During the 1960's, the ability of drugs to produce complete, long-term remissions, perhaps cures, in some patients with widespread, progressive cancer has been unequivocally established. A significant number of patients have been reported free of symptoms of acute leukemia and several other relatively rare types of malignancy for 5 to 10 years and even longer after chemotherapy. These rare diseases include choriocarcinoma, a highly malignant cancer that arises from the placenta; Burkitt's lymphoma, a type of cancer seen most frequently in African children; Wilms' tumor, a type of kidney cancer in children probably of congenital origin; and a few other childhood tumors.
Recent research on cells has suggested that these types of cancer are rapidly growing tumors, and that the types, such as cancers of the lung, colon-rectum, and breast, which are poorly responsive to drugs, are slowly growing tumors. It is suggested that the differences between the rapid and slow tumors are mainly due to the presence of a large fraction of non-dividing (resting) cells in the slow tumors. Non-dividing cells are less sensitive than dividing cells to the destructive action of most cancer drugs. Drug schedules worked out in experimental model systems have yielded the successful treatments for rapidly growing human cancers; intensive research is in progress to devise effective drug regimens for the slowly growing ones, which constitute the major cancers that afflict man.
Advances in treatment by surgery and irradiation, or a combination of both techniques, have gradually increased the 5-year survival rate to about 35 percent, or 1 out of 3 cancer patients. However, the conventional methods of treatment are not effective for the majority of patients, whose disease is disseminated, such as in the leukemias and related lymphomas and in the "solid" tumors that have spread to other parts of the body. Hope for survival of patients with these cancers rests on successful development of a method such as chemotherapy, which will permit complete and selective destruction of cancer without harm to the patient.
The modern era of cancer chemotherapy research is barely 30 years old. It began with the work of C. B. Huggins, University of Chicago, suggesting a rational basis for the antitumor effect of castration or female sex hormone therapy in patients with disseminated cancer of the prostate. In the early 1940's, the anticancer effectiveness of the nitrogen mustard compounds was discovered as a byproduct of the military investigation of chemical warfare agents. The nitrogen mustards are related chemically to mustard gas, a poison war gas known since the late 1800's. The best known compound, called nitrogen mustard, is used in the treatment of malignant diseases of the lymph system (the infection-fighting system), such as Hodgkin's disease.
Cancer chemotherapy took a giant step forward with the observation in 1947 by S. Farber and his colleagues of the Children's Cancer Research Foundation that acute leukemia in children could respond to drugs. Aminopterin, the first drug, was displaced soon by a closely related one, methotrexate, which is one of the main drugs in use today for the treatment of leukemia and also several other types of cancer.
Methotrexate is a folic acid antagonist; the idea for its use for controlling the proliferation of abnormal white blood cells in leukemic children was suggested by Dr. Farber's observation that folic acid, a B vitamin, stimulated the acute leukemic process.
In the 1950's, with the availability of a handful of drugs capable of restraining the relentless progress of cancer, came the realization that curative chemotherapy is a scientifically feasible goal. The National Cancer Institute then took the first steps toward organization of a broadly based national chemotherapy program, whose major objective at the present time is to select from among thousands of synthetic and natural chemicals those few with potential for curing human cancer and to work out effective and safe methods for administering cancer drugs to patients.
The philosophy that the individual patient's best interests are paramount is the guiding principle of modern clinical investigation of cancer drugs. No treatment of proved value is denied a patient merely to permit the study of a new method of treatment. An individual patient who would be harmed by continuing in a study is shifted to another type of therapy. Weighing the risks of new drug therapy against the benefits for the prolongation of useful life for each patient is an integral part of chemotherapy research.
Among the highly responsive cancers, choriocarcinoma stands out as potentially curable and preventable by the techniques currently available. Best results have been obtained by the sequential use of methotrexate and dactino-mycin, an antibiotic. Of a group of 100 patients with widespread disease, 67 have been in complete remission for longer than 1 year; 30 have been free of evidence of their disease for longer than 5 years; and some are believed to be cured.
Nearly half of the cases of choriocarcinoma are preceded by a hydatidiform mole, a condition occurring in an abnormal pregnancy. The presence of an unusually high level of a hormone after the pregnancy is terminated is a sign that the development of choriocarcinoma is highly likely. However, if drugs are given, development of the malignancy is generally prevented; the hormone level returns to normal.
In children with acute leukemia, modern treatment with intermittent administration of high doses of several drugs in combination and special supportive care induces remissions in a high percentage of the patients. The median survival, or time of survival of half the patients, in some specialized centers is at least 2 1/2 years. Many of the patients now under treatment may survive longer than 5 years. The direction of future research is to prolong the durations of remission until cure is regularly predictable, and to extend the complex treatments now available to patients at the major research centers to those in average hospitals so that all patients will have equal prospects for long-term survival.
The majority of cancers are not at the present time curable by drugs. Cancers such as those of the lung, colon-rectum, and breast, the three most common types of malignancy in the United States, are not usually treated with drugs unless the conventional methods, surgery and radiotherapy, have failed or cannot be used at all.
Patients with these diseases obtain relief from pain, temporary lessening of symptoms, and, in some instances, increased survival from treatment with available cancer drugs. New methods of drug treatment, based on recent information about the growth rates of solid tumors in animals and man, offer better prospects for chemical control. The new techniques include administration of high doses of drugs in combination and in intermittent "pulses" timed to kill cancer cells more rapidly than they multiply and to allow recovery of normal cells from drug damage.
Research to find new leads to the chemical control of cancer deals in large measure with growth of cells. Cancer is considered to be a disease of cells: one or more cells may escape from the regulatory controls of the body; they multiply, and they compress, invade, and destroy normal tissues; they break away from the site of origin of the malignant change and, transported through the blood or lymph, start new growths known as metastases. If not removed or destroyed, the cancer eventually kills the host in which it grows.
Much interest is focused on the DNA (deoxyribonucleic acid) of a cell, for this "master" chemical molecule contains genetic information coded into its structure. It is believed that the malignant change occurs in a cell's DNA, resulting from the action of a virus, cancer-inducing chemical, or other factor, with the production of new, heritable characteristics for the cell. DNA reproduces itself; thus, the genetic information is passed from one generation to the next. DNA also directs the life processes of a cell; the most important product is proteins, the basic structural and functional matter of living things. Many drugs effective against cancer act on some stage of the sequences concerned with nucleic acid synthesis and metabolism, the sum of all the life processes.
Cancer drugs may be classified on the basis of their effects on cell chemistry. Alkylating agents, which include the well known nitrogen mustard, are general cell poisons. Studies have suggested that they act by cross-linking certain components in the DNA and thus they inhibit its replication. Antimetabolites are substances that structurally resemble essential constituents of normal metabolic processes and are therefore taken up by the cell. An antimetabolite competes with the natural metabolite; it cannot be used by the cell and it blocks a pathway in the synthesis of DNA. Methotrexate, 6-mercapto-purine, 5-fluorouracil, and cytosine arabinoside are different types of antimetabolites.