[CANCER RESEARCH 39, 3248-3253, August 1979]
0008-5472/79/0039-0000$02.00
Time-Temperature Relationship in Hyperthermic Treatment of Malignant
and Normal Tissue in Vivo1
Jens Overgaard2 and Herman D. Suit3
Edwin L. Steele Laboratory of Radiation Biology, Department of Radiation Medicine,
Massachusetts
Massachusetts
General
Hospital,
Harvard
Medical
School,
Boston,
02114
ABSTRACT
effect is greater (e.g. , a high tumor effect and low damage to
normal tissue).
The effect of hyperthermia on normal and tumor tissue was
A few previous studies have partly focused on these prob
studied following water bath heating of a methylcholanthrene
lems. Westemmank(31 ) and, more recently, Ovengaard and
induced fibrosarcoma (FSaI) isotransplanted into the feet of Overgaard (2i , 23) studied the time-temperature relationship
C3H mice. The time-temperature relation for the 50% tumor required to obtain control in solid animal tumors. Overgaamd
control dose over the temperature range of 41 .5—45.5°
showed and Overgaard found that, at 41 .5—43°,
a doubling of treatment
a log linear relationship which followed a biphasically modified time for each 0.5°reduction in treatment temperature is me
Amrheniusplot. At temperatures above 43°,there was a 50% quired for equivalent responses. In the Westermark study, the
reduction in heating time to obtain the 50% tumor control dose treatment time could be reduced to one-half for each 1°in
for each 1°increase in temperature, corresponding to an crease in temperature between 44 and 48°.Both investigations
activation energy of 140 kcal/mol. At temperatures below 43°, used low-frequency electromagnetic diathermy, a technique
the curve was steeper, with a tendency to double the treatment which may give a somewhat heterogeneous heat distribution,
time for each 0.5°reduction in temperature (activation energy, especially in the tumor periphery, and the method used is
approximately 230 kcal/mol).
therefore not optimal in order to obtain a quantitative animal
Normal tissue damage in the tumor-bearing foot was esti tumor response (20). Furthermore, the technique by which
mated at two levels with a 50% response dose assay. Severe Westermark measured the tumor temperature is questionable
normal tissue damage showed a time-temperature relationship (23, 31).
similar to the tumor response, thus indicating no variation in
Cnile(3, 4), on the other hand, studied the effect of Sarcoma
therapeutic ratio at different temperatures. However, for slight 1 80 tumors inoculated into the feet of mice and treated by a
tissue damage, the therapeutic ratio increased with decreasing water bath. This technique achieved a uniform heating of the
temperatures, yielding a better therapeutic ratio at lower tem small tumor volumes. Crile observed a parallel response in the
peratures.
tumor and severe normal tissue damage, which was especially
The time-temperature relationship obtained in the FSal fibro
established at temperatures higher than 43°.He showed, like
sarcoma is supported by other studies and points to a general Westermank, that at 43°and above a doubling of the treatment
time-temperature relationship for hyperthermic tumor destruc
time was necessary for each 1°reduction in the temperature.
tion.
At lower temperatures, the observations by Cnile were some
what divergent. Because the number of animals in his study
INTRODUCTION
was small, there is some uncertainty as to the quantitative
evaluation of the data. Furthermore, the Sarcoma 180 tumor is
The ability of moderate heat treatment to eradicate expeni highly antigenic, and spontaneous tumor regressions were
mental tumors in vivo has been established for numerous frequently observed.
animal tumor systems (3, 4, 6, 7, 14, 15, 19, 20, 23—25,29,
The present experiments have been undertaken to study the
30).
relationship between temperature and time using 2 end points
There is an intense interest in applying this modality to the of tissue response: (a) permanent regression of a tumor grow
treatment of human cancer, either alone or in combination with ing in the foot pad; and (b) late damage to the tissue of the
other modalities, e.g. , ionizing radiation (1, 2, 9, 10, 13, 19, tumor-bearing foot. The temperatures studied covered the
28).
range 41.5—45.5°.
In planning preclinical investigations, we have been con
cenned with several questions, 2 of which are under current
study: (a) the time-temperature relationship required to obtain
the same tumor response and the time-temperature relationship MATERIALS AND METHODS
required to obtain specified levels of tissue damage; (b) to Animal Tumor System
determine if there is a temperature at which the therapeutic
Male and female C3Hf/Sed mice, 10 to 12 weeks old, from
our defined-flora and specific-pathogen-free colony were used
(26). Cell suspension was prepared by a nonenzymatic tech
nique from fourth- or fifth-generation isotmansplantsof FSaI, a
CAl 331 1 and the Danish Cancer Society.
methylcholanthrene-mnducedfibrosancoma (26). For transplant,
2 Present
address:
The
Institute
of Cancer
Research,
Radiumstationen,
OK
1 Supported
in
part
by
Department
of
Health,
Education
and
Welfare
Grant
8000 Aarhus C, Denmark. To whom requests for reprints should be addressed.
3 Andres
Soriano
Director
of
Cancer
Management,
Massachusetts
Hospital.
Received December 28, 1978; accepted April 26, 1979.
3248
General
2 to 5 x i o@viable tumor cells (trypan blue dye exclusion test)
in a 2.5-j@lvolume were injected into the foot pad. The tumor
transplant take rate was >95%.
CANCER
RESEARCH
VOL. 39
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1979 American Association for Cancer Research.
Time-Temperature
Hyperthermic Treatment
Treatments were performed on tumors with a volume of
about 200 cu mm as determined from the 3 diameters using
the formula Di x D2 x D3 x (ir/6). This treatment size was
normally obtained about 10 days after challenge. Unanesthe
tized mice were fixed in a special jig by tape in such a way that
the tumor-bearing leg could be immersed in a circulating water
bath with the tumor about 1 cm below the water surface.
Special care was taken to avoid impairment of blood flow in
the limb. The water bath temperature was measured with a
thermometer calibrated against a standard thermometer certi
fied by the National Bureau of Standards. Temperature was
held to within ±0.05°of the desired level by a thermostat
control system. In the initial experiments, the intratumoral tern
perature was measured by a 25-gauge needle probe (YSI
Model 46 Tele Thermometer; Yellow Spring Instrument Corn
pany, Yellow Spring, Ohio). Intratumoral temperature stabilized
at 0.2°below water bath temperature with 2 mm of immersion.
All temperatures mentioned in this paper refer to water bath
temperatures. Animals could be kept in the treatment position
for up to 12 hr without major problems.
Score for heat-induced
Relationship
in Heat Treatment
Table 1
normal tissue damage to the tumor-bearing
foot
Score
Status of damage
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Doubtful change from normal hair on foot. Less than 1- x 1-mm scar
at tumor site.
Slight reddening, no hair on foot.
Red foot and/or slight edema and/or atrophic hairless scar.
Edema of whole foot and/or free tendons at site of scar.
Fused toes and/or edema (more than 2.0).
Severe edema and/or moist reaction in 1 spot.
Moist reaction on entire foot.
4.0
Loss of 1 toe.
4.5
5.0
6.0
Loss of 2 or more toes.
Loss of foot.
Loss of foot through ankle.
a dry crust, which usually persisted for about 1 week. The
crust would normally fall off spontaneously, leaving a pale
hairless scar approximately 2 mm in diameter providing that
complete regression was achieved. In some cases, there was
a defect in the skin, and the underlying tendons were exposed.
In most cases, the foot healed with a normal skin covering,
which included negrowth of hair.
In almost all tumors which ultimately were not controlled,
Evaluation of Results
there was grossly evident tumor at the time of detachment of
the crust. This recurrence grew with approximately the same
Tumor Evaluation. The mice were followedtwice weekly for
doubling time as that of the untreated tumor. In tumors treated
the first 30 days and then with weekly intervals up to I 20 days
with very low heat doses, only a 2- to 3-day inhibition of growth
after treatment. Animals with tumors that were not controlled
by the treatment were sacrificed when their tumor reached was noted followed by normal growth.
Typically, the control or failure could be estimated within a
2000 Cu mm. At completion of an experiment, local control
few
weeks. On only very few occasions (<2%) was a tumor
results were tabulated and the TCD504values were calculated
found
to recur locally after total disappearance. The longest
(27). Excluded from the analysis were animals which died
time
from
treatment to definitive disclosure of a recurrent tumor
tumor free during the 120-day period. Only tumor-free surviving
was
about
5 weeks (Chart 1).
animals were counted as cured. Failure meant local negrowth
Dose Response. Table 2 shows the treatment time acquired
of tumors, plus a few mice without tumor in the foot, but with
at a given temperature to achieve 50% local control in a FSaI
negnowthoutside the treated area (e.g. , in the hip). Mice which
tumor. The dose-response curves for tumor control at 41.5,
had a partial on total leg amputation following high-dose treat
42.5, 43.5, 44.5, and 45.5°are presented in Chart 2. These
ment were scored as local controls.
curves have almost parallel slopes on the logit-log dose grid
Normal Tissue Evaluation. The status of the normal tissue
used in Chart 2, suggesting that there is no temperature
in the tumor-bearing foot was scored together with the tumor
dependent difference in the dose response in the range be
response. Because the acute damage could be modified by the
presence of tumor, late reactions at 120 days were recorded tween 41 .5 and 45.5°.
Time-Temperature Relation. The relationshipbetween time
and calculated. The scoring protocol is presented in Table 1.
and temperature required to obtain equivalent tumor control
The late reactions of tumor-bearing feet are described in terms
(TCD50)is shown in Chart 3, which demonstrates a modified
of RD50values (computed in the same manner as TCD50)for 2
Arrhenius plot of the TCD50obtained at different temperatures
levels of damage. The therapeutic ratio is defined in this report
between 41 .5 and 45.5°. The time-temperature relationship
as RDso:TCDso.
followed a variable pattern. Above 43°,a 1°reduction in the
treatment temperature will result in a doubling of treatment time
RESULTS
required to obtain an equivalent therapeutic effect. However,
below 43°,the curve is steeper, with a tendency to maximally
Effect on Tumor Tissue
double the treatment time required for an equivalent effect for
Tumor Reaction. Generally, the initial gross response was each 0.5°reduction in treatment temperature.
independent of the treatment time or temperature used in this
study.
Effect on Normal Tissue
Immediately after treatment, there was slight cyanosis and
Foot Reaction. The acute normal tissue reaction in the foot
prominent edema. By 24 to 48 hr, the overlying skin in most
tumors was dark blue or black. By that time, the edema had increased with temperature or treatment time. In treatments at
decreased, and the skin overlying the tumors had turned into low temperatures (4i .5°),themewas no noticeable change in
the non-tumor-bearing part of the foot immediately after treat
ment. At higher temperatures, the acute changes were mainly
4 The
abbreviations
used
are:
TCD@,
time
at hyperthermia
that
achieves
in the form of edema which was in some instances severe and
control of one-half of the treated tumors; RD@,time at hyperthermia that elicits
later developed into necrosis of the peripheral part of the foot.
a specific level of normal tissue reaction in one-half of the treated feet.
AUGUST 1979
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1979 American Association for Cancer Research.
3249
J. Overgaard
and H. D. Suit
This occasionally could result in amputation of toes or in partial
or complete loss of the foot. The progression of the normal
tissue damage reached a maximum within 2 to 3 weeks after
treatment; when amputation occurred, it was during that time.
100
After the acute damage, there was normally a moderate repair
or reconstruction before more chronic conditions were estab
lished about 3 to 4 weeks after treatment. In general, a corre
lation between acute and chronic damage was noted even
though the acute reaction was often difficult to evaluate be
cause the tumor response itself interfered with observations of
the damage to normal tissues of the foot. No significant change
in the normal tissue reaction occurred beyond i month follow
ing treatment (Chart 4).
Dose Response. The RD50at a given temperature between
42°and 45.5°is shown in Table 2. Level 1 response was the
lowest degree of definitive tissue change. This was mainly
cosmetic and did not produce functional defects. On the other
hand, the damage at Level 4 was severe, was irreversible, and
involved pronounced impairment of the function of the limb and
loss of at least one toe. Dose-response curves for Levels I and
4 were of a common slope for all temperatures tested. This
slope was approximately the same as found for the tumor
response curve (Chart 2). However, a RD50value for the Level
4 foot damage could not be obtained at 4i .5 and 42°at the
maximum exposure times which were feasible in our expeni
mental set-up.
Time-Temperature Relation. Chart 5 shows modified Am
rhenius plots of the time-temperature relationship of heat treat
%
90
80
70
60
50
40
30
20
10
0
10
DAYS
20
AFTER
30
40
ment
causing
damage
to
the
mouse
foot
at
2
specific
levels.
For Level 4 damage, themeis a log linear time-temperature
relationship in the temperature interval 42.5—44.5°
with an
activation energy of 140 kcal/mol.
The Level 1 damage has a steeper time-temperature curve
with an activation energy of about 200 kcal/mol at 42—44.5°.
TREATMENT
Chart 1. Time to clearance of tumor or to local failure following single hyper
thermic treatment at 41 .5—45.5°.
A definitive estimate of tumor response was
obtained within 40 days after treatment. No additional changes occurred in the
remainder of the 120-day observation period.
90 -
41.5'
80 70
-
It:
@
@
Chart 2. Dose-response curves to obtain tumor control in the FSal
fibrosarcoma in vivo. An approximately parallel response is found at
60
:73
k. 5Q
.
14J
40
41 .5—45.5°.
Bars, 95% confIdence limit.
@
30
20
to
1_
I
I
I
10
III))
I
IIIjJ
1000
100
HEATING TIME IN MINUTES
Table2
Effect of hyperthermia
on tumor control
and normal tissue
damageLevel
1Level4Thera
Thera
TreatmentpeuticpeutictemperatureTCD@
(mm)ratio41.5°644
(mm)
RD@(mm)ratioRD@
(580@716)842.0271
(159—1406)1.7542.5205
(242—393)
(241—390)1.504S.0107(184—229)
(80-14@)
(153-176)1.5343.587.7
(98.0—188)1.5344.543.3
(79.9—96.8)
(42.9—92.5)1.4545.51
473
270 (233—312)1.32307
137 (124-150)1.28164
95.5 (84.4-108.4)1.09135
(34.3—54.8)
(24.8—34.6)1.@Sa 8.9 (15.8—22.4)
36.7 (20.5—65.6)0.8563
14.5 (6.9—30.6)0.7629.3
Numbers
inparentheses,
95% confidence limit.
3250
CANCERRESEARCHVOL. 39
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1979 American Association for Cancer Research.
Time-Temperature
Relationship
in Heat Treatment
1000
1000
C
0
o—@_______0Level
4
@l)
C———@Level
1
100
-
100
____________________
42°
43―
10 —
41
J
450
440
10 —
41°
TEMPERAfl/RE
Chart 3. Time-temperature relationship to obtain a hyperthermic isoeffect
aCD@@@)
in the FSal fibresarcoma in tnvo. For temperatures higher than 43°,this
modified Arrhenius plot has an activation energy of I 40 kcal/mol. For lower
temperatures, the activation energy increased towards approximately 230 kcal/
mel. Bars, 95% confidence limit.
42°
43°
44°
45°
TEMPERA
TI/RE
Chart 5. Time-temperature relationship to hyperthermic isoeffect (RD@)at 2
different levels of normal tissue damage. The modified Arrhenius curves show a
log-linear relationship for Level 1 damage between 42 and 45.5° with an
activation energy of 200 kcal/mei. For the Level 4 damage estimated in the
temperature range 42.5 to 45.5°,the activation energy is 149 kcal/mol.
1000
—
level
level
C,,
14j
.—
:3
4
00
1
LOIn
c@c3
—:::: 425°
1.@
43 5°
100
.
°-
k.
:73
I'..
44@5 0
0
U,
Lu
TEMPERATURE
10
30
120
DAYS AFTER TREATMENT
Chart 6. Therapeutic ratio for 2 specific levels of normal tissue damage. The
therapeutic ratio for the mild skin damage [RD,@(Level 1):TCD@]decreased with
increasing temperatures at 42—45.5°.
However, for the severe Level 4 damage,
a constant therapeutic ratio of 1.5 is observed at 42.5—45.5°.
Chart 4. Relationship between early and late damage to the tumor-bearing
feet after local hyperthermia at 42.5, 43.5, or 44.5°.Ne significant variations
were observed between damages recorded 30 or 120 days after treatment.
41 .5—44.5°
was able to locally eradicate 50% of the FSaI
fibrosarcomas growing in the C3H mouse foot without causing
Therapeutic Ratio
major change in the normal tissue.
The relationship between temperature and time for the TCD50
Chart 6 shows the therapeutic ratios (RDso:TCDse)for single
was,
fontemperatures @43°,
a decrease in treatment time by
treatments at 42—45.5°.
For severe chronic damage (Level 4),
a factor of 2 for each degree increase in temperature. This
the therapeutic ratio is constant at 1.5 for treatment tempera
tunes @42.5°,
but for the Level 1 response the therapeutic ratio corresponds to an activation energy of approximately 140
decreased from a value of @1
.75 at 42°down to 0.75 at 45.5°. kcal/mol. For temperatures lower than 43°, the activation
energy appears to increase with decreasing temperature up to
about 230 kcal/mol; this corresponds approximately to a dou
DISCUSSION
bling of the treatment time for each 0.5°reduction in temper
The present findings showed that hyperthermic treatment at ature.
AUGUST 1979
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1979 American Association for Cancer Research.
3251
J.
Overgaard
and
H.
D. Suit
Table3
@
Comparison
energies at ‘low
â‘
€˜
and
ofactivationtumorsystemsLow
‘high
‘
‘
temperatures
in different
temperature
temperatureActivaHigh
tion energyTemperature ergya
(kcal/Tumor
(kcal/
mel)Ref.Sarcoma
mel)
systemrange
Activa
tion en
Temperature
range
@138
42.0—48.0°
41 .0—42.5
278
42.5—43.5
.5—43.0
FSalb
43.0—43.5
(24)sarcoma44.0—48.0
MMCb41
227
312
43.0—45.5
43.5—45.0
4)Walker 18041.0—42.0°
HBb43.5—47.0
a Calculated
by least-square
b Based on TCDSO or similar
138Crile(3,
120
(1 1)
138Johnson
Overgaard and Over
(20, 23)
140
Present study
138gaard Robinson et a!.
139Westermark
(31)
fits of published
data.
dose-response
data.
The time-temperature relationship observed at temperatures was steeper with a tendency to treatment time doubling for
above 43°is in agreement with other studies of experimental 0.5°reduction in treatment temperature.
tumors heated in vivo, both by a water bath (3, 4, 11, 24, 25)
For mild degrees of skin damage, the time-temperature me
and by diathermy (20, 31). Also the tendency to an increased lationship was steeper, resulting in relatively less tissue dam
activation energy observed at temperatures below 42.5—43.5° age at lower temperatures.
However, at none of the temperatures where severe normal
has previously been observed in other studies (3, 20, 23, 24)
tissue damage could be produced (42.5—44.5°)was any
(Table 3). These data point towards a biphasic time-tempera
change in the therapeutic ratio observed. This observation is in
tune relationship for tumor control in vivo.
Since a similar biphasic pattern with approximately the same agreement with other reports on the time-temperature relation
activation energies has also been obtained from in vitro survival ships.
curves from different mammalian cell lines (2, 5, 13), a general
time-temperature relationship to hyperthermic destruction is REFERENCES
suggested by these studies.
1. Cavaliere, R., Ciocatto, E. C., Giovanella, B. C., Heidelberger, C., Johnson,
Our study showed that in the range of 42.5—45.5°
the time
R. 0., Margottini, M. , Mondovi, B. Moricca, G., and Ressi-Fanelli, A. Selec
tive heat sensitivity of cancer cells. Biochemical and clinical studies. Cancer,
to obtain severe normal tissue damage (Level 4) was parallel to
20: 1351-1381. 1967.
the time to obtain tumor control, namely, no variation in thera
2. Connor, W. G., Garner, E. W., Miller, R. C., and Boone, M. L. M. Prospects
for hyperthermia in human cancer therapy. Radiology, 123: 497—503,1977.
peutic effect at temperatures 42.5°(Chart 6; Table 2). At
3. Crile, G. Heat as an adjunct to the treatment of cancer. Cleve. Clin. 0. . 28:
lower temperatures, the treatment time was not sufficiently long
75-89, 1961.
to obtain RD50values for Level 4 damage since very few mice
4. Crile, G. The effects of heat and radiation on cancers implanted on the feet
of mice. Cancer Res., 23: 372—380,1963.
showed severe reaction. Our impression, not an experimental
5. Dewey, W. C., Hopwood, L. E., Sapareto, S. A., and Gerweck, L. E. Cellular
fact, is that the normal tissue damage was relatively less (i.e.,
responses to combinations of hyperthermia and radiation. Radiology, 123:
increasing therapeutic gain) at lower temperatures.
463-474, 1977.
6. Dickson, J. A., and Muckle, 0. C. Total-body hyperthermia versus primary
An increasing therapeutic gain at low temperatures is sup
tumor hyperthermia in the treatment of the rabbit VX-2 carcinoma. Cancer
ported by the observation that the RD50values for Level 1
Res., 32: 1916—1923,1972.
7. Dickson, J. A., Shah, S. A., Waggott, D. . and Whalley, W. B. Tumor
damage showed a steeper time-temperature relation than did
eradication in the rabbit by radiofrequency heating. Cancer Res., 37: 2162—
the TCD50and the RD50(Level 4) responses. This results in a
2169, 1977.
higher therapeutic ratio at a low temperature if the ratio is
8. Field, S. B. The response of normal tissues to hyperthermia alone or in
combination with x-rays. In: C. Streffer (ed), Cancer Therapy by Hyper
based on the mild Level 1 damage (Chart 6; Table 2).
thermia and Radiation. Proceedings of the 2nd International Symposium.
An activation energy of about 140 kcal/mol for severe tissue
Essen 1977. pp. 37—48.Munich: Urban and Schwarzenberg, 1978.
damage has been observed in a number of different tissues
9. Har-Kedar, I., and Bleehen, N. M. Experimental and clinical aspects of
hyperthermia applied to the treatment of cancer with special reference to
heated to temperatures above 42°(3, 4, 8, 12, 16-1 8). [For
the role of ultrasonic and microwave heating. Adv. Radiat. Biol., 6: 229—
further discussion, see the comprehensive review by Field
266, 1976.
(8)]. Accordingly, the time-temperature relationship appears to 10. Hyperthermia in the treatment of the cancer patient. Cancer (Phila.), 37:
2075-2083, 1976.
be similar for tumor control and severe normal tissue damage,
11. Johnson, H. J. The action of short radio waves on tissues. Ill. A comparison
at least for temperatures above 42.5—43°.
of the thermal sensitivities of transplantable tumours in vivo and in vitro. Am.
J. Cancer, 38: 533-550, 1930.
The higher activation energy observed for the mild skin
M. P., Ahier, R. G.. and Field, S. B. The response of the mouse ear to
damage may indicate that the 2 levels of damage are caused 12. Law,
heat applied alone or combined with x-rays. Br. J. Radiol., 51: 132—138,
by different mechanisms or targets. However, the significance
1978.
13. Leith, J. T., Miller, R. C., Garner, E. W., and Boone, M. L. M. Hyperthermic
of these findings must still be understood.
potentiation. Biological aspects and applications to radiation therapy. Can
The time-temperature relationship to achieve TCD50values
car (Phila.), 39: 766—779,1977.
for heat treatment of the FSaI tumor was found to follow a log 14. Marmor, J. B., Hahn, N., and Hahn, G. M. Tumor cure and cell survival after
localized radiofrequency heating. Cancer Res., 37: 879—883,1977.
linear relationship which at temperatures @43°
corresponds to
15. Mendecki, J., Friedenthal, E., and Botstein, C. Effects of microwave-induced
a doubling of the treatment time for each degree of reduction
local hyperthermia on mammary adenocarcinoma in C3H mice. Cancer Res..
36:2113-2114,1976.
in the temperature. At temperatures below 43°,the relationship
3252
CANCERRESEARCHVOL. 39
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1979 American Association for Cancer Research.
Time- Temperature
16. Meritz, A. R., and Henriques, F. C. Studies of thermal injury. II. The relative
importance of time and surface temperature in the causation of cutaneous
burns. Am. J. Pathol., 23: 695-720, 1947.
Relationship
in Heat Treatment
of mouse mammary tumors. In: C. Streffer (ed), Cancer Therapy by Hyper
thermia and Radiation. Proceedings of the 2nd International Symposium,
Essen 1977, pp. 242—244.Munich: Urban and Schwarzenberg, 1978.
17. Morris, C. C.. Myers, R., and Field, S. B. The response of the rat tail to
25. Suit, H. D. Hyperthermic effects on animal tissues. Radiology, 123: 483-
hyperthermia. Br. J. Radiel., 50: 576-580, 1977.
18. Okumura, Y., and Reinhold, H. S. Heat sensitivity of rat skin. Eur. J. Cancer,
26. Suit, H. D., Sedlacek, R., Wagner, M., Orsi, L., Siiobrclc, V., and Rothman,
14:1161—1166,
1978.
19. Overgaard, J. The effect of local hyperthermia alone, and in combination
with radiation, on solid tumors. In: C. Streffer (ad.), Cancer Therapy by
Hyperthermia and Radiation. Proceedings of the 2nd International Sympo
sium, Essen 1977, pp. 49—61
. Munich: Urban and Schwarzenberg, 1978.
20. Overgaard, J. Biological effect of 27. 12 MHz short-wave diathermic heating
in experimental tumors. IEEE Trans. Microwave Theory Tech.. MTT-26:
523—529.
1978.
21 . Overgaard, K. tiber Wärmetherapiebosartiger Tumoren. Acta Radiol., 15:
89-100, 1934.
22. Overgaard, K., and Okkels, H. Uber den Einfluss der WÃ rmebehandlungauf
Woods Sarkem. Strahlentherapie, 68: 587-61 9, 1940.
23. Overgaard, K., and Overgaard, J. Investigations on the possibility of a
thermic tumour therapy—I. Short-wave treatment of a transplanted isolo
gous mouse mammary carcinoma. Eur. J. Cancer, 8: 65—78,1972.
24. RobInson, J. E., McCready, W. A., and Slawson, R. G. Thermal sensitivities
487, 1977.
K. J. Effect of Corynebacterium parvum on the response to irradiation of a
C3H fibrosarcoma. Cancer Res., 36: 1305-1314, 1976.
27. Suit, H. D., Shalek, R. J., and Wette, R. Radiation response of C3H mouse
mammary carcinoma evaluated in terms of cellular radiation sensitivity. In:
Cellular Radiation Biology, M. D. Anderson Hospital and Tumor Institute at
Houston, pp. 514—530.Baltimore: Williams & Wilkins, 1965.
28. Suit, H. D., and Shwayer, M. Hyperthermia: potential as an anti.tumor agent.
Cancer (Phila.), 34: 122—1
29, 1974.
29. Thrall, D. E., Gerweck, L. E., Gillette, E. L., and Dewey, W. C. Response of
cells in vitro and tissues in vivo to hyperthermia and x-irradlation. Adv.
Radlat. Blol., 6: 21 1—227,1976.
30. Thrall, D. E., Gillette, E. L., and Bauman, C. L. Effect of heat en the C3H
mouse mammary adenocarcinoma evaluated in terms of tumor growth. Eur.
J. Cancer, 9: 871 -875, 1973.
31 . Westermark, N. The effect of heat upon rat tumors. Scand. Arch. Physiol.
52: 257-322, 1927.
AUGUST 1979
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1979 American Association for Cancer Research.
3253
Time-Temperature Relationship in Hyperthermic Treatment of
Malignant and Normal Tissue in Vivo
Jens Overgaard and Herman D. Suit
Cancer Res 1979;39:3248-3253.
Updated version
E-mail alerts
Reprints and
Subscriptions
Permissions
Access the most recent version of this article at:
http://cancerres.aacrjournals.org/content/39/8/3248
Sign up to receive free email-alerts related to this article or journal.
To order reprints of this article or to subscribe to the journal, contact the AACR Publications
Department at [email protected].
To request permission to re-use all or part of this article, contact the AACR Publications
Department at [email protected].
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1979 American Association for Cancer Research.