In/. J Radrnrron Oncology Biol Phys, Vol. 20, pp. 1297-1303 Printed in the U.S.A. All rights reserved.

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I

??Brief Communication

REDUCED INCIDENCE OF BONE METASTASES IN IRRADIATED AREAS AFTER EXTERNAL RADIATION THERAPY OF PROSTATIC CARCINOMA HANS JACOBSSON, M.D.*

AND INGEMAR N&LUND,

M.D.+

Karolinska Hospital, P.O. Box 60500, S- 104 0 1 Stockholm, Sweden Fourteen males, out of 380 patients, treated with radiation to the central pelvis and lumbar spine for poorly differentiated prostatic carcinoma were analyzed in retrospect. The dose of radiation to the bones of the target area was 5,000 cGy. The patients showed no signs of metastases at bone scintigraphy performed in connection with the treatment. In an average of 34 months after finishing radiotherapy, the patients developed metastases at bone scintigraphy. The pattern was similar in all patients. The treated target area appeared as a “cold zone” surrounded by more or less homogenously and strongly increased activity of the axial skeleton, characteristic of bone metastases. Radiography, which was performed in 11 patients, confirmed widespread metastatic disease sparing the target area. This was interpretated as bone metastasis being precluded by the irradiation. The most probable explanation of this finding is eradication in situ of distant micrometastases already present in the bone marrow at the time of treatment. An alternate explanation is a reduced implantation of later seeded blood-born metastases as an effect of the irradiation. The characteristic pattern of this phenomenon must be recognized at bone scintigraphy. Bone metastasis,

Bone scintigraphy,

Prostatic carcinoma, Radiotherapy.

previously irradiated bone. Our experience with this finding, which so far we have seen only in patients with prostatic carcinoma, is reported and illustrated below.

INTRODUCIION

The initial effect of radiation of normal bone at scintigraphy is said to be increased radioisotope uptake of the treated bone volume (4, 15). However, we never have observed this. Also, reduced activity, which is generally agreed to be the long-term effect of radiation therapy (1, 4) is in our experience often not seen. When seen, the reduction of activity is often small. This may be explained by the phenomenon being dose-dependent. A dose of 2,000 cGy with normal fractionation is considered necessary for this effect to become overt (7). The mechanism behind the reduced activity has been attributed to damage of small vessels leading to reduced perfusion of the irradiated bone (1, 14) as well as to injury of cellular elements (2 1). In contrast, when the skeleton becomes generally involved by metastases after irradiation of the primary tumor region, we have found this phenomenon to be drastically enhanced. In such cases, the irradiated bone still has maintained normal or reduced radioisotope uptake, strongly contrasting with the surrounding increased radioisotope accumulation due to the tumor invasion of the unirradiated bone. Initially, when encountering this phenomenon, it caused diagnostic confusion, since little has been reported on the distribution of new metastases to

METHODS

AND MATERIALS

Patients The report is comprised of 14 male patients out of a population of 380 men who underwent external radiation therapy during 1978-85 because of poorly differentiated prostatic carcinoma. The mean age at onset of radiotherapy of the patients studied was 65 years, ranging between 55 and 78 years. In all cases the diagnosis was verified by fine needle aspiration biopsy (5). There were no signs of metastases at the first bone scintigraphy, which was performed in all patients as a routine procedure in connection with the radiotherapy. The diagnostic work-up also included determination of serum levels of acid and alkaline phosphatases to exclude patients with distant metastases. After radiotherapy, the patients underwent between one and three bone scintigraphic examinations. The indications for these examinations were local pain or elevated acid phosphatases. In most cases with a positive bone scan, a complementary radiographic examination was performed. In one patient, a bone marrow scintigraphy was also performed.

* Dept. of Diagnostic Radiology.

Reprint requests to: Hans Jacobsson, M.D.

+ Dept. of Oncology

Accepted

(Radiumhemmet). 1297

for publication

14 November

1990.

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I. J. Radiation Oncology ?? Biology 0 Physics

June 199 I, Volume 20, Number 6

Radiation therapy Irradiation was given with 8 MV X ray. The first 5,000 cGy was given with an anterior and posterior open field with block technique according to Figure 1, with fractionation of 160 cGy, 5 days a week to the middle of the false pelvis. After a 2-week rest, the treatment was completed with two small lateral fields of 2,000 cGy to the prostate with fractionation of 200 cGy. Only the first 5,000 cGy included the sacrum and the lumbal region, which is of interest in this study. Scintigraphic examinations Bone scintigraphy was performed as analogous registrations of the axial skeleton with a gamma camera* equipped with a low-energy general-purpose parallell-hole collimator, 3 hours after the injection of 500 MBq 99T~mmethylendiphosphonate. Bone marrow scintigraphy was performed using the same technique 30 minutes after the injection of 500 MBq 99Tcm-nanocolloid of human albumin.

RESULTS

The 14 patients underwent between one and three bone scintigraphic examinations up to 112 months after finishing radiotherapy. In five patients, the first examination after radiotherapy was negative for bone metastases. Two of these patients exhibited a normal pattern of activity distribution, identical to the examination prior to radiotherapy, and three cases showed a slightly decreased bone activity in the irradiated target area. The average time after finishing radiotherapy to the appearance of metastases at bone scintigraphy was 34 months, ranging between 6 and 99 months. Since only five patients had preceding negative scan after radiotherapy, a more precise timing of the scintigraphic appearance of bone metastases cannot be established in retrospect. The examinations yielded a similar pattern in all 14 cases. Outside the 5,000 cGy irradiated target area, which included the central pelvis and most of the lumbar spine (Fig. l), the examined skeleton exhibited multiple “hot spots” of moderately to strongly increased activity, in some cases coalescing to larger areas of irregularly increased uptake (Figs. 2 and 3). In these latter cases, the radiation field was sharply demarcated. One case exhibited a pattern of “super-scan”, that is, generally increased uptake by the axial skeleton with reduced renal activity, corresponding with diffuse symmetrical bone metastases (23). A complementary bone marrow scintigraphy was performed in one patient. This demonstrated considerably reduced activity in the target area and, outside this area,

* Maxicamera WI, USA.

or Gigacamera,

General

Electric, Milwaukee,

Fig. 1. Target area receiving 5,000 cGy in 14 patients treated with external irradiation for poorly differentiated prostatic carcinoma.

“cold spots” corresponding to “hot spots” at the bone scintigraphy. The latter is most likely due to the normal marrow being replaced by metastatic tissue (Figs. 2b and c) (12, 18). In 13 patients the relative bone activity distribution in the target area remained normal, strongly contrasting with the surrounding increased activity in the diseased bone. In one patient there was a small area of moderately increased activity in the central sacrum which may be attributable to a metastasis, although this could not be verified by radiography. Otherwise, this patient showed an activity pattern similar to the rest of the patients. Eleven of the 14 patients had a complementary radiographic examination in connection with the first positive bone scintigraphy. This examination included the target area and appropriate parts of the axial skeleton. There was a good correlation between the radiographic findings and the bone scintigraphy. No signs of metastases could be seen in the irradiated osseous structures, whereas the surrounding bone exhibited irregular and sometimes very dense sclerotic changes. These lesions were typical of bone metastases from prostate carcinoma and in general they corresponded with the areas of increased uptake at the scintigram (Fig. 3). In one patient osteolytic lesions were mixed with the osteosclerotic changes. Six patients had a repeat bone scintigram 8 to 16

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1. J. Radiation Oncology 0 Biology 0 Physics

(top)

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been shown to reduce the frequency of brain metastases (16). Outside this, minimal information regarding the prophylactic effect of radiation therapy for potential systemic metastatic disease is available. We have found one report evaluating prophylactic skeletal radiation therapy in reducing the incidence of bone metastases (8). In that prospective study, the entire pelvis was irradiated by a single dose of 800 cGy prior to the treatment of prostatic carcinoma. The authors felt that this diminished the frequency of bone metastases. In another, retrospective, analysis it was concluded that a dose of 1,OOO-1,600 cGy in 5 weeks, obtained by the addition of an anterior parasternal portal at postmastectomy radiation therapy for Stage II breast carcinoma, significantly reduced the incidence of metastases to the mid-dorsal vertebrae (9). In a

second retrospective analysis, a significant reduction of metastasis in the lumbar spine was observed in patients treated with 3,000-5,000 cGy irradiation to the para-aortic and pelvic regions for prostate cancer, compared to patients irradiated to the pelvis only ( 13). In contrast to these three reports, where a reduced incidence of sporadic metastases is reported, our cases were observed because of their striking appearance at routine scintigraphy. Consequently, this makes them represent a retrospective selection not allowing statistical conclusions. Nevertheless, the prophylactic effect of radiotherapy in these cases is illustrated by the strong reduction of activity in the target area compared with adjacent bone. Initially, this finding caused diagnostic confusion since we had not seen similar images before. Despite this, sharply demarcated and sym-

Bone metastasis after irradiation 0 H. JACOBSON

AND I.NASLUND

(right)

Fig. 3. Dorsal bone scintigraphic views and corresponding radiographs of the spine and pelvis of a male treated in January-March 1985, at the age of 63 years, for prostatic carcinoma with external irradiation according to Figure 1. (a) Bone scintigraphy from November 1984 showing normally distributed activity. (b) Concomitant radiographs exhibiting no signs of metastases. (c) Bone scintigraphy from October 1988 showing skeletal involvement of metastases outside the target area. The demarcation is indicated by arrows. (d) Concomitant radiographs confirming general skeletal involvement of metastases outside the target area. The demarcation is indicated by arrows.

metrical changes with a polygonal shape, like these photopenic areas, are unbiological findings and must be interpreted as potential artifacts. It could be argued that the absence of increased activity in the target area may be caused by impaired capacity of the bone to express increased radioisotope uptake secondary to the irradiation, even in the presence of metastases, rather than the region actually being spared from metastatic involvement. However, this seems unlikely. Strongly increased activity at bone scintigraphy due to insufficiency fractures of irradiated bone has been described by several authors (3, 17), and we have encoun-

tered patients with increased activity in irradiated areas caused by degenerative joint disease. In addition, the findings at complementary radiographic examination, which 11 patients underwent, parallelled the pattern at scintigraphy with no evidence of metastasis within the target area. The rationale for adjuvant radiation therapy in the studies previously described has been to eradicate, at sites of predilection, clinically non-overt metastases early disseminated (2, 8, 16). Micrometastases can be controlled with lower radiation doses than those required for a palpable tumor. This, since cell killing by radiation essentially

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June 199 I, Volume 20, Number 6

right)

Fig. 3. (Contd)

is an exponential function of dose, as well as microaggregates of malignant cells are less likely to contain hypoxic cells, making them more radiosensitive (23). The possibility that the reduced incidence of overt metastases in the target area may be caused by a subsequent decreased implantation of blood-borne metastases to the irradiated bone, rather than micrometastases being eradicated in situ, has only been discussed by one author ( 13). The “tumor bed effect” is known from experimental systems for many years (6, 10, 22). This implies the inhibiting effect of irradiation of connective tissues on the growth of subsequently transplanted tumor cells. The minimum dose necessary for this effect is 500- 1,000 cGy acute exposure, and it may persist up to more than 1 year between irradiation and tumor grafting (10, 22). Most investigators have concluded that the tumor bed effect is caused by radiation-induced damage on the host vascular and supportive tissue necessary for tumor growth (22). Especially

the endothelial cells of the capillaries have been found radiosensitive (20). Also, irradiated bone is subject to permanent changes, both on a cellular and vascular level ( 1, 14, 21). In addition, the active bone marrow is very radiosensitive, and doses as low as 400 cGy can cause a significant marrow depression (1). At higher doses, as in these patients, the marrow may become permanently ablated (cf. Fig. 2c) (19). Since metastases are believed to migrate to bone via persistent bone marrow ( 12, 18), this mechanism may be influenced by changes of the microenvironment of the marrow after irradiation. In the previously mentioned report on the prophylactic effect of irradiation on bone metastases in patients treated for breast cancer, the dose to the bone marrow was much lower than in our patients, and in a range allowing recovery of active marrow (9). This fact, in combination with the concept that in poorly differentiated prostatic carcinoma distant micrometastases are often already

Bone metastasis after irradiation 0 H. JACOBSON AND I.NASLUND

present at the time of treatment ( 1I), favors the hypothesis that the eradication of these micrometastases at least partly explains the reduced activity in the target area of our patients. In conclusion, these findings show that irradiation with high doses can be effective in preventing or delaying bone metastases in prostatic carcinoma. Whether adjuvant ir-

1303

radiation with smaller doses can be used as a prophylaxis against metastases to bones at high risk from prostatic carcinoma, cannot be stated from this study. Our observations are derived from a restricted group of patients irradiated with high biological doses. The characteristic picture of this phenomenon must be recognized at bone scintigraphy.

REFERENCES 1. Bell, E. G.; McAfee J. G.; Constable W. C. Local radiation

2.

3. 4.

5.

6.

7.

8.

9.

10.

11.

12.

damage to bone and marrow demonstrated by radioisotopic imaging. Radiology 92: 1083- 1088; 1969. Burgers, J. M. V.; van Glabbeke, M.; Busson, A.; Cohen, P.; Mazabraud, A. R.; Abbatucci, J. S.; Kalifa, C.; Tubiana, M.; Lemerle, J. S.; Voute, P. A.; van Oosterom, A.; Pons, A.; Wagener, Th.; van der Werf-Messing, B.; Somers, R.; Duez, N. Osteosarcoma of the limbs. Report of the EORTCSIOP 03 trial 20781 investigating the value of adjuvant treatment with chemotherapy and/or prophylactic lung irradiation. Cancer 6 1: 1024-103 1; 1988. Cooper, K. L.; Beabout, J. W.; Swee, R. G. Insufficiency fractures of the sacrum. Radiology 156: 15-20; 1985. Cox, P. H. Abnormalities in skeletal uptake of “Tc” polyphosphate complexes in areas of bone associated with tissues which have been subjected to radiation therapy. Brit. J. Radiol. 47:851-856; 1974. Franz&n, S.; Giertz, G.; Zajicek, J. Cytological diagnosis of prostatic tumors by transrectal aspiration biopsy: a preliminary report. Brit. J. Urol. 32: 193-196; 1960. Frankl, 0.; Kimball, C. P. Ueber die Beeinflussung von Mausetomoren durch RBntgenstrahlen. Wien. Klin. Wochenschr. 27:1448-1450; 1914. Hattner, R. S.; Hartmeyer, J.; Wara, W. M. Characterization of radiation-induced photopenic abnormalities on bone scans. Radiology 145:161-163; 1982. Hazra, T. A.; Giri, S. Prophylactic pelvic girdle irradiation in the treatment of prostatic carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 7:8 17-8 19; 198 1. Hercbergs, A.; Werner, A.; Brenner, H. J. Reduced thoracic vertebrae me&stases following post mastectomy parastemal irradiation. Int. J. Radiat. Oncol. Biol. Phys. 11:773-776; 1985. Hewitt. H. B.: Blake E. R. The growth of transplanted murine tumors in pre-irradiated sites. Br. J. Cancer 22:808824; 1968. Hilaris, B. S.; Whitmore, W. F.; Batata, M.; Barzell, W. Behavioral patterns of prostate adenocarcinoma following an “‘1 implant and pelvic node dissection. Int. J. Radiat. Oncol. Biol. Phys. 2:631-637; 1977. Ito, Y.; Okuyama, S.; Suzuki, M.; Sakurai, M.; Sato, T.; Takagi, H. Bone marrow scintigraphy in the early diagnosis of experimental metastatic bone carcinoma. Cancer 3 1: 1222-1230; 1973.

13. Kaplan, I. S.; Bagshaw, M. A.; Valdagni, R. The role of preemptive irradiation in the reduction of spinal metastases in prostatic cancer. In: Catalona, W. J., Coffey, D. S., Karr, J. P., Eds. Clinical aspects of prostate cancer. New York: Elsevier; 1989:46-56. 14. King, M. A.; Casarett, G. W.; Weber, D. A. A study of irradiated bone: I. Histopathologic and physiologic changes. J. Nucl. Med. 20:1142-l 149; 1979. 15. King, M. A.; Weber, D. A.; Casarett, G. W.; Burgener, F. A.; Corriveau, 0. A study of irradiated bone. Part II: changes in Tc-99m pyrophosphate bone imaging. J. Nucl. Med. 2 1: 22-30; 1980. 16. Komaki, R.; Cox, J. D.; Whitson, W. Risk ofbrain metastasis from small cell carcinoma of the lung related to length of survival and prophylactic irradiation. Cancer Treat. Rep. 65:811-814; 1981. 17. Lundin, B.; BjGrkholm, E.; Lundell, M.; Jacobsson, H. Insufficiency fractures of the sacrum after radiotherapy for gynaecological malignancy. Acta Oncol. 29:2 1 l-2 15; 1990. 18. Otsuka, N.; Fukunaga, M.; Sane, T.; Yoneda, M.; Saito, N.; Tanaka, H.; Tomomitsu, T.; Yanagimoto, S.; Muranaka, A.; Morita, R. The usefulness of bone-marrow scintigraphy in the detection of bone metastases from prostatic cancer. Eur. J. Nucl. Med. 11:319-322; 1985. 19. Parmentier, C.; Morardet, N.; Tubiana, M. Late effects on human bone marrow after extended field radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 9:1303-1311; 1983. 20. Reinhold, H. S.; Buisman, G. H. Radiosensitivity ofcapillary endothelium. Brit. J. Radio]. 46:54-57; 1973. 21. Sengupta, S.; Prathap, K. Radiation necrosis of the humerus. A report of three cases. Acta Radio]. (Ther.) 12:313-320; 1973. 22. Summers, W. C.; Clifton, K. H.; Vermund, H. X-irradiation of the tumor bed. I. A study of the indirect actions of radiation on transplantable tumors. Radiology 82:69 I-703; 1964. 23. Withers, H. R.; Peters, L. J. Biologic aspects of radiation therapy. In: Fletcher, G. H., Ed. Textbook of radiotherapy, 3rd edition. Philadelphia: Lea and Febiger; 1978: 103- 180. 24. Whitherspoon, L. R.; Blonde, L.; Shuler, S. E.; McBumey, D. B. Bone scan patterns of patients with diffuse metastatic carcinoma of the axial skeleton. J. Nucl. Med. 17:253-257; 1976.