus chemotherapy improves survival compared to EXTREME in PD-L1 negative patients 1. The impact of pembrolizumab in patients with CPS 1-19 also remains unclear (exploratory analysis showed HR 0.86,95% CI: 0.66-1.12) 6.
Second-Line Systemic Therapy
For patients progressing within 6 months of platinum therapy:
Nivolumab (anti-PD-1 inhibitor) is both FDA and EMA-approved 1
Pembrolizumab is FDA-approved for all patients and EMA-approved for PD-L1 TPS ≥50% 1
Third-Line and Beyond
After progression on both platinum-based chemotherapy and anti-PD-1 inhibitors, no standard of care exists 1.
EXTREME regimen can be reconsidered as second-line after progression on immunotherapy in fit patients 1
- Retrospective data shows ORR 30%, median PFS 3.6 months, median OS 7.8 months 1
Cetuximab monotherapy is FDA-approved after platinum failure (not based on randomized data) 1
- Median OS: 5.2-6.1 months in prospective single-arm studies 1
Taxanes ± cetuximab ± methotrexate are frequently used but lack randomized trial evidence 1
Critical Prognostic Factors
Negative prognostic indicators that should inform treatment intensity decisions include 1:
- ECOG performance status ≥1
- Weight loss >5%
- Prior radiation therapy
- Hypopharyngeal or oral cavity primary site
- Well to moderate tumor differentiation
- Malignant hypercalcemia (indicates end-stage disease)
Essential Supportive Care Measures
- Nutritional status must be optimized and maintained throughout treatment 1, 7
- Dental rehabilitation should be completed before any radiation therapy 1, 7
- DPD testing is recommended before initiating 5-FU-based regimens 1
Common Pitfalls to Avoid
- Do not assume all recurrent disease is incurable - aggressive evaluation for salvage surgery or re-irradiation is essential as these offer superior survival 2
- Do not use pembrolizumab monotherapy in PD-L1 negative patients - EXTREME remains the standard 1
- Do not delay treatment initiation - postoperative therapy should begin within 6-7 weeks of surgery 1
- Do not overlook performance status - patients with ECOG ≥2 may not tolerate aggressive combination regimens and should receive modified approaches 1