Causes And Patterns Of Mortality In Patients With Lethal Germ Cell Tumor (Gct)

421 Background: Most metastatic GCTs are cured with cisplatin-based chemotherapy. Clinical factors of adverse GCT-specific survival have been identified, however patterns of death are not well-defined and would inform clinical care and biological investigation. Methods: This multi-institutional study pooled data of male pts with death related to GCT from high-volume adult GCT academic centers (Dana-Farber Cancer Institute, Memorial Sloan Kettering Cancer Center, Indiana University) over 20 years (1997-2017). Pts were annotated for site, stage, IGCCC risk, histology, primary therapy and relapse variables (including relapse histology, metastatic (met) burden, salvage and palliative therapies), and detailed cause of GCT death. Cox regression assessed associations with survival. Results: The pooled cohort of 620 pts comprised 90% non-seminoma, 21% mediastinal primary and at diagnosis, 59% were stage III, 64% poor risk; 48% received high-dose chemotherapy plus transplantation. Median survival (OS) from first relapse after metastasis was 12.0 mos. Leading causes of death were chemorefractory GCT (83.1%), secondary somatic malignancy (SSM) arising from teratoma (9.4%), acute toxicity (4.5%), late toxicity (2.3%) and progressive untransformed pure teratoma (0.8%). Late relapse (relapse >2 years after 1st-line therapy) occurred in 11.3% at a median of 5.9 yrs. Of these pts, 1/3 were stage I at initial diagnosis and 75% were good or intermediate risk at met diagnosis, and were more likely to have SSM histology/death vs early relapse. Late relapsing disease (HR 0.48, p<0.0001) and presence of SSM (HR 0.74, p=0.017) were associated with longer OS from first relapse after metastasis. Brain metastasis at any time occurred in 29.8%, associated with poorer OS. Conclusions: Comprehensive characterization of GCT-related death reveals a predominant pattern of mortality marked by de novo metastatic, poor-risk disease with subsequent early relapse and death due to chemorefractory non-teratomatous GCT. By contrast, a subset of pts with late-relapsing disease are more likely to have SSM-teratoma and a protracted clinical course. Lethal late relapses frequently occurred beyond 5 years, emphasizing the importance of long-term follow-up.