CHRONOLOGY OF EVENTS IN THE SCIENTIFIC EVALUATION OF IPT AND THE TREATMENT OF CANCER
by Dr. Steven G. Ayre, M.D.
October 1989: Poster presentation at the Forty-second Annual Symposium on Fundamental Cancer Research, The University of Texas, M.D. Anderson Cancer Center entitled “Breast carcinoma treated by a regimen of low-dose chemotherapy and insulin: report of four cases and pharmacokinetic considerations”.
December l990: Publication in the European Journal of Cancer (letter) entitled “Neoadjuvant low-dose chemotherapy with insulin in breast carcinomas” (Eur. J Cancer, 26, 1262-1263, 1990).
February 1991: Oral presentation at the Third International Congress on Neoadjuvant Chemotherapy, Paris, France, February 6-9, 1991. Title: “Insulin plus low-dose CMF as neoadjuvant chemo-hormonal therapy for breast carcinomas”. A write-up of this talk appeared in the July-August 1991 issue of Oncology News (Vol. 17, No. 4).
June 1991: Began correspondence with Reps. Patricia Schroeder & Constance Morella, co-chairpersons of the Congressional Caucus on Women’s Issues in response to their “Breast Cancer Challenge” which was issued to the medical profession in June, 1991. The “Breast Cancer Challenge” charged American researchers and physicians to come up with an effective treatment for breast cancer by the year 2000.
July 18, 1991: Sent a letter to Susan Love, M.D. of the Faulkner Breast Center in Boston, Massachusetts, informing her of IPT and its possible safety and efficacy in the neoadjuvant chemohormonal treatment of breast cancer. Dr. Love is the chief medical spokesperson for the Breast Cancer Coalition.
October 1991: As a result of the correspondence with the “Breast Cancer Challenge”, I received a copy of a letter from Bernadine Healy, M.D., Director, National Institutes of Health, addressed to Rep. Constance Morella (Dated October 23, 1991). This letter discussed IPT, and mentioned that the matter had been referred to the National Cancer Institute’s Division of Cancer Treatment, Cancer Therapy Evaluation Program (CTEP).
December 2, 1991: IND submission to the FDA of a protocol entitled “Neoadjuvant combination chemohormonal therapy for the treatment of breast carcinoma using CMF plus insulin”. The intent of this protocol was to perform a small pilot study using IPT and low-dose chemotherapy in the treatment of subjects newly diagnosed with breast cancer (Stages I-IIIB). The Principal Investigator for this study was Ira J. Piel, M.D., F.A.C.P., a medical oncologist-hematologist affiliated with the Illinois Masonic Medical Center in Chicago, IL.
December 2, 1991: Received letter from Susan Love, M.D. in her capacity as coordinator, Breast Cancer Coalition Research Task Force, informing me of the Research Hearings to be held in Washington, D.C., on February 5 & 6, 1992, and inviting me to attend.
December 2, 1991: As a result of correspondence between myself and Dr. Bernadine Healy (dated November 11, 1991), as well as between Rep. Constance Morella and Dr. Healy, I received a letter from Michael A. Friedman, M.D., Associate Director, CTEP, informing me that Ms. Diane Bronzert would be getting in touch to discuss grant application procedures to fund IPT studies.
December 30, 1991: Submission made to Kay Dickerson, Ph.D., of the Breast Cancer Coalition Research Hearings, requesting time to offer oral testimony at the Hearings on the use of IPT with low-dose chemotherapy for the neoadjuvant treatment of breast cancer.
December 31, 1991: FDA rules on IND submission. Protocol is put on clinical hold. The reasoning behind this decision was that there are safe and effective forms of treatment for early stages of breast cancer already in existence, and that denying subjects the value of these treatments would put them at unreasonable and significant risk of illness or injury. I was informed that the only appropriate group of patients for the study of any new therapy would be patients for whom standard appropriate therapy had failed, and whose disease had progressed, i.e. patients with Stage IV disease.
January 24, 1992: Received letter from Charles L. Vogel, M.D., Medical Director, South Florida Comprehensive Cancer Centers, and Moderator of the Clinical Science Session of the Breast Cancer Coalition Research Hearings. Dr. Vogel stated that IPT must still be considered an unorthodox therapy needing scientific corroboration of its effectiveness. I was invited to attend the Research Hearings as an observer. Dr. Vogel also informed me of the NCI’s initiative to evaluate unorthodox or non-conventional medical therapies, and referred me to Michael Hawkins, M.D. of the National Cancer Institute’s Cancer Therapy Evaluation Program to discuss the matter further.
January 25, 1992: Telephone conversation and subsequent correspondence sent to Michael .J. Hawkins, M.D., Chief of Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment, National Cancer Institute. (This is the same division of NIH to which Dr. Healy had referred me in her letter of October 23,1991). My correspondence to Dr. Hawkins included an informational brochure on IPT, plus a copy of the ”on-clinical-hold” breast cancer protocol.
January 28, 1992: Received official written confirmation from Gregory Burke, M.D., Ph.D., Director, Division of Oncology and Pulmonary Drug Products, Office of Drug Evaluation 1, Center for Drug Evaluation and Research concerning the FDA’s ruling placing the lPT/breast cancer protocol on clinical hold. His letter reiterated the recommendation that the most appropriate group of breast cancer patients to first be studied/treated with IPT would be subjects with Stage IV metastatic breast cancer who had failed primary therapy with standard approved treatment modalities.
February 1, 1992: Received correspondence from Dr. Hawkins at CTEP making a similar recommendation as that from Dr. Burke at the FDA. The best breast cancer population to study would be women with metastatic disease who had not previously received chemotherapy for their metastatic disease (adjuvant therapy would be permitted if they recurred more than 6 or 12 months after their last chemotherapy treatment). Also included in this mailing was a document prepared by the CTEP entitled, “Preparation of a Best Case Series and the Conduct of Pilot Clinical Trials Using Unconventional Cancer Treatments”. Dr. Hawkins also offered generous collaboration and assistance in the design and review of protocols for the proposed clinical studies.
February 5 & 6, l992: Breast Cancer Coalition Research Hearings held in Washington, D.C. Comments were made about IPT during Session 3 (Clinical Science) mentioning that the therapy was a novel therapeutic idea in need of clinical confirmation. These comments were entered into the written testimony of the Hearings.
May l, 1992: Submission to the Cancer Therapy Evaluation Program (CTEP) of a “Best Case Series” of IPT treatment involving a variety of different cancers. The intent of this submission was to introduce the CTEP to the historical context of the practice of IPT abroad, and to demonstrate the kinds of clinical results that have been experienced with this practice over the last several decades.
June 25, 1992: Telephone conversation initiated by Michael J. Friedman, M.D., Associate Director of NCI’s Cancer Therapy Evaluation Program, with information to the effect that CTEP was proceeding with an investigation of a number of unconventional cancer therapies, including IPT, and that a decision on their evaluation would be forthcoming by the end of July, 1992.
June 29,1992: Received correspondence from Charles L. Vogel, M.D. of The Mount Sinai Comprehensive Cancer Center in Miami Beach, Florida. Having reviewed a copy of the Best Case Series on IPT, Dr. Vogel expressed interest in performing a trial of IPT in the treatment of patients with advanced breast cancer. Current plans are to develop a new IND submission to the FDA for treating Stage IV breast cancer patients with IPT, and with Dr. Vogel acting in the capacity of Clinical Investigator for this proposed study.
July 20, 1992: Submitted response to FDA’s letter of 1/28/92 that had put the original IPT protocol submission on clinical hold. In this letter of response, the argument in favor of treating women newly diagnosed with breast cancer was pursued further. The minimal risks of the protocol were emphasized as well as the benefit s (breast conservation, quality of life under treatment). It was argued that theoretical arguments against such a program of study would seem less important than practical observations made over several decades of practice with IPT, and that women with newly diagnosed breast cancer should he given the option of breast-preserving treatment for their disease.
August 21, 1992: Received notification from the FDA that the July 29 IND submission had been put on clinical hold for reasons similar to those given for putting the first IND submission on hold. (See Dec 31/9l and Jan 28/92 above).
September 25, 1992: Notified by Mary McCabe, R.N., Clinical Trials Specialist with CTEP that their agency was interested in insulin potentiation of chemotherapy, and that a process of review was underway to determine the most appropriate way of scientifically evaluating IPT.
April 23, 1993: Notified by Mary McCabe that CTEP had decided not to proceed with any formal investigation of IPT. (Note: I believe the decision on the part of CTEP here was more of a political one than scientific. CTEP was at that time very much involved with the evaluation of autologous bone marrow transplantation (ABMT) treatment for breast cancer, and didn’t want to take on another therapy for evaluation that would compete with this very expensive and “high-tech” approach to breast cancer treatment.
May 27, 1993: Materials on IPT sent to the newly established Office of Alternative Medicine (OAM) at the National Institutes of Health. In subsequent communications with Dr. Michael Eskinazi at OAM I was given the opinion that IPT was more mainstream medicine than alternative therapy, and that it should be evaluated through established channels for evaluating such medical discoveries.
July 22, 1993: Received a telephone call from Dr. Michael Hawkins – formerly with CTEP, and now with the Georgetown University Medical Center, Division of Medical Oncology – offering to perform an animal study to investigate the workings of IPT. Dr. Hawkins indicated that should the results of the animal studies be supportive of the IPT concept, there was the possibility that clinical trials of IPT in the management of Stage IV breast cancer might thereafter be undertaken at Georgetown University.
August 25, 1993: Received a formal written proposal from Dr. Hawkins concerning the animal study, complete with itemized budget for same. Fund raising efforts for this study were begun through a not-for-profit corporation called Medical Renaissance Foundation, an entity that had been established expressly for the purpose of funding IPT-related research.
December 14-15, 1993: Attended the Secretary’s Conference to establish a National Action Plan on Breast Cancer at the National Institutes of Health in Bethesda, Maryland. Materials on IPT were accepted and made available for review in the Conference’s Reference Room.
December 1993: Notified by a friend and business associate, Mr. Rich Moret of the advertising firm of Moret Worldwide and China West in Tucson, Arizona, that there was a developing interest in studying and possibly practicing IPT in the far east.
January 11, 1994: Received a call from Ms. Shirl Thomas at the Office of the Secretary of Housing and Urban Development, in Washington, D.C. The Secretary himself – the Honorable Henry G. Cisneros – was a personal friend of one of the Mexican physicians responsible for pioneering the practice of IPT – Donato Perez Garcia y Bellon, M.D. Following the Christmas holiday season during which the two had spent much time together in San Antonio, and during which time Dr. Perez Garcia had discussed IPT at some length with his friend, Mr. Cisneros had instructed Ms. Thomas to contact me on his behalf with the offer of whatever help he and his office might be able to give to help promote the scientific study and development of IPT in the United States.
March 4, 1994: Received a letter from Hassan S. Rifaat, M.D. President of Texas Health Innovators, a private not-for-profit corporation with the following mission statement: 1) To expedite the objective scientific evaluation of health care innovations, 2) To promote the public and professional distribution of such scientific evaluations, 3) To promote and facilitate access to the health care innovations that work. 4) To achieve our goals in the most time and resource efficient way. Dr. Rifaat stated that IPT had been highly recommended to him by Michael J. Friedman, M.D., Associate Director of NCI’s Cancer Therapy Evaluation Program – whose office had declined to formally study IPT back in September 1992. I informed Dr. Rifaat of the ongoing initiatives for the study of IPT with the animal study at Georgetown University Medical Center and developments in China. The possibility of funding for research was discussed.
March 24, 1994: Presentation made to the Cancer Treatment Research Foundation of the Cancer Treatment Centers of America requesting funding for the animal study at Georgetown University Medical Center.
April 1994: Collaborative efforts for the study of IPT undertaken with medical personnel at the Xuzhou Medical College Cancer Center in Xuzhou, China. Personal visit to Xuzhou by Dr. Ayre in July of 1994. Revised IPT protocol and funding for studies being arranged.
May 2, 1994: Acceptance of grant request to the Cancer Treatment Research Foundation to fund an animal study at Georgetown University Medical Center. This study was designed to investigate the effects of insulin on adriamycin cytotoxicity on human breast cancer cell explants in athymic nude mice.
May 1996: Completion of the animal study at Georgetown University Medical Center with inconclusive results. Difficulty with the study model – translating the IPT protocol from human subjects to athymic nude mice – was considered to be a contributing factor in the failure to scientifically document IPT effects to enhance tumor cell killing in the human breast cancer cell explants.
January 1997: Tony Mastromarino, Ph.D., Director of Scientific Research, Office of the Vice-President, M.D. Anderson Cancer Center in Houston, Texas, communicated his interest in IPT to Mary Ann Richardson, Ph.D., from the UT School of Public Health, who is co-PI of the OAM-funded Center for Alternative Research in Cancer there. Dr. Mastromarino had been responsible for the 1989 invitation to the Drs. Perez Garcia and Dr. Ayre to prepare their poster presentation for M.D. Anderson’s Forty-second Annual Symposium on Fundamental Cancer Research (see the first entry in this Chronology, page 1).
February 1997: Dr. Richardson conducts a site visit at the office of Dr. Perez Garcia in Tijuana, Mexico, and subsequently invites the Drs. Perez Garcia and Dr. Ayre to come to an OAM meeting to be held in Bethesda in August.
August 4-6, 1997: NIH/OAM Conference on “Monitoring and Evaluation Approaches for Integrated Complementary and Alternative Medicine Cancer Practices” held in Bethesda, MD. The purpose of the Conference was to launch an initiative to facilitate entry of extant cancer protocols into a Phase II clinical trials environment. The name of this initiative was “Practice Outcomes Monitoring Evaluation System” (POMES). Dr. Ayre presented a paper entitled “Best Case Series Approach: Insulin Potentiation of Chemotherapy.”
September 1997: Protocol for a multicenter prospective clinical trial of IPT in the treatment of stage IV cancers of the breast, lung, and ovary submitted to, and approved by, the Institutional Review Board of the Great Lakes College of Clinical Medicine at their fall meeting – September 16 – 20, 1997, in Pittsburgh, PA.
April 1999: Received an invitation from Jeffrey D. White, M.D., Director, Office of Cancer Complementary and Alternative Medicine to present a Best Case Series on the clinical experience with IPT before the members of the Cancer Advisory Panel of the National Center for Complementary and Alternative Medicine at the National Institutes of Health. This presentation has been scheduled for September 18, 2000, in Bethesda, Maryland.
September 18, 2000: Best Case Series on the clinical experience with IPT presented before the members of the Cancer Advisory Panel of the National Center for Complementary and Alternative Medicine at the National Institutes of Health. Recommendations of the Panel were to have a larger prospective trial of IPT conducted on cancer cases, and to have that data presented to the Panel as a Best Case Series.
February 22, 2001: Presentation of a talk entitled “Insulin Potentiation Therapy – a Renaissance in Cancer Chemotherapy” made before the Spring Conference of the International Oxidative Medicine Association in Las Vegas, Nevada.
April 2001: Received a phone call from Paul Carbone, M.D., former Director of the University of Wisconsin (Madison) Comprehensive Cancer Center offering to provide expert assistance for the conduct of a prospective clinical trial on Insulin Potentiation Therapy. Discussions re possible NCI funding for this proposed study undertaken with Dr. Jeff White, Director of the National Center for Cancer Complementary and Alternative Medicine.
May 11, 2001: Insulin Potentiation Therapy: A Renaissance in Cancer Chemotherapy. Oral presentation at the Spring Conference of the American College for Advancement in Medicine in Nashville, TN, on May 11, 2001