Early Identification of Therapeutic Failure in Nonseminomatous Germ Cell Tumors by Assessing Serum Tumor Marker Decline During Chemotherapy: Still Not Ready for Routine Clinical Use
Authors: Guy C. Toner
Journal: Journal of Clinical Oncology (2004)

Serum tumor markers play a vital role in the excellent outcomes now expected for men with testicular cancer. The relative survival for all cases of testicular cancer is approximately 96% at 5 years. Serum tumor markers contribute to these excellent outcomes by aiding diagnosis, permitting surveillance alone after orchiectomy as a principal strategy for early-stage nonseminoma, determining prognosis (and therefore optimal treatment) for patients requiring chemotherapy, and allowing early identification of relapse in the post-treatment setting. In this issue of the Journal of Clinical Oncology, Fizazi et al report an analysis of predicted time to normalization of serum tumor markers during the first cycle of chemotherapy in men with metastatic nonseminomatous germ cell tumors (NSGCT). The major serum tumor markers, alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG), were considered individually and jointly. Based on a marker value measured before and after the first cycle of chemotherapy, the expected time to reach normal marker levels was predicted, assuming an exponential decline. Patients who had a prolonged predicted time to normal marker values (AFP 9 weeks or HCG 6 weeks) had inferior progression-free and overall survival compared with the remaining patients. These differences were predominantly seen in those patients with a poor prognosis as classified by the International Germ Cell Consensus Classification (IGCCC). The prognostic value was confirmed in multivariate analyses in this poor-prognosis subgroup. The authors conclude that estimating predicted time to marker normalization is a valuable prognostic tool and could potentially be used to determine an early change in therapy for those patients with poor expected outcomes with initial standard therapy. Indeed, the authors report that this methodology will be incorporated into a multi-institutional clinical trial for poor-prognosis NSGCT, in which patients with a prolonged predicted time to normalization will be randomly assigned to either continue standard chemotherapy or switch to a more intensive regimen. Failure of marker values to return to normal after orchiectomy or chemotherapy indicates residual or refractory malignancy (unless another cause is identified). Conversely, values that rapidly return to normal portend a good prognosis. The analysis of Fizazi et al aims to further refine our ability to use marker values during chemotherapy to improve identification of patients destined to experience treatment failure. This is potentially of greatest utility in cases that do not fit into either of the categories above, ie, those with marker values that reach normal levels greater than 2 to 3 weeks after starting therapy. A brief review of marker biology is warranted. After complete resection of germ cell tumors, marker levels reduce in an exponential fashion with a half-life for clearance of AFP and HCG from the circulation of approximately 5 to 7 days and 1 to 2 days, respectively. After chemotherapy, an increase in marker levels may be seen in the first 7 to 10 days, presumably because of release of marker proteins from lytic neoplastic cells. This increase, or marker surge, is unpredictable, as it only occurs in some cases and the degree of increase is variable. A number of studies of marker decline after chemotherapy have suggested that AFP values should JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 19 OCTOBER 1 2004