Long-term outcomes and late effects for childhood and young adulthood intracranial germinomas

Germ cell tumors (GCTs) are broadly classified as gonadal and extragonadal. Extragonadal GCTs comprise 5% of all GCTs.1 It is hypothesized that these tumors either develop from abnormal migration of primordial germ cells, which originate in the embryonic yolk sac and migrate to the gonads during fetal development, or from misdirected pluripotent embryonic cells.2 The CNS is one of the most common sites of extragonadal GCTs.3,4 Approximately half of the CNS GCTs occur in the pineal gland. The incidence of CNS GCTs is rare at 0.1 per 100 000 person-years in the United States, and they represent 3%–5% of CNS tumors in the pediatric population.5 Males are more commonly affected than females, with an incidence ratio of 3:1.2 There are 2 broad histological categories of CNS GCTs: germinomatous and nongerminomatous. Germinomatous GCTs (GGCTs) are histologically analogous to seminoma of the testes and dysgerminoma of the ovaries. Nongerminomatous GCTs (NGGCTs) comprise a heterogeneous group of tumors that include embryonal carcinoma, choriocarcinoma, teratoma, and mixed germ cell tumor. Histology serves as an important prognostic factor. The 5-year overall survival (OS) for GGCTs is >90%. NGGCTs have 5-year OS ranging widely from 8% to 94% with an average of ∼75%.6,7 However, regardless of histology, the intent of treatment is cure, as these tumors are very sensitive to radiation and chemotherapy. Radiation plays a central role in the treatment paradigm for this disease and can be associated with late treatment-related toxicities such as secondary neoplasms, endocrine deficiencies, and stroke. Historically, all of these tumors were treated with craniospinal radiation; however, the current standard of care for localized GGCTs is whole ventricular radiation with a boost to the primary. Craniospinal radiation continues to be a part of treatment for those who have disseminated disease and those with NGGCTs. A current Children's Oncology Group (COG) trial is examining the efficacy of reducing the radiation dose in patients with GGCTs who have complete response to chemotherapy because neoadjuvant chemotherapy has shown promising results in phase II trials.8–10 Chemotherapy alone, however, has been shown to result in inferior survival outcomes, and therefore radiation remains the cornerstone of curative therapy.11 Given the favorable prognosis of GCTs compared with other pediatric CNS tumors, long-term treatment-related toxicities are especially relevant. The Childhood Cancer Survivor Study (CCSS), which characterized the mortality experience of 20 483 survivors, shows that with increasing years of follow-up, there is an increase in mortality attributable to treatment-related causes (eg, secondary neoplasms, cardiac death, pulmonary death, and infection) and a decrease in mortality attributable to primary cancer or recurrence.12,13 A Surveillance, Epidemiology, and End Results (SEER)-based analysis of mortality in 5-year survivors of pediatric CNS tumors also showed that survivors are at an increased risk for death due to cardiovascular disease, cerebrovascular disease, and secondary neoplasms.14 However, data specifically related to late effects in CNS GCT survivors are very limited. To our knowledge, there have not been any analyses of late causes of mortality in pediatric and young adult CNS GCTs. Our goal was to assess the causes of mortality and late effects in 5-year survivors of pediatric and young adult CNS GCTs.