Abstract
Osteosarcoma is the most common malignant bone tumor affecting children and adolescents. The biological behavior is consistent with the premise that pulmonary micrometastases are present at diagnosis in the majority of patients. These are silent and undetected on imaging studies. They usually surface six to twelve months following amputation of the primary tumor and if untreated are responsible for the patients demise. Until the 1970s the tumor was generally considered to be chemoresistant. However, in the early 1970’s, two chemotherapeutic agents were found to be active in osteosarcoma. These comprised Adriamycin (doxorubicin) and high-dose Methotrexate with Citrovorin factor rescue (Leucovorin rescue). The administration of high-dose Methotrexate following amputation alone or in combination with other agents yielded a cure rate of 40-65 percent. This was attributed to the destruction of the pulmonary micrometastases. The improved survival due chemotherapy did not go unchallenged. The Mayo Clinic adduced data to suggest that there had been a “natural improvement” in the cure rate over several years and that it should not necessarily be assumed that chemotherapy, particularly high-dose Methotrexate, was responsible for the improvement. The veracity of historical controls and the efficacy of high dose Methotrexate were also disputed by additional claims from the Mayo Clinic. Principal among these was recent advances in diagnostic techniques i.e. CT lung and radionuclide bone scans.
To resolve the problem a multi-institutional randomized osteosarcoma trial (MIOS) was launched. A series of patients was treated by amputation and postoperatively with multiagent chemotherapy comprising high-dose Methotrexate Adriamycin, Cisplatin, Bleomycin, Cyclophosphamide and Dactinomycin. A second series of patients was treated with amputation only (concurrent controls). Treatment by amputation and postoperative adjuvant chemotherapy achieved a 66 percent two-year disease-free survival. In contrast, patients treated by amputation alone garnered a significantly worse outcome: less than 20 percent survival. The latter was comparable to survival in the historical control series. Chemotherapy was thus found to be effective and comparison of the results with historical controls was validated.
The above experience was further substantiated by an additional concurrent randomized trial. An editorial by James Holland in the Journal of Clinical Oncology commented on the results of the randomized trial(s) and offered suggestions for the conduct of future trials. The acceptance of chemotherapy as an integral and essential component for the treatment of osteosarcoma launched a new era in the conquest of this disease.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Santayana G. The Life of Reason, or The Phases of Human Progress. 2nd ed. New York: Scribner; 1936.
Friedman M, Carter SK. The therapy of osteogenic sarcoma: current status and thoughts for the future. J Surg Oncol. 1972;45:482-510.
Cade S. Osteogenic sarcoma. A study based on 113 patients. J R Coll Surg Edinb. 1955;l:79-111.
Farber S, Diamond LK, Mercer RD, et al. Temporary remissions in children in acute leukemia produced by folic acid antagonist 4-aminopteroyl-glutanic acid (aminopterin). New Engl J Med. 1946;238:787-793.
Golden A, Mantel N, Greenhouse SW, et al. Effect of delayed administration of Citrovorin factor on the antileukemic effectiveness of aminopterin in mice. Cancer Res. 1954;14:43-48.
Burchenal JH. Human leukemias. Bibl Hematol. 1975;40:65-77.
Djerassi I, Abir E, Boyer GL, et al. Long term remissions in childhood acute leukemia: use of infrequent infusions of methotrexate: supportive roles of platelet transfusions and citrovorum factor. Clin Pediatr. 1966;5:502-509.
Zager RF, Frisby SA, Oliverio VT. The effects of antibiotics and cancer chemotherapeutic agents in the cellular transport and antitumor activity of methotrexate in L1210 murine leukemia. Cancer Res. 1973;33:1670-1676.
Jaffe N. Recent advances in the chemotherapy of osteogenic sarcoma. Cancer. 1972;30:1627-1631.
Jaffe N, Frei E III, Traggis D, Bishop Y. Adjuvant methotrexate treatment and citrovorum factor in osteogenic sarcoma. New Engl J Med. 1974;291:994-997.
Skipper HE, Schabel FM, Wilcox WS. Experimental evaluation of potential anticancer agents. XIV. Further study of certain basic concepts underlying chemotherapy of leukemia. Cancer Chemother Rep:. 1964;35:1-28.
Laster WR Jr, Mayo JG, Simpson-Herren L, et al. Success and failure in the treatment of solid tumors. II. Kinetic parameters and cell cure of moderately advanced carcinoma. Cancer Chemother Rep. 1969;53:169-188.
Schabel FM Jr. Concepts for systemic treatment of micro-metastases. Cancer. 1975;35:15-24.
Goorin AM, Delorey M, Gelber RD, et al. Dana-Farber Cancer Institute/The Children’s Hospital adjuvant chemotherapy trials for osteosarcoma: three sequential studies. Cancer Treat Symp. 1985;3:155-159.
Goorin AM, Perez-Atayde A, Gebhardt M, et al. Weekly high dose methotrexate and doxorubicin for osteosarcoma: The Dana Farber Cancer Institute/The Children’s Hospital Study III. J Clin Oncol. 1987;5:1178-1184.
Rosen G, Nirenberg A, Caparros B, et al. Osteogenic sarcoma: eight-percent, three-year disease-free survival with combination chemotherapy (T-7). Natl Cancer Inst Monogr. 1981;56:213-220.
Sutow WW, Gehan EA, Vietti TG, et al. Multidrug chemotherapy in primary osteosarcoma. J Bone Joint Surg Am. 1976;58:629-633.
Pratt C, Shanks E, Hustu O, et al. Adjuvant multiple drug chemotherapy for osteosarcoma of the extremity. Cancer. 1979;39:51-57.
Muggia FM, Louie AC. Five years of adjuvant chemotherapy: more questions than answers. Cancer Treat Rep. 1978;62:30-36.
Rab CT, Ivins JC, Childs RE, et al. Elective whole lung irradiation in the treatment of osteogenic sarcoma. Cancer. 1976;38:939-942.
Taylor WF, Ivins JG, Dahlin D, et al. Osteogenic sarcoma experience at the Mayo Clinic, 1963–1974. In: Terry WD, Windhorst D, eds. Immunotherapy of Cancer. Present Status of Trials in Man, Progress in Cancer Research and Therapy, vol. VI. New York: Raven Press; 1978:257-269.
Taylor WF, Ivins JC, Prichard DJ, et al. Trends and variability in survival among patients with osteosarcoma: a 7-year update. Mayo Clin Proc. 1985;60(2):91-104.
Frei E III, Blum R, Jaffe N. Sarcoma: natural history and treatment. In: Terry WD, Windhorst D, eds. Immunotherapy of Cancer. Present Status of Trials in Man, Progress in Cancer Research and Therapy, vol. VI. New York: Raven Press; 1978:248-255.
Gehan EA, Sutow WW, Urube Botero T, et al. Osteosarcoma. The MD Anderson experience 1850–1974. In: Terry WD, Windhorst D, eds. Immunotherapy of Cancer. Present Status of Trials in Man, Progress in Cancer Research and Therapy, vol. VI. New York: Raven Press; 1978:271-282.
Miké V, Marcove RC. Osteogenic sarcoma under the age of 21. Experiences at Memorial Sloan Kettering Cancer Center. In: Terry WD, Windhorst D, eds. Immunotherapy of Cancer. Present Status of Trials in Man, Progress in Cancer Research and Therapy, vol. VI. New York: Raven Press; 1978:282-293.
Marcove RC, Mike V, Hajek JV, et al. Osteogenic sarcoma in childhood. NY State J Med. 1971;71:855-859.
Campanacci M, Bacci G, Bertoni F, et al. The treatment of osteosarcoma of the extremities: twenty years’ experience at the Instituto Ortopedico Rizzoli. Cancer. 1981;48:1569-1581.
Bacci G, Gherlinzoni F, Picci P, et al. Adriamycin-methotrexate high dose versus Adriamycin-methotrexate moderate dose as adjuvant chemotherapy for osteosarcoma of the extremities: a randomized study. Eur J Cancer Clin Oncol. 1986;22:1337-1345.
Bacci G, Picci P, Calderoni P, et al. Full lung tomograms and bone scanning in the initial workup of patients with osteogenic sarcoma. A review of 126 cases. Eur J Cancer Clin Oncol. 1982;18:967-971.
Muhm JR, Prichard DJ. Computed tomography for detection of pulmonary metastases in patients with osteogenic sarcoma. Proc Am Assoc Cancer Res. 1980;21:593.
Cohen M, Provisor A, Smith WL, et al. Efficacy of whole lung tomography on diagnosing metastases from solid tumors in children. Radiology. 1981;141:375-378.
Gordon RE, Mettler FA Jr, Wicks J, et al. Chest x-rays and full lung tomograms in gynecologic malignancy. Cancer. 1983;52:559-562.
Wilimas J, Hammon E, Champion J, et al. The value of computerized tomography (CT) as a routine follow-up procedure for patients with Wilms tumor. Am Soc Clin Oncol. 1983;2:80 (Abstr 34).
Jaffe N, Farber S, Traggis D, et al. Favorable response of metastatic osteogenic sarcoma to pulse high dose methotrexate with citrovorin rescue and radiation therapy. Cancer. 1973;31:1367-1373.
Jaffe N, Watts H, Fellows K, et al. Local en bloc resection for limb preservation. Cancer Treat Rep. 1978;62:217-223.
Jaffe N, Frei E III, Traggis D, et al. Weekly high-dose methotrexate-citrovorum factor in osteogenic sarcoma pre-surgical treatment of primary tumor and of overt pulmonary metastases. Cancer. 1977;39:45-50.
Frei E, Jaffe N, Gero M, et al. Guest editorial. Adjuvant chemotherapy of osteogenic sarcoma: progress and perspectives. J Natl Cancer Inst. 1978; 60:3-10.
Jaffe N, Frei E III, Watts H, et al. High dose methotrexate in osteogenic sarcoma: a 5-year experience. Cancer Treat Rep. 1978;62:259-264.
Jaffe N. Progress report on high-dose methotrexate (NSC-740) with citrovorum rescue in the treatment of metastatic bone tumors. Cancer Chemother Rep. 1974;58:275-280.
Jaffe N, Traggis D. Toxicity of high-dose methotrexate (NSC-740) and citrovorum factor (NSC-3590) in osteogenic sarcoma. Cancer Chemother Rep. 1975;6:31-36.
Pitman SW, Parker M, Tattersall MH, et al. Clinical trial of high-dose methotrexate (NSC-740) with citrovorum factor (NSC-3590) – toxicologic and therapeutic observations. Cancer Chemother Rep. 1975;6:43-49.
Jaffe N, Frei E III, Traggis D, et al. High-dose methotrexate with citrovorum factor in osteogenic sarcoma. Progress report II. Cancer Treat Rep. 1977;61:675-679.
Jaffe N, Traggis D, Cassady JR, et al. Multidisciplinary treatment for macrometastatic osteogenic sarcoma. Br Med J. 1976;2:1039-1041.
Jaffe N, Link M, Traggis D, et al. The role of high dose methotrexate in osteogenic sarcoma. Sarcomas of soft tissue and bone in childhood. Natl Cancer Inst Monogr. 1981;56:201-206.
Edmonson JH, Green SJ, Ivins JC, et al. A controlled pilot study of high-dose methotrexate as postsurgical adjuvant treatment for primary osteosarcoma. J Clin Oncol. 1984;2:152-156.
Carter SK. Adjuvant chemotherapy in osteogenic sarcoma.The triumph that isn’t? J Clin Oncol. 1984;2:147-148.
Jaffe N. Adjuvant chemotherapy in osteogenic sarcoma. J Clin Oncol. 1984;2:1179-1181.
Carter SK. Reply: adjuvant chemotherapy in osteosarcoma. J Clin Oncol. 1984;2:1181.
Feinstein AR, Sosin DM, Wells CK. The Will Rogers phenomenon. Stage migration and new diagnostic techniques as a source of misleading statistics for survival in cancer. N Engl J Med. 1985;312:1604-1608.
Goorin AM, Frei E III, Abelson HT. Adjuvant chemotherapy for osteosarcoma: a decade of experience. Surg Clin North Am. 1981;61:1379-1389.
Kolate GB. Dilemma in cancer treatment. Science. 1980;209:792-794.
Brostrom LA, Apairsi T, Ingimarsson SN, et al. Can historical controls be used in current clinical trials in osteosarcoma? Metastasis and survival in a historical and concurrent group. Int J Radiat Oncol Biol Phys. 1980;6:1717-1721.
Lang EB, Levin AS. Is it ethical not to conduct a prospectively controlled trial of adjuvant chemotherapy in osteosarcoma? Cancer Treat Rep. 1982;66:1699-1704.
Jaffe N, van Eys J, Gehan E. Response to: “Is it ethical not to conduct a prospectively controlled trial of adjuvant chemotherapy in osteosarcoma?”. Cancer Treat Rep. 1983;67:743-744.
Cox DR. Regression models and life tables (with discussion). J R Stat B. 1972;187-220.
Jaffe N, Smith E, Abelson HT, et al. Osteogenic sarcoma: alterations in the pattern of pulmonary metastases with adjuvant chemotherapy. J Clin Oncol. 1983;1:251-254.
Jaffe N, Traggis D, Cohen DG. The impact of high dose methotrexate in the management of osteogenic sarcoma. In: Proceedings of the Twelfth International Cancer Congress, vol. 10. Oxford: Pergamon Press; 1979:175-179.
Link MP, Vietti TJ. Reply: Role of adjuvant chemotherapy in the treatment of osteosarcoma. Cancer Treat Rep. 1983;67:744-745.
D’Angio GJ, Evans AE. Bone tumors – a commentary. In: D’Angio GJ, Evans AE, eds. Bone Tumours and Soft-Tissue Sarcomas, Progress in Cancer Research and Therapy, vol. VI. Baltimore, MD: Edward Arnold; 1985:121-124.
Rosen G, Murphy ML, Huvos AG, et al. Chemotherapy en bloc resection and prosthetic bone replacement in the treatment of osteogenic sarcoma. Cancer. 1976;37:1-11.
Rosen G, Marcove RC, Huvos AG, et al. Primary osteogenic sarcoma: eight year experience with adjuvant chemotherapy. J Cancer Res Clin Oncol. 1983;106(Suppl):55-67.
Link MP, Goorin AM, Miser A, et al. The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. New Engl J Med. 1986;314:1600-1606.
Eilber FR, Dauglass HI Jr, Mendel ER, et al. Adjuvant Adriamycin and cisplatin in newly-diagnosed nonmetastatic osteosarcoma of the extremity. J Clin Oncol. 1986;4:353-362.
Holland JF. Adjuvant chemotherapy of osteosarcoma: no runs, no hits, two men left on base. J Clin Oncol. 1987;5:4-6.
Winkler K, Bielack S. Chemotherapy for osteosarcoma. Semin Orthop. 1988;3:48-58.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2009 Springer Science+Business Media, LLC
About this chapter
Cite this chapter
Jaffe, N. (2009). Adjuvant Chemotherapy in Osteosarcoma. In: Jaffe, N., Bruland, O., Bielack, S. (eds) Pediatric and Adolescent Osteosarcoma. Cancer Treatment and Research, vol 152. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-0284-9_11
Download citation
DOI: https://doi.org/10.1007/978-1-4419-0284-9_11
Published:
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4419-0283-2
Online ISBN: 978-1-4419-0284-9
eBook Packages: MedicineMedicine (R0)