Jayant Radhakrishnan
Chicago, Illinois, United States

Dr. William Bradley Coley graduated with a B.A. in the Classics from Yale College. He then taught Latin and Greek in Portland, Oregon, for two years before entering Harvard Medical School. After completing the three-year Harvard course in two years, he passed a competitive examination and was appointed an intern in surgery at New York Hospital (now Weill Cornell Medical Center). Within a year, he became a clinical assistant in the hernia clinic at the Hospital for the Ruptured and Crippled (R & C), now called Hospital for Special Surgery, and the next year, he was also appointed to the staff of the New York Cancer Hospital, the Memorial Sloan-Kettering Cancer Center today.^1,2 Coley made too many contributions as a general surgeon to enumerate here, but those he made to the management of groin hernias and sarcomas are worthy of reappraisal.

In those days, hernias were managed with trusses in the United States, as half the cases recurred after surgical repairs. Furthermore, pneumonia, wound infection, sepsis, and even death were common sequelae of surgery. Initially working with Dr. William Bull,^3,4 and then by himself, he revolutionized hernia surgery. He introduced the Bassini technique to American surgeons. His first attempt at it was a dismal failure. The operation took too long, the wound suppurated, and the hernia recurred. He tried a different suture material, began disinfecting the operative site and the hands of the surgical team scrupulously, and persisted until he achieved excellent results.⁴ For the benefit of other surgeons, he published detailed accounts of hernias and hydroceles in both sexes, adults and children.^5-9 Even Lord Joseph Lister was impressed by his technique and results.¹

Dr. Coley was also committed to the cure of cancer, especially sarcomas. His interest arose from the tragic outcome of one of his first patients. She was an eighteen-year-old woman who sustained a trivial injury to the back of her right hand in July 1890.¹⁰ In September, the pain and swelling increased, so she was referred to Dr. Coley. He found a fusiform swelling on the dorsum of the fifth metacarpal bone. After re-examining her on two more occasions, he thought it was subacute periosteitis. When he incised the swelling, a small amount of thin sanguinous fluid escaped. The tissues were gray and firm to the touch. On October 14, he formally explored the wound as the swelling and pain had both increased. The persistence of pain and swelling eventually led him to biopsy the lesion, and on November 6, the pathological diagnosis of alveolar, round cell sarcoma was made (Reference 10, Figure 1). On November 8^th he carried out a mid-forearm amputation. She had no metastatic lesions at that time. Three weeks later, she had a bout of severe epigastric pain, which subsided spontaneously. On December 11^th a small nodule was noted in the upper right breast. The next day, two more nodules appeared, and she developed neuralgic pain in her left thigh. The nodules enlarged and became so painful that she required opiates. Her epigastric pain recurred, and she developed anesthesia of the chin. By January 1^st she became jaundiced. She continued to deteriorate and died on January 23, 1891. No autopsy was carried out, but she had visible metastases all over her body.

To try and understand the disease, Coley audited ninety unpublished sarcoma cases treated at New York Hospital in the preceding fifteen years. After completing the review, he wrote, “Nature often gives us hints to her profoundest secrets, and it is possible that she has given us a hint which, if we will but follow, may lead us on to the solution of this difficult problem.”¹⁰ He was referring to the salutary effect of erysipelas on a patient with round cell sarcoma of the neck that Dr. Bull had operated upon five times in three years for recurrent disease. (Case 1 of Reference 10 and Figure 1 in Reference 11. Not case 7.) On the last occasion, the tumor was deemed too large to excise. A wound 5 inches by 2 inches was left to heal by granulation. Still, two weeks after the procedure, the patient suffered two consecutive attacks of erysipelas. The tumor disappeared, granulations resolved, the wound scarred over, and the patient was disease-free seven years later.

Around this time, Fehleisen had determined that erysipelas was caused by Streptococcus erysipelatis (now Streptococcus pyogenes). Based on anecdotal reports, he and Bruns had induced erysipelas in cancer patients with some success. Coley added nine more cases to their list. In six, the erysipelas occurred spontaneously while he inoculated bouillon cultures of streptococcus into the tumor in three patients.¹⁰ From these initial unsophisticated experiments published in 1891, he learned that both a febrile reaction and erysipelas must develop for the tumor to regress. Furthermore, daily inoculations were required, not every inoculation produced a reaction, and every tumor did not respond to the same degree. He was also aware that the inoculations themselves might be lethal, so he advised starting with small quantities of Streptococcus and to increase the dose based upon the patient’s tolerance. He also noted that tumor pain disappeared immediately after the injection.

In his next publication, he presented the earlier cases in great detail and observed that stored streptococcal cultures lost their efficacy in about six months. Daily inoculations had to be administered until the tumor resolved completely, and then inoculations continued in smaller doses at varying intervals for an additional three to four months. He also started using safer porcelain- filtered cultures that separated out the organisms, as he now believed the toxin and not the microbe was the active agent.¹¹ In this series of thirty-eight cases of an equal number of carcinomas and sarcomas, 7 of 17 sarcomas were disease-free one to seven years after development of erysipelas, while only 3 of 17 carcinomas responded. One patient each with a carcinoma and a sarcoma died of erysipelas. His results were not believed.

Next, he started using a combination of toxins of Streptococcus erysipelatis and Bacillus prodigiosus (now Serratia marcescens) to potentiate the toxin. When some physicians informed him that they were unable to duplicate his results, he, with Dr. Alexander Lambert and Mr. BH Buxton, developed a more stable preparation which enabled accurate dosing. He also explained the steps for preparing the toxin in great detail for their benefit. Following the change, quite a few doctors informed him of their satisfactory results with the toxin,¹² and by 1896 he published results in 160 patients with sarcomas.¹³ In this publication, he discussed details for preparing the toxin, the dosage schedule, and results in individual cases. He continued to refine the toxin and standardize its development, potency, and dosage over the years with the help of Drs. Martha Tracy and S.P. Beebe.¹⁴ Many still continued to doubt his therapy; however, doctors faced with hopeless, inoperable, or recurrent cancers used them with apparently good results. By the time he presented his paper to the Royal Society of Medicine, he had treated 500 cases with just three deaths from the toxin.¹⁴

One of the reasons for hesitation in using Coley’s toxin at the time, was that the pathogenesis of malignancies was unclear. Therefore, trying to explain the mechanism of action of the toxins was adding conjecture to conjecture. Furthermore, producing the toxin was labor intensive and expensive, formulation was not standardized, the potency had to be assayed, and dosage carefully regulated for individual patients to avoid killing them. The results were also questioned because in some patients, the toxin was inoculated into the tumor while others received intravenous or intramuscular injections. Some patients were also treated with other therapies while receiving the toxin. Finally, radiation therapy had been developed by the early twentieth century and immediately demonstrated excellent results. Prominent physicians of the time, including James Ewing of Cornell, Ernest Codman of Harvard and Massachusetts General Hospital, and Joseph Bloodgood of Johns Hopkins distrusted his results, and even questioned the veracity of diagnoses of his successful cases when he submitted them to the Bone Sarcoma Registry.

Dr. Coley was appointed the third Surgeon-in-Chief at R & C from 1925 to 1933 even though he was a general surgeon. He retired from practice on learning that he had acromegaly. He died at R & C after surgery for diverticulitis in 1936. Undoubtedly, he influenced the surgery of hernias and sarcomas and also proved the efficacy of aseptic surgery. It is worth noting that at a time when patients had no rights, he respected their anonymity. Other writers divulged his patients’ names.^1,2 His son, Bradley Coley, an orthopedic surgeon at Memorial Hospital,¹⁵ and his daughter, Helen Coley Nauts,¹⁶ unsuccessfully tried to resurrect his reputation after his death.

Coley’s toxins were used sporadically in the US until the Kefauver-Harris drug efficacy amendment was passed in 1962 pursuant to the thalidomide catastrophe in Europe. Toxins were now re-classified as “new drugs” that could only be used in clinical trials in the US. Therefore Parke-Davis stopped producing them. In Germany, production was discontinued in 1990 when their Federal Institute of Drugs and Medical Devices refused to re-approve it. However, under certain circumstances, German physicians can use unapproved medicines that they have specially compounded, provided they do not give them away or sell them. This is based upon the principle of Therapiefreiht (therapy freedom) whereby a physician can use an unapproved treatment if they consider it to be applicable based upon their medical knowledge and there is no well-established or more efficacious treatment available.¹⁷

Lately, interest in cancer immunotherapy has brought Coley and his toxins out of mothballs. In some circles, he is being hailed as the “father of cancer immunotherapy.” Even though he believed cancer was caused by microbes and he did not quite understand how his toxins “restore the weakened or lost immunity,”¹⁴ he was a century ahead of the rest of the scientific community in the management of cancer because he was a meticulous observer who employed his clinical acumen to good effect. It appears we will never know the true efficacy of Coley’s toxins as there appear to be no plans to evaluate them.

References

1. Burdick CG (1937). William Bradley Coley. 1862-1936. Ann Surg 105(1):152-5. doi: 10.1097/00000658-193701000-00015
2. Levine DB (2008). The hospital for the ruptured and crippled: William Bradley Coley. Third surgeon-in-chief 1925-1933. HSS J 4(1):1-9. doi: 10.1007/s11420-007-9063-2
3. Bull WT, Coley WB (1893). II. Observations on the mechanical and operative treatment of hernia at the hospital for the ruptured and crippled of New York. Ann Surg 17(5):527-41. doi: 10.1097/00000658-189301000-00121
4. Bull WT, Coley WB (1898) Observations upon the operative treatment of hernia at the Hospital for the Ruptured and Crippled. Ann Surg 28(5):577-604. PMCID: PMC1427161 PMID: 17860647
5. Coley WB (1892). Hydrocele in the female: with a report of fourteen cases. Ann Surg 16(1):42-59. doi.org/10.1097/00000658-189207000-00002
6. Coley WB (1895). The operative treatment of hernia, with a report of two hundred cases. Ann Surg 21(4):389-437. doi: 10.1097/00000658-189521060-00038
7. Coley WB (1895). The operative treatment of hernia in children: with a report of one hundred and thirty-three cases. Reprinted from Am J Med Sci May 1895. Identifier101742493.nlm.nih.gov Identifier-ark ark:/13960/t9z11390z
8. Coley WB (1896). The disadvantages of nonabsorbable sutures in operations for the radical cure of hernia. Reprinted from the NY Med J for February 29, 1896.
9. Coley WB (1909). Inguinal hernia in the female. Ann Surg 50(3):609-29. doi: 10.1097/00000658-190909000-00008
10. Coley WB (1891). Contribution to the knowledge of sarcoma. Ann Surg 14(3):199-220. doi: 10.1097/00000658-189112000-00015
11. Coley WB (1893). The treatment of malignant tumors by repeated inoculations of erysipelas. With a report of ten original cases. Am J Med Sci 105(5):487-516. https://wellcomecollection.org/works/hr8t3qgn
12. Coley WB (1895). The treatment of inoperable malignant tumors with toxins of erysipelas and bacillus prodigiosus. Reprinted from Medical Record January 19. https://wellcomecollection.org/works/jecf76jj
13. Coley WB (1896). The therapeutic value of the mixed toxins of streptococcus erysipelas and bacillus prodigiosus in the treatment of inoperable malignant tumors, with a report of one hundred and sixty cases. Am J Med Sci September 1,1896. doi:10.1097/00000441-189609000-00001
14. Coley WB (1910). The treatment of inoperable sarcoma by bacterial toxins (the mixed toxins of Streptococcus erysipelas and Bacillus prodigiosus). Proc Roy Soc Med 3(Surg Sect), 1-48. PMCID: PMC1961042 PMID:19974799
15. Coley BL (1949). Neoplasms of bone and related conditions. Their etiology, pathogenesis, diagnosis and treatment. New York Paul B. Hoeber Inc. Identifier neoplasmsofboner00cole Identifier-ark ark:/13960/t4vh6q06p
16. Coley-Nauts H, McLaren JR (1990). Coley toxins-the first century. Adv Exp Med Biol 267:483-500. doi: 10.1007/978-1-4684-5766-7_52
17. Wienke, A (September 2001).”Therapiefreiheit contra Wirtschaftlichkeitsgebot” [Therapeutic freedom versus scientific mandatory cost saving]. HNO (in German). 49 (9). Berlin: Springer Verlag: 762-763. doi:10.1007/s001060170051. PMID 11593781. Accessed September 15, 2024