Effects of Radiation Therapy on Growing Long Bones

Effects of Radiation Therapy on Growing Long Bones ARTHUR A. DE SMET, LAWRENCE A. KUHNS, JUAN V. FAYOS,2 AND JOHN F. HOLT Characteristic radiographic changes were seen in six of 14 children who received radiation therapy to the epiphyseal plate of a long bone. These changes, which include metaphyseal sclerosis, metaphyseal fraying, and epiphyseal plate widening, resemble rickets. In three patients, these changes were followed by development of a broad metaphyseal band of increased density. The absence of metaphyseal changes may indicate sterilization of cartilage cells and may be predictive of significant limb shortening. Irradiation of the epiphyseal plate of a growing long bone produces limb shortening, overtubulation, and bowing of the irradiated bone [1 1. Radiographic changes in the metaphyseal region are less well documented [2], prompting this study of the pattern and significance of the changes seen after irradiation of long bones in children. Materials and Methods Ewing s sarcoma is one of the few indications for long bone irradiation in a child. Therefore, we examined the records of all 1 07 patients who received radiation therapy at University Hospital for this tumor from 1 935 to 1 975. We identified 14 children (nine male, five female) who received irradiation to a long bone epiphyseal plate and had both charts and radiographs available for review. All the patients were less than 1 5 years old at the time of radiation therapy and were followed. for a minimum of 6 months. Seven patients were followed for 1-3 years and three for more than 3 years. In eight patients, the primary tumor was in the irradiated long bone. In the other six, a long bone epiphyseal plate was included in the radiation field for a tumor of the scapula or iliac bone. Irradiation was carried out using 60Co teletherapy except for one patient who was treated with 37Cs radiation. The common practice was to include the entire bone where the tumor arose and to use opposing fields whenever possible. Each prescribed field was treated daily with a midplane dose of 1 80-200 rad. The total dose varied from 4,000 to about 5,1 00 rad given in 5-6 weeks. The higher doses were given to patients entering the study more recently. The charts were reviewed to determine the radiation dose to the epiphyseal plate. associated chemotherapy. and clinically measured limb discrepancy. Radiographs were evaluated for findings previously reported [1] as being secondary to irradiation: (1) growth plate widening, (2) metaphyseal fraying. (3) metaphyseal sclerosis, (4) abnormal tubulation, and (5) premature epiphyseal fusion. Each of these findings was considered present only when confirmed by comparison with the opposite side (fig. 1). The lengths of the irradiated bone and the bone on the opposite side were also measured whenever possible. Results During the study two postirradiation changes were noted which have not been reported previously-a band of increased density-in the metaphysis and hip joint space widening. Three of the six patients who had metaphyseal abnormalities (fig. 2A) later developed a broad band of increased density in the metaphysis (fig. 2B). Two of the five patients who had irradiation to the proximal femur developed persistent widening of the hip joint space (fig. 3). The proximal femoral epiphyseal ossification centers were of equal size for each of these two cases. Widening of the joint space was first seen 8 months after irradiation for one patient and 1 0 months for the other, and was still present on their last examinations at 1 9 and 23 months, respectively. Osteoporosis was frequently observed in the irradiated bone. We did not evaluate this finding because etiologies other than irradiation, such as chemotherapy and especially disuse of the involved limb, are possible. The pattern of radiographic changes which developed after irradiation is shown in figure 4. Metaphyseal abnormalities were first noted 5-11 months after therapy Fig. 1.-Case 1. Film 8 months after radiation therapy showing widening of growth plate with fraying and sclerosis of metaphysis in right tibia and fibula. Biopsy site and sclerosis seen at primary site of tumor. Left leg normal. Received April 8. 1976; accepted after revision July 16, 1976. Department of Radiology. c. S. Mott Children s Hospital and University of Michigan Medical Center. Ann Arbor, Michigan 48109. Address reprint requests to L. R. Kuhns. 2 Department of Radiation Therapy. University of Michigan Medical Center. Ann Arbor, Michigan 48109. Am J Roentgenol 127:935-939, 1976 935

936 DE SMET ET AL. J Fig. 2.-case 3. A, Films 5 months after irradiation showing osteoporotic right proximal humerus with widening of growth plate and thin line of metaphyseal sclerosis. Scapular tumor is healing. Left shoulder is normal. 8. Films 11 months later showing that growth plate widening and thin line of sclerosis have cleared on right. Broad radiodense metaphyseal band has appeared. Left side remains normal. began. Widening, fraying, and sclerosis tended to occur together or in various combinations (figs. 1, 2A, and 3). The metaphyseal band was a later change which often disappeared leaving a normal metaphysis. Widening and sclerosis persisted for long periods in two cases (46 and 62 months) (fig. 5). Abnormal bone modeling was seen in only one patient who had overtubulation. Over the periods of observation, epiphyseal fusion occurred in two children and was symmetric. None of the above changes were seen in a metaphyseal region out of the treatment field. There was no retardation of ossification of an irradiated epiphysis. Table 1 shows the correlation between the clinical and radiologic data. Case 7 had a very narrow but unfused epiphyseal plate at the time of irradiation. Precise radiation field localization was not available for cases 11 and 14. In addition their epiphyseal plates were at the edge of the therapy portal, so the administered dose to bone was probably much lower than the listed maximum. Except for cases 1 1 and 1 4, the epiphyseal plate radiation doses were similar in the groups with and without radiographic changes. Discussion Irradiation of the end of a growing long bone in a child has been shown to produce distinctive radiographic changes near the epiphyseal plate. These are not generalized changes due to a systemic or metabolic abnormality, since they were seen only when an epiphyseal plate was included in the treatment field. These changes also occur in the absence of chemotherapy as shown by case 1

IRRADIATION OF GROWING LONG BONES 937 0 2 4 C 8 10 a a is IC 20 22?lizaeuevsU)M r i i-i i i r i-i l--r-i T-C, tiou)ml Fig. 3.-case 6. Film 10 months after therapy showing osteoporotic left femur with widening of growth plate and fraying of metaphysis. Left hip joint space clearly widened superiorly. and the patient of Frantz [3] who was irradiated for a hemangioma of the leg. Epiphyseal plate widening and metaphyseal sclerosis and fraying after long bone irradiation have been noted briefly in only four previous reports [1-4]. None of these reports evaluated the pattern of development of these changes. The high incidence of observed metaphyseal changes (six of 1 4) in our survey is surprising in view of the paucity of reported cases. Our series is biased only in -that patients had to survive at least 6 months and charts and radiographs had to be available. Our data represent the first clinical correlation of the histologic work by Hinkel in rats [5] and Reidy et al. in dogs [6]. They observed that the epiphyseal plate increases substantially in width after irradiation. This increase is due to increased layers and swelling of the cartilage cells and correlates with the growth plate widening seen on radiographs. Metaphyseal sclerosis is explained by the increased mineral deposition and deficient chondroclasis and osteoclasis at the zone of cartilage removal resulting from irradiation [7]. Metaphyseal fraying corresponds to the sharp prolongations of unresorbed calcified matrix which extend far proximally into the metaphysis where the cartilage cells are normally removed [5]. We feel the animal data help to explain the radiologic findings in our patients, because similar changes were observed in postirradiation radiographs of the rat [8] and dog [6] where histologic correlation was possible. Unfortunately no histologic material was available from our own series. Postirradiation epiphyseal plate widening, metaphyseal sclerosis, and metaphyseal fraying might be mistaken for rickets. However, the selective changes at only one joint easily differentiate postirradiation changes from systemic rickets. The radiologist should be aware when viewing radiographs of only one joint that such rachitiform changes may be due to radiation. The broad metaphyseal band of increased density has not been reported previously and we were unable to find a ioinl JoiN) JoiN) JOiNT WiOCOiNG CRAVING : sciaosis[ Patient # WiD(NiNG SAND NORMAL :: 0 WiDINiNG FRAYiNG SCLEROSiS WiD(N1PIG I I NGRMAL... WiD(NiNG[ I. -.-.--._..-1 SCIL;:! ----I 3 WiDSNiNG NOBMAL O(NNG FRAYiNG I SCLEROSiS I.-- - *id(ning *= - - - I FRAYiNG..... -..., - sclcrosis.. JOiNT *io(ning I I NORMA). w:d(n:ng SCLEROSiS JOINT WID(NiNG I. 1 1.1. 1. 1 1, 1.1 1..1. 0 2 4 6 B id I) 4 5 1$ 20 72 21 TiNDPOST-iRRADiATiON Fig. 4. - Pattern of development and subsequent clearing of observed radiographic changes. histologic counterpart. This band is apparently a manifestation of bone repair and frequently resolves leaving normal trabeculae. Widening of the hip joint after irradiation has also not been reported previously. This observation is particularly puzzling in view of its delayed onset and lack of correlation with known histologic changes. The most obvious explanation would be delayed ossification of the epiphyseal center, but this was not confirmed by measurements of the affected epiphysis and its contralateral equivalent. Two alternative explanations include cartilage hypertrophy or joint effusion, both which seem unlikely. There is no apparent cause for an effusion 8 or 1 0 months after irradiation. Previous studies of hyaline cartilage irradiation have shown either no effect [8] or cartilage atrophy [6]. A traction arthrogram [9] could be helpful in ruling out an effusion, but we have not yet had an opportunity to try this technique. Although our series is small, a pattern as to eventual limb shortening is suggested by table 1. Where measurements were available, limb shortening of greater than 1 cm was seen in one of five patients with radiographic metaphyseal abnormalities, but in three of four patients without metaphyseal changes. The other patient in the latter group had a measurement only at 3 months, so subsequent limb discrepancy may have developed. We suggest that the lack of appearance of these distinctive metaphyseal abnormalities in an irradiated bone may predict substantial limb shortening. In two recent cases (not shown in table 1) that had distal extremity irradiation, stress lines appeared on the nonirradiated side. These lines failed to appear in the

938 DE SMET ET AL. TABLE 1 Clinical and Radiologic Data Time of Limb Postirradiation I rradiated E piphyseal 5 hortening Measurement Case No. Age and 5ex Primary Site Epiphyseal Plate Dose (rad) Chemotherapy (cm) (mo) With postirradiation changes: 1 2, F Distal tibia Same 4,050 0.4 8 2 8, M Proximal fibula Proximal tibia 4,236 + 0.5 13 3 5, F Scapula Proximal humerus 5,094 + NA.. 4 7, F Scapula Proximal humerus 5,073 + 1.7 47 5 5, F Pubis Proximal femur 5,000 + 0 23 6 6, M Ilium Proximal femur 3,920 + 0.9 19 Without postirradiation changes: 7 1 4, M Proximal femur Same 5,050 NA.. 8 3. M Proximal humerus Same 4,089 + 3.0 1 1 9 1 4, F Distal femur Same 4,698 1.3 19 10 1 1, M Proximal femur Same 4,000 + 2.5 26 1 1 8. M Ilium Proximal femur 5,1 20 + NA.. 1 2 5, M Proximal humerus Same 4,800 + 0.3 3 1 3 6. M Metatarsal Same 5,000 + NA.. 14 14, M Scapula Proximal humerus 5,1 1 5 + NA.. Note-All patients treated with 60Co except case 8 who was treated with 37Cs. Opposing fields used in all cases except single field in cases 3. 4. and 14. NA - not available irradiated metaphysis, and significant bone length discrepancy ensued (fig. 6). A larger study would be required to confirm the prognostic implications of these observations. Experimental work does support our hypothesis. Several investigators [5, 6, 8] have reported that the epiphyseal plate usually returns to normal after showing disruption and fraying. However, if the dose administered is too great, the cartilage cells may be sterilized. In these cases, there would be no radiographic metaphyseal changes, and limb shortening would be most pronounced. In our material, the lack of development of radiographic changes in several patients was probably due to other factors. In case 7, the epiphysis was almost fused. In cases 1 1 and 1 4, the epiphyseal plate may not have received a sufficient dose of irradiation. Radionuclide bone scanning might be useful in predicting limb discrepancy. Scanning has been helpful in the diag-

IRRADIATION OF GROWING LONG BONES 939 nosis of Legg-Perthes disease [10]. Only two of our patients had bone scans after radiation therapy, and these scans showed no change from pretherapy scans. We plan a prospective experimental study to determine the value of radionuclide studies in predicting the severity of limb shortening. REFERENCES 1. Rutherford H, Dodd GD: Complications of radiation therapy -growing bone. Sem Roentgenol 9: 1 5-28, 1974 2. Probert JC, Parker BR: The effects of radiation therapy on bone growth. Radiology 114:1 55-162, 1975 3. Frantz CH: Extreme retardation of epiphyseal growth from roentgen irradiation. Radiology 55:720-724, 1950 4. Heald JH, Soto-Hall R, Hill HA: Ewing s sarcoma. Am J Roentgenol9l:1167-1171, 1964 Fig. 6.-Typical postirradiation changes in right distal growth plate of patient treated with systemic chemotherapy and 3.800 rad to right hand and wrist for soft tissue sarcoma between proximal metacarpals. Prominent transverse stress line appeared in left radial metaphysis (arrowheads) and its distance from growth plate increased. After 1 1/2 years, difference in radial lengths was 7 mm. 5. Hinkel CL: The effect of roentgen rays upon the growing long bones of albino rats. II. Histological changes involving endochondrial growth centers. Am J Roentgenol 49:321-348. 1943 6. Reidy JA, Lingley JR. Gall EA. Barr JS: The effect of roentgen irradiation on epiphyseal growth. II. Experimental studies upon the dog. J Bone Joint Surg [Am] 29:853-873, 1947 7. Hinkel CL: The effect of irradiation upon the composition and vascularity of growing long bones. Am J Roentgenol 50:516-526, 1943 8. Barr JS, Lingley JR. Gall EA: The effect of roentgen irradiation on epiphyseal growth. I. Experimental studies upon the albino rat. Am J Roentgenol 49: 104-1 1 5. 1943 9. Martel W, Poznanski AK: The value of traction during roentgenography of the hip. Radiology 94:497-503, 1970 10. Danigelis JA, Fisher RL. Ozonoff MB. Sziklas JJ: 99mTc polyphosphate bone imaging in Legg-Perthes disease. Radiology 115:407-413, 1975