Clinical Trials in Cancer Patients:

An Introduction

C. Gordon Zubrod

Comprehensive Cancer Center of the State of Florida, University of Miami School of Medicine, Miami

As chairman of today's session, I extend my thanks to the Kroc Foundation and to the panel members for making these discussions possible. The objec- tives of this meeting are to review the recent history of randomized clinical trials in cancer, to assess the advances in medical practice that have resulted, and to ask whether we are smart enough to distinguish between those trials that are fruitful and those that are not. Before calling up our first speaker, I wish to take the chairman's prerogative of 10 minutes to give an eyewitness view of some of the forces and individuals that led to the first randomized clinical trials in cancer. There were two streams of influence---infectious dis- ease chemotherapy and comparative studies of analgesics and hypnotic drugs. The infectious disease component started with the wartime malaria studies. Although no randomized trials were undertaken, the renal physiologists, Shannon, Earle, Berliner, and Taggart, and the pharmacologists, Brodie and Udenfriend, designed highly quantitative trials of antimalarial drugs with special attention to pharmacokinetics and to the immunological response of the host [1]. Dr. Chalmers was part of this team and, of course, later went on to many studies in controlled trials. That remarkable man, E.K. Marshall, Jr., of Johns Hopkins, who played the key role in the clinical use of the sulfonamides, had a good deal to do with the malaria trials and after the war I joined him in studies of penicillin [2]. The group at Johns Hopkins made a number of contributions to controlled trials.

About this time the studies of streptomycin in pulmonary tuberculosis by the Medical Research Council were published and had a profound influence on the Johns Hopkins group [3]. We had formed a clinical trials committee-- Mac Harvey, Marshall, Tommy Turner, Perrin Long, and Bill Cochrane---and had intense discussions of the ethics and methodology of trials. The first clinical study of penicillin in pneumococcal pneumonia at Johns Hopkins was not randomized [4]. The second trial [5] was our first effort at a randomized trial and these were continued over winters for six years. When Tumulty and

Received June 14, 1982; accepted July 1, 1982. Address reprint requests to: C. Gordon Zubrod, M.D., Director, Comprehensive Cancer Center of the

State of Florida, University of Miami School of Medicine, P. O. Box 016960 (D8-4), Miami, FL 33101, USA.

Controlled Clinical Trials 3:185-187 (1982) © Elsevier Science Publishing Co., Inc. 1982 52 Vanderbilt Ave., New York, New York 10017

185 0197-2456/82/030185-03502.75

186 c. Gordon Zubrod

I went to St. Louis for a year (1953-54), the pneumonia trials were transported and Tom Frei, chief resident on the medical service, had his first introduction to randomized trials [6].

In the early 1950s, Dr. Lou Lasagna and Dr. A1 Owens joined Marshall's department and became interested in the active metabolites of chloral hydrate. This led to a clinical trial of chloral hydrate and trichloroethanol, which in- troduced us all to the problems of subjective bias and methods of blind studies [7]. Lasagna went on to work extensively with Henry Beecher at Harvard on many similar problems.

In 1954, when I went to the NCI, Jim Holland was just leaving to go to Roswell Park, and we agreed to join forces in the study of acute leukemia in children. A protocol was developed and a comparative study started. When Tom Frei and Jay Freireich came to NCI in 1955, this effort expanded into the acute leukemia B group, which Dr. Holland headed for so many years. This group was responsible for the first randomized trial in leukemia, published in 1958 [8].

In 1954, Congress had created the CCNSC to stimulate work in chemo- therapy of cancer. Dr. Ravdin was chairman of the clinical panel, and Dr. Holland and I were members. At the first meeting I drew attention to the methodologies of clinical trials in infectious disease and hypnotic drugs and passed around a reprint of Dr. Lasagna's on clinical trials [9]. I convinced Chalmers, Lasagna, and Owens to become interested in cancer so that much of the past came full circle. This led to the formation, in 1955, of the Eastern Solid Tumor group and the first randomized trial in solid tumors [10]. Other institutions became interested, a granting mechanism was developed and a protocol committee was formed. In addition to myself, this committee had as members Marv Schneiderman, Wayne Rundles, and the late Arnold Se- ligman. For 3-4 years it approved every protocol of the newly developing cooperative groups and had a profound influence on randomized trials in cancer.

REFERENCES

1. Shannon JA, Earle DP, Berliner RW, Taggart JV: Studies on the chemotherapy of the human malarias. I. Method for the quantitative assay of suppressive anti- malarial action in vivax malaria. J Clin Invest 27:66-74, 1948 (Suppl)

2. Zubrod CG: Comparative efficiency of single and multiple dosage regimens of the penicillins: Bull Johns Hopkins Hosp 81:40(Y-410, 1947

3. Medical Research Council: Streptomycin treatment of pulmonary tuberculosis. Brit Med J 2:769-783, 1948

4. Tumulty PA, Zubrod CG: Pneumococcal pneumonia treated with aqueous peni- cillin at twelve hour intervals. N Eng J Med 239:1033-1036, 1948

5. Austrian R, Mirick GS, Rogers DE, Sessoms SM, Tumulty PA, Vickers WH Jr, Zubrod CG: The efficacy of modified oral penicillin therapy of pneumococcal lobar pneumonia. Bull Johns Hopkins Hosp 88:264-269, 1951

6. Frei E III, Auner CR, Van Metre TE Jr, Zubrod CG: A comparison of the efficacy of tetracycline and penicillin in the treatment of pneumococcal pneumonia. New Eng J Med 252:173-176, 1955

Clinical Trials in Cancer Patients 187

7. Owens AH, Marshall EK Jr, Broun GO, Zubrod CG, Lasagna L: A comparative evaluation of the hypnotic potency of chloral hydrate and trichloroethanol. Bull Johns Hopkins Hosp 96:71-83, 1955

8. Frei E III, Holland JF, Schneiderman MA, Pinkel D, Selkirk C, Freireich EJ, Silver RT, Gold CL, Regelson W: A comparative study of two regimens of combination chemotherapy in acute leukemia. Blood 13:1126-1148, 1958

9. Lasagna L: The controlled clinical trial: Theory and practice. J Chron Dis 1:353-358, 1955

10. Zubrod CG, Schneiderman M, Frei E III, Brindley C, et al: Appraisal of methods for the study of chemotherapy of cancer in man: Comparative therapeutic trial of nitrogen mustard and thiophosphoramide. J Chronic Dis 11:7-33, 1960