What chemotherapy regimens are recommended for unresectable or borderline‑resectable thymoma (including neoadjuvant and adjuvant use) and what special considerations are needed for patients with myasthenia gravis?

Chemotherapy for Unresectable or Borderline-Resectable Thymoma

For unresectable or borderline-resectable thymoma, cisplatin-based combination chemotherapy is the standard neoadjuvant approach, with cisplatin/doxorubicin/cyclophosphamide (CAP) or cisplatin/etoposide being the preferred regimens, followed by surgical reassessment and postoperative radiotherapy. 1

Neoadjuvant Chemotherapy Regimens

First-Line Regimens

• Cisplatin/doxorubicin/cyclophosphamide (CAP) is the preferred combination for neoadjuvant therapy in locally advanced thymoma 1
• Cisplatin/etoposide is an equally acceptable alternative regimen 1
• Administer 2-4 cycles before reimaging to reassess tumor resectability 1
• Polychemotherapy is superior to single-agent therapy 1

Treatment Sequencing

• For small treatment volumes: concurrent chemoradiotherapy is recommended 1
• For bulky tumors: sequential therapy with chemotherapy first, followed by radiation, is preferred 1
• Resection may be performed before radiotherapy in the sequential approach 1

Stage-Specific Recommendations

Stage III (Locally Advanced)

• Neoadjuvant chemotherapy is standard for initially unresectable disease 1
• After chemotherapy response, surgery should be offered if complete resection becomes achievable 1
• If complete resection remains impossible at thoracotomy, maximal debulking with clip placement for residual tumor is recommended 1
• Postoperative radiotherapy (55-60 Gy) is mandatory after resection 1

Stage IVA (Pleural/Pericardial Involvement)

• Same neoadjuvant approach as Stage III applies 1
• Surgery is only recommended if pleural and pericardial metastases can be completely resected 1
• For extensive bilateral pleural disease not amenable to resection, chemotherapy with or without sequential radiotherapy is the standard 1

Adjuvant Therapy

Post-Resection Management

• Adjuvant radiotherapy is recommended after complete resection of Stage III/IVA thymoma (50-54 Gy for R0, 60 Gy for R1/R2 resection) 1
• Adjuvant chemotherapy is NOT routinely recommended after R0-R1 resection of thymoma 1
• Adjuvant chemoradiotherapy may be considered after debulking/R2 resection (cisplatin/etoposide with 60 Gy) 1

Definitive Therapy for Unresectable Disease

When Surgery Remains Impossible

• Chemotherapy concurrent with or sequential to radiotherapy is the standard approach 1
• Cisplatin/anthracycline-containing regimens are most commonly used 1
• Carboplatin/paclitaxel or cisplatin/etoposide can be combined with radiation therapy 2
• Total radiation dose of 60-66 Gy is recommended for definitive treatment 1

Special Considerations for Myasthenia Gravis

Critical Management Points

• Appearance of myasthenia gravis symptoms during follow-up should trigger immediate evaluation for recurrence, as autoimmune syndromes can herald disease relapse 1
• Systematic immunological assessment including anti-acetylcholine receptor antibodies should be performed at baseline 3, 4
• Complete blood count, serum protein electrophoresis, and anti-nuclear antibodies should be obtained 3, 4

Chemotherapy Safety Concerns

• Immune checkpoint inhibitors carry significantly higher toxicity risks in thymic epithelial tumors compared to other malignancies 2
• Pembrolizumab causes grade 3-4 myocarditis in 5-9% of thymic carcinoma patients 2
• Overall severe immune-related adverse events occur in 15% of patients 2
• Checkpoint inhibitors are NOT recommended for thymoma due to these risks 2

Common Pitfalls to Avoid

• Do not use adjuvant chemotherapy routinely after complete resection—it is not supported by evidence 1
• Do not assume unresectability without neoadjuvant therapy trial—chemotherapy can convert 60-77% of patients to resectable status 5
• Do not perform bilateral phrenic nerve resection due to severe respiratory morbidity 1
• Do not use fine-needle aspiration for diagnosis—core-needle or surgical biopsy is required before neoadjuvant therapy 1, 3
• Do not use immunotherapy as standard treatment for thymoma given the high toxicity profile 2

Response Assessment and Surgical Timing

• Reimaging should be performed after 2-4 cycles of neoadjuvant chemotherapy 1
• Expected response rates to neoadjuvant chemotherapy range from 66-77% partial response, with 11% complete response 5
• Complete resection rates improve to 62.5% after neoadjuvant therapy in initially unresectable disease 5
• Surgical clips should be placed to mark residual tumor for radiation planning 1