For citations to the original sources of data quoted in this section, click [link to PDF A1] or [link to PDF A2].

A scientific review of 897 cancer patients treated with various formulations of Coley Fluid up to 110 years ago found that complete regression and 5-year survival occurred in 46% of the 523 inoperable cases and 51% of the 374 operable cases. These results are comparable to modern 5-year survival rates. The National Cancer Institute estimates overall 5-year cancer survival at 35% in 1950-54 and 63.8% in 1992-98.

To determine comparable rates of 10-year survival, in 1999 researchers compared historical Coley Fluid patients with matched controls from the National Cancer Institute’s Surveillance Epidemiology End Result database. The study found higher rates of 10-year survival for Coley Fluid patients compared to modern patients in kidney cancer (33% to 23%), ovarian cancer (55% to 29%) and sarcoma (50% to 38%).

However, retrospective studies may underestimate the efficacy of Coley Fluid because there was a wide variability in potency between the more than 20 different formulations of Coley Fluid used to treat cancer patients, and there were no standard clinical protocols for the administration of Coley Fluid.

To illustrate the importance of formulation, the chart below compares 5-year survival rate by formulation for 137 historical sarcoma patients who received Coley Fluid therapy:

To illustrate the importance of clinical protocol, the chart below compares 5-year survival rate by length of therapy for the same group of historical sarcoma patients:

The following sections summarize the nine clinical studies of Coley Fluid in patients with cancer published from 1962 to 2006. Three of these studies were randomized controlled trials. In addition, a review is provided on 13 Cancer Research Institute monographs covering results of Coley Fluid treatment in various tumors types. Finally, one non-cancer investigation, a study of the effect of Coley Fluid on depression is discussed.

Randomized controlled trials in patients with cancer

Johnston B. Clinical effects of Coley's Toxins. 1. Controlled study. 2. A seven-year study. Cancer Chemother Rep 1962;21:19-68.

Purpose: To evaluate the clinical effect of Coley Fluid on patients with inoperable metastatic neoplasms. Methods: Thirty-four patients with inoperable metastatic neoplasms were treated with Coley Fluid. Coley Fluid was administered intravenously 5 days per week, unless tumors were easily accessible in which case intratumoral injections were administered every 4th or 5th injection day. The initial dose was 0.05 ml Coley Fluid in a 1:20 dilution. Doses were increased incrementally to produce a fever between 38.8-40.0^oC. Coley Fluid was administered for 3 weeks, and continued for subsequent cycles 3 times per week unless there was disease progression. An additional 37 patients received a typhoid vaccine as a control group, treated in the same manner. Patients were randomized to one of the two groups and given identical nursing care and supportive therapy. No restrictions were placed on food or fluid intake during therapy. Results: Only one of the typhoid treated patients showed any improvement of short duration and questionable significance. In the group treated with Coley Fluid, 16 patients showed some improvement. Of the 16, nine showed objective improvement. The others had subjective changes, such as decreased pain and reduced need for narcotics (n=7). One patient showed a significant increase in weight (15 lbs) and two had decreased bleeding. All patients had severe chills and fever as was expected. Major side effects were occasional dyspnea and cyanosis during chill, occasional pain in the area of the tumor, and occasional nausea and vomiting. Nausea and vomiting was more common in the typhoid treated group. There was no depression of marrow activity, white cells or platelets. Occasionally there was a drop in hemoglobin or hematocrit, but only in those with bleeding to explain blood loss. Renal function studies showed no specific alterations, except in the typhoid treated group, where albuminuria was observed in 6 out of 37 patients (16.2%). Liver function studies were not altered in the Coley Fluid treated group, while one typhoid treated patient developed hepatic insufficiency with jaundice (without evidence of liver metastases) and a second had an elevation of alkaline phosphatase. No adverse effects were noted on the cardiovascular system.

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 [abstract]. Proc Am Soc Clin Oncol 1983;24:56.

Purpose: To evaluate the effect of Coley Fluid on the response and survival of patients with advanced nodular lymphoma. Methods: Fifty-six patients with nodular lymphomas (stages II-IV) were treated with the NHL-4 protocol. Coley Fluid was administered in a randomized fashion one week prior to chemotherapy. Twenty-six patients in the Coley Fluid therapy group and 30 in the control group. Results: The overall complete and partial response rates were 62% and 32%, respectively. The complete response rate of vaccinated patients was 85% vs 44% for non-vaccinated patients. Relapses occurred in 20% of Coley Fluid-treated complete response patients vs 42% of non-Coley Fluid-treated complete response patients. The survival duration of patients treated with Coley Fluid was significantly better than non-Coley Fluid patients (p= 0.029); however the median follow-up was only 34.3 months. This study was reported in abstract form and adverse effects of the treatment were not mentioned.

Tang ZY, Zhou HY, Zhao G, 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 Coley Fluid on patients with hepatocellular carcinoma as an adjuvant to surgery or chemotherapy and radiotherapy. Methods: Eighty-six patients (81 male, 5 female) with histologically proven hepatocellular carcinoma were entered in the trial from March 1985 to June 1988. The patients were divided into two series:

1. Palliative Resection (n=38): resection was followed by intravenously cisplatin chemotherapy two weeks after surgery. In this series, 19 received Coley Fluid and 19 were controls. Coley Fluid (0.05 ml in 2 ml saline) was infused intravenously daily or every other day for 6-40 injections (mean 12).
2. Unresectable HCC (n=48): all received hepatic artery plus intraarterial cisplatin infusion plus radiotherapy, 25 received Coley Fluid and 23 were controls. Coley Fluid (0.05 ml in 2 ml saline) was infused daily or every other day through a hepatic arterial catheter for 9-49 injections (mean 23).

Results:

1. The one- and two-year survival rates for the Coley Fluid 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 the Coley Fluid group and 39%, 25% and 20% for the control (p= 0.07, 0.09, 0.07, respectively).
3. Side effects included chills followed by mild fever (37.5-38.5^oC) and rarely cyanosis following Coley Fluid injection. No other side effects were reported. There were no abnormal laboratory tests.

Uncontrolled clinical series in patients with cancer

Johnston BJ, Novales ET. Clinical effect of Coley's toxin. II. A seven-year study. Cancer Chemother Rep 1962;21:43-68.

Purpose: This study followed the randomized Johnston trial, which suggested that some neoplasms respond to this type of therapy. This study was undertaken to classify the types of tumors that will respond. Methods: 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 Fluid were included in the analysis. Coley Fluid was administered intravenously 5 days per week, unless tumors were easily accessible in which case intratumoral injections were administered every 4th or 5th injection day. The initial dose was 0.05 ml Coley Fluid in a 1:20 dilution. Doses were increased incrementally to produce a fever between 38.8-40.0^oC. Coley Fluid was administered for 3 weeks, and continued for subsequent cycles 3 times per week unless there was disease progression. No restrictions were placed on food or fluid intake during therapy.

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). Three showed a gain in weight in addition to reduced pain. Objective improvement occurred for 30 patients, which 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 temporary being followed by recurrence and/or metastasis.

Chandler JJ, Stark DB, Allen CV, Fletcher WS. Treatment of cancer by bacterial toxins. Am Surg 1965;31:443-49.

The investigators studied Coley Fluid treatment in 21 patients with various tumors. Coley Fluid was injected intravenously and when accessible intratumorally. The starting dose and dosing increments were not stated, but presumably similar to the study by Johnston (1962). Dosages were increased gradually to produce a fever in the range of 38.3-40.3^oC. Patients received injections 5 days a week for three weeks followed by biweekly to weekly injections. Three patient groups were treated. The first group included six patients with operable cancers including melanomas and sarcomas, which also received surgery and in some patients chemotherapy or radiotherapy. One patient with melanoma of the left temporal region was treated with surgery + Coley Fluid (45 injections) and was clinically free of disease at the time of reporting two years later. One other patient with melanoma was well following discharge receiving a limited number of injections (15 injections of Coley Fluid) and surgery. This patient had a surgically treated recurrence one year later, but was well at the time of reporting. The other 4 patients died of their disease with no objective benefit from Coley Fluid treatment. In the second group, Coley Fluid was used as palliative treatment in seven patients following the failure of conventional treatment and advancement of disease. All patients but one received a very limited number of injections and died of their disease. One patient with melanoma who received 52 injections over a period of 14 months was in good health at the time of reporting, but had multiple nodules present. In a third group, eight patients with advanced disease and tumors that were considered radio-resistant were given Coley Fluid followed by palliative radiation to localized symptomatic areas. Six of eight patients were considered to have definitely benefited. All but one patient subsequently succumbed to their disease. One patient with a fibrosarcoma who had a dramatic reduction and disappearance of multiple tumor masses was alive at the time of reporting, with some residual evidence of malignant disease. Reported effects of Coley Fluid included fever, chills, fatigue, and pain and increased temperature at the tumor site following injection. This occurred commonly in non-injected lesions and it was noted that Coley Fluid often aided in revealing lesions not previously apparent. The symptomatic effects of Coley Fluid were reported to be short-lived and resolved in several hours as the temperature fell. In one case there was an episode of moderate hypotension that was considered dose related. The effects of Coley Fluid were reported to be mild in comparison to the side effects observed following chemotherapy.

Axelrod RS, Havas HF, Murasko DM, Bushnell B, Guan Coley Fluid. Effect of the mixed bacterial vaccine on the immune response of patients with non-small cell lung cancer and refractory malignancies. Cancer 1988;61:2219-30.

Purpose: Clinical series of patients with advanced cancer treated with Coley Fluid. Methods: Twelve patients were evaluated following treatment with one or more cycles of treatment with Coley Fluid. Eight patients with refractory malignancy were treated with Coley Fluid only (0.1 ml Coley Fluid in 100 ml normal saline intravenously) twice weekly for 3-16 weeks (colorectal cancer, pancreatic cancer, chronic lymphatic leukemia, hepatoma [two patients], and sarcoma [three patients]). Four patients with advanced non-small cell lung cancer were treated with Coley Fluid in combination with low-dose cyclophosphamide, day 1; cisplatin, day 15; and Coley Fluid, 0.1 ml intravenously, days 5, 7, and 9. Two control subjects received cyclophosphamide and cisplatin alone. The cycle was repeated every 28 days. Plasma interferon levels, interleukin-2 production by peripheral lymphocytes, and lymphocyte subpopulations were monitored.

Results: Survival after the start of treatment in the refractory cancer group ranged from 34-650 days (the latter alive at the time of reporting), mean 197 days. In the group with lung cancer, survival in the Coley Fluid treated group ranged from 105-306 days (the latter alive at the time of reporting) with a mean of 279 days, and in the control group, survival was 16 and 19 days. Adverse effects included chills (68%), fever (23%), increased respiratory rate (33%), blood pressure increase (25%) or decrease (5%), nausea (11%), and in less than 5%, wheezing, cyanosis, vomiting, and headache. Interferon levels and interleukin-2 production showed increased or sustained values in general. In some patients, B-cells and helper T-cell populations increased, whereas T-suppressor cell numbers declined. In this pilot study, cancer patients treated with MBV showed objective evidence of immune stimulation with acceptable toxicity.

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;14:411-17.

Purpose: To study the effect of Coley Fluid in advanced melanoma patients. Methods: 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, consisting of two isolated limb perfusions. The patients were injected intravenously with Coley Fluid. 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. The objective was to reach a temperature of 39^oC or higher using stepwise increases in concentration. No alcohol or antipyretics were allowed during treatment. Metoclopramid was used for nausea, tramadol for pain as indicated. Injections were administered at 8 am. Drinks were allowed subsequent to the peak in temperature followed by a light dinner.

Results: All but two patients reached the desired temperature. In three of the 15 cases, the treatment resulted in a total remission (disease free at the time of reporting for 32, 21, and 15 months). These 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. TNF-a levels were elevated with temperature. Marked increase in monocytes was noted 24-48 hours after injection. Soluble fibrin doubled by 24 hours after injection. Side effects of the therapy included fever, nausea, headache, back pain and occasionally herpes labialis. Some muscular weakness was noted in most patients and a few experienced diarrhea. None of the side effects were long lasting, nor did they cause an interruption of treatment.

Havas HF, Axelrod RS, Burns MM, Murasko D, Goonewardene M. Clinical results and immunologic effects of a mixed bacterial vaccine in cancer patients. Med Oncol Tumor Pharmacother 1993;10:145-58.

Purpose: To determine effect of Coley Fluid upon malignant disease and immunological parameters: interleuken-2 (IL-2), plasma interferon (IFN) and tumor necrosis factor (TNF). Methods: Eleven patients 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. Coley Fluid was given (as a single agent for all except the AIDS patient) initially intravenously and subsequently by intramuscular injection twice weekly for a range of 51 to 457 days. One ml of Coley Fluid was diluted into 100 ml normal saline for intravenous injections and a 1:10 dilution was used for intramuscular injections. 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: 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 intravenous administration of Coley Fluid 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 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. No statistical analysis of the immune data was performed due to the diverse patient population and different number of treatments and assays. 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.

Bajenov LG, Nasrullaev AM, Bajenova TL. Analgesic effect of the analogue to Coley’s vaccine [Abstract]. 2nd World Congress on Regional Anaesthesia and Pain Therapy, Rio de Janeiro, March 2006.

Purpose: To examine the effect of Coley Fluid on cancer pain and tumor regression. Methods: Coley Fluid was used in patients with stage 3 or 4 cancer, primarily cancer of the stomach, liver and pancreas. The study focused on Coley Fluid administration in subjects with severe cancer-associated pain (rated as 4 or 5 on a pain scale of 5) was carried in 16 patients. For 8 (50%) of these subjects, analgesic drugs provided only moderate pain relief. Patients were treated primarily with intramuscular injections, and intratumoral injections when possible (for externally accessible disease). Concentrations of Coley Fluid were increased from 0.01 ml up to 3-5 ml within 21-28 days, following a 1-2 weeks rest period, the course of treatment was repeated.

Results: By the end of the first course, 5 (31.3%) discontinued all analgesic medications, while varying degrees of analgesic dose reductions were obtained in the remainder. In general, patients were observed to have an improved appetite and sense of well-being, improved biochemical and clinical parameters, with at least partial tumor regression observed in 7 (43.8%) patients.

Cancer Research Institute monograph series

William Coley, his contemporaries, and many subsequent physicians published hundreds of papers on patients treated with Coley Fluid. Coley alone reported treating over 1,000 patients with advanced inoperable tumors (Coley 1926). Coley kept detailed clinical records and endeavoured to follow-up all his patients with advanced cancer treated with Coley Fluid. He reported an estimated 10% survival rate, which was defined as survival from 3 years to many decades following initiation of therapy. He also treated countless operable cases from which survival estimates cannot be determined. His survival estimates in these advanced cases are remarkable in light of the fact that he generally could only keep patients in the hospital for a limited duration of a few weeks, with follow-up being relegated to the patient’s family physician. It was during this latter period when recurrences most often appeared as the physicians often did not appreciate the necessity of repeated injections, fever, and prolonged follow-up.

Coley’s daughter, Helen Coley Nauts, founded the Cancer Research Institute to study in greater detail Coley Fluid therapy and other cancer immunotherapies. A Cancer Research Institute sponsored retrospective review (Nauts 1982) was undertaken to examine the efficacy of Coley Fluid in operable and inoperable cancers (Table 2) and possible factors associated with prolonged survival of treated subjects.

Review of the 5-year survival of 897 microscopically confirmed cancers:

The treatment-associated factors that were correlated with prolonged survival included: potency of the vaccine preparation (i.e. particularly Type XI, used from 1907-1922), site of injection (i.e. intratumoral injections), dose increments to maintain elevated febrile reactions (i.e. ~38.5-40^oC), frequency of injections (i.e. daily or every other day), and duration of treatment (i.e. > than 3 months).

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. Monograph No. 4. Cancer Research Institute 1966.

Type of Study: Retrospective review
Methods: Giant cell tumor of the bone, n=57 (the 66 cases mentioned in the title are not identified in the monograph) All but three of the cases were microscopically confirmed. Of the entire group, 38 received surgery and 10 received radiation before Coley Fluid.

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.

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. Monograph No. 6. New York Cancer Research Institute 1969.

Type of Study: Retrospective review
Methods: Lymphoma, n=86. The records of all known cases of lymphoma that were microscopically confirmed and treated with Coley Fluid were reviewed. Coley Fluid was 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 Coley Fluid within six months of their initial diagnosis and an additional 28% within the first year and a half. One patient received Coley Fluid 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 Fluid within six months of the original diagnosis and an additional 35% within a year and a half. Six patients received Coley Fluid three to four years following the initial diagnosis.

Fowler G. Testicular cancer treated by bacterial toxin therapy as a means of enhancing host resistance. Monograph No. 7. New York Cancer Research Institute 1968.

Type of Study: Retrospective review
Methods: Series A. Testicular cancer, of the 63 patients, 20 were operable. The records of all known cases of testicular cancer that were microscopically confirmed and treated with Coley Fluid were reviewed. Operable patients are reported in series A:

(A1) Surgery + Coley Fluid started within one month of operation (n=15)
(A2) Surgery + radiotherapy + Coley Fluid 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 monograph; i.e., surgery + Coley Fluid with or without radiotherapy: 17 (75%) alive at last contact with survival times ranging from three to 58 years; average of 23.3, 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: Series B. Testicular cancer, 43 inoperable patients were given Coley Fluid. (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 Fluid.
D. "Terminal" 17 patients - one "success" who survived onset and unsuccessful surgery followed by Coley Fluid 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.

Fowler GA. Enhancement of natural resistance to malignant melanoma with special reference to the beneficial effects of concurrent infections and bacterial toxin therapy. Monograph No. 9. New York Cancer Research Institute 1969.

Type of Study: Retrospective review
Methods: Melanoma, all 28 cases were microscopically confirmed. Fourteen cases were operable and 14 were inoperable. One of the operable patients also received radiation before Coley Fluid. Two of the inoperable patients received radiation concurrent with Coley Fluid, one prior to the Coley Fluid and one patient received chemotherapy (nitrogen mustard and 5FU) prior to Coley Fluid and radiation subsequent to Coley Fluid.

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 Fluid treatments, and one patient survived for 57 years from both diagnosis and Coley Fluid 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 Coley Fluid.

Fowler GA. Beneficial effects of acute bacterial infections or bacterial toxin therapy on cancer of the colon or rectum. Monograph No. 10 (Series B). New York Cancer Research Institute 1969.

Type of Study: Retrospective review
Methods: Colorectal cancer, all 11 cases were microscopically confirmed. Only one of the 10 cases was operable when Coley Fluid 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 Coley Fluid two years after the initial diagnosis, but the others received Coley Fluid treatment 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.

Fowler G. The apparently beneficial effects of concurrent infections, inflammation or fever, and of bacterial toxin therapy on neuroblastoma. Monograph No. 11. New York Cancer Research Institute 1970.

Type of Study: Retrospective review
Methods: Neuroblastoma, n=9. All "known cases" of neuroblastoma patients treated with Coley Fluid 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 Coley Fluid, two were inoperable, and one had recurred four months after original diagnosis. Seven patients received radiotherapy. One patient received radiotherapy and chemotherapy (thiotepa) before Coley Fluid.

Results: The one case to receive only Coley Fluid remained alive and well and able to walk 58 years after onset despite having been inoperable, 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 author concluded that prolonged Coley Fluid therapy was important, but that Coley Fluid was not helpful if begun after "massive radiotherapy and chemotherapy have destroyed the immune responsiveness of patients".

Nauts HC. Enhancement of natural resistance to renal cancer: beneficial effects of concurrent infections and immunotherapy with bacterial vaccines. Monograph No. 12. New York Cancer Research Institute 1973.

Type of Study: Retrospective review
Methodology: Kidney cancer, n=11. Eleven cases consisted of three children with Wilms’ tumor and eight adults: two with carcinoma or adenocarcinoma and six with hypernephroma. Eight patients had nephrectomy, one patient had partial removal of tumor and there was no attempt at removal for two cases considered hopeless. Coley Fluid was given preoperatively for one child; all other patients received Coley Fluid postoperatively.

Results: For the one child receiving Coley Fluid preoperatively, there was no effect and the child died within a year with metastases. For four patients receiving the injections postoperatively, there was no apparent benefit, and they also died within a year of receiving Coley Fluid. 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.

Nauts HC. Multiple myeloma: Beneficial effects of acute infections or immunotherapy (bacterial vaccines). Monograph No. 13. Cancer Research Institute 1975.

Type of Study: Retrospective review
Methods: Multiple myeloma, n=12. Five patients had previous surgical removal of some of their disease and four had prior radiation. Eight patients received radiation concurrent with Coley Fluid; of these, four had received radiation previously. Four patients received radiation following Coley Fluid.

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.

Nauts HC. Ewing's sarcoma of bone: End results following immunotherapy (bacterial toxins) combined with surgery and/or radiation. Monograph No.14. Cancer Research Institute 1974.

Type of Study: Retrospective review
Methods: Ewing’s sarcoma, n=114. 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 Fluid 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 Coley Fluid therapy. Eight of the five or more years survivors, received Coley Fluid within a year following diagnosis and one patient following a recurrence at two years.

Nauts HC. Osteogenic sarcoma: End results following immunotherapy with bacterial vaccines, 165 cases or following bacterial infections inflammation or fever, 41 cases. Monograph No. 15. Cancer Research Institute 1975.

Type of Study: Retrospective review
Methods: Osteogenic sarcoma, n=165. Patients were 165 cases with osteogenic sarcoma who were operable (n=138) and included 81 (59%) who also had radiation in addition to surgery and Coley Fluid. Patients who were inoperable (n=24) included seven who had received previous surgery, but then had recurrent disease that was inoperable. Of the 24 inoperable patients, 21 (88%) received radiation in addition to Coley Fluid. 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 Coley Fluid. In summary, the percentage of operable patients receiving radiation in addition to Coley Fluid appears to be similar in both the successful and non-successful groups.

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. Monograph No. 16. Cancer Research Institute 1975.

Type of Study: Retrospective review
Methods: Soft tissue sarcoma, n=186. Case histories of patients treated with Coley Fluid 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 (62 of the 137 inoperable patients had received previous surgery followed by a recurrence of the tumor that was subsequently 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 Coley Fluid was begun was:

Inoperable primary 137 (62 recurrent)

Operable primary 49

The time from initial diagnosis to the start of Coley Fluid was within the first year following the initial surgery for most patients (80 of 105 operable and inoperable successes). There were, however, 14 patients who had already survived at least two or more years before receiving Coley Fluid 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%).

Nauts HC. Beneficial effects of acute concurrent infection, inflammation, fever or immunotherapy (bacterial toxins) on ovarian and uterine cancer. Monograph No. 18. Cancer Research Institute 1977.

Series B: Inoperable ovarian carcinoma

Type of Study: Retrospective review
Methods: Ovarian carcinoma, n=7. Seven cases of inoperable ovarian carcinoma were treated by Coley Fluid. All cases were pathologically confirmed and had been treated with Coley Fluid 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 Coley Fluid was 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 C: Operable ovarian carcinoma

Type of Study: Case report
Methods: Ovarian carcinoma, n=1. One case of operable (pathologically confirmed) ovarian carcinoma. Surgical removal was followed by daily injections of Coley Fluid 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.

Series D: Inoperable ovarian sarcoma

Type of Study: Retrospective review
Methods: Ovarian sarcoma, n=8. Eight cases of inoperable ovarian sarcoma (microscopic confirmation) were given daily injections of Coley Fluid 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

Type of Study: Retrospective review
Methods: Cervical carcinoma, n=6. Six patients with pathologically confirmed inoperable carcinoma of the cervix were given Coley Fluid injections from two months to three years.
Results: There was no improvement for two patients who each died six months later. One patient had an adverse reaction from a larger than usual dose that was injected directly into the tumor. This was associated with nausea, herpes labialis, 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 F: Operable sarcoma of the cervix

Type of Study: Case report
Methods: Cervical sarcoma, n=1. One patient was given preventative Coley Fluid 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.

Series G: Inoperable sarcoma of the uterus

Type of Study: Retrospective review
Methods: Uterine sarcoma, n=10. Ten patients with inoperable sarcomas of the uterus were treated with Coley Fluid 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.

Series H: Epithelioma of the vulva.

Type of Study: Case report
Methods: Vulva epithelioma, n=1. Date of onset was unknown. Patient received surgery followed by radiation and then Coley Fluid.
Results: Overall condition was good, but the disease recurred despite continued Coley Fluid therapy and further surgery and radiation. The patient died a little over a year after Coley Fluid treatment was begun.

Nauts HC. Breast cancer: Immunological factors affecting incidence, prognosis, and survival. Monograph No. 18. Cancer Research Institute 1984.

Type of Study: Retrospective review

Methods: Breast cancer, n=87. All 87 cases were microscopically confirmed with 17 of them operable and 70 inoperable. The 60 inoperable cases noted in the monograph 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 Coley Fluid preoperatively, five postoperatively. The beginning of Coley Fluid treatment was postoperatively 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 Fluid for three months or more, 36 carcinoma patients treated for less than three months and seven sarcoma patients treated with Coley Fluid from less than one month to seven months. Fifteen of the group receiving Coley Fluid for three months or more also received radiation and two also received chemotherapy (5FU, cytoxan and methotrexate). Nine of the less than three months Coley Fluid 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 Fluid. All of the five operable sarcoma patients survived and were free of disease from six to 67 years after diagnosis, initial surgery or surgeries and start of Coley Fluid therapy. 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 Fluid 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 Coley Fluid 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 Coley Fluid; one of them from a staphylococcal infection. Coley Fluid was tested and found to be sterile. The author stated that this was the only case of 900 treated with Coley Fluid 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 Coley Fluid to determine a survival time for the remaining patient.

Non-cancer studies

Bauer J, Hohagen F, Gimmel E, et al. Induction of cytokine synthesis and fever suppresses REM sleep and improves mood in patients with major depression. Biol Psychiatry 1995;38:611-21.

Purpose: The investigators conducted a pilot study to evaluate the impact of the application of an endotoxin-containing substance (Coley Fluid) on biological and psychological parameters in patients suffering from major depression. Methods: Mood and sleep parameters were monitored in seven drug-free, severely depressed patients before, during, and after the administration of a single dose of endotoxin. Results: All patients responded with a short pulse of increased synthesis of the cytokines tumor necrosis factor, interleukin-1, and interleukin-6 and elevated body temperature for several hours. During the night following endotoxin administration, rapid eye movement (REM) sleep was significantly suppressed, while changes in slow wave sleep were not significant. During the next day, all patients were in a significantly improved mood; however a rebound of REM sleep was observed in the second night after endotoxin administration and mood returned to pretreatment levels during the next days. Reported side effects of the treatment included apathy noted during the first 6 hours while cytokine blood levels were high. Other side effects in some of the patients included chills and muscle pain during the short phase of fever increase, transient headache, and nausea. In those subjects that did experience side effects, all symptoms disappeared within 6 hours after endotoxin administration. The results indicate a transient beneficial effect on mood from single dose treatment with Coley Fluid.