The approach to treatment of high-risk, clinical stage I, nonseminomatous or combined germ cell tumors of the testis is not written in stone. Orchiectomy followed by surveillance or chemotherapy with two cycles of bleomycin, etoposide, and cisplatin (BEP) is a favored approach by most experts. A new study (the 111 trial) presented at the 2017 Genitourinary Cancers Symposium found that one cycle of BEP was safe and as effective as two, reducing patients’ exposure to this potentially toxic chemotherapy.1
This study adds to mounting evidence in favor of one cycle of BEP in high-risk patients.— Robert Huddart, MBBS, MRCP, FRCR, PhD
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“This study adds to mounting evidence in favor of one cycle of BEP in high-risk patients,” explained lead author Robert Huddart, MBBS, MRCP, FRCR, PhD, on behalf of the 111 Trial Management Group. Prof. Huddart is Consultant in Clinical Oncology at the Royal Marsden Hospital, London.
“The 111 trial is the biggest formal, prospective trial to date investigating one cycle of adjuvant BEP in high-risk stage I nonseminomatous or combined germ cell tumors of the testis. One cycle is safely deliverable, and the 2-year recurrence rate is similar to that seen with two cycles of BEP. Adopting one cycle as the standard would reduce overall exposure to chemotherapy in this young patient population,” he told listeners.
Nonseminomatous or combined germ cell tumor of the testis is one of the most common cancers in men aged 20 to 39 years. Fifty percent of cases are nonseminomatous, and 60% to 70% of patients present with stage I disease. Lymphovascular invasion defines a high-risk cohort, with a 40% to 50% chance of recurrence on follow-up, Prof. Huddart explained.
Study Details
The single-arm 111 trial evaluated 1 cycle of BEP as adjuvant chemotherapy in 246 patients with high-risk (ie, exhibiting lymphovascular invasion) stage I nonseminomatous or combined germ cell tumors of the testis recruited at 33 UK sites. All patients received antibiotic prophylaxis and growth factor support with granulocyte-colony stimulating factor.
Ten patients dropped out of the study. More than 20% of patients enrolled in the study were over 40 years old. More than 90% were followed for more than 2 years at the time of data cutoff. Median follow-up was 39 months.
Two types of testicular cancer recurrence were noted: malignant recurrences, retreated with chemotherapy, and differentiated teratoma, managed by surgical resection. Regarding the latter, Prof. Huddart made the argument that “teratoma does not represent a true postchemotherapy relapse but is the consequence of successful treatment of subclinical malignant nonseminomatous germ cell tumors.” The goal of this novel nonrandomized phase III trial was to ensure that the 2-year malignant recurrence–free rate was at least 95%.
Major Outcomes
Acute toxicity with one cycle of BEP was as expected, with the majority of adverse events being grade 3 or 4 myelosuppression. Grade 3 and 4 adverse events included neutropenia (32.2%) and leukopenia (16.3%), but the rate of febrile neutropenia, at 6.4%, was low. The rates of all nonhematologic toxicities were low.
The major delayed toxicities of concern associated with this chemotherapy are ear and labyrinth disorders affecting hearing: 20% of patients developed grade 2 ear and labyrinth disorders, and 1% had grade 3 disorders.
The rate of malignant recurrence was 1.3%, which was well below the target of < 5%. The rate of differentiated teratoma recurrence was also 1.3%, and all teratomas were completely resected. Thus, the total recurrence rate was 2.6% in the first 2 years of follow-up.
One patient developed a malignant recurrence after data cutoff, to bring the malignant recurrence rate to 1.8%, which was still considerably lower than the < 5% target. The malignant recurrence–free rate was 97%, and the overall survival rate at 2 years was 99%.
Robust Evidence
Prof. Huddart cited four other studies to put these data in context. Across those studies plus study 111, there were 16 malignant recurrences in 1,004 patients.
“One cycle of BEP reduces the rate of malignant recurrences to 7.5% of the expected level,” he noted, adding, “This study provides robust evidence to inform the decision between adjuvant chemotherapy and intensive surveillance.” ■
Disclosure: Prof. Huddart is a partner in the Cancer Clinic London Limited Liability Partnership and has had a consulting or advisory role with Astellas and Merck Sharp & Dohme. He has received research funding from Janssen, Lilly, and Roche.
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