What are the lines of treatment regimens for oncological treatment of esophageal squamous cell cancer?

Treatment Regimens for Esophageal Squamous Cell Carcinoma by Line of Therapy

First-Line Treatment: Stage-Based Approach

For locally advanced esophageal squamous cell carcinoma, preoperative chemoradiotherapy followed by surgery (trimodality therapy) is the standard curative approach, though definitive chemoradiotherapy without surgery is equally acceptable for patients achieving clinical complete response. 1, 2, 3

Early Stage Disease (Tis-T1a N0)

• Surgery alone (endoscopic resection or surgical resection) is the treatment of choice for early-stage disease 1, 2
• Endoscopic resection achieves similar cure rates to surgery in specialized centers for carefully selected Tis-T1a N0 tumors 1, 2

Localized Disease (T1-2 N0-1 M0)

• Surgery is standard for T1-2 N0 disease, though long-term survival does not exceed 25% when regional lymph nodes are involved 1, 2
• For patients unable or unwilling to undergo surgery, definitive chemoradiotherapy is superior to radiotherapy alone 1, 2, 3
• Standard definitive chemoradiotherapy consists of cisplatin/5-fluorouracil (5-FU) combined with 50.4 Gy radiation in 1.8 Gy fractions 1, 3
• European and Japanese centers use increased radiation doses up to 60 Gy in 1.8-2.0 Gy fractions based on dose-response correlation 1

Locally Advanced Disease (T3-T4 N0-1)

The critical decision point is whether the patient will undergo surgery or definitive chemoradiotherapy:

Option 1: Trimodality Therapy (Preferred for Surgical Candidates)

• Preoperative chemoradiotherapy using cisplatin/5-FU with concurrent radiation (typically 41.4-50.4 Gy) 1, 2, 3
• Followed by transthoracic esophagectomy with two-field lymph node resection (minimum 16-18 nodes, preferably 20 nodes examined) 2, 4
• This approach increases rates of complete tumor resection, improves local control, and enhances survival compared to surgery alone 2, 3

Option 2: Definitive Chemoradiotherapy (For Non-Surgical Candidates or Complete Responders)

• Cisplatin/5-FU with 50.4-60 Gy radiation delivered definitively 1, 3
• Approximately 50% of ESCC patients achieve complete pathologic response after chemoradiotherapy 4
• For patients demonstrating clinical complete response, surgery may not provide additional benefit and definitive chemoradiotherapy is acceptable 4
• Close surveillance with early salvage surgery reserved for local tumor progression 3

Metastatic Disease (Stage IV)

First-line palliative chemotherapy consists of platinum/fluoropyrimidine combinations for patients with good performance status. 3

• Cisplatin/5-FU remains the standard first-line regimen 3, 5
• Cisplatin/paclitaxel is an alternative combination 6
• Platin/fluoropyrimidine combinations offer higher efficacy and improved quality of life compared to single agents 3
• For HER2-positive tumors (rare in squamous cell carcinoma), trastuzumab should be added to cisplatin/fluoropyrimidine 3

Second-Line and Beyond

Salvage Surgery

• Salvage esophagectomy is indicated for patients with residual or locally recurrent disease after definitive chemoradiotherapy 7, 5
• Judicious patient selection is crucial as salvage surgery carries higher morbidity 5
• Optimal timing and patient selection for salvage surgery remains under investigation 7

Palliative Interventions for Dysphagia

• Esophageal stenting is cost-effective for restoring oral nutrition in obstructive disease 2
• Single-dose 12 Gy intracavitary brachytherapy may provide better long-term dysphagia relief than stenting 2

Emerging Therapies

• Immune checkpoint inhibitors show promise and are expected to demonstrate synergistic effects with chemoradiotherapy 6, 7
• Docetaxel/cisplatin/5-FU (DCF) is a promising candidate regimen showing excellent local control and pathological remission rates 5

Critical Treatment Selection Factors

Patient fitness determines treatment intensity:

• Medically operable patients (excluding those with poor performance status, respiratory insufficiency, portal hypertension, renal insufficiency, recent myocardial infarction, or advanced peripheral arterial disease) should receive multimodality therapy 1
• Postoperative complications are more severe with chemoradiotherapy compared to chemotherapy alone, requiring careful assessment of patient tolerance 1

Tumor location influences approach:

• Upper third esophageal tumors are more suitable for definitive chemoradiotherapy with surveillance and salvage surgery if needed 3
• Lower esophageal tumors may be managed similarly to gastroesophageal junction adenocarcinomas 1

Response Evaluation Protocol

Response assessment should include:

• Symptomatic evolution 3
• Esophagogram 3
• Endoscopy with biopsies 3
• CT scan 3

Common Pitfalls

• Avoid surgery alone for T3-T4 disease, as complete resection is not possible in approximately 30% of pT3 and 50% of pT4 tumors 2
• Do not routinely perform surgery in patients achieving clinical complete response to chemoradiotherapy, as approximately 50% achieve complete pathologic response and surgery may not add benefit 4
• Late toxicities from chemoradiotherapy can be lethal even years after achieving complete response; modified regimens at 50.4 Gy reduce late toxicities without reducing efficacy 7
• Inadequate lymphadenectomy compromises staging and outcomes; ensure at least 16-18 nodes are examined 4