Commission on Non-Ionizing Radiation Protection.
"The medical use of infrared radiation has a long history. It has been widely
used in physical medicine for treatment of sports injuries, muscle aches,
pain, and some chronic diseases (Licht 1967; Vaupel and Kruger 1992, 1995).
In recent years there has been an interest in the use of IR-A sources for
hyperthermic treatment of cancers (von Ardenne 1994, 1997; Vaupel and Kruger
1995; Wehner et al. 2001). Because of the deeper penetration of IR-A, this
is used almost exclusively, and water filtering of IR to achieve pure IR-A
has been recommended in therapeutics. There are also special IR-A therapeutic
apparatuses that have been used for hyperthermic treatment of cancers and
Raynaud's syndrome (i.e., white finger disease). The typical treatment irradiance
of several therapeutic IR devices fall in the range of 800 W m_2. A German
standard (DIN 5031-10; DIN 2000) limits IR-A to 1,200 W m_2 in therapeutic
J, Yamashita K, Ishikawa T, Hosokawa H, Sumida K, Nagayama M, Kitamura S.
of Oral and Maxillofacial Anatomy, Medical Science for Oral and Maxillofacial
Regeneration, Graduate School of Health Biosciences, University of Tokushima,
3-18-15 Kuramoto, Tokushima 770-8504, Japan.
a tissue culture incubator that can continuously irradiate cells with far-infrared
radiation (FIR) of wavelengths between 4 and 20 microm with a peak of 7-12
microm, and found that FIR caused different inhibiting effects to five human
cancer cell lines, namely A431 (vulva), HSC3 (tongue), Sa3 (gingiva), A549
(lung), and MCF7 (breast). Then, in order to make clear the control system
for the effect of FIR, the gene expression concerned to the inhibition effect
by FIR were analyzed. In consequence, basal expression level of HSP70A mRNA
was higher in A431 and MCF7 cells than in the FIR-sensitive HSC3, Sa3, and
A549 cells. Also, the over expression of HSP70 inhibited FIR-induced growth
arrest in HSC3 cells, and an HSP70 siRNA inhibited the proliferation of
A431 cells by irradiation with FIR. These results indicate that the effect
of a body temperature range of FIR suppressing the proliferation of some
cancer cells is controlled by the basal expression level of heat shock protein
(HSP) 70A. This finding suggested that FIR should be very effective medical
treatment for some cancer cells which have a low level of HSP70. Still more,
if the level of HSP70 in any cancer of a patient was measured, the effect
of medical treatment by FIR can be foreseen for the cancer.
Itoh Y, Aoki S, Nakamura K, Taki T, Naruse K, Tobiume M, Zennami K, Katsuda
R, Kato Y, Watanabe M, Nishikawa G, Minami M, Nakahira M, Ukai S,Sawada
M, Kitamura A, Honda N.
of Urology, Aichi Medical University School of Medicine, Nagakute, Aichi
We evaluated the efficacy and safety of M-VAC chemotherapy combined with
mild hyperthermia, a new therapeutic strategy for advanced metastatic transitional
cell carcinoma of the urothelium. SUBJECTS AND METHODS: The subjects were
12 patients diagnosed with advanced metastatic transitional cell carcinoma
of the urothelium. For mild hyperthermia, the patients' oral temperature
was elevated to about 38 degrees C by heating for 20 min and retaining the
heat for 20 min with a far-infrared heater. The antitumor effect was evaluated
according to the RECIST, while adverse drug reactions were assessed based
on the NCI-CTC. RESULTS: The antitumor effect was rated as partial remission
(PR) in 10 of the 12 patients and stable disease in 2 patients, with an
efficacy rate of 83% (10/12). All 10 patients who had achieved PR received
three courses of treatment. Of the 12 patients, 5 died during the observation
period, with survival for 9-23 months (mean: 15.6 months). Adverse drug
reactions included myelosuppression in all patients (Grade 3 in 4 patients,
Grade 4 in 8), and gastrointestinal toxicity, such as nausea or vomiting,
which was mild (Grade 0 in 2 patients, Grade 1 in 8, Grade 2 in 1, Grade
3 in 1). CONCLUSIONS: The results of the present study suggest that M-VAC
chemotherapy combined with mild hyperthermia, which potentiates the anticancer
effect and reduces adverse drug reactions such as gastrointestinal symptoms,
is a useful and safe method for the treatment of advanced transitional cell
carcinoma of the urothelium.
Kokura S, Okuda T, Okayama T, Takagi T, Handa O, Naito Y, Yoshida N, Yoshikawa
and Immunology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
body hyperthermia (WBH) has been used clinically as an adjunct to radio-
and chemotherapy in patients with various cancers. Recently, it has been
reported that an activation of the immune system has recently been reported
as a possible contributor to the therapeutic effects of WBH. Conversely,
the glycolipid alpha-galactosylceramide (alpha-GalCer) is recognized by
natural killer (NK) T cells together with the monomorphic MHC-like antigen,
CD1d, in mice and humans. This study investigated the antitumor effects
of WBH combined with alpha-GalCer in a mouse subcutaneous tumor model of
colon cancer. METHODS: Colon26 cells were inoculated subcutaneously into
male BALB/c mice to establish subcutaneous tumor. Colon26-bearing mice were
treated with WBH using far infrared rays three times/week. Rectal temperature
was maintained for 60 min at 41 degrees C. In some experimental groups,
alpha-GalCer was intraperitoneally injected before WBH. We investigated
the therapeutic effects of WBH, alpha-GalCer and combined therapy. RESULTS:
(1) Compared with controls, WBH alone resulted in significant inhibition
of tumor growth. (2) No inhibitory effect on tumor growth was seen with
alpha-GalCer. (3) The combination of WBH and alpha-GalCer showed significant
inhibition of tumor growth and prolongation of survival. (4) Serum IFN-gamma
increased after 3 h and returned to basal levels by 24 h after alpha-GalCer
administration. (5) CTL activity was enhanced following combination therapy
with WBH and alpha-GalCer. CONCLUSION: WBH showed antitumor effects in a
mouse subcutaneous tumor model of colon cancer. Addition of alpha-GalCer
increased the efficacy of WBH, probably via enhancement of immune response.
Nagasawa H, Kiyokawa S.
Animal Research Laboratory, Meiji University, Kawasaki, Japan.
possible therapeutic benefits of irradiation with far-infrared rays (FIR)
on breast cancer, we examined combined effects of the chronic exposure to
FIR at ambient temperature (26.5-27.5 degrees C) and the whole-body hyperthermia
induced by FIR (WBH) (35-41 degrees C) on the growth of spontaneous mammary
tumours of mice. A high mammary tumour strain of SHN virgin mice born on
the normal rack or FIR rack were maintained on the respective racks until
mammary tumour appearance. When the mammary tumour size reached approximately
7 mm, some mice in each group received no further treatment (Control and
FIR groups, respectively) and the remaining mice received 3 hours of WBH
each of 5 consecutive days (C + WBH and FIR + WBH groups, respectively).
There was little difference between the control and FIR groups in the tumour
growth over 10 days of examination. On the other hand, the tumour growth
was inhibited significantly in both C + WBH and FIR + WBH groups and the
degree of inhibition was similar. The data confirmed that the chronic exposure
to FIR at ambient temperature has little effect on the growth of spontaneous
mammary tumours in mice. WBH with FIR, however, strongly inhibited the tumour
growth without deleterious side-effects, while chronic FIR irradiation itself
again had little effect in this process. This WBH regimen may serve as a
useful animal model for long-term studies of a noninvasive treatment of
B, Wust P, Ahlers O, Dieing A, Sreenivasa G, Kerner T, Felix R, Riess H.
Department of Hematology and Oncology, Charite Medical School, Humboldt-University,
Campus Virchow Clinic, D-13344 Berlin, Germany.
the term 'hyperthermia' refers to the treatment of malignant diseases by
administering heat in various ways. Hyperthermia is usually applied as an
adjunct to an already established treatment modality (especially radiotherapy
and chemotherapy), where tumor temperatures in the range of 40-43 degrees
C are aspired. In several clinical phase-III trials, an improvement of both
local control and survival rates have been demonstrated by adding local/regional
hyperthermia to radiotherapy in patients with locally advanced or recurrent
superficial and pelvic tumors. In addition, interstitial hyperthermia, hyperthermic
chemoperfusion, and whole-body hyperthermia (WBH) are under clinical investigation,
and some positive comparative trials have already been completed. In parallel
to clinical research, several aspects of heat action have been examined
in numerous pre-clinical studies since the 1970s. However, an unequivocal
identification of the mechanisms leading to favorable clinical results of
hyperthermia have not yet been identified for various reasons. This manuscript
deals with discussions concerning the direct cytotoxic effect of heat, heat-induced
alterations of the tumor microenvironment, synergism of heat in conjunction
with radiation and drugs, as well as, the presumed cellular effects of hyperthermia
including the expression of heat-shock proteins (HSP), induction and regulation
of apoptosis, signal transduction, and modulation of drug resistance by
Jia D, Liu
of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing,
cancer, whole-body hyperthermia (WBH) is highly regarded by physicians as
a promising alternative to conventional therapies. Although WBH is still
under scrutiny due to potential toxicity, its benefits are incomparable,
as diversified devices and very promising treatment protocols in this area
are advanced into Phase II and III clinical trials. Following the introduction
of the WBH principle, this paper comprehensively reviews the state-of-art
high-performance WBH devices based on the heat induction mechanisms - radiation,
convection and conduction. Through analyzing each category's physical principle
and heat-induction property, the advantages and disadvantages of the devices
are evaluated. Technical strategies and critical scientific issues are summarized.
For future developments, research directions worth pursuing are presented
in this article.
van der Zee
Center-Daniel den Hoed Cancer Center, Department of Radiation Oncology,
Hyperthermia Unit, Rotterdam, The Netherlands.
a clear rationale for using hyperthermia in cancer treatment. Treatment
at temperatures between 40 and 44 degrees C is cytotoxic for cells in an
environment with a low pO(2) and low pH, conditions that are found specifically
within tumour tissue, due to insufficient blood perfusion. Under such conditions
radiotherapy is less effective, and systemically applied cytotoxic agents
will reach such areas in lower concentrations than in well perfused areas.
Therefore, the addition of hyperthermia to radiotherapy or chemotherapy
will result in at least an additive effect. Furthermore, the effects of
both radiotherapy and many drugs are enhanced at an increased temperature.
Hyperthermia can be applied by several methods: local hyperthermia by external
or internal energy sources, regional hyperthermia by perfusion of organs
or limbs, or by irrigation of body cavities, and whole body hyperthermia.
The use of hyperthermia alone has resulted in complete overall response
rates of 13%. The clinical value of hyperthermia in addition to other treatment
modalities has been shown in randomised trials. Significant improvement
in clinical outcome has been demonstrated for tumours of the head and neck,
breast, brain, bladder, cervix, rectum, lung, oesophagus, vulva and vagina,
and also for melanoma. Additional hyperthermia resulted in remarkably higher
(complete) response rates, accompanied by improved local tumour control
rates, better palliative effects and/or better overall survival rates. Generally,
when combined with radiotherapy, no increase in radiation toxicity could
be demonstrated. Whether toxicity from chemotherapy is enhanced depends
on sequence of the two modalities, and on which tissues are heated. Toxicity
from hyperthermia cannot always be avoided, but is usually of limited clinical
relevance. Recent developments include improvements in heating techniques
and thermometry, development of hyperthermia treatment planning models,
studies on heat shock proteins and an effect on anti-cancer immune responses,
drug targeting to tumours, bone marrow purging, combination with drugs targeting
tumour vasculature, and the role of hyperthermia in gene therapy. The clinical
results achieved to date have confirmed the expectations raised by results
from experimental studies. These findings justify using hyperthermia as
part of standard treatment in tumour sites for which its efficacy has been
proven and, furthermore, to initiate new studies with other tumours. Hyperthermia
is certainly a promising approach and deserves more attention than it has
received until now.
Klinik III, Klinikum Grosshadern, Munich, Germany.
of this article is to provide an overview on the current clinical application
of hyperthermia combined with conventional treatment modalities (e.g. ionizing
radiation, chemotherapy) in the treatment of malignant disease. The clinical
application of hyperthermia with increase of tissue temperatures (range
40-44 degrees C) has been integrated in multimodal anti-cancer strategies.
This review describes selected phase I or II (n = 17) and phase III trials
(n = 16) investigating the effect of hyperthermia combined with radiotherapy
(n = 10 trials), chemotherapy (n = 15 trials), or both (n = 8 trials) in
a total of more than 2200 patients. The trials were performed in a variety
of solid tumours (e.g. melanoma, head and neck cancer, breast cancer, cancer
of the gastrointestinal or urogenital tract, glioblastoma, sarcoma) in paediatric
or adult patients. Profound research has produced a scientific basis for
the simultaneous application of hyperthermia in combination with ionizing
radiation and/or systemic chemotherapy. Hyperthermia is becoming more accepted
clinically, due to the substantial technical improvements made in achieving
selected increase of temperatures in superficial and deep-seated tumours.
At present, the combination of hyperthermia and chemotherapy or radiochemotherapy
is further tested within clinical protocols (phase II/III) in order to improve
local tumour control and relapse-free survival in patients with high-risk
or advanced tumours of different entities.
Ishigame H, Nagasawa H.
We have found
that the administration of a diet containing 5% hydroxyapatite (HAP) derived
from pig and cattle bones, and exposure to far-infrared rays (FIR) markedly
inhibited spontaneous mammary tumorigenesis in SHN mice. Thus, the effect
of combined treatment with HAP and FIR on mammary tumorigenesis was examined.
The significant inhibition of tumor development by individual treatment
with HAP or FIR was not enhanced by combined treatment; instead, the decrease
in the inhibitory effect of HAP with age was ameliorated. Associated with
this, life span was elongated and a decline in ovarian function was prevented
by HAP plus FIR. Normal and preneoplastic growth of mammary glands and plasma
component levels were not significantly affected by any treatment. The findings
indicate that HAP and FIR have characteristics common to most natural products;
in combination with other agents, they have little additive effect, when
each is highly active.
findings that free access in drinking water of the extract of coffee cherry
(CC), the residue left after the removal of coffee beans, and whole-body
hyperthermia (WBH) induced by far-infrared ray (FIR) can markedly inhibit
the growth of spontaneous mammary tumours of SHN mice, the effects of the
combined treatment with these agents were examined in this study. The significant
inhibition of tumour growth by single treatment with either CC or WBH was
not enhanced by their combination. Meanwhile, the body weight loss during
WBH was significantly decreased by CC. Normal and preneoplastic growth of
mammary glands and plasma component levels were affected little by either
treatment. The findings confirmed the "normalization effects" of CC usually
obtained with natural products and stress the need for prudence in the choice
of any agent, natural or synthetic, to be applied simultaneously to increase
the efficacy of WBH.
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