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Int. J. Radiation Oncology Biol. Phys. Vol. 6, pp. 867-870
Pergamo n Press Ltd. , 1980. Printed in the U.S.A.
036~3016/80/070867~)4502.00/0
Brief Communication
HYPERTHERMIA AND RADIATION IN COMBINATION:A CLINICAL
FRACTIONATION REGIME
IqAIM I. BICFtER, M.D., Ph.D., TALJIT S. SANDHU, Ph.D.,F~,ED W.
HETZEL, Ph.D.
Division o f Radia tion B iology and Physics, Depar tment of
Therapeutic Radiology, H enry Ford Ho spita l , Detroit ,Michigan 4
82 0 2 .A fractionation regime has been devised and clinically
tested to use a combination of hyp erthermia and low doseradiation
therapy to treat tumors w ith a curative intent. Hyperthermia is
induced using m icrowaves delivered to adefined tissue volum e
through specially designed applicators. Frequencies of 2450 915 or
300 MHz are usedaccording to the desired pen etration depth. Each
trea tment lasts for 90 minutes. The sk in is cooled by an air
jet.Tissue temperature is kept at 45C w hen hyperthermia alone is
used and at 42C in com bination with radiation.Patients are treated
twice a week with 7 2 hour intervals between treatmen ts. The
regime consists of 4 treatments ofhyperthermia alone followed b y a
w eek of rest. Thereafter each hyperthermia treatment is preceded
by a 400 radfraction of x-irradiation delivered in 4 combined
treatments to a total of 1600 rad. This low total radiation
doseallows retreatment of previously irradiated areas or organs. No
toxicity induced b y this combination has be endetected even in
areas previously radiated to high doses. Twenty-three patients have
been entered into the protocolthat encompasses 37 treatment fields.
Most tumors respond to treatment many of these with total
disappearance;skin brain breast and spinal cord are amon g the
treated areas. Melanom as and lymph omas are the most
sensitivetumors sarcomas the most resistant; adeno and squamous
cell carcinoma in between.Hypertherm ia Fractionatlon Ra diation
therapy.
INTRODUCTIONFor o ver one hundred years resul ts have been repor
tedindicating that heat can modify tumor growth. Thepioneer e ffort
of Busch3 in 186 6 verified the disappear-ance of a sarcoma in the
fact of hyperpyrexia duringerysipelas. Bruns2 and Coley5 had
similar o bservations indifferent types of tumors. The past decade
has seen arenewed interest in hyperthermia; both in the
laboratoryand in the clinic.Several investigators have reported
cure attemptsusing hyper thermia in d ifferent form s.~13 Doss and
co-workers89~7 used radiofrequency heat ing in anim al andhuman
tumors wi th excel lent resu l ts; a m ethod that wasalso tested
extensively by LeV een et al t4Recently, Horn-back et al.2 reported
their experience with the use ofmicrowaves. Suit and Schwayder18 ~9
have reviewed thel i te ra ture o f recent exper iences in h yper
thermia . S ui t18demonstrated experimentally that the tumor cure
dose(TCDs0) values for thermally resistant tumors weresignificantly
reduced, therefore advocating a combina-tion of hyperthermia and
radiation therapy. Since theoxygen enhancement ratio (OER) for
hyperthermic
damage may be close to one there is a good possibilitythat the
combination of x-irradiation and hyperthermiawill lead to a
specific effect on the hypoxic cells in thetumors. W estra and
Dewey2 also indicate that becausethe hyperthermic sensitivity of
mammalian cells isgreater in the S p hase o f the cel l replication
cycle, whichis a lso the mo st res is tant to x- i r radia t ion ,
th is could a lsolead to further enhancem ent of the therapeutic
effect ofthe combined modalit~es. Dramatic changes in cellsurvival
during hyperthermia have also been observedwhen the pH o f the cel
ls is only s l ightly al tered.~ Crile6combined heat with radiation
in the treatment of cancerof the rectum. He surgical ly pro ved
that this com binationwas effective in eradication of metastases.
Crile7 alsodemonstrated the effectiveness of hyperthermia in amouse
sarcoma and the dependence of cure on thetemperature achieved and
the length of the treatmentper iod . He a lso com bined radia t ion
and hyper thermia inthe treatments of sarcoma in huma ns. ~
Cavaliere et al.4 5documented the effect of heat on tumor cells and
thesparing of normal tissue in rats. In clinical studies,regional
perfusion with heated blood between 41-43C
Presented in par t a t Am erican Socie ty of Therapeutic
Radi-ologists , New Orleans, October 1979.W ork suppo r ted in par
t b y grant CA 257 80- 0 1 awarded bythe National Cancer Institute,
Department of Health, Educa-t ion, and W elfare .Reprint requests
to: Haim I . Bicher , M.D. , Ph.D.Accepted for publication 19 March
198 0.
867
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Hyperthermia fractionation regime H. I. BICHER et al. 869Table
2. Results
37 Fie ldstreated 23 PatientsTotal response 25P ar tia l re sp o
nse 1 1 (9 le ss th an
2 m o n thfollow-up)No response Recurrence Lo ca lMarginalC om
plicatio ns Sk in burnsGrand se izure
22 (complete lyhealed) (Neck treatment)(epilepticpatient)
the microwave power required to maintain the desiredtreatment
temperature declines following the first orsecond treatment of a
given field. Final ly, i t appears thattumor regression following
completion of treatment isvery s low and requires approximately two
months beforethe total effect is obtained.
DISCUSSIONAlthough it is still very early in this study and
longterm follow-up is not available yet, it is clear this
treat-ment regime does produce striking results in a widevariety of
cases. If only tho se fields which were treated
com pletely and available for fol low-up are co nsidered, wecan
repor t 67 .6% total respo nse, 29.7% p ar t ia l responseand only
2.7% no response. In only one patient has a localrecurrence been no
ted; possibly as a result of misal l ignedthermocouples that
resulted in artifactual temperaturereadouts. The patient is
currently being retreated.
The observations on power required to maintain aconstant tempera
ture and on tumo r regress ion t ime are
Table 3. Results by histologyFol low
No. of upfields R e s p o ns e (months)Malignant
m e l a n o m aMalignantlymphomaSquamous ce l l
CAAdenocarcinomaS a r comaGliomaOthe r(basal cell,transitional
cell)
4 3 Total 21 Partia l 25 5 Tota l 3-6
6 3 Total 23 Partial17 12 Tota l 2-55 Partial2 1 Partia
l-expired --1 No response Partial 42 2 Tota l 2-4
Total response: no tumor present at 2 months follow-up
andthereafter.Partial response: Tumor decreased in size to half or
less at 2months follow-up.Partia l response--Exp ired: Patient
deceased during or within 8weeks after treatment.both quite
interesting. Based on recent laboratory results ,it is likely that
both phenomena are related to heatinduced, physiological changes
within the tumor whichare involved in the ultimate destruction of
the tumor.Further physiolog ical s tudies are currently in prog
ress .
I t is also interesting to sp eculate on the po ssible m ean-ing
of the two marginal recurrences; they may indicatethat this
combined modality protocol is effective in thet reatmen t of m
icroscopic disease. More t ime for fo l low-up and the input of m
ore p at ients wi l l be required beforea t rue evaluat ion o f the
c l in ica l eff icacy of th is proto colcan be made.
REFERENCES1. Brenner , H.J. , Yerushalmi, A. : Combined local
hyperther-mia and x-irradiation in the treatment of
metastatictumors . Br. J . Cancer 33: 91- 95 , 1975 .2 Bruns, P. :
Die heilwirung des erysipels auf geschwulste .Beitr Klin Chir 3:
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Erysipelnzuweilen auf organistier te Ne ubildungen ausueben.
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Cancet~.~40:2854-2863, 1977.i3. Johnson, R.J.R., Sandhu, T.S.,
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