Two cycles of adjuvant carboplatin for clinical stage 1 testicular seminoma in New Zealand centres: A retrospective analysis of efficacy and long‐term events

Abstract Background Adjuvant carboplatin reduces relapse risk in clinical stage 1 (CS1) seminoma, though there is a paucity of long‐term safety data. Aim Our objective was to report long‐term outcomes of two cycles of adjuvant carboplatin dosed at area under the time–concentration curve (AUC) of 7. Methods and results We performed a retrospective analysis on treatment and outcomes of patients with CS1 seminoma who received adjuvant carboplatin from 2000 to 2016 at our centres in the Midland Region, New Zealand. Of 159 patients, median age 39 years, 153 received two cycles of carboplatin: 147 dosed at AUC7 and 6 at AUC6. Six patients had one cycle of carboplatin AUC7. One patient relapsed at 22 months and died of bleomycin pneumonitis 2 months after achieving a complete response with BEP chemotherapy. Neither RTI (present in 21.3%) nor tumor size >4 cm (in 43.3%) was predictive of relapse. Median follow‐up was 106 months. At 15 years, outcomes were: relapse‐free survival 99.4%, overall survival 91.4%, disease‐specific survival 100%, subsequent malignant neoplasm rate 7.6%, and second testicular germ cell tumor rate 3.85%. One patient had persistent grade 1 thrombocytopenia at 46 months. Conclusions These data add to the body of evidence that two cycles of carboplatin AUC7 is safe and effective adjuvant treatment for CS1 seminoma.


| INTRODUCTION
Seminoma accounts for more than half of testicular germ cell tumors (GCTs), with peak incidence at 35 to 45 years of age. 1,2 New Zealand Ministry of Health data from 2005 to 2017 show that Maori men have consistently higher rates of testicular cancer than non-Maori men. 3 About 80% of seminoma present with clinical stage 1 (CS1) disease, with an estimated relapse rate of 13% to 20% without adjuvant treatment. 1,4,5 However, the high curability at relapse has led to ongoing debate about whether optimal postoperative management is adjuvant treatment or surveillance. 1,4,6 Historically, adjuvant radiotherapy was given but was associated with increased incidence of subsequent malignant neoplasms (SMNs) and cardiovascular events. 7,8 When the MRC TE19 study showed noninferiority of a single dose of adjuvant carboplatin chemotherapy to radiotherapy, the use of adjuvant radiotherapy diminished. 7,9 3 | RESULTS

| Patient characteristics
There were 159 patients with CS1 seminoma treated with adjuvant carboplatin. Three patients who developed a metachronous contralateral CS1 seminoma within the study period were treated with adjuvant carboplatin on both occasions and are counted twice. Patient and disease characteristics are shown in Table 1. Median follow-up for survival was 106 months (interquartile range 72-159 months). Six patients had a prior history of testicular seminoma at a median of 7 (range 6-10) years earlier, three of whom had received radiotherapy. Three patients had stage S1 due to raised LDH.

| Treatment
One hundred forty-seven of 153 patients (96%) received their planned two cycles of carboplatin AUC7. Six patients received one cycle: one patient by intention, three due to adverse effects (one each of nausea and vomiting, neuropathy, and hypersensitivity reaction),

| Outcomes
One patient aged 47 years at initial diagnosis, of NZ European descent, relapsed in his para-aortic nodes at 22 months following two cycles of carboplatin dosed at AUC7, resulting in actuarial RFS of 99.4% (95% CI 95.6-100) at 15 years ( Figure 1A). He achieved a radiological complete response after four cycles of BEP but unfortunately died 2 months later of bleomycin pneumonitis precipitated by a large

| Subsequent malignant neoplasms
Eleven SMNs occurred, four of which were contralateral seminomas (   Table 3. Relapse rates were 0% to 8.6% vs 0% to 3.3% for one vs two cycles of carboplatin, respectively, though there was considerable heterogeneity of follow-up duration and study populations (  reviews and investigations for up to 10 years. 8  The 15-year non-GCT SMN rate of 7.6% also appears higher than in other studies (0.9-5%), 5,27 although the 95% CI includes zero, and there are differences in follow-up duration. Prospective studies have reported similar SMN rates between patients treated with adjuvant carboplatin compared with surveillance or the general population. 11,18 Our rates of prostate cancer and melanoma (both 0.6%) are lower than those reported by Ruf et al, 5 who noted higher-than-expected incidence (both 1.2%) among patients who had adjuvant treatment. It is likely that the SMN rates reported in our smaller sample size are not significantly different to the other studies.
Despite the national incidence of testicular cancer being higher among Maori, the proportion of Maori men in our study (28.9%) was similar to regional demographic data. 28 Similarly, there was no difference in actuarial survival between Maori and non-Maori patients (log-rank P = .854).
We acknowledge as limitations the retrospective nature of our study, lack of standardized reporting on tumor size and RTI, lack of long-term data on infertility, hypogonadism and cardiovascular disease, and the relatively small sample size.

| CONCLUSION
Our findings further support the efficacy of two cycles of adjuvant carboplatin AUC7 for CS1 seminoma and demonstrate its long-term safety, comparable with other published studies.