OCTOBER

1977

Correspondence

B

!-50% 100%

FIG.1.

Isodose curves for cancer of the cervix, (A) In coronal plane, (B) In sagittal plane, (c) Suggested shape of isodose curve.

TABLE I

THE

EDITOR—SIR, T H E EFFECT OF SEQUENCE AND T I M E INTERVALS OF COMBINED HYPERTHERMIA AND RADIATION TREATMENT OF A SOLID MOUSE MAMMARY ADENOCARCINOMA IN VIVO

PHYSICAL PROPERTIES OF RADIONUCLIDES 192 Ir

Average photon energy (MeV) Half life Number of photons (%) T R Cm2 mCi-ih"1 Maximum beta energy (MeV) HVL in lead (cm) narrow beam HVL in water (cm) narrow beam

137

Cs

134

6°Co

Cs

0.375 74 d

0.66 30 y

0.7 2y

208 5.5

85 3.3

223 8.8

200 12.9

0.67

1.17

0.66

0.31

0.2

0.51

0.56

1.04

6.3

8.15

8.2

1.25 5.3 y

11

activity, to use a source which will give a suitable dose in about one minute at first, rising to eight minutes three half lives later (i.e. in six years). With a high specific activity, a specific y ray constant similar to that of 226 Ra and an average y-energy similar to 137 Cs, intracervical nitration may be possible to produce the required isodose shape. In these respects the isotope 134 Cs, little known in radiotherapy, is probably satisfactory and its use should be explored as a possible substitute for 60 Co in high dose-rate intracavitary machines with oscillating sources. Yours, etc., F. ELLIS,

D. V. RAO, J. T. MALLAMS.

Department of Radiology, CMDNJ, New Jersey Medical School, Newark, N J . 07103, U.S.A.

The observation that moderate hyperthermia (41—43 °C) sensitizes the effect of ionizing radiation has been established quantitatively in vitro (Bronk, 1976; Thrall et al, 1976) and more recently in several studies on normal tissues in vivo (Field et al, 1977; Thrall et al, 1976; Robinson et al, 1974). This sensitizing effect has been shown to be most prominent when the heat is given simultaneously with or immediately before or after radiation (Field et al, 1977; Joshi et al, 1976; Li et al., 1976; Sapareto et al, 1976; Stewart, 1976). As a result, it has been suggested that optimal tumour destruction would be obtained by a similar treatment regimen and recent clinical studies have been based on this assumption. However, in vivo studies to date with animal tumour systems do not always support such an important relationship between the time of application of these two treatment modalities. An isologous moderately differentiated mouse mammary adenocarcinoma " C " was treated with a combination of 27.12 MHz diathermy (42.5°C for 30 min) and 250 kV X rays (800 rad). The heat was applied either before or after radiation using differing time intervals. For tumours treated simultaneously, the radiation was given at the midpoint of the 30 minute heating period. The results were evaluated in terms of delay in tumour growth (Fig. 1) and cure rate (Table I). When hyperthermia and radiation were given as a combined treatment to the mouse mammary carcinoma, there was no significant difference in the effect obtained with time intervals from 0 to 48 hours, nor could any influence of the treatment sequence be observed. No changes were observed in the overlying skin or other adjacent normal tissues. Similar results have previously been demonstrated in the HB mouse mammary carcinoma (Overgaard and Overgaard, 1974) (Table I). The difference between the effect on normal tissue and solid tumours in vivo may be explained by a selective enhanced heat sensitivity of the tumour core. Tumour cells

763

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50, No. 598 Correspondence

situated in this central area are subject to special environmental factors (e.g. acidity, hypoxia) and thus may be more sensitive to destruction by heat alone (Overgaard, 1976). Figure 2 shows a section from a tumour 48 hours after treatment at 42.5°C for 30 min. Even though this heat dose is only half that which is required for tumour cure, it can be seen that it is sufficient to produce necrosis in all the central part of the tumour leaving only a few peripheral cells viable. The 800 rods role of radiation in combined treatment may, therefore, be (•) 4 2 . 5 V 30 min. -interval - 8 0 0 rods 42.5V30 i primarily to control the more peripheral tumour cells which (o) 800 rads - interval - 4 2 . 5 V 30 min. are in a "normal environment". These cells are more radiosensitive but may have a reduced susceptibility to increasing temperature. A direct hyperthermic sensitization of the radiation effect seems to have only a small influence on the control of this mouse mammary carcinoma. The fact that hyperthermia both has a direct lethal effect INTERVAL BETWEEN TREATMENTS (HOURS) on the tumour cells and is also a radiosensitizing agent makes it important to realize which kind of treatment strategy F I G . 1. Delay in tumour growth following treatment with combined should be used in order to utilize the optimal effect. In treatradiation and hyperthermia. The radiation was applied with ment where emphasis is placed on the radiosensitizing effect different time intervals before, during or after heating. the sequence and intervals between the application of the two There were no significant differences between the various modalities is critical. Even though the most effective schedule is not yet established it is evident from the in vitro data combined treatment schedules. cited that simultaneous or at least very close application of the two components is necessary to obtain maximum sensitization. Under such conditions, some hypoxic radiosensitization of tumour cells may occur (Robinson, 1976). Otherwise the therapeutic gain is doubtful, as the degree of sensitization of both normal tissue and well-oxygenated tumour cells seems to be very similar. If, on the other hand, the treatment plan is based on the direct hyperthermic cell killing effect, the treatment should be given with doses of heat and radiation each of which is respectively sufficient to control the central and peripheral parts of the tumour. This treatment will of necessity require relatively high doses, but as the two modalities can be separated by intervals of several hours it is possible to avoid any enhanced radiation damage due to heat sensitization of the normal tissues and thereby obtain maximum therapeutic advantage. The present observations support the value of such a schedule. These results demonstrate that the action of hyperthermia when combined with radiation in vivo is not necessarily due FIG. 2. to a radiosensitizing effect. Although heat has potential for Murine mammary adenocarcinoma 48 hours after heat destruction of all malignant cells, we do have in hypertreatment (42.5°C/30 min). The tumour shows massive thermia an agent which is especially effective in destroying central necrosis (bottom) with a small peripheral rim of tumour cells situated in the acidic, hypoxic and nutritionally viable tumour cells, some in mitosis. The normal surround- deprived environment which characterize the central part of ing stromal tissue is without apparent damage. Hematoxylin- solid tumours. These tumour cells constitute a major problem as they are difficult to control by conventional Eosin 150 X. . " • * :

TABLE I EFFECT OF SEQUENCE AND INTERVAL ON TUMOUR CURE RATE*

Interval between treatments (h) Tumour C

HBf

Treatment

0

42.5°C/30 min—800 rad

1/7

4

8

12

24

48

0/8

2/8

2/9

0/9

1/5

1/6

2/11

2/9

1/8

3/7

800 rad—42.5°C/30 min 42.5°C/30 min 800 rad Controls

0/10 0/10 0/14

42.5°C/30 min—800 R 800 R—42.5°C/30 min

10/52(19%) 7/27(26%)

*Cure rate: Number of cures/number of treated. fOvergaard and Overgaard, 1974.

764

7/23(30%) 11/44(25%)

OCTOBER 1977

Correspondence radiation or chemotherapy and are a potential source of tumour regrowth and consequently of local failure. If the present observations reflect a response of tumours in general, they suggest that the optimal clinical results will be obtained following combined treatment where the modalities are applied with an intervening interval of several hours. However, our knowledge concerning the combined hyperthermia-radiation reaction in vivo is still sparse and these results demonstrate also the need for further animal experiments to evaluate optimum treatment schedules before incorporation into extensive clinical trials. Yours, etc., Cancer Research Institute and The Radium Center, DK-8000 Aarhus, Denmark.

J . OVERGAARD.

ACKNOWLEDGMENT

This study was supported by Krista and Viggo Petersenns Foundation and the Danish Cancer Society.

screen radiographs for improved diagnosis of renal osteodystrophy by Smith and Junor (1977) is somewhat outdated. It has been clearly shown that fine-detail (industrial) radiographs provide far superior image qualities than the regular (medical) radiographs, the former permitting magnified viewing (times 6 to 8) and earlier detection of subperiosteal resorption than standard radiography (Genant etal., 1975; Meema e£ a/., 1972). Furthermore, intracortical resorption cavities measuring 200 microns in diameter can be clearly visualized by this simple magnification technique ("microradioscopy") (Meema et al., 1973). Since the image resolution by xeroradiography is similar to that of regular (medical) radiographic materials, the detection of bony abnormalities is not significantly improved by xeroradiography as was also found by Smith and Junor. As for the claimed improvement in measuring metacarpal cortical thickness by xeroradiography, no statistical proof is provided, no error analysed, indeed no figures for measurements are given in the paper. The categorical statement that this measurement is "more accurate from xeroradiographs than those made from standard radiographs" is therefore without scientific foundation. Yours, etc.,

REFERENCES BRONK, V. S., 1976. Thermal potentiation of mammalian cell killing: clues for understanding and potential for H. E. MEEMA. tumor therapy. In Advances in Radiation Biology, ed. John Department of Radiology, T. Lett and Howard Adler, vol. 6, pp. 267-324 (Academic The Toronto Western Hospital, Press, New York). 399 Bathurst Street, FIELD, S. B., HUME, S., LAW, M. P., MORRIS, C , and Toronto, Ontario, MYERS, R., 1977. Some effects of combined hyperthermia Canada M5T 2S8 and ionizing radiation on normal tissues. Proceedings of International Symposium on Radiobiological Research Needed for the Improvement of Radiotherapy, 22-26 REFERENCES November, Vienna, Austria (in press). GENANT, H. K., DOI, K., and MALL, J. C , 1975. Optical JOSHI, D. S., VAN DER SCHUEREN, E., DEYS, B. F., and versus radiographic magnification for fine-detail skeletal BARENDSEN, G. W., 1976. Factors influencing the interradiography. Investigative Radiology, 10, 160-172. action between hyperthermia and ionizing radiation with MEEMA, H. E., RABINOVICH, S., MEEMA, S., LLOYD, G. J., respect to mammalian cell reproductive death. Interand OREOPOULOS, D. G., 1972. Improved radiological national Journal of Radiation Biology, 29, 183-186. diagnosis of azotemic osteodystrophy. Radiology, 102, Li, G. C , EVANS, R. G., and HAHN, G. M., 1976. Modifica1-10. tion and inhibition of repair of potentially lethal X-ray MEEMA, H. E., and MEEMA, S., 1973. Microradioscopic bone damage by hyperthermia. Radiation Research, 67, 491structure of the hand in thyrotoxicosis, renal osteo501. dystrophy and acromegaly. In Clinical Aspects of MetaOVERGAARD, J., 1976. Ultrastructure of a murine mammary bolic Bone Disease, edited by B. Frame, A. M. Parfitt and carcinoma exposed to hyperthermia in vivo. Cancer H. Duncan, pp. 10-19. (Amsterdam, Excerpta Medica, Research, 36, 983-995. International Congress Series No. 270). OVERGAARD, K., and OVEKGAARD, J., 1974. Radiation sensi-

SMITH, F. W., and JUNOR, B. J. R., 1977. Xeroradiography

tizing effect of heat. Ada Radiologica, Therapy, Physics, of the hand in patients with renal osteodystrophy. British Biology, 13, 501-511. Journal of Radiology, 50, 261-263. ROBINSON, J. E., 1976. Hyperthermia and the oxygen enhancement ratio. Proceedings of the International Symposium on Cancer Therapy by Hyperthermia and Radiation, 28-30 April, Washington, D.C., USA, American College THE EDITOR—SIR, of Radiology. DOPPLER FOR HOLES IN THE HEAD ROBINSON, J. E., WIZENBERG, M. J., and MCCREADY, W. A., From time to time lacunae are seen in routine skull films 1974. Radiation and hyperthermal response of normal that raise doubts as to whether they are due to emissory tissue in situ. Radiology, 113, 195-198. veins or to an intracranial vascular malformation. Returning SAPARETO, S. A., HOPWOOD, L. E., and DEWEY, W. C , to X-radiology in general hospitals providing a service to 1976. Combined effects of X irradiation and hyperthermia local general practitioners, to help in the present shortage, I on CHO cells for various temperatures and orders of have been able to apply in another field my research into application. Radiation Research, 67, 575. Doppler measurement in the central retinal vessels. STEWART, F. A.. 1976. The effect of combined heat and The first case presented at the Whittington Hospital as X rays on mouse skin. British Journal of Radiology, 49, one of fractured nasal bones, showed also a lacuna in the 585. frontal bone that was very suggestive of an underlying THRALL, D. E., GERWECK, L. E., GILLETTE, E. L., and vascular malformation. The patient was a four-year-old DEWEY, W. C , 1976. Response of cells in vitro and tissues girl with no clinical symptoms suggesting intracranial in vivo to hyperthermia and X irradiation. In Advances in abnormality. An appointment was made for her to be Radiation Biology, ed. John T. Lett and Howard Adler, examined using the Parks Transcutaneous Doppler vol. 6, pp. 211-227 (Academic Press, New York). equipment Model 801-A. This is intended for peripheral vascular disease and operates at 9.2 MHz. The two crystals are so small that both could be applied to the thinned area. A loud arterial pulse was heard showing that an anomalous THE EDITOR—SIR, artery was present. XERORADIOGRAPHY OF THE HAND IN PATIENTS The second case presented at St. Charles Hospital was a WITH RENAL OSTEODYSTROPHY The comparison of xeroradiographs with standard non- woman of 53 with three months frontal headache who was

765