Pediatric Annals

Malignant Bone Tumors

Norman Jaffe, MD

Abstract

1. Copel and, M. M, Primary m alignant turn ors of bone. Evaluation ot current diagnosis and treatment, Cancer 20 (1967). 738-746.

2. Miller, R. W. Fifty-two forms of childhood cancer: United States mortality experience. 1960-1966. J- Pediatr. 75 (1969), 685-6T9.

3. Lichfensiein, L. Bone Tumors, Fourth Edition. St. Louis: The C. V, Mosby Company, 1972.

4. McN eil. B. J., et al. Fluorine-18 bone scintigraphy in children with osìeosarcoma or Ewing's sarcorra. Radiology 109 (1973), 627-631.

5. Dahlin, D. C.. and Coventry, M. B. Osteogenic sarcoma: A study of 600 cases. J, Bone Joint Surg. 49-A (1967), 101-110.

6. Hayles, A.B., Dahlin, D. C., and Coventry, M. B. Osteogenic sarcoma in children. J. A. M. A. 174 (I960). 1174-1177.

7. McKenna. R. J., et al. Sarcomata of the osteogenic series (osîeosarcoma, chondrosarcoma, parosleal osteogenic sarcoma, and sarcomata arising in abnormal bone)· An analysis of 552 cases. J. Bone Joint Surg. 48-A (1966), 126.

8. Lindbom, A., Soderberg, G., and Spjut. HJ. Osteosarcoma: A review ot 96 cases. Acta Radial. (Stockholm) 56 (1961). 1-19.

9. Sweetnam, R.. Knowelden, J., and Seddon, H. Bone sarcoma. Treatment by irradiation, amputation, or a combination of the two. Brit. Med. J. 2 (1971). 363-367.

10. Dahlin. D, C., Coventry, M. B., and ScanIon, P. W. Ewing's sarcoma: A critical analysis of 165 cases. J. Bone Joint Surg. 43-A (1961), 1T5-192.

11. FaIk, S.. and Alpert, M. The clinical and roentgen aspeéis of Ewing's sarcoma. Amer. J. Med. Sc/. 250 (1965), 492-50T.

12. Bhansali. S. K.. and Desai, P. B. Ewing's sarcoma: Observations on 107 cases. J. Bone Joint Surg. 45-A (1963), 541-553.

13. Phillips, R. F., and Higinbotham, N. L. The curability of Ewing's endothelioma of bone in children. J. Pediatr. 70 (1967). 391-397.

14. Wang, C. C., and Schulz, M. D Ewing's sarcoma: A study of 50 cases treated at the Massachusetts General Hospital, 1930-1952 inclusive. W. Engi. J. Med. 248 (1953). 571-576.

15. Cortes. E. P., et al. Doxorubicin in disseminated osteosafcoma. J. A. M. A. 221 (1972), 1132-1138.

16. Gottlieb, J. A., et al. Chemotherapy ot sarcomas with a combination of adriamycin and dimethyl triazeno imidazole carboxamide. Cancer 30 (1972), 1632-1638.

17. Jaffe. N. Recent advances in the chemotherapy ot metastatic osteogenic sarcoma. Cancer 30 (1972). 1627-1631.

18. Jeffree, G. M., and Price, C. H. G. Bone tumors and their enzymes. A study of the phosphatases, non-specific esterases and betaglucuronidase of osteogenic and cartilaginous tumours, ftbroblastic and giant-cell lesions. J. Bone Joint Surg. 47-B (1965), 120-136.

19. Rosen, G., et al. High-dose methotrexate with citrovorum factor rescue and adriamycin in childhood osteosarcoma. Cancer 33 (1974), 1151-1163.

20. Dahlin, D. C. Bone Tumors: General Aspects and Data on 3987 Cases, Second Edition. Springfield, 111. : Charles C Thomas, 1967.

21. Geschickter, C. F., and Copeland, M. M. Tumors ot Bone, Third Edition. Philadelphia: J. B. Lippincott Company, 1949.

22. Ross, F. G. M, Osteogenic sarcoma. Brit. J. Radio!. 37: (1964), 259-276.

23. Marcove, R. C., et al. Osteogenic sarcoma under the age of twenty-one; a review of 145 operative cases. J. Bone Joint Surg. 52-A (1970), 411-423.

24. Acketman, L. V., and del Regato, J. A. Cancer Diagnosis. Treatment, and Prognosis, Fourth Edition. St. Louis: The C.V. Mosby Company, 1970, pp. 896-935.

25. Garrington. G. E., et al. Osteosarcoma of t he jaws. Analysis of 56 cases. Cancer 20 (1967). 377-391 .

26. Cade, S. Osteogenic sarcoma. A study based on 113 patients. J. Roy, Coll. Surg. Edinburgh 1 (1955), 79-111.

27. Lee. E. S., and MacKenzie, D.H. Osteosarcoma: A study ol the value of preoperative megavoltage radiotherapy. Brit. J. Surg. 51…

Malignant tumors of bone and cartilage represent less than 1 per cent of all malignant neoplasms.1 They account for a mortality of 1.87 per million children under 14 years of age. The incidence rises for slightly older patients, in whom these tumors are responsible for 11.97 deaths per million people between 15 and 19 years.2 A knowledge of the anatomy and histology of bone will facilitate an understanding of the varieties of tumors encountered (Figure 1). The shaft of a long bone is the diaphysis. The growing end is the epiphysis, which consists principally of cartilage. The metaphysis separates the epiphysis from the diaphysis. Bones are supplied by blood vessels, lymphatics, and nerves, each of which may give origin to neoplastic tissue. A classification of bone tumors adapted from Lichtenstein is outlined in Table I.3 Except for the occasional relationship of osteogenic sarcoma to irradiation, the cause of bone tumors in human beings is unknown.

The purpose of this article is to review the most common malignant and benign tumors of bone that occur during childhood. The symptomatology and diagnostic evaluation will be discussed. Recent advances in the management of bone tumors, particularly with respect to chemotherapy and the rationale underlying its early administration, will be presented. Major emphasis will be placed on osteogenic sarcoma and Ewing's sarcoma, since these constitute over 85 per cent of malignant bone tumors in children.

GENERAL MANAGEMENT

Clinical evaluation. A complete history and full physical examination should be obtained. Specific inquiry should be made regarding antecedent trauma or infection, although there is no evidence that either may be implicated in the cause. However, tumors have occasionally presented as osteomyelitis. The duration of symptoms may help to estimate the rate of tumor growth. Clinical examination should record the size and location of the tumor, signs of local inflammation, possible involvement of regional lymph nodes, and any functional disorder of the limb.

Most malignant bone tumors in children produce localized pain of variable duration in the affected area. The pain may be described as a severe or a dull ache and may be attributed to a sprain, arthritis, minor trauma, or "growing pains." Relief may be obtained by various maneuvers, including drawing up the legs, thereby relaxing the muscles overlying the taut periosteum. Physical examination usually does not reveal anything remarkable until several weeks or months later, when the pain has become more intense and a tumor mass is detected. Systemic symptoms are usually absent unless the tumor exerts pressure on a nerve or is far advanced with widespread métastases. At this stage the affected limb is obviously swollen, with conspicuously dilated veins on the surface. Occasionally, metastatic spread - particularly to the lungs, causing a pleural effusion and dyspnea, or to other bones - may be more troublesome than the primary tumor. The radiologie appearance varies according to the type of tumor. Radiologie evaluation. Radiographs of high quality of the entire affected bone are important. Occasionally, laminagrams of the bone may be required to determine the extent of tumor invasion into the medullary cavity or cortex, particularly in parosteal lesions. Local infiltration into the soft tissue may be noted. The bone radiographs are followed by radiologie examination of the entire skeleton and lungs. If the routine chest radiograph is normal, or if only a few métastases are noted, complete lung tomograms should be obtained. Occasionally, chest fluoroscopy may be indicated. Radioisotope fluorine bone scans have become routine for the investigation of bone tumors in most centers. In some instances, angiography may be requested to determine the extent of tumor infiltration into adjacent soft tissues.

Variable radiographie appearances may be noted (Figures 2, 3, 4, and 5). They represent a summation of the changes and are dependent on the type of tumor, extent of spread, and propensity for new bone formation. This is exemplified in osteogenic sarcoma. The sclerosing variety demonstrates variable amounts of bone destruction and new bone formation. The tumor may produce an expansile or periosteal destruction of the cortex, varied periosteal reaction and a bulky mass. As it expands beneath the periosteum, a needlelike new bone formation may be observed growing at right angles to the shaft (sunburst appearance). Elevation of the periosteum produces a triangular-shaped appearance designated Codman's reactive triangle. Variable degrees of soft-tissue infiltration may occur. In the advanced stages fractures are not infrequent, particularly in weight-bearing bones. Métastases in the lungs appear as small rounded densities of variable size. With advancing disease, these become larger and may be complicated by pleural effusion and occasionally by pneumothorax. Radiographie examination of the skeleton may reveal métastases to other bones.

Experiences with fluorine-18 bone scintigraphy in osteogenic sarcoma have shown it to be more sensitive than skeletal surveys in the detection of bony métastases.4 The investigation is particularly helpful in delineating the cause of pain due to tumor when negative results are observed on routine radiographie examination. If amputation and other surgical maneuvers are being considered, this study is important in determining the possible existence of early métastases in other bones. The detection of extraskeletal métastases with fluorine-18 is also possible in some patients.4

Figure 1. Anatomic features of a typical long bone. Although not invariable, osteogenic sarcoma is more prone to occur at the extremities (epiphysis and metaphysis) and Ewing's sarcoma in the diaphysis. Several benign tumors are also more prone to occur in particular anatomic sites. The blood vessels, lymphatics, and nerves supplying the bone may also give origin to neoplastic tissue.

Figure 1. Anatomic features of a typical long bone. Although not invariable, osteogenic sarcoma is more prone to occur at the extremities (epiphysis and metaphysis) and Ewing's sarcoma in the diaphysis. Several benign tumors are also more prone to occur in particular anatomic sites. The blood vessels, lymphatics, and nerves supplying the bone may also give origin to neoplastic tissue.

Biopsy. This is performed in the operating room with the patient under general anesthesia and a tourniquet applied to the limb above the tumor. In some centers, immediate amputation may follow biopsy after the diagnosis is obtained by frozen section. If this procedure is contemplated, it should be clearly outlined to the patient and parents before operation. Bone marrow aspirations may be obtained concurrently with the biopsy if invasion to other bony sites is suspected. Prebiopsy radiation therapy to the tumor is also advocated in some centers in an attempt to reduce the number of viable malignant cells that might metastasize during the operation. This has not altered the prognosis in patients at the Children's Cancer Research Foundation and is no longer employed in this institution.

Interdisciplinary conference. When the results of these investigations are available, an interdisciplinary conference is scheduled. This is attended by the radiologist, radiotherapist, pathologist, orthopedic surgeon, general surgeon, and pediatrie medical oncologist. The social worker and psychiatrist are advised of the decision to amputate.

Informing parents and patient. The final diagnosis and projected plan of treatment are eventually presented to the parents and patient. If an amputation is contemplated, the patient should be advised that this is being done to remove the tumor. The information should be conveyed several days before the operation to permit the patient an opportunity to ask questions and to become accustomed to the concept of losing a limb. The lesion should not be disguised as an "infection." This may invoke fear of possible amputation in the patient or his siblings should a true infection of a limb subsequently occur.

DIFFERENTIAL DIAGNOSIS OF MALIGNANT BONE TUMORS

Benign neoplastic conditions. Expert radiologie opinion frequently helps differentiate a number of these tumors, but in most instances a biopsy will be required. The following are the most frequently encountered benign tumors. Osteochondroma is the most common benign tumor of the bone. It generally affects the ends of long bones, particularly the distal femur, proximal tibia, and proximal humérus. Patients are usually under 21 years of age. It may cause significant pain and impinge on neurovascular structures. Multiple osteocartilaginous exostoses or osteochondromas are a familial disorder. They should be removed surgically, since there is a 20 per cent chance of the development of malignancy. Chondroblastoma occurs most frequently during the second decade of life. It is a benign tumor of cartilage arising in the epiphyseal area. Treatment is by local surgical resection. Occasionally, local recurrence due to implantation into an adjoining joint space may occur. In rare instances métastases have been reported, raising the question as to whether the tumor can be truly classified as benign. Chondromyxoid fibroma occurs most commonly in people between the ages of 10 and 30 years. Histologically, chondrous and myxoid elements may be found. It may occasionally be confused with chondrosarcoma because of a bizarre cellular morphology. Treatment is usually by surgical curettage. Osteoid osteoma is a small solitary lesion occurring in the bones of the legs. Treatment is by surgical resection. Osteoblastoma may occur in many sites, usually as a painful solitary tumor. Patients are usually between 10 and 35 years of age. Treatment is by curettage or excision followed by bone graft. Aneurysmal bone cyst is a benign solitary expansile lesion of bone occurring in the metaphysis in vertebral bodies and in flat bones. Large blood-filled multicystic spaces are noted on radiographie examination. It may occasionally be confused with a malignant tumor. Treatment is by surgical excision or curettage and bone grafting.

Figure 2. Osteogenic sarcoma of the right femur. Appearance on clinical examination is shown on the left. The mass on the medial side of the distal femur is apparent. On x-ray examination (right), a huge mass extends from the right side of the middle third of the femur. It lies medial to the shaft, although there is some disease on the lateral side. Irregular calcification and ossification are seen throughout the mass. The underlying femur shows mottling and an increase in density, with elevation of the periosteum along either side.

Figure 2. Osteogenic sarcoma of the right femur. Appearance on clinical examination is shown on the left. The mass on the medial side of the distal femur is apparent. On x-ray examination (right), a huge mass extends from the right side of the middle third of the femur. It lies medial to the shaft, although there is some disease on the lateral side. Irregular calcification and ossification are seen throughout the mass. The underlying femur shows mottling and an increase in density, with elevation of the periosteum along either side.

Figure 3. Lateral view of right femur (same patient as in Figure 2) several months later. following radiation therapy, demonstrates marked sclerosis ot the distal part of the shaft. There are some areas of rarefaction of bone and destruction of the cortex. Calcification arising from the bone into the soft tissues is obvious. A fr&nk pathologic fracture through the upper portion of the tumor-bearing bone has occurred.

Figure 3. Lateral view of right femur (same patient as in Figure 2) several months later. following radiation therapy, demonstrates marked sclerosis ot the distal part of the shaft. There are some areas of rarefaction of bone and destruction of the cortex. Calcification arising from the bone into the soft tissues is obvious. A fr&nk pathologic fracture through the upper portion of the tumor-bearing bone has occurred.

Figure 4. Osteogenic sarcoma In the left lilac bone (A). Two areas of sclerosis occupying the medial and lateral parts of the lilac bone are present. The "sunburst" appearance of new bone formation In the lateral sclerotic lesion Is obvious. Before hemlpelvectomy, an angiogram (B) was performed to determine the extent of soft-tissue infiltration. The investigation demonstrates gluteal branches of the left lilac artery supplying tumor vessels through a large neoplasm In the left lleum. Tumor neovascularlty extends laterally well outside the limits of the visualized bone and ossified tumor, suggesting lateral extension to the approximate limit of the outer margin of the greater trochanter.

Figure 4. Osteogenic sarcoma In the left lilac bone (A). Two areas of sclerosis occupying the medial and lateral parts of the lilac bone are present. The "sunburst" appearance of new bone formation In the lateral sclerotic lesion Is obvious. Before hemlpelvectomy, an angiogram (B) was performed to determine the extent of soft-tissue infiltration. The investigation demonstrates gluteal branches of the left lilac artery supplying tumor vessels through a large neoplasm In the left lleum. Tumor neovascularlty extends laterally well outside the limits of the visualized bone and ossified tumor, suggesting lateral extension to the approximate limit of the outer margin of the greater trochanter.

Figure 5. Osteogenic sarcoma of the sclerotic type in the proximal two-thirds of the shaft of the humérus and also the proximal eplphyseal ossification center. There is extensive destruction of the cortex, with extension ot the tumor out into the soft tissues, where it shows considerable calcification and ossification.

Figure 5. Osteogenic sarcoma of the sclerotic type in the proximal two-thirds of the shaft of the humérus and also the proximal eplphyseal ossification center. There is extensive destruction of the cortex, with extension ot the tumor out into the soft tissues, where it shows considerable calcification and ossification.

Nonneoplastic conditions that may be confused with malignant bone tumors include osteomyelitis, osteitis, bone abscess, hypovitaminoses A and D, hyperparathyroidism, fibrous dysplasia, foreign-body reaction, cortical defects, and hypoparathyroidism. Detailed history, physical examination, radiographie studies, and biochemical evaluations are obviously required to determine the exact nature of the illness.

Primary malignant bone tumors must also be distinguished from secondary malignant deposits.

PRINCIPLES OF TREATMENT

Treatment of the primary lesion. Treatment is designed with curative intent unless the disease is fairly extensive and palliation is a major consideration. Initially, eradication of the primary lesion is attempted. This may be accomplished through surgery and/or radiation therapy. Surgical ablation is usually undertaken for osteogenic sarcoma, chondrosarcoma, and fibrosarcoma. The site of amputation is dependent on the location of the primary tumor. The affected bone is sectioned at least 3 in. above the proximal limit of the intramedullary extent of tumor visible roentgenographically. If the tibia or fibula is affected, an aboveknee amputation or disarticulation through the knee joint may be performed. Lesions of the foot require a below-knee amputation. A hemipelvectomy may be performed for tumors of the innominate bone and a forequarter amputation for lesions of the upper humérus. Occasionally the surgeon may consider disarticulation of a limb a satisfactory procedure.

Most centers have introduced the practice of fitting the patient with a prosthesis immediately after surgery of the leg. It consists of a rigid dressing pylon and a foot-ankle assembly. This intermediate prosthesis permits early ambulation and improves the psychologic outlook. A definitive prosthesis can usually be fitted six to eight weeks later.

Ewing's sarcoma, reticulum cell sarcoma, and hemangioendotheliosarcoma usually respond to radiation therapy. Generally, the entire bone is irradiated. If there is failure of response, or if the location of the lesion is more amenable to surgery, it will be resected.

Ancillary treatment. The rationale underlying the early administration of chemotherapy (or other "adjuvant" treatment) is based on the biologic behavior of malignant tumors of childhood. The natural history of osteogenic sarcoma and Ewing's sarcoma would suggest that widespread submicroscopic foci of disease are present at the time of diagnosis. Thus, in osteogenic sarcoma, despite effective control of the primary lesion by surgical ablation, pulmonary métastases invariably appear within six to nine months in the majority of patients. This is the usual cause of death, with the survival rate varying between 5 and 25 per cent.5"9 Similarly, in Ewing's sarcoma, with therapy directed only at the primary tumor (surgery or radiation therapy). reports of survival rates vary between 5 and 15 per cent. 10'14 Clinically evident métastases usually appear within 12 months after diagnosis, with the lungs and other bones commonly affected, although no organ or tissue appears immune. To prevent or possibly destroy the growth of these micrometastases, other methods of treatment are employed. Chemotherapy has eradicated bulk tumor in a number of patients, 1S~17 and it is logical to assume that the potential of chemotherapy to destroy microscopic foci of disease may be even greater.

Osteogenic sarcoma. This is the most frequently encountered malignant primary tumor of bone. It presumably arises from bone-forming mesenchyme, which can give rise to spindle cells, mucoid material, cartilage, and bone. Osteoid tissue is usually seen evolving from sarcomatous stroma (Figure 6). This does not occur in chondrosarcoma. The tumor is occasionally divided into a sclerosing and osteolytic variety, but all variations may occur. Histologically different patterns may be seen if several sections are examined. Consequently, subdivisions into medullary, subperiosteal, telangiectatic, and sclerosing were considered confusing by Lichtenstein.3 Investigators have reported an elevation in the levels of serum alkaline phosphatase with osteoid-producing tumors.18'19

The tumor occurs more frequently in the younger age group. The peak ranges between 10 to 25 years, with males predominating ( the male-tofemale ratio is approximately 1.6:1 to 2:1). 5,6,20-23 Most reports describe the primary location of the tumor in the diaphysis, especially of the lower extremity,5-8'9 Approximately half of the tumors affect the femur, with 80 per cent of these arising in the distal end. Other primary sites of origin probably occur in the following order: proximal femur, proximal humérus, tibia, pelvis, jaw, and phalanges. The appearance of this tumor in the skull and other unusual sites is usually a complication of Paget's disease of bone in adults or of irradiation.24

Treatment may conveniently be considered under three major categories: surgery, radiation therapy, and chemotherapy.

Surgery. Survival in most patients with osteogenic sarcoma is generally attributed to a successful radical operative procedure. Conservative surgery for a rapidly growing tumor offers practically no hope of cure. Surgical resection is planned with the object of achieving complete tumor ablation. Occasionally this may be impossible - as for tumors of the skull, vertebra, and pelvic bones, for which radiation therapy and chemotherapy may be used. In general, the nearer the tumor to the trunk, the worse the prognosis, since local control is less certain and pulmonary métastases are more likely to occur. Conversely, the patients with osteogenic sarcomas arising in the small bones of the feet or forearm have a better than 50 per cent chance of five-year survival after surgical resection.24 Early diagnosis of disease in the mandible may perhaps also produce a more favorable prognosis.25

Radiation therapy. In view of the poor prognosis with primary surgical ablation. Cade in 1931 advocated a program of preoperative radiation therapy followed nine months later by elective amputation provided métastases had failed to appear. " Such a treatment program could avoid "futile mutilation" when death from early métastases was probably inevitable. It was considered that radiation therapy could also avert surgical resection in patients in whom an exceptionally good response was obtained, with good function of the limb and minimum disability. Subsequently, proponents for radiation therapy (at the Children's Cancer Research Foundation and elsewhere) also speculated that radiation therapy could alter the character of the tumor and initiate a specific antibody response against host tumor tolerance. Prebiopsy radiation therapy was also occasionally employed to reduce the incidence of métastases; however, the objectives of treatment with radiation therapy were not fully met. There was no change in the survival rates,27'28 and local control was not always achieved with the doses of radiation therapy administered. Consequently, tumor dissemination from a nonamputated limb remained a constant threat, and failure of local control could result in severe pain and protracted morbidity requiring delayed amputation. Clearly, additional or alternative modes of treatment were indicated.

Chemotherapy. During the past few years, several chemotherapeutic regimens have been shown to be effective in the treatment of metastatic osteogenic sarcoma. The initial therapeutic programs comprised adriamycin15'16 and high-dose methotrexate followed by citrovorum factor ("dtrovorum rescue") - J 7 Their efficacy was augmented by the addition of a number of chemotherapeutic agents, including cyclophosphamide, vincristine, and phenylalanine mustard.29*33 Many of the protocols are of an investiga tional nature and can be administered only in specialized cancer centers where adequate supportive measures are available. However, the resources and cooperation of the referring physician are usually enlisted to help in observing the patient in the intervals between treatments or assist in the administration of chemotherapeutic agents on an ambulatory basis. The preliminary results are highly encouraging and suggest that the natural history of osteogenic sarcoma has been altered. The protocol for vincristine and high-dose methotrexate followed by citrovorum factor is utilized at the Children's Cancer Research Foundation as outlined in Table 2.

Figure 6. Section of tumor from patient with osteogenic sarcoma. The tumor Is made up of spindle ceils, some of which are pleomorphic. A major portion of the tumor is composed of hyaline osteoid material. Occasional mitotlc figures are noted. H and E stain. X400.)

Figure 6. Section of tumor from patient with osteogenic sarcoma. The tumor Is made up of spindle ceils, some of which are pleomorphic. A major portion of the tumor is composed of hyaline osteoid material. Occasional mitotlc figures are noted. H and E stain. X400.)

Figura 7. Parosteal osteogenic sarcoma. (A) Lateral view of the right knee demonstrating a 7-cm. calcified and osseous mass lying behind the distal end of the femur. The mass arose from an area of the cortex of the femur. Bony destruction is not identified. There Is no Invasion of the medullary cavity. (B) Radiograph of femur following primary treatment with wide local resection of tumor. The patient has a functioning limb and has remained free of local recurrence and pulmonary métastases following vincristlne/ highdose methotrexate-citrovorum factor treatment.

Figura 7. Parosteal osteogenic sarcoma. (A) Lateral view of the right knee demonstrating a 7-cm. calcified and osseous mass lying behind the distal end of the femur. The mass arose from an area of the cortex of the femur. Bony destruction is not identified. There Is no Invasion of the medullary cavity. (B) Radiograph of femur following primary treatment with wide local resection of tumor. The patient has a functioning limb and has remained free of local recurrence and pulmonary métastases following vincristlne/ highdose methotrexate-citrovorum factor treatment.

Figura 8. Fluorine-18 bone scan in a patient with multifocal sclerosing osteogenic sarcoma. There are several areas of Increased activity that correspond to areas of tumor invasion, which were also demonstrated by radiographie skeletal survey (sphenoid sinus, proximal humerl, fifth lumbar vertebra, iliac bones, left proximal and distal femur, multiple lesions in the shaft and distal right femur, and proximal and distal tibiae bilaterally). Many of these tumors were initially not visible on routine radio - graphic examination and appeared several months later.

Figura 8. Fluorine-18 bone scan in a patient with multifocal sclerosing osteogenic sarcoma. There are several areas of Increased activity that correspond to areas of tumor invasion, which were also demonstrated by radiographie skeletal survey (sphenoid sinus, proximal humerl, fifth lumbar vertebra, iliac bones, left proximal and distal femur, multiple lesions in the shaft and distal right femur, and proximal and distal tibiae bilaterally). Many of these tumors were initially not visible on routine radio - graphic examination and appeared several months later.

SPECIAL TREATMENT STRATEGIES

Nonmetastatic osteogenic sarcoma. After appropriate investigations and confirmation of the diagnosis, immediate surgical ablation of the primary tumor is performed. This is followed by adjuvant chemotherapy for variable periods. At the Children's Cancer Research Foundation, treatment is instituted for two years.

Metastatic osteogenic sarcoma. Each patient receives individual consideration. Frequently the chemotherapeutic regimen is preceded by resection of bulk tumor. The concept underlying this approach is based on the hypothesis that chemotherapy is more effective against minimal residual disease than against relatively large tumor masses. Thus-, if the number of pulmonary métastases is small, the treatment program may advocate surgical ablation of the primary tumor and pulmonary resections followed by chemotherapy. Occasionally, surgical ablation of the primary tumor without resection of pulmonary métastases may be instituted. This is followed by chemotherapy, which may achieve a complete or partial response. In the event of a partial response, it may be possible to remove resistant métastases by surgical resection.

Table

TABLE 1CLASSIFICATION OF PRIMARY BENIGN AND MALIGNANT NEOPLASMS OF BONE

TABLE 1

CLASSIFICATION OF PRIMARY BENIGN AND MALIGNANT NEOPLASMS OF BONE

Table

TABLE 2SCHEDULE OF METHOTREXATE-CITROVORUM TREATMENT

TABLE 2

SCHEDULE OF METHOTREXATE-CITROVORUM TREATMENT

In advanced widespread metastatic disease, palliation is an important consideration. Chemotherapy forms the vanguard of treatment. When it is administered in an aggressive and systematic manner, destruction of tumor may result in an appreciable relief of pain. If the treatment proves successful, it may be possible to transfer the patient from a "palliative" category to one of "potential cure." Surgery also has a definite role in palliation. In some instances cervical cordotomy may be recommended. Occasionally, the pain in a swollen, functionless limb is so intense that relief may be possible only through surgical ablation. Recently, radiation therapy administered concurrently with chemotherapy was reported to be a useful palliative procedure and should also be considered.34

Periosteal osteogenìc sarcoma (juxtacortical osteogenic sarcoma)*'35"39 (Figure 7). This represents an uncommon variant of osteogenic sarcoma. The metaphyseal regions of the distal femur, humérus, or tibia are generally involved. The cure rate, generally with amputation, is variously reported as 53 to 80 per cent. In view of the improved outlook and the possibility of eradicating submicroscopic foci of disease with methotrexate-citrovorum treatment, wide local resection rather than amputation may permit preservation of a normal functioning limb.2*

Multifocal sclerosing osteogenic sarcoma (Figure 8). This is a rare variant of osteogenic sarcoma wherein métastases to the lungs also occur. Whether the numerous primary tumors originate independently in various areas of the skeleton or whether they represent metastatic lesions is controversial,40 In one patient treated with high-dose methotrexate-citrovorum, new foci developed in bone but pulmonary métastases failed to occur." Patients in this category are treated similarly to those who have multiple métastases.

Figure 9. Section of tumor from patient with Ewing's sarcoma. The tumor shows a monomorphism with proliferation of round or slightly oval cells. Mitotic figures are present. The cells have scanty cytoplasm and well-defined nuclei with dusty chromatin. (H and E stain, X400.)

Figure 9. Section of tumor from patient with Ewing's sarcoma. The tumor shows a monomorphism with proliferation of round or slightly oval cells. Mitotic figures are present. The cells have scanty cytoplasm and well-defined nuclei with dusty chromatin. (H and E stain, X400.)

Figure 10. (A) Lateral and (B) anteroposterior views. An expansile lytic lesion of the right fibula with a pathologic fracture in the proximal third of the shaft is visible. The entire bone is somewhat poro tic. Layers of subperlosteal new bone can be seen around a grossly invasive and destructive lesion. The medial and anterior portion of the cortex Is entirely destroyed. There is a soft-tissue mass around the lesion. Biopsy revealed a diagnosis of Ewing's sarcoma.

Figure 10. (A) Lateral and (B) anteroposterior views. An expansile lytic lesion of the right fibula with a pathologic fracture in the proximal third of the shaft is visible. The entire bone is somewhat poro tic. Layers of subperlosteal new bone can be seen around a grossly invasive and destructive lesion. The medial and anterior portion of the cortex Is entirely destroyed. There is a soft-tissue mass around the lesion. Biopsy revealed a diagnosis of Ewing's sarcoma.

Extraosseous osteogenic sarcoma. This extremely rare form of osteogenic sarcoma, involving soft tissues or viscera, has also been reported.41 Treatment here should be individualized, but it will probably follow lines similar to those adopted for patients with métastases.

Chondrosarcoma, fibrosarcoma, and Hposarcoma. These are rare tumors and are differentiated by histologie appearance and radiographie findings. The principles of treatment are similar to that for osteogenic sarcoma.

Ewing's sarcoma. This comprises between 7 and 15 per cent of all malignant bone tumors. The tumor occurs more frequently in males (the male-tofemale ratio is approximately 1.6:1) and is found most commonly in children, adolescents, and young adults. The majority of patients are between four and 25 years of age.10'11'20'24

The tumor is generally considered to arise in the marrow spaces of the interior of the affected bone rather than from osteoid tissue itself.3 Microscopic examination reveals highly anaplastic broad sheaths of tumor with polyhedral-shaped cells characterized by very scanty or pale cytoplasm. The cells have small nuclei and fine nucleoli. Intercellular substance is absent, and osteoid is never found (Figure 9). Special histochemical stains reveal the presence of gly cogen in tumor cells.42

The tumor originates in the shaft and never primarily involves the epiphysis. It usually arises in the trunk bones or bones of the extremities. Primary lesions have been reported in the femur, tibia, fibula, pelvic bones, ribs, humerus, ulna, and skull. In the early stages subparosteal and endosteal new bone formation is present. The lesion may spread to a major portion of the shaft, extend through the periosteum, and infiltrate into the soft tissue.

Radiographie studies (Figure 10). The earliest radiologie findings may appear as a roughening of the periosteum that may be confused with osteomyelitis. Invasion of the entire bone with advancing disease is not unusual. Parosteal thickening, occasionally accompanied by a laminar deposit and subperiosteal new bone formation, produces an "onion skin" appearance. This feature, often considered diagnostic of Ewing's sarcoma, is inconsistent. Ossification in the bone is absent, as it assumes a permeative destructive appearance. 43"4S Occasionally, Ewing's sarcoma may simulate a soft-tissue sarcoma because of apparent absence of bone changes.11

Fluorine-18 bone scan is more sensitive than routine radiographie examination in the detection of bony métastases in patients with this tumor. Unlike osteogenic sarcoma, these bony métastases become apparent before pulmonary métastases are visible on routine radiographie examination of the lungs.* The investigation, however, is not as sensitive as a bone marrow aspirate, which may demonstrate tumor infiltration of the bone marrow in the presence of a normal fluorine-?ß bone scintigraph and radiographie study.46

Treatment has evolved from experiences with radiation therapy, surgery, and chemotherapy.

Surgery. Current treatment programs rarely advocate surgery for Ewing's sarcoma. Occasionally, if the lesion involves a major portion of the bone and a clean operation can be anticipated, resection of a fibula may be performed. Similarly, if radiation therapy may damage the underlying lung. lesions of the rib may be treated surgically.

Radiation therapy. It is generally accepted that the treatment of primary tumor in Ewing's sarcoma is radiation therapy. With the advent of megavoltage radiation, decreased morbidity has been encountered and the entire involved bone may be treated.47"49 This therapy will generally achieve destruction of the primary lesion with preservation of useful function of the limb. The dose of radiation therapy varies between 5,000 and 6,000 rads. The initial portal of radiation therapy usually encompasses the entire bone, with a generous margin of soft tissue. After approximately 4,500 rads have been administered, the radiation portal is progressively narrowed, with the final 500 to 750 rads being delivered only to the clinically and radiologically abnormal bone and soft tissue. The duration of treatment is approximately five to six weeks.

Chemotherapy. Clinical trials have demonstrated that Ewing's sarcoma is responsive to a variety of chemotherapeutic agents. Response rates have varied from 30 to 100 per cent with use of cyclophosphamide, 50~52 actinomycin D,53 vincristine, 54 daunorubicin, 55 mithramycin,5* adriamycin,57 and BCNU.58'59 Treatment appeared to produce a temporary increase in survival, but there was no significant change in the overall results.

With the realization that local control of the primary tumor could invariably be achieved with radiation therapy, and that chemotherapy could cause regression of tumor, combinations of chemotherapy with radiation therapy were introduced. The approach yielded promising results. Periods of disease-free survival varying from three to 52 months were reported with combinations of cyclophosphamide, vincristine, daunorubicin, and adriamycin.60"64 One center recommended intrathecal treatment with methotrexate and whole-brain irradiation similar to that employed in acute leukemia;63 however, Rosen et al., in reviewing their past experience, concluded that "prophylactic central nervous system therapy" was not indicated.64

Treatment strategy in nonmetastatic disease. Since Ewing's sarcoma is responsive to radiation therapy and chemotherapy, both means of treatment are employed. Radiation therapy is delivered to the primary lesion concurrently with chemotherapy. At the Children's Cancer Research Foundation, a combination of three agents, designated "VAC" (Figure 11), is employed.65 This comprises vincristine (0.05 mg./kg., maximum dose 2 mg., administered weekly for 12 doses or more if tolerated), cyclophosphamide (10 mg./kg. /day for 10 days administered every six weeks), and actinomycin D (total 0.075 mg./kg.), administered in five to eight days every 12 weeks). When the schedule of cyclophosphamide coincides with actinomycin D, cyclophosphamide is limited to five to eight days. Therapy is interrupted if the platelet count falls below 75,000/cu. mm. or the leukocyte count below 2,000/cu. mm. The duration of treatment with chemotherapy is two years.

Figure 11. "VAC" chemotherapy is administered for two years. Vincristine is administered at weekly intervals for 1 2 or more doses if tolerated. Cyclophosphamide is administered at six-weekly intervals and actinomycin D at 1 2-weekly intervals. The total dose of actinomycin D, 0.075 mg./kg., is divided by 5 or 8 to calcúlate the daily dose administered over five to eight days. The duration of treatment is two years.

Figure 11. "VAC" chemotherapy is administered for two years. Vincristine is administered at weekly intervals for 1 2 or more doses if tolerated. Cyclophosphamide is administered at six-weekly intervals and actinomycin D at 1 2-weekly intervals. The total dose of actinomycin D, 0.075 mg./kg., is divided by 5 or 8 to calcúlate the daily dose administered over five to eight days. The duration of treatment is two years.

Treatment strategy in metastatic disease. Radiation therapy is delivered to the primary tumor and also to areas where large métastases are located. Chemotherapy alone may achieve complete regression of bulk tumor, but experiences have demonstrated that recurrences are likely to occur at such sites unless both forms of treatment are employed. Further, since relapses are more prone to occur, the duration of chemotherapy should be extended to three years.

Recent results revealed an 80 per cent cure rate in patients without métastases. The prognosis in patients with métastases was also improved.65 In the latter group, treatment with more prolonged and more intensive chemotherapy is currently under investigation.

Reticulum cell sarcoma predominates in the male patient with a ratio of 2:1. The majority of cases are found in patients between the ages of 10 to 30 years. The tumor responds to radiation therapy.66-67 Since the disease appears to metastasize late, systemic chemotherapy is generally withheld unless gross evidence of metastatic disease is present. It is similar to that used in the treatment of non-Hodgkin's lymphoma and includes vincristine, prednisone, adriamycin, and cyclophosphamide. The five-year survival rate is approximately 50 per cent . Amputation may be required if radiation therapy fails to control the primary lesion.3'20

Hemangioendotheliosarcoma has been reported in long and flat bones. It may Have many foci of origin.3'" Treatment has included surgical ablation and a variety of chemotherapeutic agents. In view of the similarity to Ewing's sarcoma, it is treated with VAC and radiation therapy at the Children's Cancer Research Foundation. Responses with high-dose methotrexate-citrovorum factor have also been noted.46

Less frequently employed methods of treatment should also be mentioned. Total-body irradiation has been tried in Ewing's sarcoma. In an attempt to produce destruction of widespread microscopic foci of disease, elective whole-body irradiation in combination with radiation therapy of the primary lesion has been advocated,69'70 Early results suggested a slightly improved survival rate and a higher rate of subsequent solitary lung métastases. Immunotherapeutic maneuvers have been advocated for the management of osteogenic sarcoma. These include transfer factor71 and the use of vaccines obtained from tumor cells.72 More information demonstrating their efficacy should be accumulated before these methods are adopted as preferred treatment.

SUMMARY AND CONCLUSIONS

The management of malignant bone tumors in children has evolved into a coordinated multidisciplinary treatment program. Initial investigations consist of radiologie studies and radioisotope bone scanning. After the diagnosis is confirmed by biopsy, a strategic plan of treatment is developed. In osteogenic sarcoma, surgery is performed for ablation of the primary tumor unless widespread clinical métastases are present. In Ewing's sarcoma, the primary tumor is treated with radiation therapy. Since submicroscopic f oci of disease are probably present in the majority of these tumors at the time of diagnosis, chemotherapeutic regimens are administered early in the treatment program. When patients have overt métastases, chemotherapy forms the vanguard of treatment. Drugs are selected on the basis of their efficacy in destroying bulk disease. The principles of treatment outlined in the management of these tumors are generally applicable to the less commonly encountered malignant bone tumors of childhood. Preliminary results are highly encouraging and may herald the possibility of prolonged control and hopefully cure in tumors that have generally proved resistant.

BIBLIOGRAPHY

1. Copel and, M. M, Primary m alignant turn ors of bone. Evaluation ot current diagnosis and treatment, Cancer 20 (1967). 738-746.

2. Miller, R. W. Fifty-two forms of childhood cancer: United States mortality experience. 1960-1966. J- Pediatr. 75 (1969), 685-6T9.

3. Lichfensiein, L. Bone Tumors, Fourth Edition. St. Louis: The C. V, Mosby Company, 1972.

4. McN eil. B. J., et al. Fluorine-18 bone scintigraphy in children with osìeosarcoma or Ewing's sarcorra. Radiology 109 (1973), 627-631.

5. Dahlin, D. C.. and Coventry, M. B. Osteogenic sarcoma: A study of 600 cases. J, Bone Joint Surg. 49-A (1967), 101-110.

6. Hayles, A.B., Dahlin, D. C., and Coventry, M. B. Osteogenic sarcoma in children. J. A. M. A. 174 (I960). 1174-1177.

7. McKenna. R. J., et al. Sarcomata of the osteogenic series (osîeosarcoma, chondrosarcoma, parosleal osteogenic sarcoma, and sarcomata arising in abnormal bone)· An analysis of 552 cases. J. Bone Joint Surg. 48-A (1966), 126.

8. Lindbom, A., Soderberg, G., and Spjut. HJ. Osteosarcoma: A review ot 96 cases. Acta Radial. (Stockholm) 56 (1961). 1-19.

9. Sweetnam, R.. Knowelden, J., and Seddon, H. Bone sarcoma. Treatment by irradiation, amputation, or a combination of the two. Brit. Med. J. 2 (1971). 363-367.

10. Dahlin. D, C., Coventry, M. B., and ScanIon, P. W. Ewing's sarcoma: A critical analysis of 165 cases. J. Bone Joint Surg. 43-A (1961), 1T5-192.

11. FaIk, S.. and Alpert, M. The clinical and roentgen aspeéis of Ewing's sarcoma. Amer. J. Med. Sc/. 250 (1965), 492-50T.

12. Bhansali. S. K.. and Desai, P. B. Ewing's sarcoma: Observations on 107 cases. J. Bone Joint Surg. 45-A (1963), 541-553.

13. Phillips, R. F., and Higinbotham, N. L. The curability of Ewing's endothelioma of bone in children. J. Pediatr. 70 (1967). 391-397.

14. Wang, C. C., and Schulz, M. D Ewing's sarcoma: A study of 50 cases treated at the Massachusetts General Hospital, 1930-1952 inclusive. W. Engi. J. Med. 248 (1953). 571-576.

15. Cortes. E. P., et al. Doxorubicin in disseminated osteosafcoma. J. A. M. A. 221 (1972), 1132-1138.

16. Gottlieb, J. A., et al. Chemotherapy ot sarcomas with a combination of adriamycin and dimethyl triazeno imidazole carboxamide. Cancer 30 (1972), 1632-1638.

17. Jaffe. N. Recent advances in the chemotherapy ot metastatic osteogenic sarcoma. Cancer 30 (1972). 1627-1631.

18. Jeffree, G. M., and Price, C. H. G. Bone tumors and their enzymes. A study of the phosphatases, non-specific esterases and betaglucuronidase of osteogenic and cartilaginous tumours, ftbroblastic and giant-cell lesions. J. Bone Joint Surg. 47-B (1965), 120-136.

19. Rosen, G., et al. High-dose methotrexate with citrovorum factor rescue and adriamycin in childhood osteosarcoma. Cancer 33 (1974), 1151-1163.

20. Dahlin, D. C. Bone Tumors: General Aspects and Data on 3987 Cases, Second Edition. Springfield, 111. : Charles C Thomas, 1967.

21. Geschickter, C. F., and Copeland, M. M. Tumors ot Bone, Third Edition. Philadelphia: J. B. Lippincott Company, 1949.

22. Ross, F. G. M, Osteogenic sarcoma. Brit. J. Radio!. 37: (1964), 259-276.

23. Marcove, R. C., et al. Osteogenic sarcoma under the age of twenty-one; a review of 145 operative cases. J. Bone Joint Surg. 52-A (1970), 411-423.

24. Acketman, L. V., and del Regato, J. A. Cancer Diagnosis. Treatment, and Prognosis, Fourth Edition. St. Louis: The C.V. Mosby Company, 1970, pp. 896-935.

25. Garrington. G. E., et al. Osteosarcoma of t he jaws. Analysis of 56 cases. Cancer 20 (1967). 377-391 .

26. Cade, S. Osteogenic sarcoma. A study based on 113 patients. J. Roy, Coll. Surg. Edinburgh 1 (1955), 79-111.

27. Lee. E. S., and MacKenzie, D.H. Osteosarcoma: A study ol the value of preoperative megavoltage radiotherapy. Brit. J. Surg. 51 (1964), 252-274.

28. Poppe, E., Liverud, K., and Efskind, J. Osteosarcoma. Acta Chir. Scand. 134 (1968), 549556.

29. Jaffe, N., et al. "Adjuvant" high dose methotrexate and citrovorum rescue (HDMC) following primary treatment of osteogenic sarcoma. Meeting of the American Association for Cancer Research. Houston, 1974. Abstract number 526.

30. Rosen, G., et al. Vincristme (VCR). high dose methotrexate (HDMTX) with citrovorum factor (CF) rescue, cyclophosphamide (CY) and adriamycin (ADR) cyclic therapy following surgery in childhood osteogenic sarcoma. Ibid. Abstract number 754.

31. Cortes, E-P., et al. Adriamycin and amputation in primary osteogenic sarcoma. Ibid. Abstract number 745.

32. Prati, H., Hustu, 0., and Shanks, E. Cyclic multiple drug adjuvant chemotherapy for osteosarcoma. Ibid. Abstract number 76.

33. Sutow, W. W., Sullivan, M. P., and Fernbach, DJ. Adjuvant chemotherapy in primary treatment of osteogenic sarcoma. Ibid. Abstract number 77.

34. Wilbur, J.R.. et al. Four drug therapy and irradiation in primary and metastatic sarcoma. Ibid. Abstract number 816.

35. Copeland, M. M. Parosteal osteoma: Differential diagnosis and treatment. In Tumors of Bone and Soft Tissue. Chicago. Year Book Medical Publishers, 1965, pp. 201-218.

36. Geschickter, C. F., and Copeland. M. M. Parosteal osteoma of bone; A new entity. Ann. Surg. 133 (1951). 790-T07.

37. Scaglietti, O, and Calandriello, B. Ossifying parosteal sarcoma; parosteal sarcoma or juxtacortical osteogenic sarcoma. J. Bone Joint Surg. 44-A (1962), 635-647.

38. Van der Heul, R. O., and Von Rönne, J. R. Juxtacortical osteosarcoma; diagnosis, treatment and an analysis of 80 cases. J. Bone Joint Surg. 49-A (1967), 415-439.

39. Johnson, R. J. Parosteal osteosarcoma. Clin Orthopaed. 68 (1970), 78-83.

40. Morse, D., Jr., Reed, J.O., and Bernstein, J. Sclerosing osteogenic sarcoma. Amer. J. Roentgenol. 88 (1962), 491-495.

41 . Fine, G., and Stout. A. P. Osteogenic sarcoma ol extraskeletal soft tissues. Cancer 9 (1956), 1027-1043.

42. Schajowicz, S. Ewing's sarcoma and reticulum cell sarcoma of bone. With special referen ce Io the histocfiemícal demonstration of glycogen as an aid to differential diagnosis. J. Bone Joint Surg. 44-A (1959), 349-356.

43. Edeiken, J., and -Modes, P. J. Roentgen Diagnosis of Diseases of Bone. Baltimore: The Williams and Wilkins Company, 1967.

44. Lodwick, G. S. The bones and joints. In Modes, PJ. (ed.). Atlas of Tumor Radiology. Chicago:Year Book Medical Publishers, 1971.

45. Swenson, P.C. The roentgenological aspects of Ewing's tumor of bone marrow. Amer. J. Roentgenol. 50 (1943), 343-353.

46. Jaffe, N. Unpublished observations, 1974.

47. Boyer, C. W., Jr., Brickner, TJ., Jr., and Perry, R. H. Ewing's sarcoma: Case against surgery. Cancer 20 (1967), 1602-1606.

48. Jenkin, R. D. T. Ewing's sarcoma; A study of treatment methods. Clin. Radiol. 17 (1966), 97-106.

49. Suit, H. D., Martin, R. G.. and Sutow, W. W. Primary malignant tumors of the bone. In Sutow, W., et al. (eds.). Clinical Pediatrie Oncology. St. Louis: The C.V. Mosby Company. 1973, pp. 473-496.

50. Sutow, W. W., and Sullivan, M. P. Cyclophosphamide therapy in children with Ewing's sarcoma. Canee/- Chemother. Rep. 23 (1962), 55-60.

51. Haggard, M. E. Cyclophosphamide (NSC26271) in the treatment of children with malignant neoplasms. Cancer Chemother. Rep. 51 (1967), 403-405.

52. Samuels. M. L., and Howe. C. D. Cyclophosphamide in the management of Ewing's sarcoma. Cancer 20 (1967), 961-966.

53. Senyszyn, JJ., Johnson, R. E., and Curran, R. E. Treatment of metastatic Ewing's sarcoma with actinomycin D (NSC-3053). Cancer Chemother. Rep. 54 (1970), 103-107.

54. Sutow, W. W. Vincristine (NSC-67574) therapy for malignant solid tumors in children (except Wilms' tumor). Cancer Chemother. Rep. 52 (1968), 4T5-4T7.

55. Sutow, W. W., et al. Evaluation of chemotherapy in children with metastatic Ewing's sarcoma and osteogenic sarcoma. Cancer Cnemother. Rep. 55 (1971). 67-78.

56. Kofman, S., Perlia, C. P., and Economou, S. G. Mithramycin in the treatment of metastatic Ewing's sarcoma. Cancer 31 (1973), 889-893.

57. Tan, C., et al. Adriamycin, an anlitumor aniibiotic in the treatment ot neoplastic disease. Cancer 32 (1973), 9-17.

58. DeVita, V.T.. et al. Clinical trials with 1,3bis (2-chloroethyl)-1-nitrosurea, NSC-409962. Cancer fles. 25 (1965), 1876-1881,

59. Palma, J., et al. Treatment of Ewing's sarcoma with BCNU. Cancer 30 (1972), 909-913.

60. Johnson, R., and Humphreys. S. R. Past failures and future possibilities in Ewing's sarcoma: Experimental and preliminary clinical results. Cancer 23 (1969), 161-166.

61. Freeman, A. I., et al. An analysis of Ewing's tumor in children at Roswell Park Memorial Institute. Cancer 29 (1972), 1563-1569.

62. Hustu, H.O., Pinkel, D., and Pratt, C.B. Treatment of clinically localized Ewing's sarcoma with radiotherapy and combination chemotherapy. Cancer 30 (1972), 1522-1527.

63. Johnson, R. E., and Pomeroy, T. C. Integrated therapy for Ewing's sarcoma. Amer. J. Roentgenol. 114 (1972), 532-535.

64. Rosen, G.. et al. Disease-free survival in children with Ewing's sarcoma treated with radiation therapy and adjuvant 4 -drug sequential chemotherapy. Cancer 33 (1974), 384-393.

65. Jaffe. N., et al. Improved outlook for Ewing's sarcoma with combination chemotherapy and radiotherapy. Meeting of the American Association for Cancer Research, Houston, 1974. Abstract number 800.

66. Coley, B. L., Higinbotham. N. L., and Groesbeck, H. P. Primary reticulum -eel I sarcoma of bone: Summary of 37 cases. Radiology 55 (1950), 641-658.

67. Wang, C. C., and Fleìschli, D.J. Primary reticulum cell sarcoma of bone with emphasis on radiation therapy. Cancer 22 (1968). 994-998.

68. Bundens, W. D., Jr., and Brighton, C. T. Malignant hemangioendothelioma of bone: Report of two cases and review of the literature. J. Bone Joint Surg. 47-A (1965), 762-772.

69. Jenkin, R. D. T., Rider, W. D., and Sonley, MJ. Ewing's sarcoma: A trial of adjuvant totalbody irradiation. Radiology 96 (1970), 151-155.

70. Millburn, L. F., O'Grady, L., and Hendrickson, F. R. Radical radiation therapy and total body irradiation in the treatment of Ewing's sarcoma. Cancer 22 (1968), 919-925.

71. Fudenberg. H.H., et al. The therapeutic uses of transfer factor. Hospital Practice 9 (1974), 95-104.

72. Marcove, R. C., et al. A clinical trial of autogenous vaccine in osteogenic sarcoma in patients under the age of 25. Surg. Forum 22 (1971), 434-435.

TABLE 1

CLASSIFICATION OF PRIMARY BENIGN AND MALIGNANT NEOPLASMS OF BONE

TABLE 2

SCHEDULE OF METHOTREXATE-CITROVORUM TREATMENT

10.3928/0090-4481-19750201-05

Sign up to receive

Journal E-contents