New Aspects in the Treatment of Neoplastic Diseases

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NEW ASPECTS IN THE TREATMENT O F The gravest problem confronting the medical profession a t the present time, undoubtedly, is the treatment of cancer. Among men and women of all ages cancer ranks second in the causes of death, while among women, ages 35-54, cancer now is first as a cause of death. Two phases of the cancer problem are critically and equally important : namely, efficient diagnosis and adequate therapy. We shall deal only with the latter in this discussion. The reader is referred to the recent review of Hornburger‘ for an evaluation of diagnostic tests. We believe that fairly efficient diagnostic aids will be developed in the Within th-e past few years considerable progress has been made in the treatment of malignant diseases. Although no “cure” has yet been discovered for cancer which is not amenable to surgery or radiation, the hope for such a cure is brighter, and many cases have had remissions ranging from a few weeks to several months and even years. The solution of the problem is being sought, and will be found, in study of the details of metabolism for tumor cells. As we understand what nutrients are essential for rapid growth of these cells, what enzymes control their metabolic processes, and wherein they vary from normal tissues, we acquire tools for inhibiting cancer development. A review of the present status of chemotherapy, the term being used in its broadest sense, for neoplastic diseases will illustrate our knowledge of tumor metabolism and may be useful as a guide for therapy and new developments. In stressing chemotherapy in this discussion, we have no intention of minimizing in any way the excellent progress which has been attained in surgical and radiation therapy for cancer. Brunschwig’ has effectively extended the surgical approach to include all stages of uterine cancer, and Adair3 has stated that in the past few years they have doubled the number of five-year cures for those with axillary disease through a greater use of

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We also wish to emphasize that all forms of treatment for neoplastic diseases stand a better chance of aiding the patient because of improvements in measures for supportive therapy. Without giving details, we must mention the better use of anesthetic agents, a wider use of transfusions with fewer transfusion reactions, and antibiotics such as aureomycin to protect against dangers from infection. Anemia is being counteracted through use field we have progress in pain-relieving surgery and new analgesics such as TEROPTERIN~Sodium Pteroyl Triglutamate to relieve pain and promote wellbeing. The nutritive status of the patient is also being maintained to better advantage because of appreciation of the need for proteins, and improved ~ understanding of electrolyte balance. The subject of chemotherapy of malignant disease has been excellently . reviewed by Gellhorn and Jones,( and Karnofsky, Burchenal and Escherr have summarized in tabular form the method of administration, therapeutic dosage, toxicology and mechanism of action for nitrogen mustard, urethane, radioactive phosphorus, aminopterin, radioactive iodine, estrogens and The nitrogen mustard used most is Methyl-bis (beta-chloroethyl) amine hydrochloride, commonly referred to as HN2. Karnofsky and associates6 have used nitrogen mustard for 35 cases of inoperable carcinoma of the lung. They obtained some alleviation of cough, dyspnea, hemoptysis, pain and weakness in 74 per cent of the patients, with regression of lesions and effusions which lasted from 2 to 8 weeks. Further courses, however, were not effective. Shullenberger and co-authors7 reported a limited usefulness of nitrogen mustard with 18 cases of Hodgkin's disease, but an unpredictable and not encouraging response in 10 cases of lymphosarcoma. Better results were obtained in 1 patient with cutaneous lymphoblastoma and 1 with polyAriel and Kanters have used nitrogen mustard in 100 cases of hetero-

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geneous neoplasms. They found it of no value for 79, w i t h 15 there was mild palliation, but 6 had a striking response. The good results were for patients who had bronchiogenic carcinoma, lymphomas and Hodgkin’s disease. Bierman and associates9 have treated 67 patients with 151 courses of HN2, 77 being single injections of 0.2-0.4 mg. per kg. and 35 single injections of 0.6 mg. per kg. They found that 13 patients with Hodgkin’s disease, who were in good or fair condition, responded better to HN2 and had remissions of about 3 months, whereas 11 patients with this disorder who were in poor or nearly moribund condition did not respond as well and had remissions of only about 11/2 months. One of the latter did not respond a t all to the HN2. With their 15 cases of lymphosarcoma, a comparable differentiation in results between those in good and those in poor condition was obtained, 4 of the former having remissions of 1 to 2 months and 9 of the latter having - a much shorter period of benefit, while 2 did not respond. Remissions of 1 to 3 months were observed for 4 patients having mycosis fungoides. These authors noted serious toxic reactions in 6 patients and thought such reactions may have influenced the early death of 4 who developed pancytopenia and hemorrhagic diatheses. The large single doses employed by these workers were neither more nor less effective than the more customary 4 to 6 day course of nitrogen mustard. Dameshek and associates10 have presented the most exhaustive review of the subject of nitrogen mustard therapy in Hodgkin’s disease, with an analysis of 50 consecutive cases. They found HN2 to have the following advantages over X-ray therapy : quick action, with simultaneous reduction of all affected lymphoid tissues; far more effective, particularly for pain relief; more effective in relief of fever and itching; and remissions when persistent X-ray therapy had failed. These authors consider that X-ray is the treatment of choice for relatively early cases, because it will then give longer remissions than HN2. The nitrogen mustard is contraindicated in patients with jaundice and hepatic dysfunction. Perhaps best results may be obtained by a judicious combination of these two forms of therapy. Bauer and Ex311 have reported on the clinical effect of nitrogen mustard in the treatment of 210 patients with neoplastic diseases. They gave 296

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courses, with 1,184 injections. The conditions helped most were: Hodgkin's disease, lymphosarcoma, follicular lymphoblastoma, reticulum cell sarcoma, and mycosis fungoides. A less dramatic response was obtained with fibrosarcoma, leukosarcoma, chondrosarcoma and monocytic leukemia. There was only slight benefit for melanosarcoma, liposarcoma and carcinoma. These authors state that nitrogen mustard is contraindicated for lymphatic and myeloid leukemias and Kaposi cell sarcoma. They found that it could relieve pain in carcinoma, leg cramps in polycythemia vera, and itching in some dermatitides. They thought that in some individuals who had become resistant to the benefits of irradiation, the use of nitrogen mustard enabled irradiation to be again effective. Burchenal, Myers, Craver and Karnofsky12 have reviewed a total of 127 cases of leukemia, including 38 of their own, who have been treated with nitrogen mustards. This form of treatment gave the most satisfactory - response with the chronic myelocytic type of leukemia, and the authors report good results in 32, fair in 6 and poor in 16. With chronic lymphocytic leukemia, good results were obtained in 15, fair in 7 and poor in 23. With acute leukemia no patient had a good result; in 6, results were fair, and in 22, were poor. Those with chronic lymphocytic leukemia who responded best were the ones who were in good condition or with a slowly progressing disease. HN2 benefited only occasional cases of acute leukemia. Pierce13 has warned against the use of nitrogen mustards in the treatment of acute leukemias, except under carefully controlled circumstances. She explains that the immediate cytotoxic effect of these agents, with rapid destruction of actively proliferative cells, will often be detrimental in a patient whose bone marrow is crowded with leukemic cells and who has only a few normal cells which might become critically damaged. Osgood and Chul4 have used marrow culture technic to study the mode of action of nitrogen mustard. They found that HN2 stopped differentiation and killed all cells less differentiated than the segmented neutrophil, but it had little or no effect on the life span of the segmented neutrophil. Barron and associates16016 have found that nitrogen mustards were powerful inhibitors of choline oxidase, acetyl choline esterase and choline acetylase, but

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the great sensitivity of bone marrow to the inhibitory action of HS2 could be reversed by choline or choline precursors. In studies of tissue metabolism, they observed a strong inhibition of pyruvate metabolism, and a lesser inhibition of oxidation of 1-amino acids and utilization of NH,, so that synthesis was interrupted for formation of carbohydrate from pyruvate, creatine from glycocyamine and methionine, urea, and glutamic acid. We are mentioning these studies on enzymes and tissue metabolism because it is likely that through such work the ultimate answer will be obtained to the problem of how best to apply cytotoxic agents in the chemotherapy of Loge and Rundles11 have reported striking benefits for 4 patients with multiple myeloma who had relief of fever, skeletal pain and acute symptoms when 4 to 6 Gm. of urethane were administered daily for 3 to 4 weeks, with 0 to 2 Gm. for 5 to 6 additional weeks. Relapses occurred for 2 patients during the 7 to 13 months of observation, but they responded to second courses of Harrington and Moloneyls had less satisfactory results with urethane and only 6 of their 11 patients with multiple myeloma obtained good remissions. These authors believed that the drug failed in those with acute forms of this disease, and while urethane was not a cure, it could temporarily control the more chronic cases. Lapides19 has stated urethane to be of no clinical value in the treatment of “androgen independent” carcinoma of the prostate, and that perhaps the beneficial changes observed by some might have been the result of a nonspecific type of “stress” action since the toxic agent may have stimulated the pituitary-adrenal pattern of response to stress. Lapides cautioned that critical evaluations must be based upon objective evidence and not upon subjective phenomena. have a possible synergistic effect in depressing mouse chloroleukemia 1394, but the combination of the two drugs did not appear to have any increase

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in toxicity for the mice. He plans to test combinations of other chemotherapeutic agents which increase the life-span of leukemic mice. Piercei3has reported that urethane was effective in controlling chronic leukemia, the benefit obtained permitting ambulatory management. Because such patients require maintenance therapy, repeated hematologic examinations are necessary as a guide to early recognition of a depressant effect on the bone marrow. Paterson and associates21 have compared the urethane treatment of chronic leukemia with results obtained from X-ray therapy of the spleen. They concluded that strikingly similar changes were induced by the urethane and by the radiotherapy. Gellhorn and Jones' have summarized the data for 108 patients with leukemia who have been treated with urethane.- In 40 patients with acute leukemia, urethane did not alter the course of the disease. In 46 cases of chronic myelogenous leukemia, immediately satis-- factory responses were obtained in 30; but only 11 of 29 patients with chronic lymphatic leukemia were benefited. Gellhorn and Jones4 have discussed the theory and results of therapy for stilbamidine, particularly in the treatment of multiple myeloma. Snapperz2 reported temporary improvement in about 70 per cent of patients, with relief of pain although the Bence-Jones protein was not affected. Brewer23 found some clinical improvement in only 2 of 6 cases, with relief of pain as the outstanding feature; and Propp and co-authors24 reported no arrest or remission in 5 patients although 2 had some relief from pain. More recently, Snapper and associates26 reported better penetration of 2-hydroxystilbamidine into multiple myeloma cells, where a deposit could be demonstrated in nuclei as well as in cytoplasm. If radioactivity could be incorporated in a chemical which had a selective ability for penetration of tumor cells more effective therapy might be obtained. Folic A cid A ntagonists In his excellent monograph on the biochemistry of cancer, Greenstein26has

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observed that many diverse agents appear to be effective in leukemia and allied diseases, in contrast to other forms of cancer which are generally more resistant. Greenstein suggests that there may be a certain fragility, or susceptibility to damage, of the leukemic cell which should make it a focus for future efforts in chemotherapy. It is likely that when actual details of action are ultimately learned, specificity of action will become more apparent. Certainly the new work on antagonists for pteroylglutamic acid is illustrating the clinical application of inhibition of cellular processes. Farber and associates27-~0were the first to report the beneficial effect of folic acid antagonists for patients with leukemia and other forms of incurable cancer. They found that the best guide for regulating dosage of folic acid antagonists in the therapy of leukemia, was a daily white blood count, withclinical observation of the patient, noting, in particular, diarrhea or stomatitis. Signs of toxicity could be controlled by decreasing, or suspending, thedose temporarily for a few days. As their study progressed, and they obtained more skill in observing and regulating their patients, toxicity became less of a problem, and children have now been treated daily for more than a year without the appearance of stomatitis, severe diarrhea or depletion of bone marrow.~lThe daily maintenance doses of the pteroylglutamate antagonists employed by these workers at the present time are : AMINO-TEROPTERIN* Aminopterin and A-Methopterin are those chiefly used. Farber and his associates have employed very critical standards for evaluating the degree of remission obtained by the children in their studies. No remission was considered to be complete unless the peripheral blood was entirely normal; the lymph nodes, liver and spleen had decreased in size; there were no petechiae or other evidence of hemorrhage; the bone marrow showed less than 7 per cent blast cells; and the child exhibited normal development and activity. The results were analyzed30 for their first 59 leukemic patients who were treated for 21 days or longer with the folic acid antagonists. Improvement, for those with favorable responses, was usually noted within the first 3 weeks of therapy. A total of 48 remissions were

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obtained in 40 of these patients, while no remissions occurred in 19 of the children. O n the basis of first responses only, 15 had complete remissions and another 15 had partial remissions caused by the folic acid antagonists. Complete and partial remissions were associated with infection in only 6 and 4 of the children, respectively. In his last summary31Farber reports that 200 patients with acute leukemia have now been treated with Aminopterin, A-Methopterin, or other of the 4-amino folic acid antagonists, and clinical improvement of important degree was observed in from 50 to 66 per cent of these patients, the variation occurring with different compounds of the series. The longest survival thus far has been 22 months after onset of the disease. Patients with chronic leukemia, however, have responded very little, if a t all, except 1 child who has had …