What is the role of neoadjuvant chemotherapy in the management of testicular cancers?

Neoadjuvant Chemotherapy Has No Established Role in Testicular Cancer Management

Neoadjuvant chemotherapy is not a standard treatment approach for testicular cancer, as chemotherapy is administered after orchiectomy (adjuvant) or as primary treatment for metastatic disease, not before initial surgical management. The fundamental treatment paradigm for testicular cancer begins with radical inguinal orchiectomy for diagnosis and local control, followed by risk-stratified management based on stage, histology, and tumor markers 1.

Why Neoadjuvant Chemotherapy Is Not Used

Orchiectomy Must Come First

• Radical inguinal orchiectomy is the mandatory initial step for both seminoma and non-seminoma, providing definitive histologic diagnosis, accurate staging information, and local tumor control 1.
• Tumor markers (AFP, HCG, LDH) must be measured before orchiectomy and followed until normalization to guide subsequent treatment decisions 1.
• Delaying orchiectomy to administer chemotherapy first would compromise diagnostic accuracy and staging, as the primary tumor provides critical pathologic information including histologic subtype, vascular invasion, and risk stratification 1.

The Single Exception: Neoadjuvant Carboplatin Before Radiotherapy

• One narrow investigational approach exists: neoadjuvant carboplatin before radiotherapy for stage IIA seminoma may reduce relapse rates according to a single-center pilot study, but this strategy requires further validation and is not standard practice 1.
• This represents carboplatin given before radiotherapy (not before orchiectomy), and remains experimental with insufficient evidence for routine recommendation 1.

Standard Treatment Paradigms Instead

For Clinical Stage I Disease

• Seminoma Stage I: Surveillance is the preferred strategy (99% survival regardless of approach), with adjuvant carboplatin (AUC 7 × 1 cycle) or radiotherapy reserved for select high-risk patients who cannot comply with surveillance 1, 2.
• Non-Seminoma Stage I with high risk (vascular invasion): Two cycles of adjuvant BEP chemotherapy after orchiectomy reduces relapse from 40-50% to <5%, representing true adjuvant (not neoadjuvant) therapy 1, 3, 4.

For Stage II Disease

• Stage IIA/B Seminoma: First-line chemotherapy (BEP × 3 cycles or EP × 4 cycles) or radiotherapy are standard options after orchiectomy, not before 1.
• Stage IIA Non-Seminoma: Nerve-sparing RPLND or primary chemotherapy (BEP × 3 cycles) after orchiectomy, with treatment decisions based on marker status and lymph node size 1, 5.

For Advanced/Metastatic Disease

• Primary chemotherapy with BEP is standard treatment for stage IIB/IIC and stage III disease, administered after orchiectomy and staging are complete 1.
• Good prognosis patients receive 3 cycles of BEP; intermediate/poor prognosis patients receive 4 cycles of BEP 1.

Critical Pitfalls to Avoid

Never Delay Orchiectomy

• Attempting neoadjuvant chemotherapy before orchiectomy would be considered a deviation from standard care, as it delays definitive diagnosis and local control without any demonstrated benefit 1.
• Even in advanced metastatic disease with life-threatening complications, orchiectomy should be performed as soon as medically feasible, typically after initial chemotherapy cycles if the patient is unstable 1.

Distinguish Adjuvant from Neoadjuvant

• The term "adjuvant chemotherapy" in testicular cancer specifically refers to treatment given after orchiectomy to prevent relapse in high-risk stage I disease 1, 3, 4.
• This is fundamentally different from neoadjuvant therapy, which would precede definitive surgical management 6.

Marker-Positive Disease Requires Immediate Systemic Therapy

• If tumor markers remain elevated or rise after orchiectomy, this indicates metastatic disease (clinical stage IS) requiring immediate chemotherapy as primary treatment for metastatic disease, not as neoadjuvant therapy 1, 5.

The Evidence Base

The extensive guideline evidence from NCCN, ESMO, and EAU consistently demonstrates that orchiectomy precedes all other treatment modalities 1. Historical studies establishing cisplatin-based chemotherapy as curative for testicular cancer all utilized chemotherapy after orchiectomy, either as adjuvant therapy for high-risk stage I disease or as primary treatment for advanced disease 7, 4. No randomized trials have evaluated true neoadjuvant chemotherapy before orchiectomy, and such an approach would be considered investigational at best and potentially harmful by delaying definitive diagnosis and local control.