Many of the recent advances in the treatment of the leukemia* and lymphomas have been associated with schedules consisting of two or more drugs given concomitantly or sequentially. Agents that produce toxicity in different organs are said to have independent toxicity. They can be combined frequently at full doses to produce increased damage to the tumor but little or no increased toxicity to the patient. Methotrexate and 6-mercaptopurine, both antimetabolites and both producing damage to the bone marrow and gastrointestinal tract, would be expected to have additive toxic effects. Data exist, however, to show that when 60 to 70 percent of the normal dose of the two drugs is combined, the combined toxicity is not greater than the toxicity of either drug alone.

Treatment Schedules Improved Combination Chemother 51

Recent research has shown that combinations of several of these six drugs have effectively, although temporarily, controlled acute granulocytic leukemia, a type of leukemia that strikes many more adults than children and against which little progress has been made until now.

An example of an effective program of combination chemotherapy is one in progress at the National Cancer Institute for the treatment of acute lymphocytic leukemia of childhood. The drugs were given in 5-day courses as follows: vincristine on Day 1; prednisolone, methotrexate, and 6-mercaptopurine on Days 1-5. These courses were separated by the minimum required interval for recovery from bone marrow and gastrointestinal toxicity. The doses of the two antimetabolites were increased as necessary during induction of remission. The doses of vincristine and prednisolone were at a maximum level from the start. Sufficient courses of the four drugs were given to induce complete remission. Four additional courses were given during the first two months of remission, and then monthly "pulses" for a period of one year, so that the total duration of combination chemotherapy during remission was approximately 14 months. Results of the study are described on page 36.

Combination chemotherapy has effectively, although temporarily, controlled acute granulocytic leukemia. This is a type of leukemia against which little progress has been made until now. Six agents are effective against this type of cancer: methotrexate, 6-mercaptopurine, methylgly oxal-bis-guanylhydrazone, cytosine arabinoside, daunomycin, and 6-methyl-mercaptopurine riboside. Only a few of the possible combinations have been tried, but most of them have been superior to the drugs used singly.

Early results of a recent study were reported in which a combination of 6-mercaptopurine and 6-methylmercaptopurine riboside produced complete remissions in 7 of 29 patients. The therapeutic effect of the drug combination was synergistic; that is, greater than that of either drug alone. In fact, preliminary clinical studies suggested that the riboside alone has very little activity against acute granulocytic leukemia.

An effective four-drug treatment for advanced Hodgkin's disease utilized a schedule consisting of six 28-day courses of nitrogen mustard, vincristine, methyl hydrazine derivative (MIH), and prednisone. The first two drugs were given on the first and seventh day of each 28-day course. The last two drugs were given continuously for the first 14 days—MIH during each of the six courses and prednisone during course 1 and 4 only. Although all patients had advanced disease, most were able to receive almost all of their treatment as outpatients. Results of the study are described on page 43.