Triethylene Melamine in the Treatment of Neoplastic Disease

The therapeutic effect of triethylene melamine (TEM) on neoplastic disease as reported by Karnofsky and collaborators³ has been confirmed in 134 patients treated over a period of eighteen months. The discovery of this chemical has permitted significant advances in practical therapy. Its effectiveness when given by the oral route and its relative freedom from disturbing side reactions, in contrast to nitrogen mustard, make optimally spaced and sustained therapy feasible. Its generalized action renders it an agent suitable for the treatment of diseases which involve tissues in widespread anatomic areas.

As summarized above in reference to different disease entities, TEM has proved to be especially useful in the treatment of the chronic proliferative diseases arising from lymphatic tissue. Localized Hodgkin’s disease and localized lymphomatous tumors continue to be best treated with roentgen irradiation.³ Combined local and systemic therapy is probably indicated in the majority of patients. In managing diffuse nonlocalized disease, TEM is a promising agent which may compare favorably with whole body irradiation and P₃₂. When the bone marrow is involved, as in chronic lymphocytic leukemia, the beneficial effect of TEM administration appears to surpass that of any other agent.

Although TEM may suppress the growth of normal bone marrow constituents to a very pronounced degree, its therapeutic effect in the myeloid proliferative diseases has been somewhat disappointing. In atypical and subleukemic granulocytic leukemia and in multiple myeloma the results have not been promising. The long term effect in polycythemia vera merits further study.³¹ In the small number of patients with chronic granulocytic leukemia in this series, the results seem to be inferior to those achieved by urethane. To evaluate the comparative merits of different therapeutic agents in this disease will require a large-scale cooperative study.³²

In acute leukemia, rapidly progressing malignant lymphomas, and in most nonhemopoietic tumors TEM therapy has been of little value. Worthwhile palliation has been observed in nasopharyngeal lymphoepithelioma and in ovarian papillary cystodemocarcinoma with metastases. Additional study of the effect of TEM on these tumors is indicated.

The critical problem in TEM therapy is the administration of therapeutically adequate amounts of the chemical while avoiding the serious hazards of overdosage. The correct dose cannot be forecast but must be determined empirically for each patient. The effective intravenous dose is one-fourth to one-half that of nitrogen mustard, or in adults 2 to 3 mg. daily for 2 to 3 days.^{3, 33} Oral doses range from these amounts upward. The effective total dose of TEM during the first 1 to 3 weeks of treatment averages 15 to 25 mg. About 1 patient in 10 will develop temporary depression of bone marrow function when given as little as 8 to 12 mg. of TEM in a span of 5 to 7 days. A few may take 10 to 15 mg. per week almost indefinitely with little result. The reaction of an individual patient to given amounts fortunately remains relatively constant, except that increased sensitivity will occasionally develop after it has been used for some weeks or months.

The considerable variation in effective close that occurs in different patients does not appear to be related to the type of disease they may have. Greater caution should be exercised, however, in those with pre-existing bone marrow damage. The chemical decomposes when in contact with organic materials, and in an acid medium. Differences in dosage requirements may possibly be due to variations in gastric acidity or to the facility with which the chemical is absorbed. Tablets containing TEM should be given to patients in a fasting state with water, and perhaps with a buffering alkali, to minimize decomposition before absorption has taken place.³

The initial oral dose of TEM should not exceed 2.5 mg. If this amount is well tolerated for 1 to 2 days, the dose may be increased to 5 mg. Although slight loss of appetite or nausea is a common occurrence, the appearance of severe anorexia, nausea, vomiting, or diarrhea indicates overdosage, either from excessively large single doses or from a cumulative effect. The WBC should be determined before each dose is given. When the prevailing count falls abruptly, it is imperative that the administration of the drug be suspended immediately until the hematologic status becomes stabilized. The full effect of a given dose may not be manifest for 10 to 14 days. Anemia or thrombocytopenia rarely develops during prolonged therapy without antecedent depression of the leukocyte count. In the present group of patients serious depression of marrow function resulted from overdosage of TEM in 10 instances. This usually subsided fully and spontaneously in 2 to 6 weeks, but it may have hastened the death of 2 patients.

Harmful effects of TEM can be avoided only by carefully regulating the amount of the chemical given. If the difference between the toxic and therapeutic doses could be increased by the administration of a compound like cysteine the safety and utility of the chemical would be enhanced.^{34, 35}

Once the initial effects of TEM have been produced and the approximate dose established for a given patient, the problem of maintaining a therapeutic effect and preventing relapse arises. The action of TEM, like that of nitrogen mustard, is transitory. Long remissions in the diseases that respond to this chemical are scarcely to be expected after brief periods of therapy. In most patients continued evidence of disease activity make it necessary to give maintenance doses at intervals no greater than 1 to 2 weeks. TEM seems to be an agent that is well adapted for sustained therapy, apparently differing in this regard from another nitrogen mustard compound (R 48) that has been effective when given by mouth.³⁶ Prolonged remissions have been maintained in some of our patients with doses as small as 1 to 2.5 mg. per week. Others have required as much as 5 mg. twice a week.

How long the administration of TEM should be continued without interruption to obtain the best long-term results in different disease entities is a matter for further study. Our policy has been to maintain treatment for at least 5 to 6 months, even though signs of disease activity may disappear sooner, before therapy is suspended and evidence of relapse awaited. Many patients will probably require the administration of TEM at close intervals, indefinitely.

Deleterious effects from sustained therapy, other than temporary depression of bone marrow function, have not been observed. Patients treated for many months have maintained their optimal body weight, have not shown undue susceptibility to infection and have not developed abnormalities in serum protein constituents.

The availability of a chemotherapeutic agent such as TEM, which can be used with reasonable convenience and safety without cumulative damage to normal tissues, suggests the need for reconsidering some currently accepted opinions regarding the long term management of the chronic proliferative diseases arising from lymphatic tissues. It would appear desirable to suppress the objective manifestations of disease continuously, even in the absence of clinical symptoms, and to prevent, if possible, the development of complications such as bone marrow damage. The extent to which health and longevity can be prolonged by this means is a matter for continued study.