Soft-Tissue Sarcomas
Edward F McCarthy, MD
Department of Pathology and Orthopaedic Surgery, The Johns Hopkins
Hospital, Baltimore, MD
Correspondence: Edward F. McCarthy, M.D. Department of Pathology,
Division of Surgical Pathology, The Harry & Jeanette Weinberg
Building, 401 N. Broadway/Room 2242, Baltimore, MD 21231-2410, Phone:
410-614-3653, Fax: 410-614-3766, E-mail: mccarthy@jhmi.edu
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Abstract
In 1891, William B. Coley injected streptococcal organisms into a
patient with inoperable cancer. He thought that the infection he
produced would have the side effect of shrinking the malignant tumor.
He was successful, and this was one of the first examples of
immunotherapy. Over the next forty years, as head of the Bone Tumor
Service at Memorial Hospital in New York, Coley injected more than
1000 cancer patients with bacteria or bacterial products. These
products became known as Coley's Toxins. He and other doctors who used
them reported excellent results, especially in bone and soft-tissue
sarcomas.
Despite his reported good results, Coley's Toxins came under a great
deal of criticism because many doctors did not believe his results.
This criticism, along with the development of radiation therapy and
chemotherapy, caused Coley's Toxins to gradually disappear from use.
However, the modern science of immunology has shown that Coley's
principles were correct and that some cancers are sensitive to an
enhanced immune system. Because research is very active in this field,
William B. Coley, a bone sarcoma surgeon, deserves the title "Father
of Immunotherapy."
* Other Sections▼
o Abstract
o References
Each year in the United States approximately 5000 people die from bone
and soft-tissue sarcomas.1, 2 These deaths occur despite innovative
techniques in surgery, new chemotherapeutic drugs, and the
sophisticated delivery of radiotherapy. Therefore, in an attempt to
reduce this death rate, new treatment modalities are being
investigated. One such treatment modality is immunotherapy.
Immunotherapy is based on the idea that a patient's immune system can
be stimulated or enhanced to attack the malignant tumors. The first
systematic study of immunotherapy for the treatment of malignant
tumors was begun in 1891 by William B. Coley (1862-1936), a bone
sarcoma surgeon (Figure 1). Coley injected streptococcal organisms
into a cancer patient in order to cause erysipelas and stimulate the
immune system. The patient's tumor disappeared, presumably because it
was attacked by the immune system. This experiment began Coley's
life-long study of immunotherapy. For the next 40 years, he treated
hundreds of patients with inoperable bone and soft-tissue sarcomas
using immunotherapy. His work was widely publicized and discussed. He
was in the ideal location to carry out his work as the Chief of the
Bone Sarcoma Unit at Memorial Hospital in New York, America's first
cancer hospital, and his work was supported by the first cancer
research grant, which he helped establish.
Figure 1
Figure 1
William B. Coley (1862-1936) from Trans Am Surg Assoc 54(1936):415.
Courtesy of the Welch Library of the History of Medicine.
Figure 1
William B. Coley (1862-1936) from Trans Am Surg Assoc 54(1936):415.
Courtesy of the Welch Library of the History of Medicine.
Not only is Coley known as the "Father of Immunotherapy," he also
became the model for the present-day clinician-scientist. First he had
inspiration: He was deeply moved by the death of his very first
patients due to widespread metastatic bone sarcoma. Second, motivated
by this inspiration, he combed the literature to find ideas about what
might be an effective treatment for cancer. Some reports suggested
that having an infection might cause tumor regression. Third,
following his study of the literature, he developed a theory for
treatment. He began to inject patients with bacteria and bacterial
products and noticed that some tumors disappeared. Finally, he
regularly published his work. During his life, Coley's work was often
severely criticized, and, at times, he was completely dismissed by the
scientific community. This occurred because his methods of treatment
and patient follow-up were not consistent, and many colleagues could
not believe his good results. However, Coley persisted. Thanks to
recent discoveries in immunology, we are now convinced that some of
his observations were correct, and that his theories may have much to
offer us today.
William Coley was born in 1862 to a very old Connecticut family. He
went to college at Yale and graduated from Harvard Medical School in
1888. He then joined the staff of the New York Hospital as an intern
on the surgical service. One of his first patients in 1890 was Bessie
Dashiell, a 17-year-old girl who had a swelling in her hand which was
diagnosed as a malignant bone tumor, most probably a Ewing's sarcoma
in her metacarpal. Despite a forearm amputation, she died of
widespread metastases within ten weeks. This rapid spread of a lethal
cancer had a profound effect on Coley. He was determined to find an
effective treatment. During a review of the records of New York
Hospital, Coley learned about a patient who, seven years previously,
had had an inoperable malignant tumor in his neck that seemed to
disappear after he developed erysipelas. The patient was discharged,
apparently without evidence of a residual tumor. Coley personally
searched for this patient by combing the tenements of Lower Manhattan.
After weeks, he finally found the patient, a German immigrant named
Fred Stein (alfred stein? Friedrich stein?), and he had no evidence
of residual cancer.
Mr. Stein's seemingly miraculous cure contrasted with Bessie
Dashiell's rapid death and inspired Coley to scour the literature
looking for other patients who had cancer remission due to a
concurrent bacterial infection. He was aware of anecdotal theories of
the beneficial effect of fever on malignant tumors. For example,
Diedier noted in 1725 that patients with syphilis developed very few
malignant tumors.3 Sir James Paget had also mentioned that an
infection may cause a regression in certain tumors. 4 In addition to
these anecdotes, Coley was able to find specific examples in the
literature. For example, in 1867, the German physician Busch reported
that a malignant tumor had disappeared when the patient contracted
erysipelas. The cause of erysipelas, a streptococcal organism, was not
known until 1881.5 Then, in 1888, Bruns intentionally injected a
cancer patient with the streptococcus organism to induce erysipelas,
and he noticed the shrinkage of the malignancy.6 Coley was able to
find approximately 47 cases in the literature documenting the
beneficial effect of infections on tumors.
Coley was convinced that having a severe infection could cause cancer
to regress. It took a great deal of courage, but in 1891 he injected
his first patient with streptococcal organisms and noticed the
shrinkage of a malignant tumor. This encouraged him to treat two other
patients with long-bone sarcomas (Figure 2). The injections appeared
to be quite dangerous, and two of his patients died of infection.
However, there was some observable shrinkage of their malignant
tumors. He published his first work describing these three patients in
1891 (Figure 3).7
Figure 2
Drawing of Coley's first bone sarcoma case treated with his toxins.
Courtesy of Annals of Surgery/Lippincott.
Figure 3
Title page to Coley's first article of 1891 describing his toxins.
Courtesy of Annals of Surgery/Lippincott.
Because of the danger of live streptococcal organisms, Coley continued
his treatments using a heat-killed streptococcal organism combined
with a second organism that we now call Serratia marcescens. This
concoction became known as Coley's Toxin. By 1893, he had tried his
toxin on ten patients, most of whom did well.8 By 1916, he had
documented 80 more cases in a monograph. 9 By the end of his career,
he had written over 150 papers on this subject and treated almost
1,000 cases. He mainly used his toxins on patients with inoperable
bone and soft-tissue sarcomas, observing that this treatment was far
less effective on other types of cancer such as melanomas and
carcinomas. Beginning in 1899, Parke Davis & Company had begun to
prepare the toxins so they were available for all physicians. They
were widely used for the next 30 years.10
As a result of his widely used treatment, as well as the fact that he
was publishing his work, Coley was much in the public eye. Early in
his career he received small donations from the Rockefeller family to
help with his research, and in 1902 he arranged a large grant from the
Huntington family that supported him and other cancer researchers.
This endowment was the first in the United States designated
specifically to study cancer.11
Despite Coley's high profile, his work came under criticism because of
inconsistencies. First, although Coley described hundreds of favorable
responses to his toxins, his patient follow-up was poorly controlled
and poorly documented. Second, there were 13 different preparations of
the toxins, and some of these were more effective than others. Third,
Coley used various methods of administration. Some toxins were given
intravenously, others intramuscularly, and some were injected directly
into the tumor. Therefore, many doctors who used Coley's Toxin did not
get the same good results that he did, and some noticed no effect at
all. Some critics went so far as to call him a charlatan. As early as
1894, the Journal of the American Medical Association (JAMA) issued a
severe criticism of the use of these toxins:
There is no longer much question of the entire failure of the
toxin injections, as a cure for sarcomata and malignant growths.
During the last six months the alleged remedy has been faithfully
tried by many surgeons, but so far not a single well-authenticated
case of recovery has been reported.12
Despite JAMA's claim, however, some physicians had success with
Coley's Toxin. Yet many of those doctors looked askance at Coley
because of his personal belief, held long after the idea had been
generally dismissed, that cancer was cause by microorganisms. Coley
held this belief until the end of his career.
Additional controversies surrounding Coley's work reflect a field
struggling to stabilize its understanding of how to treat cancer. For
example, James Ewing, perhaps the most famous cancer pathologist in
the country, was a leading opponent of Coley's work. This was a
particular problem for Coley because Ewing was Medical Director of
Memorial Hospital, and for many years was Coley's boss. Their memos to
one another reflect constant interpersonal animosity. Ewing himself
had become a fanatical supporter of radiation therapy for the
treatment of all bone tumors and repudiated any other theories for the
treatment of cancer. Ewing therefore refused Coley permission to use
his toxins at Memorial Hospital. This was ironic, because Coley had
more experience than any other surgeon in the country in treating the
small round blue cell sarcoma that still carries Ewing's name.
In addition, by 1920 Coley's work ran into serious resistance from the
Bone Sarcoma Registry. This registry, established by E. A. Codman, who
had invited Ewing and Joseph Bloodgood from Johns Hopkins to join him,
was the first cancer registry of any kind.13 Its role was to
standardize the diagnosis and treatment of all forms of bone cancer by
collecting cases from all over the country. The cases would be
evaluated by Codman, Ewing, Bloodgood, and other prominent bone
specialists. Coley had a great deal of difficulty having some of his
cases accepted by the registry, despite being the leading bone tumor
surgeon in the country. Members of the registry believed the toxins
were ineffective. In fact, during the 1920s, both Codman and Bloodgood
insisted that the excellent responses reported by Coley were often
because the patients had the wrong diagnoses.
Thus, his work gradually fell out of favor. By 1952, the Park Davis
Company no longer produced Coley's Toxin, and, in 1962 the Food and
Drug Administration refused to acknowledge Coley's Toxin as a proven
drug.14
Thus, in 1962 it became illegal to use Coley's Toxins for the
treatment of cancer.
Despite the downward spiral of Coley's treatment ideas, they never
completely died. He himself remained undeterred, holding on to his
belief in his toxins until the end of his career in 1933. He was not
alone. In fact, by the early 1930s, a few doctors had changed their
minds and were willing to accept that the toxins might be beneficial.
In 1934, The Journal of the American Medical Association reversed its
position and agreed that Coley's Toxin might be of value:
It appears, that undoubtedly the combined toxins of erysipelas and
prodigiosus may sometimes play a significant role in preventing or
retarding malignant recurrence or metastases; occasionally they may be
curative in hopelessly inoperable neoplasms; . . . The Council has,
for these reasons, retained Erysipelas and Prodigiosus Toxins-Coley in
New and Nonofficial Remedies, with a view to facilitating further
studies with the product.15
In a symposium held in 1935, Codman, apparently seeing evidence of the
toxin's benefits, reversed his position and suggested that Coley's
treatment might have some value after all.16 Also, a controlled study
done in 1962 showed a dramatic response in 20 of 93 cancer patients.17
Further acceptance of his ideas was brought about by Coley's own
children. His son Bradley (1892-1961), also an orthopaedic surgeon,
succeeded him as the head of the Bone Tumor Service at Memorial
Hospital. Bradley Coley's major textbook on bone tumors was published
in 1948, and while advocating surgery as the main treatment for bone
sarcomas, he supported the use of Coley's toxin as adjunctive
therapy.18 He believed that it would be of value in preventing
micro-metastasis. His daughter, Helen Coley Nauts (1907-2001), became
a cancer researcher and devoted her life to the study of her father's
toxins. She tabulated every patient he treated and reviewed all his
notes. She published 18 monographs and tabulated over 1000 of his
cases and noticed that in 500 of these there was near-complete
regression.19
Nowadays, orthopaedic oncologists do not use Coley's Toxins for the
treatment of bone and soft-tissue sarcomas. However, because many of
these tumors are lethal, treatment options may one day be supplemented
by immunotherapy. Since Coley's death, the field of immunology has
developed into a sophisticated specialty. Scientists are studying the
effect on tumors of such factors as tumor necrosis factor (TNF),
interferons, streptokinase and many other cytokines, all related to
the immune system.20 Indeed, vaccines are being developed for the
treatment of numerous types of cancer, particularly colon cancer and
melanoma.21 One form of immunotherapy which is consistently effective
is the installation of BCG bacilli into the bladder to treat
superficial bladder cancer.
William Coley's intuitions were correct: Stimulating the immune system
may be effective in treating cancer. He was a model of the
clinician-scientist, treating patients and using his practice to
initiate research and build theories. But he was a man before his
time, and he met with severe criticism. Despite this criticism,
however, Coley stuck with his ideas, and today we are recognizing
their potential value.
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