What is the recommended treatment for a young patient with Stage 1 Grade 3 testicular cancer?

Treatment of Stage I Grade 3 Testicular Non-Seminomatous Germ Cell Tumor

For a young patient with Stage I Grade 3 (high-risk) testicular non-seminomatous germ cell tumor after orchiectomy, adjuvant chemotherapy with one cycle of BEP (bleomycin, etoposide, cisplatin) is the recommended treatment, as it achieves a 2-year recurrence rate of only 1.3% and significantly outperforms both surveillance and surgical approaches. 1

Risk Stratification and Treatment Rationale

Stage I non-seminomatous germ cell tumors are classified by vascular invasion status into low-risk (20% relapse rate without vascular invasion) versus high-risk (40-50% relapse rate with vascular invasion present). 2 Grade 3 histology combined with Stage I disease places this patient in the high-risk category requiring adjuvant intervention rather than surveillance alone.

Why Adjuvant Chemotherapy Over Surveillance

• Surveillance carries unacceptable relapse risk: High-risk Stage I disease has a 40-50% relapse rate with surveillance alone, requiring salvage chemotherapy in nearly half of patients. 2
• One cycle BEP achieves superior outcomes: The 111 Study (largest prospective trial, n=246) demonstrated a 2-year malignant recurrence rate of only 1.3% (95% CI 0.3-3.7%) with one cycle of BEP in high-risk patients. 1
• Surveillance is reserved for low-risk disease: Guidelines explicitly state surveillance is standard only for low-risk disease (without vascular invasion). 2

Why One Cycle BEP Over Two Cycles

One cycle of BEP (bleomycin 30,000 IU on days 1,8,15; etoposide 165 mg/m² days 1-3; cisplatin 50 mg/m² days 1-2) is now the preferred adjuvant regimen based on the most recent high-quality evidence. 1

• The 111 Study showed one cycle achieves comparable efficacy to historical two-cycle regimens (1.3% vs 1-3% recurrence rates) while reducing chemotherapy exposure by 50%. 1
• Only 4 of 236 evaluable patients experienced malignant recurrence, and 3 of these 4 were cured with salvage therapy. 1
• Efficacy appears similar between one and two cycles of BEP according to ESMO guidelines. 2
• The Hellenic Cooperative Oncology Group study (n=142) using two cycles showed only 1 relapse over 79 months median follow-up, but this predates the 111 Study demonstrating one cycle sufficiency. 3

Why Chemotherapy Over Retroperitoneal Lymph Node Dissection (RPLND)

The German AUO trial AH 01/94 (n=382) definitively established chemotherapy superiority over RPLND:

• Recurrence rates: 1% with one cycle BEP versus 7.9% with RPLND (P=0.0011). 4
• Hazard ratio: 7.937-fold higher risk of recurrence with RPLND compared to chemotherapy. 4
• Two-year recurrence-free survival: 99.46% with chemotherapy versus 91.87% with surgery. 4
• RPLND is reserved only for exceptional circumstances when chemotherapy is contraindicated. 2

Specific Treatment Protocol

Pre-Treatment Requirements

• Sperm cryopreservation must be offered before chemotherapy, as BEP can impair fertility. 2
• Baseline assessment: complete blood count, renal function (creatinine, electrolytes), liver function tests. 2
• Tumor markers (AFP, β-HCG, LDH) should be measured pre-orchiectomy and monitored until normalization (AFP half-life 5-7 days, β-HCG half-life up to 3 days). 2
• Baseline pulmonary function testing should be considered given bleomycin pulmonary toxicity risk. 2

BEP Chemotherapy Regimen (One Cycle)

Administer as a single 3-week cycle: 1

• Bleomycin: 30,000 IU IV on days 1,8, and 15
• Etoposide: 165 mg/m² IV on days 1,2, and 3 (total 495 mg/m² per cycle)
• Cisplatin: 50 mg/m² IV on days 1 and 2 (total 100 mg/m² per cycle)
• G-CSF prophylaxis should be administered to reduce febrile neutropenia risk. 3, 1
• Antibacterial prophylaxis is recommended. 1

Monitoring During Chemotherapy

• Renal function and electrolytes must be monitored before each cisplatin dose due to cumulative nephrotoxicity. 5
• Watch for bleomycin pulmonary toxicity (occurs in 6-10% of patients), particularly in patients >40 years, smokers, or those with baseline lung disease. 2
• Grade 3-4 febrile neutropenia occurs in approximately 6.8% of patients despite G-CSF prophylaxis. 1

Post-Treatment Surveillance Protocol

Intensive surveillance is mandatory for at least 5 years: 2

• Years 1-2: History, physical examination, and tumor markers (AFP, β-HCG, LDH) every 3-4 months; chest X-ray every 6 months; abdominal/pelvic CT at 3 and 12 months. 2
• Year 3: Clinical evaluation and markers every 6 months; abdominal CT annually. 2
• Years 4-5: Clinical evaluation and markers every 6 months. 2
• Years 6-10: Annual clinical evaluation and markers. 2

Management of Recurrence

If recurrence occurs despite adjuvant chemotherapy (1.3% risk):

• Stage IIA-IIB relapse: Three cycles of BEP chemotherapy. 2
• Stage IIC-III relapse: Four cycles of BEP for intermediate prognosis or entry into clinical trial for poor prognosis disease. 2, 6
• All recurrences are highly salvageable with appropriate second-line therapy. 1

Critical Caveats

• Do not use carboplatin-based regimens: The randomized trial comparing carboplatin/etoposide/bleomycin (CEB) to cisplatin/etoposide/bleomycin (PEB) showed significantly higher relapse rates with carboplatin (32% vs 13%, P=0.03), including three late relapses >2 years. 7 Carboplatin cannot replace cisplatin in non-seminomatous disease.

• Bleomycin contraindications: If the patient has reduced lung capacity, emphysema, heavy smoking history, or age >40 years, consider omitting bleomycin and using EP (etoposide/cisplatin) instead, though this is less well-studied in the adjuvant setting. 2

• Avoid treatment delays: Chemotherapy must be administered without delay or dose reduction at 21-day intervals to maintain efficacy. 5

• Stage I seminoma is different: This recommendation applies only to non-seminomatous or mixed germ cell tumors; pure seminoma Stage I has different treatment algorithms favoring surveillance or single-agent carboplatin. 2, 8