Methotrexate for metastatic choriocarcinoma

Gestational choriocarcinoma arises in the uterus from cells that would normally have formed the placenta. Before methotrexate it was nearly always fatal. Most cancers could then be treated only by surgery or radiation. From 1948 Sidney Farber and his colleagues had shown that the antifolates aminopterin and amethopterin, now called methotrexate, produced remissions in children with acute lymphoblastic leukemia, but the remissions did not last.

Roy Hertz, head of the Endocrinology Section at the National Cancer Institute in Bethesda from 1946, had shown in animals that antifolates blocked estrogen-driven growth in the female reproductive tract. Min Chiu Li had trained in medicine in China and came to the United States in 1947; the revolution at home kept him from returning. Treating patients with metastatic melanoma with antifolates in the early 1950s, Li saw a sharp fall in urinary human chorionic gonadotropin (hCG). When Hertz heard of it, he suspected methotrexate might act on choriocarcinoma, a tumor that makes the same hormone. Li joined Hertz's branch at the Institute in August 1955.

To their surprise, the metastases shrank. Their 1956 paper described three women with progressing lung metastases, two with choriocarcinoma and one with chorioadenoma destruens; all improved, X-rays showed the metastases regressing, and hormone levels fell toward normal. NCI calls it the first paper to document regression of metastases on X-ray after chemotherapy. Li measured hCG as a sign of remaining disease. When methotrexate had cleared all clinical evidence of cancer but hormone levels stayed abnormal, he concluded that hidden tumor remained and kept treating. According to Vincent DeVita, a later NCI director, Li was told to stop because the treatment was too dangerous, and continued. He left the Institute in 1957. Emil Freireich, who knew him at the Institute, later said he had been fired for it.

The approach held. In 1958 Hertz and colleagues described 27 patients with choriocarcinoma and related diseases, five of them cured, and by 1962 the cure rate for the previously fatal disease was 80 percent, according to NCI. In 1960 Li reported combination chemotherapy for metastatic testicular cancer. Hertz and Li shared a Lasker Award in 1972.