Clyde O. Brindley

Appraisal of methods for the study of chemotherapy of cancer in man: Comparative therapeutic trial of nitrogen mustard and triethylene thiophosphoramide

Abstract Suggestions are made for the conduct of chemotherapy trials in patients with cancer. Application of the principles involved are illustrated in a comparative study of triethylene thiophosphoramide and nitrogen mustard in cancer of the lung and breast, melanoma, and Hodgkins disease. Neither drug was appreciably effective in cancer of the lung which had previously been irradiated or in melanoma. In cancer of the lung not previously irradiated and in cancer of the breast, 30 to 50 per cent reduction in tumor size occurred in 10 to 26 per cent of the patients. In Hodgkins disease certain factors limit the completeness of the comparison, but it is possible to draw the tentative conclusion that thio-TEPA was less active than HN2 (in the doses used) in inducing remissions. The advantages and disadvantages of this type of trial are discussed and several suggestions are made for improved experimental design.

Clinical studies of dichloromethotrexate (NSC 29630)

Dichloromethotrexate (DCM) is much superior to methotrexate (MTX) in inhibiting L1210 leukemia and C3H lymphosarcoma in mice. This greater effectiveness obtains for parenterally administered DCM and is much less apparent when DCM is given by mouth. The toxicity of DCM in animals is qualitatively similar to that produced by MTX. DCM is fifty to one hundred fold less toxic than MTX in rats and mice but only tenfold less toxic in dogs. It is concluded from clinical studies reported in this paper that: (1) The tolerated dose of DCM is fivefold that of MTX and the toxic manifestations are similar. (2) The tolerated doses of oral and iniramuscular DCM are equivalent. (3) Equitoxic, and presumably optimal, doses of oral DCM, oral MTX, and intramuscular DCM produce comparable antitumor effects in adults with lymphosarcoma and Hodgkins disease. There is complete tumor regression in 10 to 20 per cent and partial regression in another 20 to 30 per cent of patients. These tumor regressions are, in general, short‐lasting. (4) The dose response relationship is steep. A twofold difference in dose of DCM or MTX results in a significant difference in toxicity and antitumor effect. (5) There are at least four other more effective modalities of treatment for lymphoma which should be employed before conventional folic acid antagonist therapy is considered.

A CLINICAL PHARMACOLOGIC STUDY OF CHEMOTHERAPY AND X-RAY THERAPY IN LUNG CANCER.

Abstract Actinomycin D and 5-fluorouracil, given with x-ray in a dosage regimen sufficient to produce definite but tolerable gastrointestinal and marrow toxicity, did not increase the percentage of patients with carcinoma of the lung showing shrinkage of lesions in the irradiated field. There was no evidence of a more rapid onset of shrinkage of the tumor or of an additive effect at subtotal doses of x-ray. Patient survival was not affected beneficially by the addition of the chemotherapeutic agents. Toxicity was not correlated with responses induced. Patients classified as responders to therapy lived longer than those classified as nonresponders.

FURTHER COMPARATIVE TRIAL OF TRIETHYLENE THIOPHOSPHORAMIDE AND MECHLORETHAMINE IN PATIENTS WITH MELANOMA AND HODGKIN'S DISEASE.

Abstract A comparative trial was carried out by the Eastern Cooperative Group in Solid Tumor Chemotherapy in 49 patients with melanoma and 48 patients with Hodgkins disease with the two alkylating agents methyl-bis (β-chloroethyl)amine hydrochloride (HN 2 ) and triethylene thiophosphoramide (TSPA). In patients with melanoma the response rate was 12.5 per cent for 4–29 months with TSPA and zero in the comparable group treated by HN 2 . In Hodgkins disease the drugs were given at two dose levels, one near the maximum tolerated dose and the other at one-half of this. At the higher dose level significant tumor reduction occurred in 50 per cent of the patients for a median of 44 days with HN 2 and in 59.1 per cent of patients for a median of 36 days with TSPA. These results are not significantly different and suggest that at equal toxicity the drugs have similar antitumor effects in patients with Hodgkins disease. At the low dose level the response rate with TSPA was only 11.1 per cent. A statistically significant difference was found between the response rate with low and with high doses of TSPA. Too few cases were studied to draw conclusions referable to HN 2 in regard to optimal dose for this drug. Evidence was obtained that for the alkylating agent TSPA the antitumor effects in patients with Hodgkins disease are dose dependent and that there is a relationship between degree of toxicity and antitumor effects.

Comparative trial of chemotherapy and radiotherapy in patients with non-resectable cancer of the lung☆

Abstract Two hundred and nineteen patients with carcinoma of the lung were studied in three treatment groups in a cooperative in-hospital study. Of these patients, 196 had not received prior therapy. Treatment group I was given a mean of 3,843 tissue r., treatment group II a mean of 37.8 mg. of nitrogen mustard therapy and 3,658 tissue r. simultaneously and treatment group III 41.0 mg. nitrogen mustard therapy followed by 3,633 tissue r. In evaluating shrinkage in tumor size, benefits as determined by votes of the investigators and over-all survival curves, essentially no beneficial differences emerged for any one treatment group. Toxicity was slightly greater in group II, and treatment time extended for these same patients. No difference in toxicity or survival time appeared between 250 kv. or 2 Mev radiotherapy equipment. Data and discussion are presented to indicate that in this study survival time is independent of the form of treatment administered but that natural selection alone determines the patients with longer survivorship. The routine use of radiotherapy and mechlorethamine treatment, therefore, is questioned.

Cardiac Hodgkin's disease a clinical, hemodynamic, and angiocardiographic evaluation of a case

Abstract A unique case of cardiac involvement by Hodgkins disease has been demonstrated by cardiac catheterization and angiocardiography. An excellent response was obtained with radiotherapy.

A comparative study of optimal medical care with and without azaserine in multiple myeloma.

A comparative clinical study of optimal medical care plus azaserine versus optimal medical care plus a placebo was accomplished in 20 patients with multiple myeloma. Azaserine was originally studied in myeloma because of reported effects on a plasma cell neoplasm in mice. The controlled study was undertaken because suggestive activity in myeloma had previously been seen. The 9 azaserine‐treated patients sustained more toxicity than the 11 placebo‐treated patients. No important difference in tumor behavior was detectable between the azaserine and placebo‐treated groups as determined by physical examination or the several hematologic, biochemical, and roentgenologic measurements made.