What is the treatment plan for a patient with unresectable oesophageal squamous cell carcinoma and a Combined Positive Score (CPS) of 5, and would radiation therapy (RT) with Tomotherapy (28 fractions) be a reasonable approach?

Treatment Plan for Unresectable Esophageal Squamous Cell Carcinoma with CPS 5

For this patient with unresectable esophageal squamous cell carcinoma and CPS 5, first-line treatment should be nivolumab plus chemotherapy (cisplatin/5-FU or carboplatin/paclitaxel), as immunotherapy combined with chemotherapy is the standard of care for this population. 1

Systemic Therapy Recommendations

Primary Treatment Approach

• Nivolumab plus chemotherapy is recommended for patients with esophageal squamous cell carcinoma and PD-L1 tumor proportion score (TPS) ≥1%, which your patient's CPS of 5 satisfies 1
• Alternative option: Nivolumab plus ipilimumab (dual immunotherapy without chemotherapy) is also acceptable for patients with PD-L1 TPS ≥1% 1
• Pembrolizumab plus chemotherapy becomes the preferred option if CPS ≥10, but with CPS 5, nivolumab-based regimens are more appropriate 1

Chemotherapy Backbone Options

• Cisplatin plus 5-fluorouracil (CF) remains the traditional standard chemotherapy regimen 1, 2
• Carboplatin plus paclitaxel is widely used due to favorable toxicity profile and is the regimen used in the CROSS trial 1
• Both regimens show equivalent efficacy in retrospective comparisons 1

Role of Radiation Therapy

When RT Should Be Considered

Definitive chemoradiotherapy (CRT) is indicated for unresectable esophageal squamous cell carcinoma when the goal is locoregional control and the patient has good performance status. 1, 3

Radiation Dose and Fractionation

• Standard dose: 50.4 Gy in 28 fractions (1.8 Gy per fraction) is the established regimen based on RTOG 85-01 and INT 0123 trials 1
• Alternative: 50 Gy in 25 fractions (2 Gy per fraction) is also acceptable 1
• Doses >50.4 Gy do not improve outcomes and increase toxicity without survival benefit 1
• Tomotherapy at 28 fractions delivering 50.4 Gy is reasonable if using 1.8 Gy per fraction, as this matches the standard definitive CRT dose 1

Concurrent Chemotherapy with RT

• Cisplatin plus 5-FU (CF) is the traditional standard when combined with 50.4 Gy radiation 1
• Carboplatin plus paclitaxel (weekly) is commonly used due to better tolerability, though not directly compared to CF in phase III trials for definitive treatment 1
• FOLFOX (5-FU, leucovorin, oxaliplatin) showed equivalent efficacy to CF in the phase III setting and may be more convenient 1

Clinical Decision Algorithm

Step 1: Assess Performance Status and Treatment Goals

• If ECOG 0-1 and goal is cure/long-term control: Consider definitive CRT with systemic therapy 1, 4
• If metastatic disease or poor performance status: Prioritize systemic immunotherapy-chemotherapy without RT 1

Step 2: Determine Treatment Sequence

For unresectable localized disease:

• Option A (Preferred for CPS 5): Nivolumab plus chemotherapy for 4-6 cycles, then reassess for consolidative RT if responding 1
• Option B: Definitive concurrent CRT (50.4 Gy/28 fractions with cisplatin/5-FU or carboplatin/paclitaxel), followed by consideration of maintenance immunotherapy (investigational) 1, 3

For metastatic disease (M1 LYM or distant metastases):

• Systemic therapy only: Nivolumab plus chemotherapy, with palliative RT reserved for symptomatic sites 1, 4

Step 3: Technical RT Considerations

• Use 3D conformal RT at minimum; IMRT or VMAT preferred to minimize dose to heart, lungs, and spinal cord 1
• Elective nodal volumes should receive ~50 Gy (biologically equivalent to 50 Gy in 2-Gy fractions) 1
• Do not exceed 50.4 Gy as dose escalation beyond this increases toxicity without benefit 1

Critical Caveats and Pitfalls

Common Errors to Avoid

• Do not use RT alone without chemotherapy for unresectable disease—concurrent CRT significantly improves survival over RT alone (median survival 14 vs 9 months, 5-year OS 27% vs 0%) 1
• Do not delay systemic therapy in favor of RT planning if metastatic disease is present—systemic control takes priority 1
• Do not assume CPS and TPS are interchangeable—guidelines specify TPS ≥1% for nivolumab regimens, though CPS ≥5 also supports immunotherapy use 1

Late Toxicity Considerations

• Grade 3+ late adverse events occur in ~15% of patients receiving definitive CRT, including cardiopulmonary toxicity in 8% 4
• Treatment-related mortality is ~4% with definitive CRT for unresectable disease 4
• Salvage surgery after CRT carries increased morbidity if RT doses exceed 55 Gy 1

Monitoring and Salvage Planning

• Plan salvage strategy before starting CRT—endoscopic or surgical salvage options should be discussed upfront for residual/recurrent disease 3
• 5-year overall survival for unresectable LA-ESCC with definitive CRT is ~20%, emphasizing the need for systemic therapy integration 4

Specific Answer to Tomotherapy Question

Yes, Tomotherapy delivering 50.4 Gy in 28 fractions (1.8 Gy per fraction) is reasonable and appropriate for definitive treatment of unresectable esophageal squamous cell carcinoma, as this matches the standard dose-fractionation established by RTOG 85-01 and endorsed by multiple guidelines. 1 However, this should be delivered concurrently with chemotherapy (cisplatin/5-FU or carboplatin/paclitaxel), not as RT alone. 1 Given the patient's CPS 5, strongly consider incorporating nivolumab either before, during (investigational), or after CRT to optimize systemic disease control. 1, 5