Background
Coley toxins (sometimes referred to as mixed bacterial vaccines, or MBV) were one of the first attempts to utilize the immune system to counteract cancer. Although once considered unorthodox, immune modulators or stimulators or biological response modifiers are now a recognized part of immunotherapy and may be adjuvant (accessory) to conventional surgery, chemotherapy and radiation for some cancers.
The formula for Coley toxins was the innovation of William B. Coley, MD, the attending bone surgeon from 1893 until 1936 at Memorial Hospital in New York City (now Memorial Sloan Kettering Cancer Center). Coley is credited with pioneering work in the field of immunotherapy based upon the work of earlier physicians in Germany. The physician.s interest in the subject developed when he lost his first cancer patient, a young girl with a sarcoma who died of metastatic cancer in spite of radical surgery. When Coley reviewed a hundred cases of sarcoma treated during the previous decade, he noted that patients who developed bacterial infections after surgery fared better than those who did not. For example, one patient with four instances of recurrent inoperable sarcoma of the neck had regressions of the sarcoma after infections with erysipelas (a superficial streptococcal infection of the skin)1,2.
Coley injected live cultures of streptococcus to produce erysipelas in 10 patients and assessed their responses as follows: "The unmistakable improvement that followed the repeated injections, even when no erysipelas was produced, especially in sarcoma, suggested that a portion, if not all, of the beneficial influence was due to the toxins instead of the living germ, and this led to experiments with the toxins alone"3.
Because of these observations and the difficulties involved with using live cultures, he began using heat killed streptococcus1,3; however, this type of streptococcus did not produce equally effective reactions4. To increase the virulence of the cultures, he added a non-pathogenic organism, Bacillus prodigiosus (later called Serratia marcescens). Due to complications with this formula, it was later combined with heat killed gram positive Streptococcus pyogenes. Components of Coley toxins eventually included exotoxins, enzymes, other proteins and endotoxins 5,6. Different formulations with varying degrees of effectiveness were produced until 1953 by the Parke Davis, Buxton and Tracy Pharmaceutical Company7.
For over 40 years, Coley and other physicians in the New York City area used these toxins to treat patients with a variety of cancers. Eleven different retrospective site-specific reviews of the progress notes concerning all of these known cases were subsequently compiled and published by his daughter, Helen Coley Nauts. She and her colleagues documented 896 cases treated with Coley vaccine as of 19692. A retrospective review of selected subsets of these cases was published by the former University of Texas Center for Alternative Medicine Research in Cancer8 and is described in the Summary of Research section of this web site.
Tests in mice in 1958 demonstrated regressions of Sarcoma 37, and it was determined that the bacterial strain and type of growth played a significant role in the potency. During the 1980s, Coley toxins were again tested in mice with sarcomas at Temple University in Pennsylvania. Control mice had no regressions, whereas mice treated with the mixed toxins had up to 100% regressions with certain preparations. None of the mice with regressions had regrowth of tumors during the two to four months observation period. The authors of that study concluded that it "compares favorably with other biological response modifiers because of its enhancing effects on the immune response and oncolytic properties at non-toxic levels"6.
Three authoritative articles have been published since 2003 that further evaluate Dr. Coley.s role as the .Father of Immunology.47-49.
Proposed Mechanisms of Action
Immune System Mechanisms
According to the background section of a randomized clinical trial in the late 1980s, "mechanism of antitumor effect of MBV or streptococcal preparations has become clearer in recent years, including: induction of interferon, augmentation of natural killer cell activity, stimulation of lymphoid tissues, activation of macrophages, induction of serum factor that causes necrosis of tumors, as well as stimulation of interleukin-25." (Interleukin II, or IL-2, is a well-known conventional immunotherapy and Bacillus Calmette Guerin (BCG), another vaccine, is used in conventional immunotherapy for bladder cancers9-11.)
Related in vitro research with bacteria, mice and human cells has continued to explore potential mechanisms of action. In the 1980s, Japanese researchers attempted to determine the active agents in Coley toxins and BCG and concluded that it must be the bacterial DNA itself. In the early 1990s, Arthur Krieg at the University of Iowa reported that bacterial toxins provoked immune responses by human DNA when certain unmethylated sequences within bacterial DNA matched the same sequences in human DNA that were methylated. He also determined that the bacterial sequences that stimulated human DNA immune responses differed from the bacterial sequences that stimulated murine (mouse) immune responses12.
One of the biologically active ingredients in Coley toxins is a lipopolysaccharide (LPS) which causes hyperthermia. This purified LPS induces a fever of 104-105°F for three to four hours that enhances lymphocyte activity and boosts tumor necrosis factor (TNF). Although this purified LPS has caused regression of sarcoma tumors in mice, it was only at levels that were lethal to 30% of the mice. In contrast, mixed bacterial toxins were associated with similar regressions in mice with lethal effects of 15% or less depending on the dose6.
Coley and more recent researchers have emphasized that some tumor types appear to be more susceptible to the toxins than others, in particular, sarcomas or other tumors of mesenchymal origin such as renal and ovarian carcinomas and possibly some lymphomas1,13,14. The immunological effects of this treatment require that it only be given to patients whose immune systems have not been previously compromised by chemotherapy or other factors1,15. Persons with previous positive reactions to tuberculosis (TB) skin tests may be more sensitive to effects of these bacterial toxins15.
Non-immune Mechanisms
Helen Coley Nauts also noted the possibility of non-immune mechanisms derived from bacterial enzymes such as streptokinase44. In 2004, Zacharski and Sukhatme proposed a further development of this theory in which streptokinase, as a plasminogen, combines with and activates the host plasminogen which is the inactive pre-cursor of plasmin, a potent enzyme. Plasmin can subsequently initiate protease cascades capable of degrading a variety of plasma and extracellular matrix proteins47. Plasminogen activators such as streptokinase have been associated with some regressions of cancer in studies reviewed by Zacharski and others50.
Toxicity
Patients may experience shaking chills, fevers and nausea. Although this usually subsides within 12-24 hours, injections are usually repeated daily and continue for weeks to months1. Adjustment of doses and supportive care measures are discussed by Wiemann and Starnes15.
According to Helen Coley Nauts, certain patients should not be given the toxins because they will not respond, those with severe hepatic insufficiency due to metastatic disease or other pathology, those with severe heart conditions or those who are near death16.
Charles Starnes, PhD, of Amgen Corporation, has cautioned that the final product needs to be analyzed by current methods and procedures such as the LAL test for lipopolysaccharide (LPS) and the ELISA test for the presence of the streptococcal exotoxins17.
Current Situation
Charles Starnes at AMGEN in California15 and Dr. Lloyd J. Old, retired from Sloan-Kettering Institute18, have used the toxins experimentally within the laboratory4. The Coley Pharmaceutical Group, a private biotechnology company, is conducting research with specific genetic sequences that may have contributed to the therapeutic effects of Coley toxins19.
The Waisbren Clinic in Milwaukee, Wisconsin, treats patients with cancer with a mixed bacterial vaccine consisting of modified Coley toxins plus 10 strains of the heat killed streptococcus bacteria which causes burn infections, plus BCG, transfer factor donated by relatives of patients, and a strain of lymphoblastoid lymphocytes combined with Epstein-Barr virus 20. An uncontrolled clinical series study by that center is reviewed within the Summary of Research and Annotated Bibliographic sections of this therapy review. Further information concerning the treatment at that clinic is available at that web site21.
The toxins are reportedly being used outside the U. S. in Mexico22, Guatemala23, Germany24 and the People.s Republic of China (Beijing Children.s Hospital and Shanghai5).
According to the American Cancer Society.s Guide to Complementary Alternative Cancer Methods, "Scientific evidence suggests Coley toxins or the mixed bacterial vaccine (MBV) may have a therapeutic role in the treatment of cancer in a combined treatment approach." However, they also comment that much has been learned about the science of immunology and practice of immunotherapy since Coley.s time and that modern immunotherapy is likely to be of greater value25.
Coley toxins therapy has also been reviewed by Wiemann and Starnes in the Department of Pharmacology of Amgen, Inc.15
Summary of Research
Amount and Type of Research
A search of the scientific literature databases of Medline with OVID and PubMed and SCOPUS (includes Medline, Embase, CINAHL and other databases) between June 1, 2004, and July 31, 2006, identified six articles, but just two of these were applicable to Coley.s toxins as a treatment for cancer. Those two new articles are now noted in the background47,48 and mechanisms of action sections sections47. No new human studies were identified.
A search of the scientific literature databases of Medline and Embase between 1/1/2001 and 5/31/2004 had identified one applicable article, but no new studies. Previous reviews of the literature and other sources between 1/1/1997 and 12/31/2000, had identified four articles applicable to cancer in human subjects. Initial reviews that ended in October of 1997 had identified 76 references, of which 67 (88%) were applicable to cancer in human and animal subjects and we had retrieved 64 (96%).
The combined total of 71 applicable and retrieved articles has been classified into the following types of information:
Human
Animal
In vitro
Reviews
Other
31
5
2
9
24*
* Two articles were part of general references concerning alternative/complementary medicines9,26.
Of the human related articles, we coded the studies (30) by the following study designs (listed in generally recognized order for strength of evidence):
Study Design
No. of Studies
Randomized Controlled Blinded Clinical Trial
0
Randomized Controlled Clinical Trial
3
Non-Randomized Controlled Trial /Prospective Cohort
0
Controlled trial/Prospective Cohort with Historical (Literature) Controls
0
Prospective Cohort/Clinical Series/ Trial with No Controls
5
Case-Control Study
0
Retrospective Cohort with Historical Controls
1
Retrospective Cohort with No Controls
16
Best Cases
1*
Case Reports
4
Total Human Studies
30
*This best case series is not one of the current NCI recognized best case series in which the documents for each case are reviewed by an independent panel of oncology experts. (It was contained in one of the clinical series articles along with the clinical series reported in that article3).
Summary of Human Research
Three of the 30 human studies reported in the literature were randomized controlled clinical trials5,27,28, five were clinical series20,24,29, one was a best case series within the article for another case series3), 16 were retrospective reviews16,30-40, (series B, D, E, G )41, one study was a comparison of four of these historical cohorts with more recent historical controls8 and two articles concerned four case reports41,42.
The three clinical trials examined patients with liver carcinoma (n=86)5, inoperable metastatic disease from various cancers (n=71)27 or nodular lymphoma (n=56)28. In the first trial, patients were divided into two series receiving two different forms of conventional therapy with each conventional treatment group randomized to receive mixed bacterial vaccines (MBV) or not. The two subgroups of patients receiving conventional treatment with MBV had higher survival rates, but the differences were not significant5.
In the second trial comparing results of patients with metastatic disease receiving Coley toxins with those receiving typhoid vaccine, nine of 34 patients receiving Coley toxins were reported to show objective response and seven showed subjective improvement (e.g., decrease in pain) compared to one of 37 patients receiving typhoid vaccine who showed any improvement27.
In the third clinical trial of 26 patients who had advanced nodular lymphoma and received Coley toxins pre-chemotherapy, 85% had a complete response compared to a 44% complete response rate for the 30 patients who received chemotherapy only (p=0.029). Median follow-up was 34.3 months28.
The first clinical series was reported by Dr. Coley and concerned approximately 160 patients (exact number not clear in article) with sarcomas, carcinomas, and epitheliomas of various primary sites. The results for this series were summed up by Dr. Coley who stated, "Of the cases of sarcoma, nearly half showed more or less improvement; the variety that showed the greatest improvement was the spindle-celled; that which showed the least, the melanotic3." Details of 13 cases that were especially noteworthy in this series are reported in the article. This best case series was of ten cases treated by other doctors. Complete regression was obtained for two cases at one and two years following treatment. One case that regressed, however, recurred after "a number of months". Although complete regressions occurred for the other seven cases, insufficient time had elapsed to confirm the permanence of the regressions3.
Most patients in the remaining four clinic series were inoperable or had received previous conventional therapy followed by progressive disease. For the clinical series of patients with melanoma24, three obtained total remission, one was stable for five months and 11 showed progression of disease. In the clinical series of the 139 patients with various cancers20, 54 patients (39%) were alive at the end of this 10-year study. In seven cases, tumor size reduction occurred when the vaccine was injected directly into the tumor. In 18 of 24 cases, with carcinoma of the lung grade III (poor prognosis), survival was "longer than expected" from historical data. In the clinical series of 93 patients with various cancers43, there was either subjective or objective improvement for 50 patients (54%). The objective improvement experienced by 30 patients consisted of a decrease in size of lesions, nodes or liver disease and included three patients in whom subsequent biopsies were negative for malignancy and two for whom autopsies detected no evidence of cancer. These objective improvements only remained until last contact for five of the patients. A small clinical series of 11 patients with various types of cancer was followed to determine effects of MBV upon disease and certain immune parameters29. No patients achieved a complete remission and just one patient had a partial response, but transitory immune responses occurred for a few of the patients.
Eighteen monographs compiled by Helen Coley Nauts consisted of compilations of Dr. Coley.s progress notes for all known cases of microscopically confirmed disease in patients who either had concurrent infections or were actually treated with Coley toxins. (This evaluation is limited to those patients who were actually treated with the toxins and includes patients with the following types of cancer: testicular (n=63)30 ,lymphosarcoma (analogous to current term of "lymphoma") (n=86)31, sarcoma of soft tissues other than lymphosarcoma (n=186)16, neuroblastoma (n=9)32, osteogenic sarcoma (n=165), Ewing.s sarcoma of bone (n=100)33, giant cell tumor of bone (n=57)37, breast (n=75 carcinomas and 12 sarcomas)34, melanoma (n=28)35, colon-rectum (n=11)36, renal cancer (n=11)38, multiple myeloma (n=12)39, inoperable ovarian carcinoma (n=7) (series B)41, inoperable ovarian sarcoma (n=8) (series D)41, inoperable cervical carcinoma (series E)41, inoperable uterine sarcoma (series G). Three articles are not summarized because they duplicated case reports in other articles44-46. Separate reviews of the 17 studies within the remaining 11 articles follow.
A retrospective review of testicular cancer patients30, reported that 13 of the 15 patients (87%) who were treated with surgery plus toxins alone were alive at last contact with a median follow up time of 14 years with the two deaths occurring at less than one year. Of the five patients treated with surgery plus radiation plus toxins, four (80%) were alive at last contact with follow up times ranging from 37 to 43 years (median of 41.5 years). The one death was at one year and three months. The 43 inoperable patients received Coley toxins alone with 14 of them (33%) surviving five or more years.
Of the 86 lymphosarcoma patients31, 32 (17%) survived five or more years; 11 of these also received radiation, and 21 received the Coley toxins alone. For sarcomas of the soft tissues other than lymphosarcoma16, there were 67 of 137 patients (49%) with inoperable primaries treated with toxins that survived four or more years with seven of them also having received radiation. Of the 49 operable patients, there were 35 (71%) who survived four or more years with six of them also having received radiation. In a later analysis of this review and comparison with historical controls, the former University of Texas Center for Alternative Medicine removed the round cell sarcoma cases from this series and combined them with other soft tissue sarcomas8.
Three of nine patients with neuroblastoma32 achieved long term remissions of five, 20 and 58 years. The only patient to receive Coley toxins alone was the one who survived 58 years.
For 165 patients with osteogenic sarcoma40, 45 (34%) survived from four to 57 years, with a median of 31 years. Over half of these long term survivors were also treated with both surgery and radiation, 10 (22%) were also treated with surgery, and three inoperable patients (7%) were also treated with radiation. Only nine of the 100 patients with Ewing.s sarcoma of the bone33 survived at least five years. Of these nine patients, two received surgery, four received radiation and three received both surgery and radiation in addition to the toxins. For 57 patients with giant cell tumor of the bone37, survival time was four or more years for 47 (82%), with seven having received previous radiation and 11 receiving radiation subsequent to the treatment with toxins.
For breast cancer patients34, there were 17 who were operable at the time of treatment with the toxins, 12 with carcinoma and five with sarcoma. None of the carcinoma patients received radiation or chemotherapy, while one of the patients with sarcoma received radiation. Nine of the 12 operable carcinoma patients (75%) survived for five or more years. All of the five operable sarcoma patients survived from six to 67 years. Of the 63 inoperable carcinoma patients, six patients (9.5%) survived from eight to 16 years. Of the seven inoperable sarcoma patients, two (29%) survived for eight and 48 years. This series was one of four for whom stage of disease and survival have been compared with a more recent cohort of cancer patients by the former University of Texas Center for Alternative Medicine*.
For the 28 cases with melanoma35, half were operable and 10 of these 14 operable cases (71%) (one of whom also received radiation) survived for five or more years. Nine of the 14 inoperable cases (64%) survived for five or more years.
Of 11 patients with cancer of the colon or rectum36, one received surgery and three received radiation. Seven cases (64%) survived for five or more years, with two of the survivors also receiving radiation. The retrospective review of 11 patients with renal (kidney) cancer38 reported five patients with positive responses and survival times ranging from nine to 59 years following diagnosis.
Of 12 patients treated with Coley toxins for multiple myeloma39, ten also had surgery and/or radiation. These ten patients had survival times ranging from five months to ten years with a median of 3.5 years. Each of the two patients who did not receive radiation survived five years.
Several series consisted of patients with gynecological cancers. Of seven patients with inoperable ovarian carcinoma, four had complete regressions and survived 11 or more years; however, one of the four also had radiation40 (B series). Of eight patients with inoperable ovarian sarcinoma, four patients had complete regressions and survived five or more years40 (D series). Of six patients with inoperable carcinoma of the cervix, two had positive responses and survived two and 27 years40 (E series). Of 10 patients with inoperable sarcoma of the uterus, eight had a complete response with three of them lost to follow-up at one and one half, four and six years and the other seven surviving 18 or more years40 (G series).
Selected groups of patients within these retrospective cohorts treated with Coley toxins were separately analyzed by the former University of Texas Center for Alternative Medicine, utilizing current concepts of staging and survival analysis. The cumulative survival of these Coley.s patients was then compared with the survival of patients in the 1983 cohort of cancer patients in the database maintained by the National Cancer Institute (Survival Epidemiology End Results (SEER)). Based upon numbers of cases and/or apparently positive effects, four groups were chosen for this comparison: soft tissue sarcomas16,31, breast34, renal38 and ovarian41 cancers. The patients chosen for comparison were those who had received surgery for the primary, but not radiotherapy. (Chemotherapy was not available during the decades in which Coley patients were treated.)8.
This University of Texas comparison of Coley patients treated between 1890 and 1960 with 1983 U. S. patients was not able to detect any significant differences in survival. The comparison was limited, however, by small sample sizes, rudimentary technology for the staging of Coley patients, and a possible selection bias for the Coley patients. This possible selection bias concerned some of the Coley patients who had already survived for long periods of time before receiving the toxins (although the analysis attempted to control for this factor). Because of limitations of the SEER software available at the time, only initial treatment with radiotherapy was excluded from the cohort of SEER patients. Given the advances in surgical techniques and medicine in general, any cohort of modern patients would be expected to have better survival than those treated in previous decades, yet no such advantage was detected for the modern group in this comparison8.
One of four separate case reports concerned a woman with breast carcinoma whose lung metastases progression was halted for three months; however, she died eight months after treatment42. Following surgical removal of an ovarian carcinoma, one patient treated with the toxins had a baby and lived for 51 years41 (C series). A patient with Coley toxins given preventatively following a hysterectomy for cervical sarcoma lived for 39 years without recurrence41 (F series). Another patient with epithelioma of the vulva and metastases received surgery, radiation, and Coley toxins, but the cancer recurred and the patient died a year later41 (H series). Other impressive case reports have been found on the internet23, but these either lack detailed information or have not been recently updated so are not summarized.
A table with brief summaries of these studies in human subjects is in the following document.
Coley Toxins Summary of Human Research Table
Conclusions
Coley toxins therapy has shown evidence of significant effectiveness prior to chemotherapy in one randomized trial of patients with advanced nodular lymphoma. Survival was no worse for selected patients than comparable patients in a more recent cohort of U. S. patients treated with surgery. Lack of demonstrated efficacy in some studies may relate to the testing in a variety of cancer types rather than specifically for cancers with demonstrated efficacy in animal studies.
Descriptions of these studies and sources for the data are provided in the Annotated Bibliography.
Annotated Bibliography
Human Studies
Randomized Controlled Trials
5Tang ZY, Zhou HY, Zhao G, Chai LM, Zhou M, Lu JZ, et al. Preliminary result of mixed bacterial vaccine as adjuvant treatment of hepatocellular carcinoma. Med Oncol & Tumor Pharmacother 1991;8:23-8.
Purpose: To investigate the effect of mixed bacterial vaccine (formerly known as Coley toxin) on patients with hepatocellular carcinoma.
Type of Study: RCT
Methods: (Hepatocellular carcinoma) Eighty-six patients with pathologically proven HCC were entered in the trial from March 1985 to June 1988. The patients were divided into two series:
1.
1. Palliative Resection (n=38) - in this series 19 received MBV and 19 were controls
2. Unresectable HCC (n=48) - all received hepatic artery + intraarterial cisplatin infusion + radiotherapy, 25 received MBV and 23 were controls.
Results:
1.
1. The one- and two-year survival rates for MBV group and control were 75% vs 58%, (p = 0.19) and 45% vs 39%, (p = 0.23), respectively.
2. The one-, two- and three-year survival rates were 59%, 41% and 41% for MBV group and 39%, 25% and 20% for the control (p= 0.07, 0.09, 0.07, respectively).
28Kempin S, Cirrencione C, Myers J, et al. Combined modality therapy of advanced nodular lymphomas (NL): The role of nonspecific immunotherapy (MBV) as an important determinant of responses and survival. Proc Am Soc Clin Oncol 1983;24:56.
Meeting abstract.
Purpose: To evaluate the effect of MBV (mixed bacterial vaccine) on the response and survival of patients with advanced nodular lymphoma.
Type of Study: RCT
Methods: (Lymph - nodular lymphomas) Fifty-six patients with NL (stages II-IV) were treated with the NHL-4 protocol. MBV (a heat-killed preparation of S. progenies and Ser marcescens) was administered in a randomized fashion one week prior to chemotherapy. Twenty-six patients in the therapy group and 30 in the control.
Results: The overall complete (CR) and partial response rates were 62% and 32%, respectively. The CR rate of vaccinated patients was 85% vs 44% for non vaccinated patients. The survival duration of patients treated with MBV was significantly better than non-MBV patients (p= 0.029); however the median follow-up was only 34.3 months.
27Johnston B. Clinical effects of Coley's Toxins. 1. Controlled study. 2. A seven-year study. Cancer Chemotherapy Reports 1962;21:19-68.
Purpose: To evaluate the clinical effect of Coley toxin on patients with inoperable metastatic neoplasms.
Type of Study: RCT
Methods: (Various) Thirty-four patients with inoperable metastatic neoplasms were treated with Coley toxin. An additional 37 patients were treated with the typhoid vaccine as the control group. Patients were randomized as to which group they would belong; the two groups were given identical nursing care and supportive therapy.
Results: Only one of the typhoid treated patients showed any improvement of short duration and questionable significance. In the group treated with Coley toxin, 16 patients showed some improvement. Of the 16, nine showed objective improvement. The others had subjective changes, such as decreased pain.
Note: A second non-controlled part of this study for 93 patients who met the same criteria as in the first study is summarized separately in the next citation.
Uncontrolled Clinical Series
43Johnston BJ, Novales ET. Clinical effect of Coley's toxin. II. A seven-year study. Cancer Chemotherapy Reports 1962;21:43-68.
Purpose: Disease response (Following the results of the preceding study27 which suggested that some neoplasms respond to this type of therapy, this study was undertaken to classify the types of tumors that will respond.)
Type of Study: Clinical series
Methods: (Various) All 93 patients had histologically proven and progressing neoplasms, had been off all other therapy for at least two and one half months and conventional modes of therapy had either been used or were considered to be unbeneficial to the types of neoplasms in these patients. Only patients receiving more than 10 injections of Coley toxins were included in the analysis.
Results: No improvement of any kind was shown by 43 (46%) of the patients. Of the remaining 50 (54%) subjective improvement occurred for 20 patients consisting of decreased pain (19) and decreased dyspnea and cough (1). Objective improvement occurred for 30 patients who consisted of decrease in size of lesions, nodes or liver disease. Three patients had subsequent biopsies, which were negative, and there was no cancer found at the autopsy for one patient. Improvements for 25 of the 30 patients were, unfortunately, temporary being followed by recurrence and or metastasis.
24Kolmel KF, Vehmeyer K, Gohring E, Kuhn B, Wieding JU. Treatment of advanced malignant melanoma by a pyrogenic bacterial lysate. A pilot study. Onkologie 1991;14:411-7.
Purpose: To study the effect of pyrogenic bacterial lysate (Coley toxins) on advanced melanoma patients.
Type of Study: Clinical series
Methods: (Melanoma) Fifteen patients (eight female and seven male) with advanced melanoma were selected. The patients with clinically diagnosed with metastasizing melanoma, histologically or by X-ray, and were all under the age of 70. Only one patient had systemic therapy, which was two isolated limb perfusions. The patients were injected with pyrogenic bacterial lysate consisting of streptococci and Serratia marcescens. Depending on the tolerance of the first injection, the intravenous application continued weekly up to 12 injections. In case of progression, the therapy was discontinued after the sixth injection and in case of remission, the treatment was continued longer than 12 injections until a complete remission was observed. A complete health examination of the patients was taken before the therapy and one each after the sixth and 12th injections.
Results: In three of the 15 cases, the treatment resulted in a total and long lasting remission. (The three cases had skin metastases). In another case with inguinal lymph node metastases, a five month period of stability was achieved. The remaining 11 patients showed further progression of the disease. Side effects of the therapy included fever, nausea, headache, back pain and occasionally herpes labialis.
3Coley WB. Further observations upon the treatment of malignant tumors with the toxins of erysipelas and Bacillus prodigiosus with a report of 160 cases. John Hopkins Hospital Bulletin 1896;7:175.
Purpose: a) Disease response and survival
Type of Study: a) Clinical series
Methods: a) (Ninety-three sarcoma of the bone or soft tissue, 10 sarcoma or carcinoma, 62 carcinoma and epithelioma, seven other) Dr. Coley summarized the results for 160 cases which he had treat with the toxins. All of these cases were either extensive, recurrent and/or inoperable at the time of treatment.
Results: a) Of the cases of sarcoma, "nearly one-half showed more or less improvement. The spindle-celled sarcomas showed the most improvement, the melanomas the least. Thirteen of the "best cases" of this series are reported in detail in the article. Also given and reported below under b) are 10 best cases of various other doctors.
20Waisbren BA. Observations on the combined systemic administration of mixed bacterial vaccine, Bacillus Calmette-Guerin, transfer factor, and lymphoblastoid lymphocytes to patients with cancer, 1974-1985. Journal of Biological Response Modifiers 1987;6:1-19.
Purpose: To present the results of 139 cancer patients treated with combined immunomodulation that consisted of Bacillus Calmette-Guerin (BCG), transfer factor and mixed bacterial vaccine combined with Coley toxins.
Type of Study: Clinical series
Methods: Individuals who had a histologically proven neoplasm that had reasonable chance of causing death were selected for treatment. Thirty-eight patients were treated after obvious failures of maximum chemotherapy and/or radiation, because of either organic toxicity or emotional overload. Patients with Hodgkin.s disease or lymphomas always were accepted in the project only after they had failed on traditional therapy. Forty-eight patients had only immunomodulation therapy due to their tumor not being expected to respond to any other therapy or because they had refused chemotherapy. Fifty-three patients were given concomitant treatment with either radiation or chemotherapy. All 139 patients received treatment in the form of MBV.
Results: According to the authors, the results suggested that combined immunomodulation therapy is well tolerated and safe, and that this approach on a prima facie basis had a salutary effect on the courses of a number of the patients treated.
Best Case Series
Purpose: b) Disease response and survival
Type of Study: b) Best cases
Methods: b) Ten cases reported by other physicians are summarized below.
Results: b) Complete regression observed for two cases at one and two years following treatment. One case regressed and then recurred, and seven cases regressed but not enough time had elapsed to know the permanence of the regression.
2Nauts HC. Bacterial products in the treatment of cancer: Past, present and future. International Colloquium on Bacteriology and Cancer 1982. (Review)
This review about Coley toxins contains a compilation of the known cases of microscopically confirmed cancers treated with Coley toxins as of 1969. The article contains a table on page 8 that summarizes these cases by site, but those cases were also reported in separate articles. Accordingly, we have separately evaluated each of these nine separately published retrospective review articles below. Although each of the reviewed articles contains additional summaries concerning patients who spontaneously developed infections of various kinds along with the cancer, we have only reviewed those cases that were purposefully treated with Coley toxins.
30Fowler G. Testicular cancer treated by bacterial toxin therapy as a means of enhancing host resistance. New York Cancer Research Institute, Inc. 1968;Monograph #7.
Purpose: Survival
Type of Study: Retrospective review
Methods: (Testicular) Of the 63 patients, 20 were operable. The records of all known cases of testicular cancer that were microscopically confirmed and treated with Coley toxins were reviewed. Operable patients are reported in series A:
(A1) Surgery + toxins started within one month of operation (n=15)
(A2) Surgery + radiotherapy + toxins started within one month of operation (n=5)
Results:
(A1) Thirteen of 15 alive at last contact with follow-up times ranging from three to 58 years; average 18 years, median 11.5 years. The two deaths were at less than one year.
(A2) Four of five alive at last contact with follow-up times ranging from 37 to 43 years; average 41 years, median 41.5 years. One death at one year and three months.
(A1 & A2 combined as reported in paper; i.e., surgery + Coley with/without xrt) Seventeen alive at last contact with survival times ranging from three to 58 years; average of 23.26, median 14. Three deaths at five months, "less than one year" and 15 months. Fourteen patients (70%) survived five or more years from diagnosis.
Methods: B. inoperable - 43 patients were given Coley toxins. (All but two patients had prior surgical removal of the primary and six also had prior radiation followed by recurrence/metastasis.)
Results: The inoperable patients are described in the following subsections of the monograph:
B. Inoperable "successes" nine patients - Follow-up times ranged from 2.5 to 20 years; average nine, median 6.5
C: Inoperable "failures" 17 patients - Follow-up times range from rapid progression and death to three years with an average of a little over one year for 15 of the patients. Two of these patients survived six and 8.5 years from the start of Coley toxins
D. "Terminal" 17 patients- one "success" who survived onset and unsuccessful surgery followed by toxins for 23 years and 16 "failures" due to rapid progression and death. For the combined inoperable patients, 14 of 43 patients (33%) survived five or more years from diagnosis.
31Nauts, H.C. and Fowler, G.A.. End results in lymphosarcoma treated by toxin therapy alone or combined with surgery and/or radiation or with concurrent bacterial infection. New York Cancer Research Institute, Inc. 1969;Monograph #6.
Purpose: Disease response and survival
Type of Study: Retrospective review
Methods: (Lymphatic system) n=86. The records of all known cases of lymphosarcoma that were microscopically confirmed and treated with Coley toxins were reviewed. Coley toxins were given alone or combined with surgery and/or radiation.
Results: With "success" defined as alive and well at least five years from onset of the cancer, there were 32 (37%) "successes" and 54 (63%) "failures". Of the successes, over half (53%) were treated with the toxins within six months of their initial diagnosis and an additional 28% within the first year and a half. One patient received the toxins following a recurrence four years after the initial diagnosis. Eleven were also treated with radiation. For the group who did not survive at least five years (failures), 33% received Coley toxins within six months of the original diagnosis and an additional 35% within a year and a half. Six patients received the toxins three to four years following the initial diagnosis.
16Nauts HC. Beneficial effects of immunotherapy (bacterial toxins) on sarcoma of the soft tissues, other than lymphosarcoma: end results in 186 determinate cases with microscopic confirmation of diagnosis, 49 operable, 137 inoperable. Cancer Research Institute, Inc. 1975;Monograph #16 .
Purpose: Disease response and survival
Type of Study: Retrospective review
Methods: (Soft tissues - other than lymphosarcoma) n=186. Case histories of patients treated with Coley toxins taken from published articles and unpublished case histories from attending physicians or hospital records. Follow-up of vital and health status obtained by personal interview or correspondence with either the patient or the physician. Surgery was the first treatment for all patients except those deemed inoperable. (Note that 62 of the 137 inoperable patients had received previous surgery followed by a recurrence of the tumor that was inoperable.) Radiation was received by seven of the 70 inoperable "successes"* and six of the 35 operable successes. Nine of the 67 inoperable "failures" and nine of the 14 operable "failures" received radiation. All cases were histologically confirmed. There were 83 females and 103 males with ages ranging from: six months to 73 years. The age ranges were similar in each group except for the operative "failures" group that did not include any children. The stage of disease when the toxins were begun was:
* Inoperable primary 137 (62 recurrent)
* Operable primary 49
The time from initial diagnosis to the start of Coley toxins was within the first year following the initial surgery for most patients (Eighty of 105 operable and inoperable successes). There were, however, 14 patients who had already survived at least two or more years before receiving the toxins including one patient who had survived for six years, two for eight years, one for 14 years and one for 45 years.
Results: *With "success" defined as alive and well four or more years after onset, there was an overall success rate of (56%) for the total group. For the inoperable primary group, there were 70 of 137 patients (51%) who survived three or more years and 67 (49%) who survived four or more years. For the 49 patients in the operable primary group there were 35 patients who survived four or more years (71%).
32Fowler G. The apparently beneficial effects of concurrent infections, inflammation or fever, and of bacterial toxin therapy on neuroblastoma. New York Cancer Research Institute, Inc. 1970;Monograph #11.
Purpose: Disease response and survival
Type of Study: Retrospective review
Methods: (Neuroblastoma) n=9 patients. All "known cases" of neuroblastoma patients treated with Coley toxins and microscopically confirmed were reviewed. Five of the patients were infants, one was two, one was three, one was 14 and one was 31 years old. Six of the patients were metastatic before receiving the Coley, two were inoperable, and one had recurred four months after original diagnosis. Seven patients received radiotherapy. One patient received radiotherapy and chemotherapy (thio-TEPA) before the toxins.
Results: The one case to receive just Coley toxins remained alive and well and able to walk 58 years after onset despite having been inoperable and metastatic and a quadriplegic at diagnosis. Two additional patients achieved long term remissions of five and 20 years. Five other patients achieved regression of the disease within weeks, but it recurred within the next few months. The infant who received both radiation and chemotherapy rapidly deteriorated and died. The authors concluded that prolonged toxin therapy was important but that toxins were not helpful if begun after "massive radiotherapy and chemotherapy have destroyed the immune responsiveness of patients".
33Nauts HC. Ewing's sarcoma of bone: End results following immunotherapy (bacterial toxins) combined with surgery and/or radiation. Cancer Research Institute, Inc. 1974;Monograph # 14.
Purpose: Disease response and survival
Type of Study: Retrospective review
Methods: (Bone - Ewing.s sarcoma) One hundred fourteen patients less 14 who had questionable or unavailable tissue sections. The records of all "known" cases of Ewing.s sarcoma with microscopic confirmation treated with Coley toxins with and without surgery and/or radiation were reviewed.
Results: Nineteen of 100 patients (19%) survived five or more years and nine (9%) of these survivors were without disease at last contact. Those who did not survive at least five and a half years included 53 patients without evidence of metastases and 38 patients with evidence of metastases at the start of toxin therapy. Eight of the five or more years survivors, received the Coley toxins within a year following diagnosis and one patient following a recurrence at two years.
34Nauts HC. Breast cancer: Immunological factors affecting incidence, prognosis, and survival. Cancer Research Institute Inc. 1984;Monograph #18.
Purpose: Disease response and survival
Type of Study: Retrospective review
Methods: (Breast) All 87 cases were microscopically confirmed with 17 of them operable and 70 inoperable. (The 60 inoperable noted in article is incorrect since the subgroups total 70 which when added to the 17 operable yields 87.) All but one of the inoperable patients had a cancer that had recurred following previous surgery. Of the 17 patients who were operable, 12 had carcinoma and five had sarcoma. Four of the carcinoma patients received the Coley toxins preoperatively, five post-operatively. The beginning of the toxin treatment was post operatively for nine patients; one and two years after the surgery for two patients and unknown for one patient. No radiation or chemotherapy was noted for these patients. Of the five operable sarcoma patients, one also received radiation. The 70 inoperable patients were summarized by the author in three groups: 27 carcinoma patients treated with Coley toxins for three months or more, 36 carcinoma patients treated for less than three months and seven sarcoma patients treated with the toxins from less than one month to seven months. Fifteen of the group receiving toxins for three months or more also received radiation and two also received chemotherapy (5FU, cytoxan and methotrexate). Nine of the less than three months toxin group also received radiation. None of the inoperable sarcoma patients received radiation.
Results: Of the 12 operable carcinoma patients, nine (75%) survived for five or more years from the initial onset of cancer and the start of Coley toxins. All of the five operable sarcoma patients survived and were free of disease from six to 67 years after diagnosis, initial surgery (-ies) and start of toxins. Of the 27 inoperable carcinoma patients treated for three months or more, 13 survived from one to four years, six from eight to 16 years and eight had unknown initial dates or were lost to follow up. The six long term survivors had all received radiation in addition to Coley toxins and surgery. Of the 36 inoperable carcinoma patients treated for less than three months, the longest survival time was that of one patient who survived for two years following the start of toxin treatment. Nineteen died within the first three months, five within six months, 19 at one year and the remaining six unknown. Two of the inoperable sarcoma patients, died within the first couple of months of the start of the toxins; one of them from a staphylococcal infection. (The toxins were tested and found to be sterile. The authors stated that this was the only case of 900 treated with the toxins who developed septicemia.). Two other patients survived for eight and 48 years. Two patients were lost to follow up at two years or less and there was insufficient information concerning the start date for the toxins to determine a survival time for the remaining patient.
35Fowler GA. Enhancement of natural resistance to malignant melanoma with special reference to the beneficial effects of concurrent infections and bacterial toxin therapy. New York Cancer Research Institute, Inc. 1969;Monograph #9.
Purpose: Disease response and survival
Type of Study: Retrospective review
Methods: (Skin-melanoma) All 28 cases were microscopically confirmed. Fourteen cases were operable and 14 were inoperable. One of the operable patients also received radiation before the toxins. Two of the inoperable patients received radiation concurrent with the toxins, one prior to the toxins, and one patient received chemotherapy (nitrogen mustard and 5FU) prior to the toxins and radiation subsequent to the toxins.
Results: Ten of the 14 operable cases (71%) survived five or more years. One of these patients survived for 31 years from diagnosis and 26 years from the Coley toxin treatments, and one patient survived for 57 years from both diagnosis and toxin treatment. One patient listed as having survived 26 years from diagnosis did not have any dates of diagnosis or treatment reported. Nine of the 14 inoperable cases (64%) survived for five or more years. One of these nine patients survived 41 years and one survived 30 years from initial diagnosis and toxin treatment.
36Fowler GA. Beneficial effects of acute bacterial infections or bacterial toxin therapy on cancer of the colon or rectum. New York Cancer Research Institute, Inc. 1969;Monograph #10. (Series B)
Type of Study: Retrospective review
Methods: (Colon-rectum) All 11 cases were microscopically confirmed. Only one of the 10 cases was operable when toxin therapy was begun. Three cases also received radiation.
Results: Survival from initial diagnosis ranged from seven months to 35 years with seven of the 11 cases surviving five years or more. One of the five year survivors received the toxins two years after the initial diagnosis, but the others received them within the first couple of months. Two of these long term survivors also received radiation as did one patient who only survived for 21 months.
37Nauts HC. Giant cell tumor of bone: End results following immunotherapy (Coley toxins) alone or combined with surgery and/or radiation, 66 cases and concurrent infection, four cases. Cancer Research Institute, Inc. 1976;Monograph #4.
Purpose: Disease response and survival
Type of Study: Retrospective review
Methods: (Bone-giant cell tumor) n=57. (The 66 cases mentioned in the title are not identified in the article.) All but three of the cases were microscopically confirmed. Of the entire group, 38 received surgery and 10 received radiation before the toxins.
Results: Success was defined as four or more years of survival from initial diagnosis and 47 patients fit these criteria. Of these successful patients, 34 had received previous surgery, seven had received previous radiation and two had received both. Subsequent surgery was necessary for three of these patients, radiation for 11 patients and both for four patients. Of the 10 non-successful patients, four had received prior surgery, two had received prior radiation and one had received both. Two of the patients had subsequent surgery and five had subsequent radiation.
44Nauts HC, Fowler GA, Bogatko FH. A review of the influence of bacterial infection and of bacterial products (Coley's toxins) on malignant tumors in man. Acta Medica Scandinavica 1953;145(Suppl 276):1-103.
Purpose: Disease response and survival
Type of Study: Review of selected cases
Note: This article, published in 1953, includes a compilation of 30 selected cases treated with Coley toxins for a variety of cancers. These cases were later included in monographs by Helen Coley Nauts specifically devoted to each of these cancer types. Following are reviews of the seven cancer specific series published in four separate monographs:
38Nauts HC. Enhancement of natural resistance to renal cancer: beneficial effects of concurrent infections and immunotherapy with bacterial vaccines. New York Cancer Research Institute, Inc. 1973;Monograph #12.
Purpose: Disease response and survival
Type of Study: Retrospective review
Methodology: (Kidney) There were 11 cases consisting of three children with Wilms. tumor and eight adults: two with carcinoma or adenocarcinoma and six with hypernephroma. (An additional three cases were treated with serums other than Coley toxins: Trypanosome cruzi, Borrel.s serum and horse and goat serum.) Eight patients had nephrectomy, one patient had partial removal of tumor and there was no attempt at removal for two cases considered hopeless. The toxins were given pre-operatively for one child; all other patients received them post-operatively.
Results: For the one child to receive them pre-operatively, there was no effect and the child died within a year with metastases. For four patients receiving the injections post-operatively, there was no apparent benefit, and they also died within a year of receiving the toxins. Five patients had a positive response with survival times ranging from at least nine years to 59 years after onset of the cancer. One patient.s tumor regressed but he was lost to follow up.
39Nauts HC. Multiple myeloma: Beneficial effects of acute infections or immunotherapy (bacterial vaccines). Cancer Research Institute, Inc. 1975;Monograph #13.
Purpose: Disease response and survival
Type of Study: Retrospective review
Methods: (Bone marrow - multiple myeloma) Twelve cases were treated with Coley toxins. Five patients had previous surgical removal of some of the disease and four had prior radiation. Eight patients received radiation concurrent with the Coley toxins; of these, four had received radiation previously. Four patients received radiation following the Coley toxins.
Results: Of the two patients who did not receive any radiation, one had a complete response and lived five and one half years after onset but died from pneumonia. An autopsy revealed no evidence of malignancy. The other patient also lived five years but had a recurrence of disease and pathologic fractures. All of the patients who also had radiation had their malignancy either progress or reactivate. The survival times of this last group ranged from five months to 10 years with a median of three to four years.
40Nauts HC. Osteogenic sarcoma: End results following immunotherapy with bacterial vaccines, 165 cases or following bacterial infections inflammation or fever, 41 cases. Cancer Research Institute, Inc. 1975;Monograph #15.
Purpose: Disease response and survival
Type of Study: Retrospective review
Methods: (Osteogenic sarcoma) Patients were 165 cases with osteogenic sarcoma who were operable (138) and included 81 (59%) who also had radiation in addition to surgery and Coley toxins. Patients who were inoperable (24) included seven who had received previous surgery but now had recurrent disease that was inoperable. Of the 24 inoperable patients, 21(88%) received radiation in addition to the toxins. Success was defined as no evidence of disease following treatment.
Results: There was an overall success rate of 34% (45 patients) whose survival times ranged from four to 57 years with a median of 31 years. This group consisted of 42 patients out of the original group of 96 operable patients and three patients from the original group of 27 inoperable patients. Of the 45 successful patients, 26 (58%) were also treated with both surgery and radiation, 10 (22%) were also treated with surgery and three (inoperable patients) (7%) were also treated with radiation. Of the 120 non-successful patients, there were 96 operable patients (83 patients whose primary was operable and 13 whose recurrent disease was operable). Of this non-successful operable group, 55 (57%) had received radiation in addition to the toxins. In summary, the percentage of operable patients receiving radiation in addition to the toxins appears to be similar in both the successful and non-successful groups.
41Nauts HC. Beneficial effects of acute concurrent infection, inflammation, fever or immunotherapy (bacterial toxins) on ovarian and uterine cancer. Cancer Research Institute, Inc. 1977;Monograph #17. (Only the four series reporting actual treatment with Coley toxins rather than naturally occurring infections are reviewed below.)
Series B: Inoperable ovarian carcinoma
Purpose: Disease response and survival
Type of Study: Retrospective review
Methods: (Ovarian) Seven cases of inoperable ovarian carcinoma were treated by Coley toxins. All cases were pathologically confirmed and had been treated with the toxins for at least one month. Excluded were "terminal" cases that had only received from six to 11 injections.
Results: Three patients initially improved but the cancer recurred as soon as the toxins were stopped (one patient had refused further injections). Four patients had complete regressions of their malignancies and survived 11, 13, 21 and 22 years. One of these successful cases was also treated with radiation.
Series D: Inoperable ovarian sarcoma
Purpose: Disease response and survival
Type of Study: Retrospective review
Methods: (Ovarian) Eight cases of inoperable ovarian sarcoma (microscopic confirmation) were given daily injections of toxins from one month to one year sometimes with rest periods.
Results: One patient died within one month possibly from the toxic effects of the tumor sloughing. Three cases had an initially positive response (shrinkage or disappearance of the tumor), but one had a recurrence and death at two years, one died of pneumonia possibly caused by a metastasis to the lung four years later and the third patient died of a recurrent, inoperable tumor at two years. Four patients had positive responses with complete disappearance of the cancer and survivals of five, eight, 12 and 12 years.
Series E: Inoperable carcinoma of the cervix
Purpose: Disease response and survival
Type of Study: Retrospective review
Methods: (Cervical) Six patients with pathologically confirmed inoperable carcinoma of the cervix were given Coley toxins injections from two months to three years.
Results: There was no improvement for two patients who each died six months later. One patient had a dangerous reaction from a larger than usual dose that was injected directly into the tumor. This was associated with nausea, herpes, deafness and vertigo. Nevertheless, she recovered and had a subsequent injection which also produced a severe reaction from which she again recovered. She remained alive and well for four years after which the cancer recurred and she died. One patient was able to walk again and discontinued her morphine because of the relief from pain but died within a year of treatment. Two patients had positive responses: one patient who had been treated for three years had a gradual regression of the masses and lived for another 27 years, dying from flu and pneumonia at age 79. The other patient who had a positive response was treated for eight months after which the masses completely disappeared but she died suddenly from a heart attack two years later at age 68.
Series G: Inoperable sarcoma of the uterus
Purpose: Disease response and survival
Type of Study: Retrospective review
Methods: (Uterus) Ten patients with inoperable sarcomas of the uterus were treated with Coley toxins from two months to two years and, in one case, for six years.
Results: Two patients had a partial regression of the primary tumor but the lung metastases grew for one patient, and she died in two months; the other patient lived for six years and died during a subsequent surgical attempt to remove the tumor. Eight patients had a complete response with disappearance of the tumor. Three of these patients were alive and well when lost to follow up at 1.5, four and six years. The other seven patients had survival times ranging from 18 to 37 years.
End of Series Compiled by Helen Coley Nauts
29Havas HF, Axelrod RS, Burns MM, Murasko D, Goonewardene M. Clinical results and immunologic effects of a mixed bacterial vaccine in cancer patients. Medical Oncology and Tumor Pharmacotherapy 1993;10(4):145-58.
Purpose: To determine effect upon malignant disease and the immunological parameters: interleuken-2 (IL-2), plasma interferon (IFN) and tumor necrosis factor (TNF).
Type of Study: Clinical series
Methods: (Various) Patients were 11 with various cancers including one patient with Kaposi.s sarcoma and AIDS who had either failed or refused conventional therapy or for whom no conventional therapy was available. Levels of TNF were undetectable for all patients at the start of the study. Mixed bacterial vaccine (current name for the original Coley toxins, MBV) was given (as a single agent for all except the AIDS patient) initially by i.v. and subsequently by injection twice weekly for a range of 51 to 457 days. Complete remission was defined as disappearance of all evidence of tumor; partial response was defined as a decrease of at least 50% in the measurable areas of the disease with no appearance of new lesions or progression of other lesions.
Results:
Disease response: No patient achieved complete remission, one patient had a partial response, four patients had stable disease, one patient had a minor response and the remaining five patients had progressive disease.
Toxicity: There was mild fever and chills following the i.v. administration of MBV but no adverse reactions to the injections.
Immune parameters: IFN levels rose for three of the eight patients tested but dropped again for two of these patients. TNF levels rose to a detectable level for one patient and to a high level for another patient; however, this latter patient also had AIDS and was also taking the immune boosting drug, AZT. IL-2 levels rose and surpassed the levels of two normal control patients for four patients but dropped again for three of these patients. "Because of the diverse patient population and different number of treatments and assays, no meaningful statistical analysis of the (immune) data could be performed." The performance status as measured by the Karnofsky scale improved from 60% to 80% for one patient and bone pain completely disappeared for another patient.
8Richardson, MA, et al. Coley Toxins Immunotherapy: A Retrospective Review.
Purpose: Survival
Type of Study: Retrospective review with historical controls
Methods: (kidney, ovary, breast, soft tissue) Four series of cases were compiled from five of the retrospective reviews by Helen Coley Nauts for the cancers of the kidney38, ovary41, breast34 and soft-tissues16,31. Cases selected were those that had actually been treated with the Coley toxins (rather than naturally occurring infections), had not been also treated with radiotherapy and were not duplicates of case descriptions that had already been identified in other monographs. In addition, the sites chosen initially appeared to have promising survival outcomes. Controls were selected from the Surveillance Epidemiology End Result (SEER) population-based cancer registry maintained by the National Cancer Institute. The controls selected had been diagnosed in 1983 and were matched to cases on age, sex, ethnicity, site, stage and absence of initial radiation treatment. Surgery was acceptable since the patients treated with Coley toxins had also received surgery. Although comparable diagnostic equipment was not available during the time of Coley toxins treatments (1890-1960) an attempt was made to assess a stage for each case based upon the staging guidelines of the SEER registry. Survival from initial diagnosis was assessed with a Cox proportional hazards model.
Results: The only significant difference found between the Coley and the later SEER cohort groups was in the Soft tissue group, but that difference disappeared after adjusting for stage of disease (P <1.3 (95% Confidence Interval (C.I.) 0.7-2.3). The non-significant differences between the adjusted kidney cancer groups and the other cancer groups may have occurred because these series were too small to detect differences and indicated by the wide confidence intervals. The following table compares the stage-adjusted groups by the Cox proportional Hazard risk of death by year. Various limitations of this type of study such as small sample sizes and differences in available staging technology are discussed in the article.
Case Reports
42Chandler, J.J., et al. Coley toxins and chemotherapy in treatment of breast carcinoma: Case report.
Purpose: To report the 28th case of breast carcinoma and discuss treatment with Coley toxins and chemotherapy.
Type of Study: Case report
Methods: (Breast carcinoma) Patient was white, menopausal and 37 years old admitted to the hospital in Feb. 1962, for reasons other than cancer, at which time a mass of 5 x 5 cm in the right breast was noticed.
Results: Radical mastectomy in February 1962 followed by pulmonary metastases in October. Therapy with filter-sterilized mixed bacteria Coley toxin was begun in December along with chemotherapy. In February 1963, a definite regression of the pulmonary nodules was seen for the first time, but within three months, increased number of tumor metastases were again seen on chest roentgenograms. The patient died July 3, 1963, 18 months following mastectomy. The authors concluded that the rapid progression of pulmonary metastases was halted for a short period of time through combined treatment with bacterial toxins followed by an oral alkylating agent.
41Nauts Series C: Operable ovarian carcinoma
Purpose: Disease response and survival
Type of Study: Case report
Methods: (Ovarian) One case of operable (pathologically confirmed) ovarian carcinoma. Surgical removal was followed by daily injections of the toxins for six months, a rest period of three weeks, more semi-weekly injections with "occasional" rest intervals for four months, for a total duration of 10 months.
Results: There was no recurrence and the patient delivered a full-term baby three years later. She was last known to be alive 51 years later.
41Nauts Series F: Operable sarcoma of the cervix
Purpose: Disease response and survival
Type of Study: Case report
Methods: (Cervical) One patient was given preventative Coley toxins for one year following a hysterectomy for a pathologically confirmed sarcoma of the cervix.
Results: She remained alive and well for 39 years after which she developed carcinoma of the colon and died at age 81.
41Nauts Series H: Epithelioma of the vulva.
Purpose: Disease response and survival
Type of Study: Case report
Methods: (Vulva) Date of onset was unknown. Patient received surgery followed by radiation and then Coley toxins.
Results: Overall condition was good, but the disease recurred despite continued toxins and further surgery and radiation. The patient died a little over a year after Coley toxin treatment was begun.
Reference List
1. Starnes CO. Coley's toxins in perspective [see comments]. Nature.357. 1992;357(6373):11-2.
2. Nauts HC. Bacterial products in the treatment of cancer: Past, present and future. International Colloquium on Bacteriology and Cancer 1982.
3. Coley WB. Further observations upon the treatment of malignant tumors with the toxins of erysipelas and Bacillus prodigiosus with a report of 160 cases. John Hopkins Hospital Bulletin 1896;7:175.
4. Nauts HC. Personal communication. 1996 Nov.
5. Tang ZY, Zhou HY, Zhao G, Chai LM, Zhou M, Lu JZ, et al. Preliminary result of mixed bacterial vaccine as adjuvant treatment of hepatocellular carcinoma. Med Oncol & Tumor Pharmacother 1991;8:23-8.
6. Havas HF, Schiffman G. Bushnell B, Dellaria M, Axelrod RS, Shanahan T, et al. The effect of bacterial vaccine on tumors and immune response of ICR/Ha mice. Journal of Biological Response Modifiers.9. 1990;9:194-204.
7. Nauts HC. Coley toxins: 1893-1995 and beyond. (Unpublished paper)1995 May;1-37.
8. Richardson MA, Ramirez T, Russell NC, Moye LA. Coley toxins immunotherapy: a retrospective review. Alternative Therapies in Health and Medicine 1999 May;5(3):42-7.
9. Falcone R. Adjuvant vaccine therapies. The Complete Guide to Alternative Cancer Therapies: What You Need to Know to Make an Informed Choice. 1994;166-9.
10. Zlotta AR, Drowart A, Van Vooren JP, et al. Superficial Bladder tumors and increased reactivity against mycobacterial antigens before Bacillus Calmette-Guerin therapy. Journal of Urology 1998;159(6):1885-91.
11. Anonymous. Physicians' Desk Reference. Montvale, N. J. Medical Economics, 2001.
12. Hollow T. Coley Toxin's Hidden Message. The Scientist.2001:19-22.
13. Rook G. Tumours and Coley's toxins. Nature.357. 1992;357(6379):545.
14. Starnes CO. Coley's toxins [letter; comment]. Nature.360. 1992;360(6399):23.
15. Wiemann B, Starnes CO. Coley Toxins, tumor necrosis factor and cancer research: a historical perspective. Pharmacology and Therapeutics.64. 1994;64:529-64.
16. Nauts HC. Beneficial effects of immunotherapy (bacterial toxins) on sarcoma of the soft tissues, other than lymphosarcoma: end results in 186 determinate cases with microscopic confirmation of diagnosis, 49 operable, 137 inoperable. Cancer Research Institute, Inc. 1975;Monograph #16 .
17. Starnes C. Personal Communication. 1998 Oral communication to Mary Ann Richardson.
18. Old LJ, Boyse EA. Current enigmas in cancer research. The Harvey Lectures.67. 1973;67:273-315.
19. Bratzler R, President and CEO. CpG ImmunoPharmaceuticals Changes Name to Coley Pharmaceutical Group [Web Page]. 2000. (Accessed 1910 Oct 1).
20. Waisbren BA. Observations on the combined systemic administration of mixed bacterial vaccine, Bacillus Calmette-Guerin, transfer factor, and lymphoblastoid lymphocytes to patients with cancer, 1974-1985. Journal of Biological Response Modifiers 1987;6:1-19.
21. Waisbren Burton A Sr. A scientific essay regarding a 25-year experience in the treatment of cancer with multiple immunotherapy modalities [Web Page]. (Accessed 2001 Jul 31).
22. Workshop on Alternative Medicine. Alternative Medicine: Expanding Medical Horizons. A Report to the National Institutes of Health on Alternative Medical Systems and Practices in the United States. Washington, DC: US Government Printing Office, 1992.
23. Bradova V, Web master. Coley's Toxins Menu [Web Page]. 1999. (Accessed 1910 Nov 1).
24. Kolmel KF, Vehmeyer K, Gohring E, Kuhn B, Wieding JU. Treatment of advanced malignant melanoma by a pyrogenic bacterial lysate. A pilot study. Onkologie 1991;14:411-7.
25. American Cancer Society. American Cancer Society's Guide to Complementary Alternative Cancer Methods.2000:366-67.
26. Workshop on Alternative Medicine. Coley toxins. Alternative Medicine: Expanding Medical Horizons. A Report to the National Institutes of Health on Alternative Medical Systems and Practices in the United States, Washington, DC: US Government Printing Office 1992;170.
27. Johnston B. Clinical effects of Coley's Toxins. 1. Controlled study. 2. A seven-year study. Cancer Chemotherapy Reports 1962;21:19-68.
28. Kempin S, Cirrencione C, Myers J, et al. Combined modality therapy of advanced nodular lymphomas (NL): The role of nonspecific immunotherapy (MBV) as an important determinant of responses and survival. Proc Am Soc Clin Oncol 1983;24:56.
29. Havas HF, Axelrod RS, Burns MM, Murasko D, Goonewardene M. Clinical results and immunologic effects of a mixed bacterial vaccine in cancer patients. Medical Oncology and Tumor Pharmacotherapy 1993;10(4):145-58.
30. Fowler G. Testicular cancer treated by bacterial toxin therapy as a means of enhancing host resistance. New York Cancer Research Institute, Inc. 1968;Monograph #7.
31. Nauts HC, Fowler GA. End results in lymphosarcoma treated by toxin therapy alone or combined with surgery and/or radiation or with concurrent bacterial infection. New York Cancer Research Institute, Inc. 1969;Monograph #6.
32. Fowler G. The apparently beneficial effects of concurrent infections, inflammation or fever, and of bacterial toxin therapy on neuroblastoma. New York Cancer Research Institute, Inc. 1970;Monograph #11.
33. Nauts HC. Ewing's sarcoma of bone: End results following immunotherapy (bacterial toxins) combined with surgery and/or radiation. Cancer Research Institute, Inc. 1974;Monograph # 14.
34. Nauts HC. Breast cancer: Immunological factors affecting incidence, prognosis, and survival. Cancer Research Institute Inc. 1984;Monograph #18.
35. Fowler GA. Enhancement of natural resistance to malignant melanoma with special reference to the beneficial effects of concurrent infections and bacterial toxin therapy. New York Cancer Research Institute, Inc. 1969;Monograph #9.
36. Fowler GA. Beneficial effects of acute bacterial infections or bacterial toxin therapy on cancer of the colon or rectum. New York Cancer Research Institute, Inc. 1969;Monograph #10.
37. Nauts HC. Giant cell tumor of bone: End results following immunotherapy (Coley toxins) alone or combined with surgery and/or radiation, 66 cases and concurrent infection, four cases. Cancer Research Institute, Inc. 1976;Monograph #4.
38. Nauts HC. Enhancement of natural resistance to renal cancer: beneficial effects of concurrent infections and immunotherapy with bacterial vaccines. New York Cancer Research Institute, Inc. 1973;Monograph #12.
39. Nauts HC. Multiple myeloma: Beneficial effects of acute infections or immunotherapy (bacterial vaccines). Cancer Research Institute, Inc. 1975;Monograph #13.
40. Nauts HC. Osteogenic sarcoma: End results following immunotherapy with bacterial vaccines, 165 cases or following bacterial infections inflammation or fever, 41 cases. Cancer Research Institute, Inc. 1975;Monograph #15.
41. Nauts HC. Beneficial effects of acute concurrent infection, inflammation, fever or immunotherapy (bacterial toxins) on ovarian and uterine cancer. Cancer Research Institute, Inc. 1977;Monograph #17.
42. Chandler JJ, Crisera RV, Fletcher WS. Coley's toxins and chemotherapy in treatment of breast carcinosarcoma: case report. American Surgeon 1969 May;35(5):377-83.
43. Johnston BJ, Novales ET. Clinical effect of Coley's toxin. II. A seven-year study. Cancer Chemotherapy Reports 1962;21:43-68.
44. Nauts HC, Fowler GA, Bogatko FH. A review of the influence of bacterial infection and of bacterial products (Coley's toxins) on malignant tumors in man. Acta Medica Scandinavica 1953;145(Suppl 276):1-103.
45. Nauts HC. Sarcoma of the soft tissues, other than lymphosarcoma, treated by toxin therapy; end results in 186 determinate cases with microscopic confirmation of diagnosis: 49 operable, 137 inoperable, by Helen C. Nauts and others. New York Cancer Research Institute, Inc. 1959;(Monograph #3).
46. Nauts HC. The beneficial effects of bacterial infections on host resistance to cancer: end results in 449 cases. Cancer Research Institute, Inc. 1980;Monograph #8.
47. Zacharski LR, Sukhatme VP. Coley's toxin revisited: Immunotherapy or plasminogen activator therapy of cancer? J Thromb Haemost 2005;3:424-27.
48. McCarthy EF. The toxins of William B. Coley and the treatment of bone and soft-tissue sarcomas. The Iowa Orthop J 2006;26:154-58.
49. Cann SAH, van Netten JP, van Netten C. Dr William Coley and tumour regression: a place in history or in the future. Postgrad Med J 2003;79:672-80.
50. Zacharski LR, Ornstein DL, Gabazza EC, D'Alessandro-Gabazza CN, Brugarolas A, Schneider J. Treatment of malignancy by activation of the plasminogen system. Semin Thrombos Hemostas 2002;28:5-17.
