A phase I study of fever-range whole body hyperthermia (FR-WBH) in patients with advanced solid tumours: correlation with mouse models

Various studies in animal tumour models have revealed the potential of fever-range whole body hyperthermia (FR-WBH) to be used in cancer therapy. To determine the safety of FR-WBH treatment in the clinic, patients with advanced solid tumours were heated in the outpatient setting to 39-39.5°C for 3 or 6h, or 39.5-40°C for 6h using the Heckel-HT 2000 apparatus. These WBH treatments were well tolerated, with no significant adverse events related to cardiac, hepatic, renal or pulmonary systems. In the majority of patients, flow cytometric analysis of peripheral blood leukocyte populations indicated that there were transient decreases in the number of circulating T lymphocytes and a concomitant decrease in the number of L-selectin positive lymphocytes in the peripheral blood. These findings closely mimic the affects seen previously in pre-clinical murine studies in which this same fever-like treatment was shown to inhibit tumour growth. These studies have established the safety of this treatment and will allow for future clinical trials where application of FR-WBH treatment can be combined with other anti-cancer therapies, including immunotherapy and chemotherapy.

[1]  D. Spriggs,et al.  Rationale and clinical status of 41.8 degrees C systemic hyperthermia tumor necrosis factor, and melphalan for neoplastic disease. , 1997, Anticancer research.

[2]  M. Caligiuri,et al.  Tumor cell apoptosis, lymphocyte recruitment and tumor vascular changes are induced by low temperature, long duration (fever‐like) whole body hyperthermia , 1998, Journal of cellular physiology.

[3]  M. Mentzel,et al.  Systemic hyperthermia and ICE chemotherapy for sarcoma patients: rationale and clinical status. , 1997, Anticancer research.

[4]  Eduardo G. Moros,et al.  Phase III study of interstitial thermoradiotherapy compared with interstitial radiotherapy alone in the treatment of recurrent or persistent human tumors: A prospectively controlled randomized study by the radiation therapy oncology group , 1993 .

[5]  D Machin,et al.  Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: results from five randomized controlled trials. International Collaborative Hyperthermia Group. , 1996, International journal of radiation oncology, biology, physics.

[6]  A. Hart,et al.  Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumours: a prospective, randomised, multicentre trial , 2000, The Lancet.

[7]  G. Wilding,et al.  A pilot study of melphalan, tumor necrosis factor-α and 41.8 °C whole-body hyperthermia , 1999, Cancer Chemotherapy and Pharmacology.

[8]  M. Dewhirst,et al.  Clinical experience with a multi-element ultrasonic hyperthermia system: analysis of treatment temperatures. , 1990, International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group.

[9]  E. Repasky,et al.  Fever-range hyperthermia enhances L-selectin-dependent adhesion of lymphocytes to vascular endothelium. , 1998, Journal of immunology.

[10]  J. Larkin,et al.  Total body hyperthermia and preliminary results in human neoplasms. , 1976, Surgical forum.

[11]  T L Phillips,et al.  Survival benefit of hyperthermia in a prospective randomized trial of brachytherapy boost +/- hyperthermia for glioblastoma multiforme. , 1998, International journal of radiation oncology, biology, physics.

[12]  P Grigsby,et al.  Phase III study of interstitial thermoradiotherapy compared with interstitial radiotherapy alone in the treatment of recurrent or persistent human tumors. A prospectively controlled randomized study by the Radiation Therapy Group. , 1996, International journal of radiation oncology, biology, physics.

[13]  X. Y. Wang,et al.  Effect of fever-like whole-body hyperthermia on lymphocyte spectrin distribution, protein kinase C activity, and uropod formation. , 1999, Journal of immunology.

[14]  A. Smith,et al.  Clinical Effects of Whole-body Hyperthermia in Advanced Malignancy , 1974, British medical journal.

[15]  J. Bull,et al.  Therapeutic efficacy of long duration-low temperature whole body hyperthermia when combined with tumor necrosis factor and carboplatin in rats. , 1994, Cancer Research.

[16]  S. George,et al.  Phase I study of melphalan alone and melphalan plus whole body hyperthermia in dogs with malignant melanoma. , 1991, International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group.

[17]  T. Feyerabend,et al.  Local hyperthermia, radiation, and chemotherapy in recurrent breast cancer is feasible and effective except for inflammatory disease. , 2001, International journal of radiation oncology, biology, physics.

[18]  Anderson Rm,et al.  Whole-body hyperthermia and chemotherapy for treatment of patients with advanced, refractory malignancies , 1982 .

[19]  J. Overgaard,et al.  Randomised trial of hyperthermia as adjuvant to radiotherapy for recurrent or metastatic malignant melanoma , 1995, The Lancet.

[20]  J. Bull,et al.  Long duration-mild whole body hyperthermia of up to 12 hours in rats: feasibility, and efficacy on primary tumour and axillary lymph node metastases of a mammary adenocarcinoma: implications for adjuvant therapy. , 1997, International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group.

[21]  E. Butcher,et al.  Lymphocyte trafficking and regional immunity. , 1999, Advances in immunology.

[22]  E. Repasky,et al.  Use of Mild, Whole Body Hyperthermia in Cancer Therapy , 2000, Immunological investigations.

[23]  Elizabeth A. Repasky,et al.  Comparison of the effects of two different whole body hyperthermia protocols on the distribution of murine leukocyte populations , 2000, International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group.

[24]  E. Repasky,et al.  Distribution of HSP70, protein kinase C, and spectrin is altered in lymphocytes during a fever‐like hyperthermia exposure , 1997, Journal of cellular physiology.

[25]  R. Issels,et al.  Hyperthermia in oncology. , 2001, International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group.

[26]  S. Tsukagoshi,et al.  Recurrent ovarian clear cell carcinoma: complete remission after radiation in combination with hyperthermia; a case study and in vitro study. , 2000, Cancer biotherapy & radiopharmaceuticals.

[27]  J. Black,et al.  Dynamic association of L-selectin with the lymphocyte cytoskeletal matrix. , 1999, Journal of immunology.

[28]  M. Dewhirst,et al.  Phase I evaluation of mitoxantrone alone and combined with whole body hyperthermia in dogs with lymphoma. , 1996, International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group.

[29]  T. Miller,et al.  End results in reticulum cell sarcoma of bone treated by bacterial toxin therapy alone or combined with surgery and/or radiotherapy (47 cases) or with concurrent infection (5 cases) , 1971, Cancer.

[30]  M. Amichetti,et al.  Report of long-term follow-up in a randomized trial comparing radiation therapy and radiation therapy plus hyperthermia to metastatic lymph nodes in stage IV head and neck patients. , 1994, International journal of radiation oncology, biology, physics.

[31]  M. Mentzel,et al.  Ifosfamide, carboplatin and etoposide (ICE) combined with 41.8 degrees C whole body hyperthermia in patients with refractory sarcoma. , 1996, European journal of cancer.

[32]  H. Suit,et al.  Hyperthermia: Potential as an anti‐tumor agent , 1974, Cancer.

[33]  R. Burd,et al.  Characterization of mild whole-body hyperthermia protocols using human breast, ovarian, and colon tumors grown in severe combined immunodeficient mice. , 1999, Infectious diseases in obstetrics and gynecology.

[34]  J. Dean,et al.  Whole-body hyperthermia and chemotherapy for treatment of patients with advanced, refractory malignancies. , 1982, Cancer treatment reports.

[35]  T. Matsuda.  [Hyperthermia in the treatment of cancer]. , 1986, Gan no rinsho. Japan journal of cancer clinics.

[36]  F. Gibbs,et al.  Hyperthermia in the treatment of cancer: Perspectives on its promise and its problems , 1984, Cancer.

[37]  S. Evans,et al.  Tyrosine kinase-dependent regulation of L-selectin expression through the Leu-13 signal transduction molecule: evidence for a protein kinase C-independent mechanism of L-selectin shedding. , 1997, Journal of immunology.

[38]  R. Burd,et al.  Fever-range hyperthermia dynamically regulates lymphocyte delivery to high endothelial venules. , 2001, Blood.

[39]  J. Bull,et al.  Apoptosis in tumors and normal tissues induced by whole body hyperthermia in rats. , 1995, Cancer research.

[40]  E. Repasky,et al.  Regulation of Leukocyte-Endothelial Cell Interactions in Tumor Immunity , 1998 .