Prof. Robert Huddart
Standard post-orchiectomy treatment in the United Kingdom involves either surveillance followed at recurrence by three cycles of bleomycin, etoposide (500 mg/m2), and cisplatin (BE500P), or two cycles of adjuvant bleomycin, etoposide (360 mg/m2), and cisplatin (BE360P). The adjuvant approach has a 2-year recurrence-free rate of 98%, but delivers 33% more chemotherapy, while the lower chemotherapy exposure requires intensive surveillance.
“Evidence has begun to accumulate that maybe one cycle is enough,” said Robert Huddart, PhD, of the Institute of Cancer Research, in London, during an Oral Abstract Session on February 17. Using only one cycle, he said, would reduce the burden of chemotherapy on the patient and the health care resource usage.
The study was designed as a single-arm phase III trial because there are robust data available on the two-cycle BE360P option and on surveillance, and a non-inferiority trial comparing the different chemotherapy approaches would be prohibitively large. The trial enrolled 246 patients at 33 sites in the United Kingdom (10 were found ineligible following registration and were replaced) with histologically proven NSGCTT or mixed germ cell tumors of the testis, with vascular invasion of the primary tumor into the testicular veins or lymphatics. All patients were over 16 years of age, and the median age was 31 years. Almost all patients had a performance status of 0 (96.2%). The cohort was split almost evenly between patients with NSGCTT and patients with mixed histology (53.7% vs. 46.3%).
Patients received bleomycin 30,000 IU on days 1 or 2, 8, and 15; cisplatin 50 mg/m2 on days 1 and 2; and etoposide 165 mg/m2 on days 1, 2, and 3. They also received supportive care including prophylactic G-CSF and antibiotics; Prof. Huddart noted that the investigators “were keen to try to minimize the risk of neutropenic sepsis.”
The patients were followed for a median of 39.9 months. At 2 years, there were three malignant recurrences, for a 2-year event rate of 1.3% (95% CI [0.4%, 4.0%] and a malignant recurrence-free survival rate of 98.7%. Prof. Huddart said that based on the confidence interval, they can exclude a malignant recurrence rate of 5.0% at 2 years, which was the study’s target.
Overall survival at 2 years was 99.0%. There were three deaths during the study, including one from testicular cancer and one from a second primary cancer.
Prof. Huddart said the toxicity profile was as expected. Among 233 patients with available data regarding toxicity at end of the chemotherapy cycle, 32.2% experienced grade 3/4 neutropenia. Other common acute grade 3/4 toxicities included leukopenia(16.3%), febrile neutropenia (6.4%), and thrombocytopenia (3.4%).
Most patients (90.9%) experienced some delayed toxicity (6-24 months), though most were either grade 1 (59.4%) or grade 2 (28.0%). Dyspnoea, ear and labyrinth disorders, and psychiatric disorders were among the more common delayed toxic effects, and Prof. Huddart said the effects on hearing are the only concerning late issues.
“Adoption of this protocol would reduce the overexposure to chemotherapy in a young patient population,” Prof. Huddart said.
Noel Clarke, MBBS, FRCS (Eng), ChM, FRCS (Urol), of the Christie Hospital NHS Foundation Trust, in the United Kingdom, was the Discussant for this abstract, and called it an “excellent study.” He agreed that the BEP regimen is quite toxic, and reducing exposure is useful, but there are reasons to avoid simply giving this to every patient. There is still some toxicity with the single cycle, and there is some proportion of patients who would never fail and require chemotherapy after being treated with surveillance.
Still, Prof. Clarke noted that “there is a price to pay if one goes on to surveillance, fails, and requires three cycles of BEP.” The single-cycle option appears safe and effective, and Prof. Clarke said this study makes it clear that two cycles of adjuvant therapy are unnecessary.