Coley's Toxins—The First Century

Townsend Letter for Doctors and Patients,  June, 2004  by Helen Coley Nauts

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In January, 1893 W. B. Coley, a young New York surgeon treated his first case of cancer with the mixed bacterial toxins of Streptococcus pyogenes and Bacillus prodigiosus (now known as Serratia marcescens). This bedridden male, aged 19 had an inoperable sarcoma of the abdominal wall and pelvis (16X13 cm.) involving the bladder with incontinence. Only biopsy had been performed. Injections in or near the tumor caused reactions up to 40[degrees]C or more, and complete regression occurred in four months. He remained well until death from a heart attack 26 years later. (1)

Back in 1939, when we began our analysis of Coley's method the following questions needed to be answered: was there sufficient clinical and experimental evidence to justify the conclusion that the method had therapeutic value? If so, what factors governed success or failure? Why did the method not achieve wider recognition? If the conclusions to these questions warranted further study we asked ourselves what can be done to make the Coley's toxins consistently effective in most types of neoplastic disease. (2)

Factors that seemed vital to success or failure

1. Variability of preparations used

No comprehensive textbook on the method had been published by Coley, although he was working on one at the time of his death in 1936. He made every effort to obtain unequivocal diagnoses by eminent pathologists from the beginning. However he did not recognize the great importance of obtaining potent, stable preparations of the mixed toxins to avoid variability from different formulae or from batch to batch. (1,2) Coley had no bacteriological training at all and relied on others to make the preparations.

The first observation brought out by our long-term study was that at least 13 different preparations had been used during Coley's active years, (1892-1936), of which three were considerably more potent than the rest, Buxton VI, Tracy X and Tracy XI. Unfortunately the first two commercial preparations (Parke, Davis & Co.) IX and XII were very weak and the English preparation (Lister Institute VIII) was even weaker, so very few English surgeons achieved success. (1,2) These weaker preparations did not produce adequate febrile reactions. (3) (Figure 1)

In 1902 a patient with recurrent inoperable lymphoma of the pectoral region and axilla reported to Coley that it took 8 minims of the Parke Davis IX to give the same febrile reaction as 1/4 minim of the Buxton VI. (6) Despite such a clear-cut case, Coley does not seem to have attempted to remedy the situation.

Coley seemed to be unaware of this problem until 1911 when he gave a clinical lecture at Guy's Hospital in London and he discussed it briefly in his response to the vote of thanks, ending with the remark "success depends on the preparation...."

Finally in May 1915, Tuholske of St. Louis wrote him about a case of extensive sarcoma of the pharynx and nasopharynx with almost complete obstruction--a tracheotomy was imminent. (1,3) Even massive doses of Parke Davis XII had had no effect at all. Coley then sent him the Tracy XI (see below for details relating to technique). This case made him contact Parke Davis and get them to work more closely with Tracy and so Type XIII was made considerably more potent than XII. (1,2)

2. Technique of administration

Although Coley published 143 papers or monographs on his method between 1893 and 1936, (8) they did not give sufficient detail on how to administer the toxins, i.e. site, dosage, frequency and duration, and the optimum febrile reaction to aim for. The Tuholske case illustrates the importance of these factors. First, the danger of stopping the injections too soon, even if complete regression has occurred. Although complete regression occurred in six weeks, the disease recurred on the opposite side in about three months with evidence of brain metastases. Second, the injections for the recurrence were given subcutaneously or intramuscularly in the deltoid or scapular regions with very poor absorption. Not until given in the abdominal wall did good febrile reactions occur, and the recurrence disappeared, but the symptoms of brain metastases persisted. The patient went into coma for 3-1/2 weeks. No further injections were given. With supportive treatment he regained consciousness and made a complete recovery. He remained well until death from coronary occlusion 33 years later. (3)

a. Duration

Coley himself did not recognize the extreme importance of duration of treatment, especially in the inoperable cases, until 1926 when Christian and Palmer succeeded in curing a reticulum cell sarcoma of the tibia recurrent in the stump after amputation with extensive metastases near the umbilicus and in the left inguinal region. In discussing this case in 1927 Coley stated "I am quite willing to admit that, had the patient been under my care, he would probably not have been alive today.... I am almost certain that I should not have continued the treatment after three months when not only had no improvement been noticed, but marked increase had taken place in the metastatic tumors and especially in the recurrent tumor of the stump (from 17-31 inches). In the second place I am quite sure that I should not have dared to increase the dose to such a large amount (2 cc). However, it was not until these large daily doses were given that the improvement continued until all the tumors had disappeared.... I feel that many of the past failures might have resulted otherwise had larger doses and more frequent injections been given." (1)