medwireNews: A single cycle of adjuvant bleomycin, etoposide, and cisplatin may be enough to reduce rates of malignant recurrence in men with high-risk, stage I, nonseminomatous or combined testicular germ cell tumors, suggests the 111 study.
“Despite the unavoidable limitation of being a single-arm study, 111 achieved its aim, with a malignant failure rate of just 1.3% and very low levels of serious short-term and delayed toxicity,” say Robert Huddart, from The Institute Of Cancer Research in London, UK, and co-investigators.
They believe that the phase 3 trial confirms the single-cycle regimen as the new standard adjuvant therapy for this patient population.
The study authors explain that the current standard post-orchiectomy management options in Europe for these patients are either adjuvant chemotherapy with two cycles of bleomycin, etoposide 360 mg/m2 plus cisplatin (BE360Px2) or surveillance with three cycles of bleomycin, etoposide 165 mg/m2, and cisplatin 50 mg/m2 (BE500Px3) on relapse.
Noting the importance of exposing patients to the minimum treatment required, the team sought to confirm the findings from smaller studies showing the efficacy of just one cycle of bleomycin, etoposide 165 mg/m2, and cisplatin 50 mg/m2 (BE500Px1).
Huddart and colleagues note that “[t]he pragmatic decision to rely on a nonrandomised trial design was made in light of the rarity of the patient group under study and the low expected event rate in the study population.”
Among the 236 trial participants who received BE500Px1 over a 3-week period, there were four cases of malignant relapse based on histologic examination and/or rising tumor markers over a median follow-up of 49 months, occurring at 6, 7, 13, and 27 months after enrollment, respectively.
Therefore, the 2-year malignant relapse rate was 1.3%, with 95% confidence intervals of 0.3–3.7% using the exact binomial probabilities method and 0.4–4.0% using the Kaplan–Meier method.
This meant that a 2-year rate of 5% or more could be excluded with both methods, where the 5% cutoff was chosen as an acceptable relapse rate after BE500Px1 based on existing data and the experience of key experts and trial collaborators, report the researchers in European Urology.
The rate of malignant relapse at the 4-year mark was 1.8%, and the 2-year relapse-free and overall survival rates were 97% and 99%, respectively.
Forty-one percent of patients experienced at least one acute emergent adverse event (AE) of grade 3 or 4 within 4 weeks of BE500Px1 treatment, with neutropenia (32%), leukopenia (17%), and febrile neutropenia (6.8%) the most common AEs of these grades.
The incidence of late emergent grade 3–4 AEs was low, say Huddart et al, with rates of 2.6% at 2–12 months, 0.9% at 18–24 months, and 1.6% after 24 months.
They also emphasize that “any toxicity developing after BE500Px1 has to be balanced against the greater risk of toxicity with the higher doses that would be given to the 50% of patients expected to relapse on a surveillance programme.”
The team adds: “Post-treatment fertility indices will be reported separately, but on the basis of published data following BE360Px2 it is unlikely that serious impairment of spermatogenesis will be demonstrated following one cycle.”
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