About 12 years ago National Cancer Institute scientists reported encouraging evidence that drugs could substantially suppress metastatic (widespread) choriocarcinoma, a rare, highly malignant type of cancer that arises during the child-bearing process. Choriocarcinoma and two other conditions, hydatidiform mole and chorioadenoma destruens (or invasive mole) are grouped under the term "trophoblastic disease," used to designate abnormalities of the chorion, the organ that normally develops into the afterbirth, or placenta. Nearly half of the cases of choriocarcinoma are preceded by a hydatidiform mole.

If untreated, choriocarcinoma usually spreads rapidly through the uterus and then to the lungs and brain, and may kill the patient within a year. However, a variability in biological behavior of trophoblastic tumors has been observed, possibly because of the graftlike quality of the fetal tumor tissue in the maternal host. As a consequence, the outcome of any individual case is not predictable, and the clinical course may be the result of a precarious balance between factors of host resistance and tumor progression. At any point, a patient may rid herself of tumor or, much more often, the tumor may spread in such a way as to lead to her death.

Cancers Highly Responsive To Drug Treatment

DISEASE EFFECTIVE DRUGS

chorlocarcinoma

methotrexate dactinomycin vinblastine

acate childhoodleukemia

methotrexate

6-mercaptopurine prednisone (also prednisolone) vincristine cyclophosphamide cytosine arabinoside daunomycin

1,3-bis(2-chloroethyl)- 1-nitrosourea (BCNU)

Wilms' tumour

dactinomycin vincristine sulfate (in combination with surgery and radiotherapy)

hourblastoma

cyclophosphamide vincristine sulfate (in combination with surgery and/or radiotherapy)

rhabdomyosarcoma

dactinomycin vincristine cyclophosphamide (in combination with surgery and/or radiotherapy)

retinoblastoma

triethylene melamine (TEM) (in combination with surgery and/or radiotherapy)

Burkitt's tumour

cyclophosphamide vincristine melphalan orthomerphalan dactinomycin cytosine arabinoside

testicular cancer

nitrogen mustard methotrexate dactinomycin chlorambucil

Hodgkin's disease (advanced)

nitrogen mustard thioTEPA cyclophosphamide vincristine vinblastine methyl hydrazine derivative streptonigrin methotrexate prednisone

A high percentage of patients with malignant diseases now recognized as rapidly growing tumors has responded to treatment with combinations of drugs given in intermittent schedules and in high doses. Complete remissions for extended periods have been produced in some patients, and a few have been symptom-free for 5 to 10 years and even longer after treatment with drugs.

Choriocarcinoma produces increasing amounts of a pregnancy hormone, chorionic gonadotropin, and this can be measured in the body fluids of patients by a number of techniques including assessment of its stimulating effect on the weight of the uterus of a mouse. Measurement of the amount of hormone present also serves as a useful indicator of the patient's response to drug treatment.

Early animal experiments by R. Hertz of the National Cancer Institute showed that a vitamin, folic acid, is necessary for the normal enlargement of the womb during pregnancy. Other investigators learned that the developing embryo also requires folic acid in great abundance and that it will die if this is lacking. Dr. Hertz and his colleagues reasoned that a cancer like choriocarcinoma, arising as it does from a part of the embryo and spreading through the uterus, might also be suppressed by a lack of folic acid. Methotrexate, a folic acid antagonist, was the first drug selected for treatment of choriocarcinoma patients and it was found effective against their disease. Later, vinblastine and actinomycin D (also called dactinomycin), an antibiotic, were used with good results in certain patients who developed resistance to methotrexate.

Two series totaling more than 100 patients with widespread trophoblastic disease have been treated with these three drugs. Best results were obtained by the sequential use of methotrexate and actinomycin D: complete remission occurred in 37 of 50 patients (74 percent). The importance of early diagnosis was observed; many more patients with a relatively low concentration of urinary chorionic gonadotropin achieved remissions than did those with initially high urinary concentrations. Two out of every three patients (67) from both series have been in complete remission for longer than one year; 30 patients have been free of evidence of their disease for longer than 5 years; and some are believed to be cured.

Investigators in other studies of smaller groups of patients have reported that choriocarcinoma and invasive mole respond also to treatment with 6-mercaptopurine and diazo-oxo-norleucine.

On the basis of an 80 to 90 percent chance of eradicating metastatic tumor if treatment is initiated early, a test with drugs instead of surgical removal of the uterus was undertaken at the National Cancer Institute in patients whose disease had not spread from the site of origin. In almost all of a group of nearly 70 patients, such treatment induced complete remissions; a few patients in whom chemotherapy failed entered remission following surgery for removal of the womb. A number of the patients treated with drugs have since completed normal pregnancies.

Dr. Hertz and his associates have recently demonstrated the importance of determining gonadotropic activity in the urine of patients with abnormal pregnancies, particularly when a hydatidiform mole is discovered. If the amount of hormone in the urine does not decrease to normal 30 to 60 days after pregnancy is terminated, the development of choriocarcinoma is highly likely. However, if drugs are given when a high titer of hormone persists, it returns to normal and choriocarcinoma is prevented. Thus the condition generally can be cleared within 4 to 6 weeks, preserving the health of the patient as well as her reproductive capacity.