Drug-resistance patterns assessed from tumor marker analysis

We analyzed the levels of the tumor markers alpha-fetoprotein and human chorionic gonadotropin during the course of treatment in 19 patients with nonseminomatous germ cell tumors. We calculated the fractional tumor kill at each cycle using assumptions of exponential tumor growth and exponential marker decay and assumptions assuring that marker production reflects the size of the clonogenic tumor. The observed pattern of decrease was compared with three theoretical models. The first (Skipper) assumes that sensitive and resistant populations are present at the beginning of treatment. The second (Goldie and Coldman) assumes an initially sensitive population with mutation causing subsequent treatment resistance. Both models, under a wide range of parameter values, predict a much more rapid decrease in fractional tumor kill per treatment cycle than was observed. A model in which there are four clones of differing sensitivity at the start of treatment was able to adequately describe the observed time course of tumor killing.