The 111 Study: A Single-arm, Phase 3 Trial Evaluating One Cycle of Bleomycin, Etoposide, and Cisplatin as Adjuvant Chemotherapy in High-risk, Stage 1 Nonseminomatous or Combined Germ Cell Tumours of the Testis

Abstract

Background: Standard management in the UK for high-risk stage 1 nonseminoma germ cell tumours of the testis (NSGCTT) is two cycles of adjuvant bleomycin, etoposide (360 mg/m²), and cisplatin (BE₃₆₀P) chemotherapy, or surveillance.

Objective: To test whether one cycle of BE₅₀₀P achieves similar recurrence rates to two cycles of BE₃₆₀P.

Design, setting, and participants: A total of 246 patients with vascular invasion-positive stage 1 NSGCTT or combined seminoma + NSGCTT were centrally registered in a single-arm prospective study.

Intervention: One cycle comprising bleomycin 30000 IU on days 1, 8, and 15, etoposide 165 mg/m² on days 1-3, and cisplatin 50 mg/m² on days 1-2, plus antibacterial and granulocyte colony stimulating factor prophylaxis.

Outcome measurements and statistical analysis: The primary endpoint was 2-yr malignant recurrence (MR); the aim was to exclude a rate of ≥5%. Participants had regular imaging and tumour marker (TM) assessment for 5 yr.

Results and limitations: The median follow-up was 49 mo (interquartile range 37-60). Ten patients with rising TMs at baseline were excluded. Four patients had MR at 6, 7, 13, and 27 mo; all received second-line chemotherapy and surgery and three remained recurrence-free at 5 yr. The 2-yr MR rate was 1.3% (95% confidence interval 0.3-3.7%). Three patients developed nonmalignant recurrences with localised teratoma differentiated, rendered disease-free after surgery. Grade 3-4 febrile neutropenia occurred in 6.8% of participants.

Conclusions: BE₅₀₀P is safe and the 2-yr MR rate is consistent with that seen following two BE₃₆₀P cycles. The 111 study is the largest prospective trial investigating one cycle of adjuvant BE₅₀₀P in high-risk stage 1 NSGCTT. Adoption of one cycle of BE₅₀₀P as standard would reduce overall exposure to chemotherapy in this young population.

Patient summary: Removing the testicle fails to cure many patients with high-risk primary testicular cancer since undetectable cancers are often present elsewhere. A standard additional treatment in Europe is two cycles of chemotherapy to eradicate these. This trial shows one cycle has few adverse effects and comparable outcomes to those seen with two cycles.

Keywords: Adjuvant therapy; BEP; Chemotherapy; NSGCTT; Phase III trial; Surveillance; Testicular cancer.

Fig. 1

CONSORT diagram. * Ineligibility confirmed by central review. Patients followed-up but data are not included within the primary intention-to-treat analysis in accordance with the statistical analysis plan.

Fig. 2

Recurrence rate estimated using the Kaplan-Meier method.