The use of intermittent schedules of drugs to achieve selective toxicity has been called "pulsing" therapy. Such "pulsing" is intended to schedule the administration of a drug at such intervals as to provide a rest period for recovery of normal cells before the cancer cells multiply back to baseline.

An example of the effectiveness of pulsing drugs in acute leukemia was found in a study in which remissions were significantly prolonged in children receiving maintenance doses of methotrexate intramuscularly twice a week, rather than orally once a day (page 64).

In another study, a method for maintaining remissions in children with acute lymphocytic leukemia was developed based on infrequent infusions ("pulses") of large doses of methotrexate. Sixty percent of the total dose was infused rapidly within five minutes as a "priming" dose and the remaining 40 percent by drip-infusion during the next 4 hours. Such an infusion was given on 2 consecutive days and the procedure was repeated at intervals of 3 to 4 weeks. These treatments were supplemented with the usual antileukemic agents (cyclophosphamide, prednisone, 6-mercaptopurine, and vincristine) as needed (page 38).

Pulsing Drug Therapy 52

"Pulsing" therapy is the use of intermittent schedules of drugs to achieve selective toxicity. A drug is administered at such intervals as to provide a rest period for recovery of normal cells before the cancer cells multiply back to baseline. A study showed that remissions were significantly prolonged in leukemic children receiving maintenance doses of methotrexate intramuscularly twice a week, illustrated here by the dark boxes, rather than orally once a day.

Administration of the new drug, cytosine arabinoside (Ara-C) by a "pulsing" technique produced complete remissions in 19 of 40 patients with acute granulocytic leukemia treated in a recent clinical study. Ara-C was administered to the patients slowly, in moderate, intravenous doses for 4 hours a day for 4 consecutive days, then repeated at approximately 1-week intervals. Each infusion was preceded by a "priming" dose one-sixth as large as the main dose. Given in this manner, Ara-C was significantly more effective than in earlier regimens using lower doses or rapid injection.

This schedule was developed when it was learned that Ara-C is rapidly deactivated in the blood and quickly becomes ineffective. Slow, continuous infusion in moderate doses allows the drug to achieve increased destruction of leukemic cells. Toxicity to the bone marrow was not as serious as that associated with the use of other antileukemic agents.

Of the 40 patients in the study, 31 were adults and 9 were children. Of the adults, 14 achieved complete remission, 4 partial remission, and 13 failed to respond. Among the children, 5 achieved complete remission, 1 partial remission, and 3 failed to respond. The average duration of complete remission was estimated to be at least 3 months at the time of reporting.

Other Techniques

A technique for adjusting drug dosage to the rate of growth of the cells in a patient's tumor was reported within the past year. A mitotic count based on the rate of cell division in the tumor was taken as an indication of its growth rate.

Twenty-three patients with mycosis fun-goides, a type of malignant lymphoma, were treated with methotrexate once a week. Eight patients responded completely to this drug schedule; the others showed less response or none. When the mitotic counts of all the patients were studied, it was found that those with the lowest mitotic counts, that is, those with more slowly dividing cells, had shown 100 percent response to the treatment; those with the highest mitotic counts had shown the least response. Accordingly, patients unsuccessfully treated with methotrexate on the once-a-week schedule were given the drug twice a week. Two patients who had not responded on the original schedule achieved complete remission on the new schedule.

Ommaya pump

A technique for administering high concentrations of drugs to the brain was developed by Dr. Ayub K. Ommaya, National Institute of Neurological Diseases and Stroke. The illustration shows the system, which utilizes a permanent tube placed in the lateral ventricle la natural cavity in the brain) and a tiny silicone capsule inserted beneath the scalp. The drug is delivered into the capsule, which serves as a reservoir. The capsule has an clastic dome which is compressible and allows it to be used also as a simple pump. Finger tip pressure on the dome forces the drug into the ventricle.

Other approaches are concerned with the possibility that after treatment isolated nests of cancer cells are left in certain areas of the body. Many protective membranes and barriers within the body limit the free movement of drugs. One such area lies within the central nervous system: the barriers that separate blood from the cerebrospinal fluid and the brain are of such a nature that most of the effective cancer drugs are unable to achieve high concentrations within the brain and spinal fluid. A high percentage of patients with acute leukemia have malignant cells within the central nervous system. When these cells multiply and cause symptoms, the condition is called meningeal leukemia (page 36).

A technique for exposing all the surfaces of the brain and meninges (sheathing membranes) to a high concentration of drugs involves inserting a tube into the lateral ventricle (a natural cavity in the brain) and perfusing the whole region with relatively high concentrations of antileukemic drugs. Another technique is the use of drugs designed to pass the blood-brain barrier and enter the brain and spinal compartments. One such compound, BCNU, has been shown to be active in meningeal leukemia. Its effectiveness as an adjunct to the drug therapy of acute leukemia has not yet been thoroughly assessed.

Other Techniques 54

The technique of plasmapheresis makes it possible to obtain large numbers of platelets from blood. Platelets and plasma are removed from whole blood and the red cells returned to the donor. Now one adult donor can supply a major portion of the platelets needed by a child with leukemia to prevent or stop hemorrhage.

Areas other than the central nervous system also seem to harbor nests of leukemic cells. A variety of organs, such as kidney, liver, and testis, have been shown to contain significant numbers of leukemic cells. The adjunctive use of a highly diffusible compound like BCNU has been suggested for possible effectiveness in penetrating relatively poorly perfused areas within these organs.

Isolation perfusion is a technique for administering a drug to a tumor in amounts larger than would be safe by systemic means. It involves isolating a tumor-bearing extremity, for example, and delivering high concentrations of the drug to the tumor site by dripping it into the arterial supply and removing it from a vein. Regressions of tumors have been reported in malignant melanoma (a type of cancer that usually develops from a mole) and epidermoid cancer of the head and neck. However, no claims are made for increased survival of patients, and investigators in general regard this type of therapy as a research procedure.

Another means of increasing the dosage of a cancer drug with relative safety is the use of an "antagonist" of the drug. For example, studies disclosed the ability of citrovorum factor, a natural metabolite obtained from liver extracts, to reverse the toxic effects of the antimetabolite, methotrexate, when given before or at the same time as the drug. The increased use of the techniques of intensive, intermittent therapy with combinations of cancer drugs has in general replaced this technique in the past several years.