Br Med J: first published as 10.1136/bmj.4.5946.679 on 21 December 1974. Downloaded from http://www.bmj.com/ on 6 November 2021 at UK NHS and HE Athens Access.

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BRITISH MEDICAL JOURNAL 21 DECEMBER 1974 679

PAPERS AND ORIGINALS

Clinical Effects of Whole-body Hyperthermia in Advanced

Malignancy
R. T. PETTIGREW, JEAN M. GALT, C. M. LUDGATE, A. N. SMITH
British Medical_Journal, 1974, 4, 679-682 molten wax at 50°C to prevent evaporation of sweat and insulate
the body. The overall effect is to raise the body temperature
by 3 to 6° an hour depending on body weight. Previous work
Summary has shown that the method is safe for treatment periods up to
Fifty-one patients in the terminal stages of cancer have eight hours provided that the temperature does not exceed
been treated with whole-body hyperthermia either alone 41-8°C and so long as there is adequate replacement of the
(38 cases) or in combination with chemotherapy (13 water and salt lost in the sweat (Pettigrew et al., 1974).
cases). Altogether 227 treatment sessions were held Thirty-eight patients have been treated with hyperthermia
averaging four hours each. The most sensitive tumours alone in 188 treatment sessions and a further 13 with hyper-
were those of the gastrointestinal tract and sarcomas. thermia in combination with cytotoxic drugs. In the first group
Breast and genitourinary tumours did not respond, and the average length of each treatment above 41°C was four hours,
lung tumours and melanomas were only partially and treatments were given at weekly intervals. In the second
responsive. Major complications were remarkably few. group treatment was given in three sessions each separated by
three days. The first lasted 90 minutes and the other two
four hours. Cytotoxic drugs were given by intravenous bolus
Introduction injection during the last treatment. Patients with malignant
melanoma were given Melphalan 1 mg/kg; the others were
Temperatures in the range of 41 to 42'C have been shown to be given cyclophosphamide 200 mg during the period of tempera-
lethal to tumour cells but not damaging to normal cells ture rise and fluorouracil 15 mg/kg and vincristine 1 mg at a
(Cavaliere et al., 1967; Vermel and Kuznetsova, 1970; temperature of 41°C.
Obergaard and Overgaard, 1972). Hyperthermia has been The response to treatment was judged favourable if there was
applied to human tumours in vivo by isolated limb perfusion, weight gain or pain relief plus either regression in tumour size
either alone or in combination with cytotoxic drugs (Cavaliere on direct measurement or pathological evidence of necrosis in
et al., 1967; Stehlin, 1969), by whole-body hyperthermia serial biopsy specimens or radiological evidence of regression.
(Warren, 1935; Henderson and Pettigrew, 1971), and by local Further evidence of heat-induced tumour necrosis was obtained
irrigation (Hall et al., 1974). This paper records the clinical at necropsy in five of the six patients who died soon after hyper-
responses of a series of patients to whole-body hyperthermia thermia.
either alone (38 patients) or in combination with cytotoxic Nineteen patients were excluded from the series. Fourteen
therapy (13 patients). All the patients were in the terminal were treated in the developmental stages of the method when
stages of their disease and unsuited to further treatment by temperatures above 40°C were not routinely used. These
conventional methods. patients did not respond, and it is now accepted that temperatures
in excess of 41°C are needed (Giovanella et al., 1970). A further
five patients with no obviously measurable tumours were
Method treated for symptomatic relief of pain only.
The method used was that described previously (Pettigrew
et al., 1974), in which the narcotized patient is covered with
Results
Western General Hospital, Edinburgh, EH4 2XU HYPERTHERMIA ALONE
R. T. PETTIGREW, M.B., F.F.A. R.C.S., Consultant Anaesthetist
C. M. LUDGATE, M.B., F.R.C.S., Surgical Registrar Though the numbers were small tumours of gastrointestinal
University of Edinburgh origin and sarcomas appeared to respond more than genito-
A. N. SMITH, M.D., F.R.C.S., Reader in Clinical Surgery urinary or breast neoplasms; lung tumours and malignant
JEAN M. GALT, B.Sc., Research Associate
melanomas showed an intermediate response (table I).
 Br Med J: first published as 10.1136/bmj.4.5946.679 on 21 December 1974. Downloaded from http://www.bmj.com/ on 6 November 2021 at UK NHS and HE Athens Access. Protected by copyright.
680 BIgTISH, MEDICAL JOURNAL 21 DECEMBER 1974

FIG. 1-Photomicrographs of liposarcoma. A and C, pences of operation scr. A fourth had a hindquarter asrutation for osteo-
tumour after rection. (Haematoxylin and eosin. A x 110. C x 2 B a
gnic wroma; two mmonths after the end of an 18-month course
D, appearances of recurrent tumour four months later after treent with
h perthermia showing total necrosis to right side and degenerate cells at of treatmens ti tumour reaurred in a heat-resistant form. A fih
left margin. (Haemitoxylin and eosin. B x 110. D x 270). patient, with an alvanoed liposarcome, died 24 hours after treat-
ment. Necropsy showed recenrt massive necrosis throughout the
turwur (fig. 1). Two had sujective improvement with pain relief,
Case Reports and a child with rhabdomyosaaro showed no response.
Carcisoma of Stomach.-.Three cases. Two anorexic patients
Sarcoma.-Eight cases. In one paient a lung deposit disappeared, who had been in great pain gained weight and were able to lead
a second showed healing of pathological fractures, and a third a relatively normal life. The thid had extensive mediastinal and
showed complete regression of a fibrosaroma recurrent in the lung metastases and died 48 hours after treatment. At necropsy

TABLE I-Results of Treatmet wth Hyperthermia Alon

Preiu Treatment
Tumour Type
No. ofPatientsP Surgery
Treated Radiotherapy Chemotherapy
Objective
Responses
Subjective
Response
No
Response
Survival from St
of Thermotherapy (Weeks)
Sarcoma .. .. 8 6 4 2 3+1* 6 1 84, 52, 20, 8, 4, 2, 1, 0-14
Gastric Cinoms3 3 0 1 2+1* 2 0 16,16,0-28
Carcinoma colon .. 4 4 0 1 2 2 2 20,8,4,0-71
Melanoma..... .. 7 7 2 2 3 4 3 12, 12, 8, 8, 4, 4, 3
Carnoma lung .. 3 0 3 0 2 3 0 24,20,4
Carcinoma brent.. 2 2 2 1 0 1 1 12,12
Ovarian c inoma, 4 4 2 3 0 0 4 24, 16, 8, 4
teratoma testes
Neuroblastoma, 3 3 3 3 1 +2* 1 0 24,0-85,0-28
nephroblastoma
Miscelaneous .. 4 2 4 4 1 1 2 32,24,12,057

* Necropsy evidence of recent tumour necrosis.

 Br Med J: first published as 10.1136/bmj.4.5946.679 on 21 December 1974. Downloaded from http://www.bmj.com/ on 6 November 2021 at UK NHS and HE Athens Access. Protected by copyright.
BRITISH MEDICAL JOURNAL 21 DECEMBER 1974 681
In one was regression of the
patient with adenocarcinoma there
primnary lung (confirmed at necropsy) (fig. 2) though the
tumour
seconday deposits remained active. The second patient, with a
squamous carcinoma, showed regression of a secondary deposit
in the lumbar spine, and the third had relief from pain but showed
no tumour regression.
Breast Canaer.-Two patients with scirrhous carcinomas were
treated, one obtaining pain relief alone.
Ovarian and Testicular Tumours.-Two testicular teratomas and
two ovarian papillary tumours showed no response to treatment.
Neuroblastoma and Nephroblastoma.-Two cildren with
neuroblastomas were treated. One showed a good initial response,
with healing of ulcerated skin over the tumour in his jaw. The
second showed initial improvement till he developed respiratory
difficulties and died two days after treatment. Necropsy showed
multiple hae.morrhagic areas of necrosis in the tumour. One child
with a nephroblastoma showed initial improvement but also died
from a respiratory arrest. At necropsy there was gross necrosis of
the tumour.
Miscellaneous Tumours.-One case of mycosis fungoides showed
initial healing and there was pain relief alone in a case of adeno-
carcinoma of the nasopharynx. One case each of chronic myeloid
leikaemia and transitional oell carcinoma of the bladder showed
no response.

HYPERTHERMIA IN COMBINATION WITH CYTOTOXIC THERAPY

The results in the 13 patients givencytotoxic drugs duringhyper-

thermia are shown in table II.
Case Reports
Gastrointestinal Tumours.-Six cases. One patient ha'd an adeno-
carcinoma of the colon with large hepatic metastases enlarging the
liver -to 12 cm below the costal margin. After treatment the liver
mass regressed to a lump 5 by 6 cm and the patient was alive
and well at six months. The second patient, with a cholangio
carcinoma of the liver, showed regression of hepatomegaly with
complete clearance of jaundice (initial bilirubin 7-2 mg/ 100 ml)
and resolution of gress ascites. The third patient had an un-
differentiated carcinoma and was admitted to hospital as an
emergency case with large-bowel obstruction. Th-ere was a mass
20 cm in diameter in his left iliac fossa and he had renal failure
due to ureteric involvement. After treatment he had complete
regression of the mass with a return of normal renal and bowel
function. A fourth patient had some regression of hepatomegaly
and the fifth showed necrosis on serial biopsy. There was sympto-
matic improvement in one patient with adenocarcinoma of the
gall bladder.
Malignant Melanoma.-Three metastatic cases. Two patients
showed regression of involved axillary nodes and the third showed
FIG. 2-Chest x-ray pictures from patient with bronchogenic carcinoma. A,
regression of hepatomegaly though her secondary nodules did not
appearances before treatment with hyperthermia. B, appearances six weeks change in size.
later after six treatment sessions. Breast Canoer.-Three cases. These patients had cancer en
cuirasse and were in severe pain. In the first two there was relief
of pain with discontinuance of opiates and regrowth of skin over

there was extensive necrosis of the tumour causing compression the tumours. One of these patients died within 12 hours of a
of the bronchus. further treatment given for recurrence three months later. There
Carcinoma of Colon.-Four cases. One patient had almost com- a,ppeared to be no pathological evidence of tumour necrosis and
plete regression of massive h-epatomegaly; a second had regression death was attributed to disseminated intravascular coagulation.
of skin noduiles on the lower abdomen. The other two cases The third patient died 48 hours after treatment with disseminated
showed no response. intravascular coagulation. In this case necropsy showed evidence
Malignant Meanoma.-Seven cases. In three cases there was of recent cell death in the tunmour metastases, which involved liver,
good initial regression of secondary deposits and pain relief. One adrenal, both kidneys, skull, uterus, pancreas, vertebrae, and dura.
patienrt had pain relief alone and three showed no response. Miscellaneous.-One case of osteoblastoma was treated. Though
Carcinoma of Lung.-Three cases of bronchogenic carcinoma. the patient had pain relief there was no regression of the tumour.

TABLE il-Results of Treatment with Hyperthermia in Combination with Chemotherapy

No. of Patients Previous Treatment Objective Subjective No Survival from Start

Tumour Type Treated Response Response Response of Thermotherapy (Weeks)
_________ ~Surgery Radiotherapy Chemotherapy |-___ ____________________
Gastrointestinal 6 4 1 1 5 5 0 32, 20, 20, 16, 12, 8
tumours
Carcinoma breast.. 3 3 3 2 2+1* 2 0 20, 12, 0-28
Melanoma .. .. 3 3 0 0 3 1 0 52, 44, 24
Osteoblastoma I.. 1 0 0 0 1 0 12

e Iecropsy evidence of recent tumour necrosis.

 Br Med J: first published as 10.1136/bmj.4.5946.679 on 21 December 1974. Downloaded from http://www.bmj.com/ on 6 November 2021 at UK NHS and HE Athens Access. Protected by copyright.
682 BRITISH MEDICAL JOURNAL 21 DECEMBER 1974
Complications treatment jaundice (Pettigrew et al., 1974). This did not occur
after treatment at 41-80C, which was therefore taken as the
Complications may arise from the method, from the physio- maximum permissible therapeutic temperature. There are
logical response to high temperatures, or from the toxic effects indications that a treatment period in excess of 20 hours would
of tumour breakdown. When one considers that these patients be needed at 41 80C to produce total tumour necrosis (Johnson,
were maintained in an unconscious state at temperatures of 1940). This treatment period may become possible with a
over 41°C for a total of about 1,000 hours complications of a greater understanding of the physiological processes which occur
major character were remarkably few. The second patient treated, at 41-8°C. Several workers have claimed that a synergism exists
in 1966, before the present controlled method was evolved, between hyperthermia and certain cytotoxic drugs (Stehlin,
developed ventricular fibrillation. This was due to her tempera- 1969; Giovanella et al., 1970). By combining the two treatments
ture reaching 43°C as a result of thermometer failure and was it may be possible to produce total tumour necrosis in a shorter
the only fatality directly attributable to induced hyperthermia. time. The rationale behind this, however, has recently been
Half of the patients developed a circumoral herpes simplex questioned (Palzer and Heidelberger, 1973 a). Though the
during the first session but not on subsequent treatments. Sore numbers in this series were small it appeared that there was an
throats, pressure sores due to prolonged immobilization during enhanced effect when hyperthermia and chemotherapy were
treatments, and superficial burns in oedematous, hypoprotein- combined.
aemic patients occurred. With any treatment regimen aiming at total tumour necrosis
Four adult patients died within 48 hours of hyperthermia; in one session the possibility of toxic products causing dele-
their deaths were associated with evidence of disseminated terious effects such as diffuse intravascular coagulation cannot
intravascular coagulation. In three necropsy showed recent be ignored (Leavy et al., 1970; Peck and Reiquam, 1973). Yet
tumour necrosis. Two children with an advanced form of with therapy given in multiple sessions other problems may be
neoplastic disease also died shortly after treatment. They were encountered. Work with transplanted animal tumours indicates
given opiates for relief of distress and died of respiratory com- that heating to a degree insufficient to produce a cure has a
plications. Another patient died of fibrosing alveolitis, possibly stimulatory effect on the spread and growth of metastases
due to repeated exposure to the hot, moist, ventilating gases (Brett and Schloerb, 1962; Dickson and Ellis, 1974) and may
then in use (Henderson and Pettigrew, 1971) or as a result of allow repair of sublethal damage to the tumour cells to take
treatment with bleomycin six months previously. place (Palzer and Heidelberger, 1973 b). Heat-resistant strains
of cultured human tumours have been produced by exposure to
sublethal hyperthermic damage (Selawry et al., 1957). In this
RECOVERY AFTER TREATMENT series some of the patients with responsive tumours who were
Narcosis is maintained during treatment with short-acting treated with multiple sessions of heating without chemotherapy
barbiturates and the patient is awake before leaving the theatre. seemed to develop less sensitive tumours. Patients who responded
Patients with sensitive tumours show evidence of a systemic to chemotherapy plus hyperthermia continued to respond to
reaction after the first treatment, especially if it is prolonged. further combined treatments given when there was tumour
They develop a persistent tachycardia with a low blood pressure recurrence.
and may remain pyrexial for up to 48 hours. Recovery takes This work was supported by a grant from the Melville Trust
place more rapidly after a subsequent treatment if'given within for Cancer Research, Edinburgh.
a week. After the first treatment patients may be managed on a We should like to thank the many consultants who referred
day-stay basis, coming into hospital on the morning of treatment cases, in particular Mr. M. A. Henderson, of the Dunmfries and
and being discharged the next day. Patients with unresponsive Galloway Royal Infirmary, who helped greatly in the early stages
tumours show no toxic effects and are fully recovered within of the work, and also Dr. Neil McLean, consultant pathologist,
eight hours. If treatment is extended beyond four or five hours Western General Hospital, for his advice and help in reporting the
post-treatment jaundice may develop. pathological findings in these patients.
Requests for reprints should be sent to Mr. A. N. Smith, De-
partment of Clinical Surgery, Western General Hospital, Edin-
burgh EH4 2XU.
Discussion
There have been no deaths during hyperthermia in over 200
treatment sessions. Of the four adult deaths occurring within References
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