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Advances in the Management of Malignant Bone Tumors in Children and Adolescents
Symposium on Pediatric Oncology
Advances in the Management of Malignant Bone Tumors in Children and Adolescents Norman Jaffe, M.D. *
A comprehensive review of the management of Ewing's sarcoma and osteosarcoma in children and adolescents appeared in the Pediatric Clinics of North America in 1976. The article provided the rationale and background for the application of chemotherapy, outlined prevailing strategies of treatment, and emphasized the multidisciplinary approach for malignant bone tumors. This complementary article will review advances and new concepts that have emerged since the publication of the original article. Diagnostic Procedures During the past 5 years, needle biopsy has received increasing prominence as a diagnostic procedure. l It is performed routinely at the M. D. Anderson Hospital and Tumor Institute; only if the material is insufficient, or the diagnosis in doubt, will an open biopsy be requested. It has been estimated that, with the assistance of good quality radiographs, needle biopsy will provide an accurate diagnosis in over 90 per cent of the cases. Needle biopsy is also useful for patients in whom limb salvage procedures are being contemplated. Radiographic examination ofthe chest-PA and lateral views-remains a standard procedure for detection of pulmonary metastases. However, pulmonary tomography and computerized axial tomography (CAT scan) of the chest are also performed in most major centers. The CAT scan is possibly a more sensitive investigation and may eventually supersede pulmonary tomography. Notwithstanding, in comparison with the standard chest radiograph, the sensitivity for detecting occult metastases by pulmonary tomography and CAT scan probably does not exceed 10 per cent. 5.6 Angiographic examinations have regained prominence. They provide *Professor, Department of Pediatrics, The University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute, Houston, Texas Supported in part by NIH Grant CA03713.
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information of the extent of neurovascular involvement in patients considered to be candidates for limb salvage procedures. They are also utilized to administer chemotherapy by the intra-arterial route and to monitor the effects of treatment. 18 A CAT scan of the tumor-bearing bone may also be requested for similar purposes and in anticipation of a limb-salvage procedure. to Ewing's Sarcoma Radiation therapy is still considered a major mode of treatment for control of the primary tumor. The dose varies from 5500 to 6500 rads. 26 The technique of delivery is important and has been emphasized in previous communications. 43 During its administration, active and passive movements to ensure optimum joint movement of the affected limb are to be implemented. A physical therapist who is well versed in the rehabilitation of patients with malignant bone tumors is invaluable in this context. Support for the administration of radiation therapy as a means for control of the primary tumor may be adduced from several recent publications. 27, 29, 38, 42, 47 The factors contributing to local control and satisfactory function are dose, tumor location, age of the patient, and treatment method,27 These factors influence the incidence and severity of acute and delayed complications. Delayed complications are joint deformity, fracture, soft tissue changes, and a second malignant neoplasm. Dose. The majority of publications indicate that 5000 to 5500 in 5 to 5V2 weeks with adjuvant chemotherapy is sufficient to achieve local control in over 90 per cent of patients with tumors of the leg, Overall, it would appear that increases in doses above 5000 rads do not yield a significant advantage in achieving local control. 27, 29 Tumor Location. In the leg, lesions of the femur appear to be more frequently associated with unfavorable functional results as opposed to other locations, The development of fractures possibly relates to excessive tumor size, large biopsies, greater stress on the proximal femur, and asymmetric muscle atrophy. Primary tumors of the hand and foot treated with 5000 rads are generally associated with functional deficits. 33,35,40 This has recently been challenged: Kinsella has reported that for selected patients radiation therapy and chemotherapy may achieve excellent tumor control and preservation of function. 29 Treatment Factors. Relatively high radiation doses, orthovoltage equipment (associated with a marked bone increase in radiation absorption), and inadequate soft-tissue shielding possibly contribute to an enhanced incidence of complications. 33 Age. The functional result is less favorable in children under 15 years of age. 27, 33 This manifests as discrepancy in leg length of up to 2.5 cm if the epiphysis of the tumor-bearing bone is patent during treatment. One report indicated that there was apparently no relationship between radiographically evident growth alterations and leg-length discrepancy or ultimate functional result;27 9 of the 11 patients in this report had open epiphyses and good function. 27 This strongly suggests that young age or radiographically open epiphyses per se is not an indication for primary amputation (as opposed to radiation treatment), Fractures probably occur
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more frequently in younger patients as a consequence of strenuous physical activities. Controversial Issues in Radiation Therapy. During recent years, controversy has surfaced with the administration of radiation treatment. This is based upon the observation that a complete local control is not invariable with this means. The failure to achieve local control may not necessarily manifest clinically. Local microscopic residual tumor has also been demonstrated at autopsy.46 (It is uncertain if this represents local failure or reseeding from metastases.) Concern has also been expressed with the frequency and intensity of the acute and delayed complications. This has prompted attempts to reduce or possibly eliminate radiation therapy as a primary treatment modality. The tactics to achieve this goal may be summarized as follows. 1. Primary treatment is administered with chemotherapy (generally vincristine, actinomycin-D, or doxorubicin (Adriamycin) and cyclophosphamide). After a satisfactory clinical and radiographic response has been achieved (generally at 3 months), surgical resection is performed. 17, 42 In this circumstance, chemotherapy is administered with the intent of achieving tumor-free margins by surgery. If this can be demonstrated, additional local therapy will not be required. However, postoperatively, chemotherapy will be maintained to destroy micrometastases. 2. Primary treatment is administered with chemotherapy for approximately 3 months. Surgical resection is then performed. However, tumorfree margins may not be apparent, and radiation therapy is then administered. The dose of radiation is usually reduced in view of the elimination of bulk tumor Cdebulking") by chemotherapy and surgery. 17, 42 This approach is being investigated with increasing frequency for tumors of the innominate bone. The foregoing strategies permit an opportunity to determine the cytoreductive potential of the chemotherapeutic regimen against bulk (and possibly microscopic) tumor. 3. Primary surgical treatment is implemented if the tumor appears immediately resectable. Postoperatively, adjuvant chemotherapy is administered. This approach is particularly suitable for expendable bones-e.g., fibula and rib, It constitutes immediate definitive treatment; however, it eliminates the opportunity to determine the potential cytoreductive effect of chemotherapy. 4. Amputation is utilized for Ewing's sarcoma of the extremities in patients under 8 years of age.40 Recommendations for this approach are based upon the knowledge that radiation therapy administered to such patients generally results in retardation of bone growth and discrepancy in limb length. However, the approach remains controversial, as may be inferred from several recent reports (vide supra).27, 29 5. Radiation therapy is usually not suitable for tumors of the phalanges, metacarpals, or metatarsals. Under these circumstances, surgical treatment is generally preferred. As indicated earlier, several authors still consider radiation and chemotherapy a viable alternative. 29 Chemotherapy. Two major chemotherapeutic combinations for definitive and adjuvant treatment have been investigated: vincristine, actinomy-
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cin-D, and cyclophosphamide (VAC); and vincristine, actinomycin-D, cyclophosphamide, and Adriamycin (VACA). 22. 37. 42 The administration of "conventional" VAC as opposed to "pulse" VAC has also been studied. 16 It would apear that no major differences have been observed. The addition of methotrexate and bleomycin to these combinations has also been reported. 42 However, it is uncertain if any major advantage has accrued. There is no evidence that either of these agents alone is effective in Ewing's sarcoma. Investigations conducted by the Intergroup Ewing's Sarcoma Study (lESS) demonstrated that the incidence of pulmonary metastases in patients treated with VAC and prophylactic pulmonary radiation and VACA was similar.37 This would imply an equipotential contribution to VAC by Adriamycin and pulmonary radiation. Either method may therefore be selected for "pulmonary prophylaxis." However, consideration should also be given to the incidence and severity of side effects and the possible need to incorporate the selected treatment in future management. Hayes et al. reported that 5 courses of a chemotherapeutic regimen comprising sequential cyclophosphamide and Adriamycin over 3 months produced responses in 19 of 23 evaluable patients. 17 The results were demonstrated by clinical, radiographic, and surgical pathologic examination of the primary tumor. This was followed by localized radiotherapy, the dose and port being dependent on the response of the induction regimen. Of particular interest was the low dose and oral administration of cyclophosphamide in the chemotherapy regimen. The study suggests that Ewing's sarcoma is very sensitive to a moderate two-drug chemotherapy of low toxicity and confirms reports that it is possible to delay radiotherapy and any extensive surgical procedure until remission is induced. Several additional chemotherapeutic regimens have also been shown to be active in Ewing's sarcoma. Campbell reported that vincristine and VM -26 have similar anti-tumor activity.3 Cornbleet demonstrated that, in relapsed patients refractory to conventional chemotherapy, complete remission may again be achieved with cyclophosphamide, followed by highdose melphalan and bone marrow autotransplantation. 9 Sequential half-body irradiation (HBI), delivered in two sessions was also found to be effective in patients with metastatic Ewing's sarcoma who relapsed after treatment with radiotherapy and multi-drug chemotherapy. Thirty-three per cent of 18 patients were alive 4 to 27 months after treatment, and in 3 there was no evidence of disease. 34 Success has also been achieved with combination chemotherapy and low-dose total body radiation. 28 Pilepich also demonstrated that intensive mutimodal treatment with chemotherapy and radiation therapy could produce prolonged diseasefree survival and possibly cure in a significant percentage of relapsed patients. 39 Prognostic Parameters. Multivariate regression analyses demonstrated that the primary site of disease was the major variable that influenced prognosis. 14. 30, 42 Patients with pelvic sites had the least favorable outcome followed by those with proximal and rib sites. The most favorable sites were distal and other. A subsequent report by Thomas noted a 52 per cent
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disease-free survival for primary Ewing's sarcoma of the ribs. 48 Smaller . primary rib tumors also carried a more favorable prognosis. 36 The 5-year survival for patients without distant metastases or for primary lesions grossly confined to bone was 87 per cent, compared with 20 per cent with extraosseous extension. Soft-tissue extension was associated with a decreased survival and was due to an increase in distant metastases as well as local failure and was independent of the location of the primary site. 36 The potential for cure was better in patients who presented with metastases as opposed to those who developed recurrent disease while on treatment. 8 Prognosis was also shown to be related to treatment: patients who received either bilateral pulmonary radiation or Adriamycin and vincristine, actinomycin-D, and cyclophosphamide had a significantly better diseasefree survial than did those treated only with vincristine, actinomycin-D, and cyclophosphamide. 37 Patients undergoing resection of the primary tumor also had a slight advantage in survival over those treated with biopsy and radiation, though the difference favoring resection was not consistent for both sexes. Individual characteristics that were of prognostic significance were blood lymphocyte count (high count favorable), polymorphonucleocyte count (high count unfavorable), and time from symptoms to diagnosis less than one month (favorable).14 Several authors also reported that serum lactate dehydrogenase (LDH) had a statistically significant correlation to survival. 14. 15 However, Rosen suggested that an elevated LDH was simply a nonspecific indicator of the size of the primary tumor.42 With the use of aggressive chemotherapy, no significant differences were noted in the disease-free survival of patients presenting with an elevated LDH or a normal LDH. A review of cases at the National Cancer Institute demonstrated that isolated meningeal or intraparenchymal central nervous system involvement in Ewing's sarcoma was uncommon. The observation did not support previous recommendations for central nervous system prophylaxis in Ewing's sarcoma. 49 Osteosarcoma
Chemotherapy. Rosen et al. reported that high-dose methotrexate with citrovorum factor rescue, Adriamycin, and a combination of bleomycin, cyclophosphamide, and dactinomycin (TIO protocol) was highly effective in osteosarcoma. 41 Treatment was generally administered for 3 months, at which stage, most patients demonstrated an excellent response. This was followed by amputation or, in selected patients, resection and insertion of an internal prosthesis. The extent of tumor destruction was gauged pathologically. Those patients in whom destruction was adequate continued to receive treatment with high-dose methotrexate, Adriamycin, and cyclophosphamide. Alternatively, if tumor destruction was considered inadequate, cis-diamminedichloroplatinum II was added to the treatment program. Utilizing this approach, an 80 to 90 per cent disease-free survival over 2 to 3 years was reported.
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Rosen et al. also suggested that MTX doses in excess of 12 gm/m 2 were required to achieve responses in patients under 10 years of age. Jaffe et al. 19 demonstrated that, in contrast to past experiences, highdose methotrexate only achieved a response of approximately 30 per cent. The result was attained when a dose of 12.5 gm/m 2 was utilized with citrovorum factor "rescue" initiated 12 hours after the completion of the MTX infusion (as opposed to 4 to 6 hours reported previously). The efficacy of the agent could not be enhanced by its administration with the intraarterial route. This observation contrasted sharply with results obtained by Rosen et al., 41 who reported responses in the vicinity of 80 per cent. An explanation for these discrepancies was not apparent. Edmonson et al. from the Mayo Clinic failed to detect any beneficial effect with the use of high-dose methotrexate as adjuvant treatment. l l The investigation was conducted by utilizing a controlled (surgery only) nonadjuvant treatment arm. Also, no significant differences in postmetastasis survival between the 2 arms were apparent. This has led to controversy in this use of adjuvant treatment (vide infra). Cis-diamminedichloroplatinum II (CDP), administered by the intraarterial route, received increasing prominence as a means of treating the primary tumor and was found to be superior to high-dose methotrexate. lB ,20 The response rate was 66 per cent for the former and 27 per cent for the latter. The intra-arterial route appeared essential for this result, since there appeared to be no discernible effect on the pulmonary metastases with concurrent responses of the primary tumor.lB Pharmacokinetic studies of cis-diamminedichloroplatinum II administered by the intraarterial route correlated with increased tumor uptake and tumor destruction. Eilber et al. reported on the treatment of the primary tumor with radiation therapy and intra-arterial adriamycin. 13 This resulted in appreciable degrees of tumor destruction. The majority of the patients then underwent a safe local resection with insertion of an internal prosthesis. Caceres et al. also reported extensive tumor destruction utilizing high-dose methotrexate, Adriamycin, and radiation therapy. 2 Treatment of the Primary Tumor. Limb salvage as opposed to amputation was adopted with increasing frequency. Central to this approach was the recommendation for the administration of preoperative chemotherapy. This appeared to improve the safety of the operation and identify an effective adjuvant regimen to destroy micrometastases perceived to be present in the majority of patients at diagnosis. Surgical treatment for limb salvage involved local resection with insertion of an internal prosthesis. For this purpose, specific criteria for patient selection were developed. 25 In lower extremity lesions, only patients who had achieved maximum or near maximum growth were considered eligible. This was related to the potential for growth in the nonaffected limb and subsequent discrepancies in limb length. Needle biopsy to establish the diagnosis was preferred, since an incorrectly placed biopsy could preclude the possibility of a successful resection. Pulmonary metastases did not necessarily constitute a contraindication, and patients with
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upper extremity lesions received individual, though generally favorable, consideration. Transmedullary amputation was adopted with increasing frequency. 24 The possibility of stump recurrences was minimized with the use of adjuvant postoperative chemotherapy. The latter probably also reduced the incidence of skip metastases. Skip metastases could occasionally also be identified pre-operatively by a conventional radiograph, radionuclide scan, or CAT scan. Rotationplasty was established as a method of treatment for selected patients. 31 These patients had distal femural lesions but, because of their age, were not considered suitable for limb salvage. The procedure involves resection of the tumor-bearing bone several centimeters proximal to the tumor margin and preservation of the neurovascular bundle. This is followed by resection of the tibia and fibula. The tibia is then rotated through 1800 and inserted into the proximal stump of the femur. In essence, an aboveknee amputation is converted to a below-the-knee amputation: the heel serves as a knee and provides improved functional rehabilitation. Biologic Treatment. A study by Caparros et al. in osteosarcoma failed to demonstrate any effect with interferon in improved survival. 4 Change in the Natural History. The application of chemotherapy was shown to alter the biologic behavior of osteosarcoma. In essence, in a majority of patients, it destroyed or prevented the development of pulmonary metastases. In many other patients, however, chemotherapy appeared only partially effective. This manifested as a reduction in the number of pulmonary metastases and a delay in their appearance. 21 In these circumstances, multidisciplinary treatment also contributed to an improved survival, particularly with the increased use of thoracotomy. The effect was clearly demonstrated by Sutow et aI., who noted that, prior to 1970, survival at the M. D. Anderson Hospital and Tumor Institute in patients with pulmonary metastases was under 2 per cent; however, in the 1970s it escalated to 40 to 50 per cent. 44 Changes in the natural history induced by chemotherapy were also observed in other, less favorable circumstances. Occasionally, indolent metastases emerged and were resistant to treatment. They were located in the heart, brain, subcutaneous tissues, and abdomen. They usually appeared with extended survival and not infrequently caused protracted morbidity and difficulties in palliation. Controversy. The advances in osteosarcoma were also marred by controversy. Investigators from the Mayo Clinic failed to elicit a substantial improvement in survival with the application of chemotherapy. 11 They also claimed that there had been a "spontaneous" improvement over the recent past. 45 This led to the publication of a report "Is It Ethical Not to Conduct a Prospectively Controlled Trial of Adjuvant Chemotherapy in Osteosarcoma?"32 The morbidity of chemotherapy was emphasized, and it was suggested that a statistically significant level of the ultimate risk-to-benefit ratio of chemotherapy should be provided. For this reason, a cooperative group elected to conduct a multi-institution prospectively randomized clinical trial with surgical treatment only (controls), and a regimen, similar to that reported by Rosen to have yielded the best results (TlO protocol).
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However, these concepts were not universally accepted, and the trial that is currently in progress was confined to a limited number of institutions. 23 The results were recently presented by Link at a Consensus Development Conference in Washington (Dec. 1984). Patients who received adjuvant therapy attained a significantly superior relapse-free survival. Giant Cell Tumors. Eftakhari et al. 12 reported on the use of intraarterial CDP on the management of giant cell tumors. He demonstrated improvement and healing with this approach. The effect could also be enhanced by embolization and infarction. Other methods of treatment included surgical curettage with insertion of autologous bone. In patients with repeated failures, radiation therapy occasionally also produced success. Eosinophilic Granuloma. Intracavitary instillation of corticosteroids was demonstrated to produce healing in solitary lesions. As a result, surgical curettage and/or radiation was not considered necessary. This procedure was particularly useful for lesions located near the epiphyseal ends of the bone. Radiation therapy delivered to these sites usually causes destruction or injury to the epiphysis and an alteration in growth. REFERENCES 1. Ayala, A. G., and Zornoza, J.: Primary bone tumors: Percutaneous needle biopsy. Radiologic-pathologic study of 222 biopsies. Radiology, 149(3):675-699, 1983. 2. Caceres, E., Zabaria, M., Vadivia, S., et al.: Local control of osteogenic sarcoma by radiation and chemotherapy. Int. J. Radiat. Oncol. BioI. Phys., 10:35-39, 1984. 3. Campbell, A. M., Eckert, R., and Waters, K. D.: VM-26 and dimethyl triazeno imidazole carboxamide in Ewing's sarcoma. Aust. Paediatr. J., 19:30-33, 1983. 4. Caparros, B., Rosen, G., and Cunningham-Rundles, S.: Phase II trial of interferon (IFN) in metastatic osteogenic sarcoma. Proc. A.A.C.R., 23:121, 1982. 5. Cohen, M., Grosfeld, J., Baehner, R., et al.: Lung CT for detection of metastases: Solid tissue neoplasms in children. A.J.R., 139:895-898, 1982. 6. Cohen, M., Provisor, A., Smith, W. L., et al.: Efficacy of whole lung tomography in diagnosing metastases from solid tumors in children. Radiology, 141 :375-378, 1981. 7. Cohen, M., Zornoza, J., Cangir, A., et al.: Direct infection of methylprednisolone sodium succinate in the treatment of eosinophilic granuloma of bone. A report of 9 cases. Radiology, 136:289-293, 1980. 8. Cormier, W. J., Gilchrist, G. S., Burgert, E. 0., et al.: Management of metastatic Ewing's sarcoma. Proc. A.A.C.R.lA.S.C.O., 21:190, 1980. 9. Cornbleet, M. A., Corringham, R. E. T., Prentice, R. G., et al.: Treatment of Ewing's sarcoma with high dose melphalan and autogenous bone marrow transplantation. Cancer Treat. Rep., 65:241-244, 1982. 10. De Santos, L., Bernardino, M. E., and Murray, J. A.: Computed tomography in the evaluation of osteosarcoma: Experience with 25 cases. A.J.R., 132:535-540, 1979. 11. Edmonson, J. R., Green, S. J., Ivers, J. C., et al.: A controlled pilot study of high dose methotrexate as postsurgical adjuvant treatment for primary osteosarcoma. J. Clin. Oncol., 2:152-156, 1984. 12. Eftekhari, F., Wallace, S., Chuang, V. P., et al.: Intraarterial management of giant cell tumors of the spine in children. Pediatr. Radiol., 12:289-293, 1982. 13. Eilber, F. R., Morton, D. L., and Grant, T. T.: En bloc resection and allograft replacement for osteosarcoma of the extremity. In Jaffe, N. (ed.): Bone Tumors in Children. Littleton, PSG Publishing Co., 1979, pp. 159-167. 14 Gehan, E. A., Nesbit, M. E., Jr., Burgert, E. 0., et al.: Prognostic factors in children with Ewing's sarcoma. N.C.!. Monogr., 56:273-278, 1981. 15. Glaubiger, D. L., Makuch, R. W., and Schwarz, J.: Influence of prognostic factors on survival in Ewing's sarcoma. N.C.!. Monogr., 56:285-288, 1981.
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16. Greer, H., Green, D., Cassady, J., et aL: lO-Years of Vincristine (V), Actinomycin D (A) and Cyclophosphamide (C) chemotherapy by intermittent (I) or bolus (B) route for Ewing's sarcoma. A.S.S.C.O., 2:74,1983 . 17. Hayes, F. A., Thompson, E. 1., Hustu, H. 0., et al.: The response of Ewing's sarcoma to sequential cyclophosphamide and adriamycin induction therapy. J. Clin. OncoL, 1:45-51, 1983. 18. Jaffe, N., Knapp, J., Chuang, V. P., et aL: Osteosarcoma: Intra-arterial treatment of the primary tumor with cis-diamminedichloroplatinum II (CDP). Angiographic, pathologic and pharmacologic studies. Cancer, 51:402-407, 1983. 19. Jaffe, N., Prudich, J., Knapp, J., et aL: Treatment of primary osteosarcoma with intraarterial and intravenous high dose methotrexate. J. Clin. OncoL, 1:428-431, 1983. 20. Jaffe, N., Robertson, R., Cangir, A., et al.: Superiority of intra-arterial (I/A) cisdiamminedichloroplatinum II (CDP) over high dose methotrexate with citrovorum factor "rescue" (MTX-CF) in the treatment of primary osteosarcoma. Proc. A.A.C.R., 25:170, 1984. 21. Jaffe, N., Smith, E., Abelson, H. T., et al.: Osteogenic sarcoma: Alterations in the pattern of metastases with adjuvant chemotherapy. J. Clin. OncoL, 1:251-254, 1983. 22. Jaffe, N., Traggis, D., Sallan, S., et al.: Improved outlook for Ewing's sarcoma (Vincristine, Adriamycin D and Cyclophosphamide) and radiation therapy. Cancer, 38:1925-1930, 1976. 23. Jaffe, N., van Eys, J., and Gehan, E.: Response to "Is it ethical not to conduct a prospectively controlled trial of adjuvant chemotherapy?" Cancer Treat. Rep., 67:743-744, 1983. 24. Jaffe, N., and Watts, H.: Multi-drug chemotherapy in primary treatment of osteosarcoma. J. Bone Joint Surg. (Am.), 48:634-635, 1976. 25. Jaffe, N., Watts, H., Fellows, K. E., et al.: Local en bloc resection for limb preservation. Cancer Treat. Rep., 62:217-223, 1978. 26. Jenkin, R. D. T.: Sarcomas of the distal extremities. Int. J. Radiat. OncoL BioL Phys., 9:1235-1236, 1983. 27. Jentzsch, K., Binder, H., Glaubinger, 0., et aL: Leg function after radiotherapy for Ewing's sarcoma. Cancer, 47:1267-1278, 1981. 28. Kinsella, T. J., Glaubiger, D., Deisseroth, A., et aL: Intensive combined modality therapy including low dose TBI in high risk Ewing's sarcoma patients. Int. J. Radiat. OncoL BioL Phys., 9:1955-1960, 1983. 29. Kinsella, T. J., Loeffier, J. S., Frass, B. A., et al.: Extremity preservation by combined modality therapy in sarcomas of the hand and foot: An analysis of local control, disease free survival and functional result. Int. J. Radiat. OncoL BioL Phys., 9:1115-1119, 1983. 30. Kissane, J. M., Askin, F. B., Foulkes, M., et al.: Ewing's sarcoma of bone: Clinicopatholgic aspects of 303 cases from the intergroup Ewing's sarcoma study. Hum. PathoL, 14:773-779, 1983. 31. Kotz, R., and Salzer, M.: Rotationplasty for childhood osteosarcoma of the distal part of the femur. J. Bone Joint Surg. (Am.), 64A:959-969, 1982. 32. Lange, B., and Levin, A. S.: Is it ethical not to conduct a prospectively controlled trial in adjuvant chemotherapy in osteosarcoma? Cancer Treat. Rep., 66:1699-1704, 1982. 33. Lewis, R. J., Marcove, R. C., and Rosen, G.: Ewing's sarcoma-Functional effects after radiation therapy. J. Bone Joint Surg., 59:325-331, 1977. 34. Lombardi, F., Lattuada, A., Gasparini, M., et al.: Sequential half-body irradiation as systemic treatment of progressive Ewing's sarcoma. Int. J. Radiat. OncoL BioL Phys., 8:1679-1682, 1982. 35. Marcove, R. C., and Rosen, G.: Radical en bloc excision of Ewing's sarcoma. Clin. Orthop., 153:86-91, 1980. 36. Mendenhall, G. M., Marcus, R. B., Jr., et al.: The prognostic significance of soft tissue extension in Ewing's sarcoma. Cancer, 51:913-917, 1983. 37. Nesbit, M. E., Perez, C. A., Tefft, M., et aL: Multimodal therapy for the management of primary non-metastatic Ewing's sarcoma of bone: An intergroup study. N.C.1. Monogr., 56:255-262, 1981. 38. Perez, C. A., Razek, A., Tefft, M., et al.: Analysis of local control in Ewing's sarcoma. Preliminary results of a cooperative intergroup study. Cancer, (0:2864-2873, 1977. 39. Pilepich, M., Vietti, T. G., Nesbitt, M. E., et al.: Radiotherapy and combination
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chemotherapy in advanced Ewing's sarcoma intergroup study. Cancer, 47:1930-1936, 1981. Pritchard, D. J.: Indications for surgical treatment oflocalized Ewing's sarcoma of bone. Clin. Orthop., 153:39-43, 1980. Rosen, G., Caparros, B., Huvos, A. G., et al.: Preoperative chemotherapy for osteogenic sarcoma: Selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy. Cancer, 49:1221-1230, 1982. Rosen, G., Caparros, B., Nirenberg, A., et al.: Ewing's sarcoma: Ten year experience with adjuvant chemotherapy. Cancer, 47:2204-2213, 1981. Suit, H. D.: Role of therapeutic radiology in cancer of bone. Cancer, 35:930-935, 1975. Sutow, W. W., Herson, J., and Perez, C.: Survival after metastasis in osteosarcoma. N.C.I. Monogr., 56:227-231, 1981. Taylor, W. F., Ivins, J. G., Dahlin, D. G., et a!.: Osteogenic sarcoma experience at the Mayo Clinic 1963-1974. In Terry, W. D., and Windhorst, D. (eds.): Immunotherapy of Cancer: Present Status of Trials in Man. New York, Raven Press, 1978, pp. 257-264. Tellis, N. C., Rabson, A. S., and Pomeroy, T. C.: Ewing's sarcoma: An autopsy study. Cancer, 41:2321-2329, 1978. Tepper, J., Glaubinger, D., Lichter, A., et al.: Local control of Ewing's sarcoma of the bone with radiotherapy and combination chemotherapy. Cancer, 46:1969-1973, 1980. Thomas, P. R. M., Faulkes, M. A., Gelula, L. A., et al.: Primary Ewing's sarcoma of the ribs: A report from the Intergroup Ewing's Sarcoma Study. Cancer, 51:1021-1027, 1983. Trigg, M. E., Glaubiger, D., and Nesbit, M. E., Jr.: The frequency of isolated CNS involvement in Ewing's sarcoma. Cancer, 49:2402-2409, 1982.
M. D. Anderson Hospital and Tumor Institute Houston, Texas 77030
Advances in the Management of Malignant Bone Tumors in Children and Adolescents Norman Jaffe, M.D. *
A comprehensive review of the management of Ewing's sarcoma and osteosarcoma in children and adolescents appeared in the Pediatric Clinics of North America in 1976. The article provided the rationale and background for the application of chemotherapy, outlined prevailing strategies of treatment, and emphasized the multidisciplinary approach for malignant bone tumors. This complementary article will review advances and new concepts that have emerged since the publication of the original article. Diagnostic Procedures During the past 5 years, needle biopsy has received increasing prominence as a diagnostic procedure. l It is performed routinely at the M. D. Anderson Hospital and Tumor Institute; only if the material is insufficient, or the diagnosis in doubt, will an open biopsy be requested. It has been estimated that, with the assistance of good quality radiographs, needle biopsy will provide an accurate diagnosis in over 90 per cent of the cases. Needle biopsy is also useful for patients in whom limb salvage procedures are being contemplated. Radiographic examination ofthe chest-PA and lateral views-remains a standard procedure for detection of pulmonary metastases. However, pulmonary tomography and computerized axial tomography (CAT scan) of the chest are also performed in most major centers. The CAT scan is possibly a more sensitive investigation and may eventually supersede pulmonary tomography. Notwithstanding, in comparison with the standard chest radiograph, the sensitivity for detecting occult metastases by pulmonary tomography and CAT scan probably does not exceed 10 per cent. 5.6 Angiographic examinations have regained prominence. They provide *Professor, Department of Pediatrics, The University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute, Houston, Texas Supported in part by NIH Grant CA03713.
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information of the extent of neurovascular involvement in patients considered to be candidates for limb salvage procedures. They are also utilized to administer chemotherapy by the intra-arterial route and to monitor the effects of treatment. 18 A CAT scan of the tumor-bearing bone may also be requested for similar purposes and in anticipation of a limb-salvage procedure. to Ewing's Sarcoma Radiation therapy is still considered a major mode of treatment for control of the primary tumor. The dose varies from 5500 to 6500 rads. 26 The technique of delivery is important and has been emphasized in previous communications. 43 During its administration, active and passive movements to ensure optimum joint movement of the affected limb are to be implemented. A physical therapist who is well versed in the rehabilitation of patients with malignant bone tumors is invaluable in this context. Support for the administration of radiation therapy as a means for control of the primary tumor may be adduced from several recent publications. 27, 29, 38, 42, 47 The factors contributing to local control and satisfactory function are dose, tumor location, age of the patient, and treatment method,27 These factors influence the incidence and severity of acute and delayed complications. Delayed complications are joint deformity, fracture, soft tissue changes, and a second malignant neoplasm. Dose. The majority of publications indicate that 5000 to 5500 in 5 to 5V2 weeks with adjuvant chemotherapy is sufficient to achieve local control in over 90 per cent of patients with tumors of the leg, Overall, it would appear that increases in doses above 5000 rads do not yield a significant advantage in achieving local control. 27, 29 Tumor Location. In the leg, lesions of the femur appear to be more frequently associated with unfavorable functional results as opposed to other locations, The development of fractures possibly relates to excessive tumor size, large biopsies, greater stress on the proximal femur, and asymmetric muscle atrophy. Primary tumors of the hand and foot treated with 5000 rads are generally associated with functional deficits. 33,35,40 This has recently been challenged: Kinsella has reported that for selected patients radiation therapy and chemotherapy may achieve excellent tumor control and preservation of function. 29 Treatment Factors. Relatively high radiation doses, orthovoltage equipment (associated with a marked bone increase in radiation absorption), and inadequate soft-tissue shielding possibly contribute to an enhanced incidence of complications. 33 Age. The functional result is less favorable in children under 15 years of age. 27, 33 This manifests as discrepancy in leg length of up to 2.5 cm if the epiphysis of the tumor-bearing bone is patent during treatment. One report indicated that there was apparently no relationship between radiographically evident growth alterations and leg-length discrepancy or ultimate functional result;27 9 of the 11 patients in this report had open epiphyses and good function. 27 This strongly suggests that young age or radiographically open epiphyses per se is not an indication for primary amputation (as opposed to radiation treatment), Fractures probably occur
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more frequently in younger patients as a consequence of strenuous physical activities. Controversial Issues in Radiation Therapy. During recent years, controversy has surfaced with the administration of radiation treatment. This is based upon the observation that a complete local control is not invariable with this means. The failure to achieve local control may not necessarily manifest clinically. Local microscopic residual tumor has also been demonstrated at autopsy.46 (It is uncertain if this represents local failure or reseeding from metastases.) Concern has also been expressed with the frequency and intensity of the acute and delayed complications. This has prompted attempts to reduce or possibly eliminate radiation therapy as a primary treatment modality. The tactics to achieve this goal may be summarized as follows. 1. Primary treatment is administered with chemotherapy (generally vincristine, actinomycin-D, or doxorubicin (Adriamycin) and cyclophosphamide). After a satisfactory clinical and radiographic response has been achieved (generally at 3 months), surgical resection is performed. 17, 42 In this circumstance, chemotherapy is administered with the intent of achieving tumor-free margins by surgery. If this can be demonstrated, additional local therapy will not be required. However, postoperatively, chemotherapy will be maintained to destroy micrometastases. 2. Primary treatment is administered with chemotherapy for approximately 3 months. Surgical resection is then performed. However, tumorfree margins may not be apparent, and radiation therapy is then administered. The dose of radiation is usually reduced in view of the elimination of bulk tumor Cdebulking") by chemotherapy and surgery. 17, 42 This approach is being investigated with increasing frequency for tumors of the innominate bone. The foregoing strategies permit an opportunity to determine the cytoreductive potential of the chemotherapeutic regimen against bulk (and possibly microscopic) tumor. 3. Primary surgical treatment is implemented if the tumor appears immediately resectable. Postoperatively, adjuvant chemotherapy is administered. This approach is particularly suitable for expendable bones-e.g., fibula and rib, It constitutes immediate definitive treatment; however, it eliminates the opportunity to determine the potential cytoreductive effect of chemotherapy. 4. Amputation is utilized for Ewing's sarcoma of the extremities in patients under 8 years of age.40 Recommendations for this approach are based upon the knowledge that radiation therapy administered to such patients generally results in retardation of bone growth and discrepancy in limb length. However, the approach remains controversial, as may be inferred from several recent reports (vide supra).27, 29 5. Radiation therapy is usually not suitable for tumors of the phalanges, metacarpals, or metatarsals. Under these circumstances, surgical treatment is generally preferred. As indicated earlier, several authors still consider radiation and chemotherapy a viable alternative. 29 Chemotherapy. Two major chemotherapeutic combinations for definitive and adjuvant treatment have been investigated: vincristine, actinomy-
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cin-D, and cyclophosphamide (VAC); and vincristine, actinomycin-D, cyclophosphamide, and Adriamycin (VACA). 22. 37. 42 The administration of "conventional" VAC as opposed to "pulse" VAC has also been studied. 16 It would apear that no major differences have been observed. The addition of methotrexate and bleomycin to these combinations has also been reported. 42 However, it is uncertain if any major advantage has accrued. There is no evidence that either of these agents alone is effective in Ewing's sarcoma. Investigations conducted by the Intergroup Ewing's Sarcoma Study (lESS) demonstrated that the incidence of pulmonary metastases in patients treated with VAC and prophylactic pulmonary radiation and VACA was similar.37 This would imply an equipotential contribution to VAC by Adriamycin and pulmonary radiation. Either method may therefore be selected for "pulmonary prophylaxis." However, consideration should also be given to the incidence and severity of side effects and the possible need to incorporate the selected treatment in future management. Hayes et al. reported that 5 courses of a chemotherapeutic regimen comprising sequential cyclophosphamide and Adriamycin over 3 months produced responses in 19 of 23 evaluable patients. 17 The results were demonstrated by clinical, radiographic, and surgical pathologic examination of the primary tumor. This was followed by localized radiotherapy, the dose and port being dependent on the response of the induction regimen. Of particular interest was the low dose and oral administration of cyclophosphamide in the chemotherapy regimen. The study suggests that Ewing's sarcoma is very sensitive to a moderate two-drug chemotherapy of low toxicity and confirms reports that it is possible to delay radiotherapy and any extensive surgical procedure until remission is induced. Several additional chemotherapeutic regimens have also been shown to be active in Ewing's sarcoma. Campbell reported that vincristine and VM -26 have similar anti-tumor activity.3 Cornbleet demonstrated that, in relapsed patients refractory to conventional chemotherapy, complete remission may again be achieved with cyclophosphamide, followed by highdose melphalan and bone marrow autotransplantation. 9 Sequential half-body irradiation (HBI), delivered in two sessions was also found to be effective in patients with metastatic Ewing's sarcoma who relapsed after treatment with radiotherapy and multi-drug chemotherapy. Thirty-three per cent of 18 patients were alive 4 to 27 months after treatment, and in 3 there was no evidence of disease. 34 Success has also been achieved with combination chemotherapy and low-dose total body radiation. 28 Pilepich also demonstrated that intensive mutimodal treatment with chemotherapy and radiation therapy could produce prolonged diseasefree survival and possibly cure in a significant percentage of relapsed patients. 39 Prognostic Parameters. Multivariate regression analyses demonstrated that the primary site of disease was the major variable that influenced prognosis. 14. 30, 42 Patients with pelvic sites had the least favorable outcome followed by those with proximal and rib sites. The most favorable sites were distal and other. A subsequent report by Thomas noted a 52 per cent
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disease-free survival for primary Ewing's sarcoma of the ribs. 48 Smaller . primary rib tumors also carried a more favorable prognosis. 36 The 5-year survival for patients without distant metastases or for primary lesions grossly confined to bone was 87 per cent, compared with 20 per cent with extraosseous extension. Soft-tissue extension was associated with a decreased survival and was due to an increase in distant metastases as well as local failure and was independent of the location of the primary site. 36 The potential for cure was better in patients who presented with metastases as opposed to those who developed recurrent disease while on treatment. 8 Prognosis was also shown to be related to treatment: patients who received either bilateral pulmonary radiation or Adriamycin and vincristine, actinomycin-D, and cyclophosphamide had a significantly better diseasefree survial than did those treated only with vincristine, actinomycin-D, and cyclophosphamide. 37 Patients undergoing resection of the primary tumor also had a slight advantage in survival over those treated with biopsy and radiation, though the difference favoring resection was not consistent for both sexes. Individual characteristics that were of prognostic significance were blood lymphocyte count (high count favorable), polymorphonucleocyte count (high count unfavorable), and time from symptoms to diagnosis less than one month (favorable).14 Several authors also reported that serum lactate dehydrogenase (LDH) had a statistically significant correlation to survival. 14. 15 However, Rosen suggested that an elevated LDH was simply a nonspecific indicator of the size of the primary tumor.42 With the use of aggressive chemotherapy, no significant differences were noted in the disease-free survival of patients presenting with an elevated LDH or a normal LDH. A review of cases at the National Cancer Institute demonstrated that isolated meningeal or intraparenchymal central nervous system involvement in Ewing's sarcoma was uncommon. The observation did not support previous recommendations for central nervous system prophylaxis in Ewing's sarcoma. 49 Osteosarcoma
Chemotherapy. Rosen et al. reported that high-dose methotrexate with citrovorum factor rescue, Adriamycin, and a combination of bleomycin, cyclophosphamide, and dactinomycin (TIO protocol) was highly effective in osteosarcoma. 41 Treatment was generally administered for 3 months, at which stage, most patients demonstrated an excellent response. This was followed by amputation or, in selected patients, resection and insertion of an internal prosthesis. The extent of tumor destruction was gauged pathologically. Those patients in whom destruction was adequate continued to receive treatment with high-dose methotrexate, Adriamycin, and cyclophosphamide. Alternatively, if tumor destruction was considered inadequate, cis-diamminedichloroplatinum II was added to the treatment program. Utilizing this approach, an 80 to 90 per cent disease-free survival over 2 to 3 years was reported.
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Rosen et al. also suggested that MTX doses in excess of 12 gm/m 2 were required to achieve responses in patients under 10 years of age. Jaffe et al. 19 demonstrated that, in contrast to past experiences, highdose methotrexate only achieved a response of approximately 30 per cent. The result was attained when a dose of 12.5 gm/m 2 was utilized with citrovorum factor "rescue" initiated 12 hours after the completion of the MTX infusion (as opposed to 4 to 6 hours reported previously). The efficacy of the agent could not be enhanced by its administration with the intraarterial route. This observation contrasted sharply with results obtained by Rosen et al., 41 who reported responses in the vicinity of 80 per cent. An explanation for these discrepancies was not apparent. Edmonson et al. from the Mayo Clinic failed to detect any beneficial effect with the use of high-dose methotrexate as adjuvant treatment. l l The investigation was conducted by utilizing a controlled (surgery only) nonadjuvant treatment arm. Also, no significant differences in postmetastasis survival between the 2 arms were apparent. This has led to controversy in this use of adjuvant treatment (vide infra). Cis-diamminedichloroplatinum II (CDP), administered by the intraarterial route, received increasing prominence as a means of treating the primary tumor and was found to be superior to high-dose methotrexate. lB ,20 The response rate was 66 per cent for the former and 27 per cent for the latter. The intra-arterial route appeared essential for this result, since there appeared to be no discernible effect on the pulmonary metastases with concurrent responses of the primary tumor.lB Pharmacokinetic studies of cis-diamminedichloroplatinum II administered by the intraarterial route correlated with increased tumor uptake and tumor destruction. Eilber et al. reported on the treatment of the primary tumor with radiation therapy and intra-arterial adriamycin. 13 This resulted in appreciable degrees of tumor destruction. The majority of the patients then underwent a safe local resection with insertion of an internal prosthesis. Caceres et al. also reported extensive tumor destruction utilizing high-dose methotrexate, Adriamycin, and radiation therapy. 2 Treatment of the Primary Tumor. Limb salvage as opposed to amputation was adopted with increasing frequency. Central to this approach was the recommendation for the administration of preoperative chemotherapy. This appeared to improve the safety of the operation and identify an effective adjuvant regimen to destroy micrometastases perceived to be present in the majority of patients at diagnosis. Surgical treatment for limb salvage involved local resection with insertion of an internal prosthesis. For this purpose, specific criteria for patient selection were developed. 25 In lower extremity lesions, only patients who had achieved maximum or near maximum growth were considered eligible. This was related to the potential for growth in the nonaffected limb and subsequent discrepancies in limb length. Needle biopsy to establish the diagnosis was preferred, since an incorrectly placed biopsy could preclude the possibility of a successful resection. Pulmonary metastases did not necessarily constitute a contraindication, and patients with
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upper extremity lesions received individual, though generally favorable, consideration. Transmedullary amputation was adopted with increasing frequency. 24 The possibility of stump recurrences was minimized with the use of adjuvant postoperative chemotherapy. The latter probably also reduced the incidence of skip metastases. Skip metastases could occasionally also be identified pre-operatively by a conventional radiograph, radionuclide scan, or CAT scan. Rotationplasty was established as a method of treatment for selected patients. 31 These patients had distal femural lesions but, because of their age, were not considered suitable for limb salvage. The procedure involves resection of the tumor-bearing bone several centimeters proximal to the tumor margin and preservation of the neurovascular bundle. This is followed by resection of the tibia and fibula. The tibia is then rotated through 1800 and inserted into the proximal stump of the femur. In essence, an aboveknee amputation is converted to a below-the-knee amputation: the heel serves as a knee and provides improved functional rehabilitation. Biologic Treatment. A study by Caparros et al. in osteosarcoma failed to demonstrate any effect with interferon in improved survival. 4 Change in the Natural History. The application of chemotherapy was shown to alter the biologic behavior of osteosarcoma. In essence, in a majority of patients, it destroyed or prevented the development of pulmonary metastases. In many other patients, however, chemotherapy appeared only partially effective. This manifested as a reduction in the number of pulmonary metastases and a delay in their appearance. 21 In these circumstances, multidisciplinary treatment also contributed to an improved survival, particularly with the increased use of thoracotomy. The effect was clearly demonstrated by Sutow et aI., who noted that, prior to 1970, survival at the M. D. Anderson Hospital and Tumor Institute in patients with pulmonary metastases was under 2 per cent; however, in the 1970s it escalated to 40 to 50 per cent. 44 Changes in the natural history induced by chemotherapy were also observed in other, less favorable circumstances. Occasionally, indolent metastases emerged and were resistant to treatment. They were located in the heart, brain, subcutaneous tissues, and abdomen. They usually appeared with extended survival and not infrequently caused protracted morbidity and difficulties in palliation. Controversy. The advances in osteosarcoma were also marred by controversy. Investigators from the Mayo Clinic failed to elicit a substantial improvement in survival with the application of chemotherapy. 11 They also claimed that there had been a "spontaneous" improvement over the recent past. 45 This led to the publication of a report "Is It Ethical Not to Conduct a Prospectively Controlled Trial of Adjuvant Chemotherapy in Osteosarcoma?"32 The morbidity of chemotherapy was emphasized, and it was suggested that a statistically significant level of the ultimate risk-to-benefit ratio of chemotherapy should be provided. For this reason, a cooperative group elected to conduct a multi-institution prospectively randomized clinical trial with surgical treatment only (controls), and a regimen, similar to that reported by Rosen to have yielded the best results (TlO protocol).
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However, these concepts were not universally accepted, and the trial that is currently in progress was confined to a limited number of institutions. 23 The results were recently presented by Link at a Consensus Development Conference in Washington (Dec. 1984). Patients who received adjuvant therapy attained a significantly superior relapse-free survival. Giant Cell Tumors. Eftakhari et al. 12 reported on the use of intraarterial CDP on the management of giant cell tumors. He demonstrated improvement and healing with this approach. The effect could also be enhanced by embolization and infarction. Other methods of treatment included surgical curettage with insertion of autologous bone. In patients with repeated failures, radiation therapy occasionally also produced success. Eosinophilic Granuloma. Intracavitary instillation of corticosteroids was demonstrated to produce healing in solitary lesions. As a result, surgical curettage and/or radiation was not considered necessary. This procedure was particularly useful for lesions located near the epiphyseal ends of the bone. Radiation therapy delivered to these sites usually causes destruction or injury to the epiphysis and an alteration in growth. REFERENCES 1. Ayala, A. G., and Zornoza, J.: Primary bone tumors: Percutaneous needle biopsy. Radiologic-pathologic study of 222 biopsies. Radiology, 149(3):675-699, 1983. 2. Caceres, E., Zabaria, M., Vadivia, S., et al.: Local control of osteogenic sarcoma by radiation and chemotherapy. Int. J. Radiat. Oncol. BioI. Phys., 10:35-39, 1984. 3. Campbell, A. M., Eckert, R., and Waters, K. D.: VM-26 and dimethyl triazeno imidazole carboxamide in Ewing's sarcoma. Aust. Paediatr. J., 19:30-33, 1983. 4. Caparros, B., Rosen, G., and Cunningham-Rundles, S.: Phase II trial of interferon (IFN) in metastatic osteogenic sarcoma. Proc. A.A.C.R., 23:121, 1982. 5. Cohen, M., Grosfeld, J., Baehner, R., et al.: Lung CT for detection of metastases: Solid tissue neoplasms in children. A.J.R., 139:895-898, 1982. 6. Cohen, M., Provisor, A., Smith, W. L., et al.: Efficacy of whole lung tomography in diagnosing metastases from solid tumors in children. Radiology, 141 :375-378, 1981. 7. Cohen, M., Zornoza, J., Cangir, A., et al.: Direct infection of methylprednisolone sodium succinate in the treatment of eosinophilic granuloma of bone. A report of 9 cases. Radiology, 136:289-293, 1980. 8. Cormier, W. J., Gilchrist, G. S., Burgert, E. 0., et al.: Management of metastatic Ewing's sarcoma. Proc. A.A.C.R.lA.S.C.O., 21:190, 1980. 9. Cornbleet, M. A., Corringham, R. E. T., Prentice, R. G., et al.: Treatment of Ewing's sarcoma with high dose melphalan and autogenous bone marrow transplantation. Cancer Treat. Rep., 65:241-244, 1982. 10. De Santos, L., Bernardino, M. E., and Murray, J. A.: Computed tomography in the evaluation of osteosarcoma: Experience with 25 cases. A.J.R., 132:535-540, 1979. 11. Edmonson, J. R., Green, S. J., Ivers, J. C., et al.: A controlled pilot study of high dose methotrexate as postsurgical adjuvant treatment for primary osteosarcoma. J. Clin. Oncol., 2:152-156, 1984. 12. Eftekhari, F., Wallace, S., Chuang, V. P., et al.: Intraarterial management of giant cell tumors of the spine in children. Pediatr. Radiol., 12:289-293, 1982. 13. Eilber, F. R., Morton, D. L., and Grant, T. T.: En bloc resection and allograft replacement for osteosarcoma of the extremity. In Jaffe, N. (ed.): Bone Tumors in Children. Littleton, PSG Publishing Co., 1979, pp. 159-167. 14 Gehan, E. A., Nesbit, M. E., Jr., Burgert, E. 0., et al.: Prognostic factors in children with Ewing's sarcoma. N.C.!. Monogr., 56:273-278, 1981. 15. Glaubiger, D. L., Makuch, R. W., and Schwarz, J.: Influence of prognostic factors on survival in Ewing's sarcoma. N.C.!. Monogr., 56:285-288, 1981.
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16. Greer, H., Green, D., Cassady, J., et aL: lO-Years of Vincristine (V), Actinomycin D (A) and Cyclophosphamide (C) chemotherapy by intermittent (I) or bolus (B) route for Ewing's sarcoma. A.S.S.C.O., 2:74,1983 . 17. Hayes, F. A., Thompson, E. 1., Hustu, H. 0., et al.: The response of Ewing's sarcoma to sequential cyclophosphamide and adriamycin induction therapy. J. Clin. OncoL, 1:45-51, 1983. 18. Jaffe, N., Knapp, J., Chuang, V. P., et aL: Osteosarcoma: Intra-arterial treatment of the primary tumor with cis-diamminedichloroplatinum II (CDP). Angiographic, pathologic and pharmacologic studies. Cancer, 51:402-407, 1983. 19. Jaffe, N., Prudich, J., Knapp, J., et aL: Treatment of primary osteosarcoma with intraarterial and intravenous high dose methotrexate. J. Clin. OncoL, 1:428-431, 1983. 20. Jaffe, N., Robertson, R., Cangir, A., et al.: Superiority of intra-arterial (I/A) cisdiamminedichloroplatinum II (CDP) over high dose methotrexate with citrovorum factor "rescue" (MTX-CF) in the treatment of primary osteosarcoma. Proc. A.A.C.R., 25:170, 1984. 21. Jaffe, N., Smith, E., Abelson, H. T., et al.: Osteogenic sarcoma: Alterations in the pattern of metastases with adjuvant chemotherapy. J. Clin. OncoL, 1:251-254, 1983. 22. Jaffe, N., Traggis, D., Sallan, S., et al.: Improved outlook for Ewing's sarcoma (Vincristine, Adriamycin D and Cyclophosphamide) and radiation therapy. Cancer, 38:1925-1930, 1976. 23. Jaffe, N., van Eys, J., and Gehan, E.: Response to "Is it ethical not to conduct a prospectively controlled trial of adjuvant chemotherapy?" Cancer Treat. Rep., 67:743-744, 1983. 24. Jaffe, N., and Watts, H.: Multi-drug chemotherapy in primary treatment of osteosarcoma. J. Bone Joint Surg. (Am.), 48:634-635, 1976. 25. Jaffe, N., Watts, H., Fellows, K. E., et al.: Local en bloc resection for limb preservation. Cancer Treat. Rep., 62:217-223, 1978. 26. Jenkin, R. D. T.: Sarcomas of the distal extremities. Int. J. Radiat. OncoL BioL Phys., 9:1235-1236, 1983. 27. Jentzsch, K., Binder, H., Glaubinger, 0., et aL: Leg function after radiotherapy for Ewing's sarcoma. Cancer, 47:1267-1278, 1981. 28. Kinsella, T. J., Glaubiger, D., Deisseroth, A., et aL: Intensive combined modality therapy including low dose TBI in high risk Ewing's sarcoma patients. Int. J. Radiat. OncoL BioL Phys., 9:1955-1960, 1983. 29. Kinsella, T. J., Loeffier, J. S., Frass, B. A., et al.: Extremity preservation by combined modality therapy in sarcomas of the hand and foot: An analysis of local control, disease free survival and functional result. Int. J. Radiat. OncoL BioL Phys., 9:1115-1119, 1983. 30. Kissane, J. M., Askin, F. B., Foulkes, M., et al.: Ewing's sarcoma of bone: Clinicopatholgic aspects of 303 cases from the intergroup Ewing's sarcoma study. Hum. PathoL, 14:773-779, 1983. 31. Kotz, R., and Salzer, M.: Rotationplasty for childhood osteosarcoma of the distal part of the femur. J. Bone Joint Surg. (Am.), 64A:959-969, 1982. 32. Lange, B., and Levin, A. S.: Is it ethical not to conduct a prospectively controlled trial in adjuvant chemotherapy in osteosarcoma? Cancer Treat. Rep., 66:1699-1704, 1982. 33. Lewis, R. J., Marcove, R. C., and Rosen, G.: Ewing's sarcoma-Functional effects after radiation therapy. J. Bone Joint Surg., 59:325-331, 1977. 34. Lombardi, F., Lattuada, A., Gasparini, M., et al.: Sequential half-body irradiation as systemic treatment of progressive Ewing's sarcoma. Int. J. Radiat. OncoL BioL Phys., 8:1679-1682, 1982. 35. Marcove, R. C., and Rosen, G.: Radical en bloc excision of Ewing's sarcoma. Clin. Orthop., 153:86-91, 1980. 36. Mendenhall, G. M., Marcus, R. B., Jr., et al.: The prognostic significance of soft tissue extension in Ewing's sarcoma. Cancer, 51:913-917, 1983. 37. Nesbit, M. E., Perez, C. A., Tefft, M., et aL: Multimodal therapy for the management of primary non-metastatic Ewing's sarcoma of bone: An intergroup study. N.C.1. Monogr., 56:255-262, 1981. 38. Perez, C. A., Razek, A., Tefft, M., et al.: Analysis of local control in Ewing's sarcoma. Preliminary results of a cooperative intergroup study. Cancer, (0:2864-2873, 1977. 39. Pilepich, M., Vietti, T. G., Nesbitt, M. E., et al.: Radiotherapy and combination
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M. D. Anderson Hospital and Tumor Institute Houston, Texas 77030