Neoadjuvant chemotherapy of osteosarcoma: results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response.

Abstract

Following observation of the predictive value of the histologic extent of tumor cell destruction after preoperative chemotherapy for metastasis-free survival (MFS) in osteosarcoma, a randomized study was undertaken with the aim of (1) sparing some patients the unpleasant side effects of highly toxic drugs like doxorubicin (DOX) and cisplatin (CPDD) by administering these drugs postoperatively only after poor response with a milder preoperative regimen, and (2) improving the prognosis of patients responding poorly to the initial treatment by use of a salvage chemotherapy postoperatively. The available patients were divided into two groups. Those in the study arm received a preoperative chemotherapy consisting of high-dose methotrexate (HDMTX) and the triple drug combination of bleomycin, cyclophosphamide, and dactinomycin (BCD) and were switched to DOX/CPDD postoperatively in case of poor response. DOX/CPDD was used besides HDMTX for initial treatment in the control arm, and BCD alternatively with CPDD/ifosfamide (IFO) for postoperative salvage treatment. The response rate of the study arm was significantly inferior to the control arm (26% v 60%; P less than .001). The actuarial 4-year MFS rate of poor responders after salvage chemotherapy also was poorest in the study arm (41%); it was unchanged in the control arm (53%) as compared with that of poor responders from the COSS-80 study without salvage chemotherapy (52%). The actuarial 4-year MFS rate of good responders was 73% in the study arm, 79% in the control arm, and not significantly different from that of the COSS-80 study (84%), although postoperative chemotherapy of good responders had been markedly shortened as compared with the COSS-80 study. The actuarial 4-year MFS rate of the study arm as a whole was inferior to that of the control arm (49% v 68%; P less than .1) and also inferior to the COSS-80 study (68%; P less than .01), indicating a failure of the employed salvage strategy in general and especially of the effort to restrict the use of the very effective but highly toxic drugs DOX and CPDD to patients resistant to a less toxic initial treatment.

Osteosarcoma of the spine

“…15 In general, however, the effect of chemotherapy is only temporary, and preoperative chemotherapy should be followed by intensive local treatment. In recent years, not only chemotherapy [7][8][9][10]17 and imaging techniques 28 but also surgical techniques 20,25,29 -31 have been developed in spinal sarcoma surgery. Kawahara et al 14 reported reconstruction after en bloc resection of the affected vertebra by osteosarcoma.…”

Intraoperative radiotherapy in the multidisciplinary treatment of bone sarcomas in children and adolescents

“…The tendency towards radical tumor surgical removal with amputation [11][12][13] has given way to programs with extremity preservation by combining surgery and neoadjuvant and adjuvant radiation therapy and chemotherapy without compromising the results in disease-free survival [14][15][16].…”

Osteosarcoma of the spine

“…In the COSS protocols COSS 80, COSS 82, COSS 86, COSS 86C, and COSS 91 [7][8][9][10] , patients were designated to receive high-dose methotrexate with leucovorin 17,18 In COSS 80 through COSS 96, both preoperative and postoperative chemotherapy were scheduled. [7][8][9][10]17 All studies were approved by the local ethics committee and/or the protocol review committee of the German Cancer Society or the German Ministry for Science and Technology.…”

“…[7][8][9][10]17 All studies were approved by the local ethics committee and/or the protocol review committee of the German Cancer Society or the German Ministry for Science and Technology. Before the initiation of treatment, informed consent was obtained from all patients or their legal guardians.…”