Editorial Comment from Dr O'Carrigan and Dr Grimison to Identification of a subgroup with worse prognosis among patients with poor-risk testicular germ cell tumor.

Abstract

The International Germ Cell Cancer Collaborative Group (IGCCCG) consensus classification published in 1997 has been widely accepted as the reference standard for prognostication in metastatic germ cell tumors.1 Adverse clinical features at presentation of non-seminoma histology, mediastinal primary site, presence of non-pulmonary visceral metastases (such as liver, brain, bone), and markedly elevated tumour marker levels (AFP, hCG and LDH) are robust discriminators of prognosis enabling stratification into good, intermediate, and poor prognosis groups. Five-year survival rates for non-seminoma published by the IGCCCG for patients treated between 1975 and 1990 were 92%, 80%, and 48% respectively;1 and in a more contemporary European series of patients treated between 1989 and 2001 improved to 94%, 83% and 71% respectively.2 Significant heterogeneity in outcomes remains, however, particularly within the poor prognosis group, where better prognostic criteria are needed to guide treatment selection and enrolment in clinical trials. In this issue, Kojima et al.3 report a retrospective cohort study of 117 consecutive patients with metastatic germ cell tumours of non-seminoma histology, gonadal primary, and intermediate or poor prognosis by IGCCCG criteria. All patients were treated at one of five university hospitals in Japan between 2000 and 2010. Five-year survival rates for intermediate and poor prognosis patients were 89% and 83% respectively, which is impressive compared to other published series above, but need to be interpreted with caution. In an attempt to identify a subgroup of poor prognosis patients with worse outcomes, Kojima et al. report that patients with both non-pulmonary visceral metastases and markedly elevated tumour markers have a worse prognosis than those patients with only one risk factor. Kojima et al. has provided valuable epidemiological data on contemporary treatment outcomes and survival within five Japanese university hospitals. It is reassuring that excellent outcomes have been achieved, and consistent with the known finding that better outcomes are achieved in institutions treating large numbers of metastatic germ cell tumours.4 Characteristics of such centers include close compliance with chemotherapy schedules and post-chemotherapy surgery.4 However outcomes may have been over-estimated by exclusion of patients with mediastinal germ cell tumours who are known to do worse, and the retrospective study design nature inherently subject to bias. We agree that there is merit in defining subgroups within the poor prognosis IGCCCG classification based on modern cohorts. Previous groups5 have identified clinical characteristics predicting worse outcomes within the poor prognosis group including extra-gonadal primary, pulmonary, liver or CNS metastases. This paper does not present any significant novel data relating to prognostication, as the authors did not explore any variables beyond existing IGCCCG prognostic factors, histology and performance status. Furthermore, the validity of Kojima et al.'s finding that those with multiple adverse IGCCCG risk factors within the poor-risk category do worse is questionable, as 46% of patients were non-evaluable with missing data and patients with extra-gonadal primary tumours, a known risk factor for poor prognosis, were excluded. To identify novel prognostic factors, the greatest gains may lie in correlative biomarker translational studies exploring markers of cisplatin resistance, defects in cell cycle checkpoints, proliferation markers or abnormalities of tumour suppressor or oncogenes. Initial response to treatment such as tumour marker kinetics may also provide valuable risk stratification. Recently published whole exome sequencing data are likely to enhance translational research in germ cell tumours.6 We also support a proposal by the Global Germ Cell Cancer Cooperative Group (G3) to update the IGCCCG classification based on contemporary clinical trial cohorts treated with modern chemotherapy regimens, providing a quality benchmark for survival outcomes in a typically highly curable disease. None declared.