Journal of Clinical Oncology The Official Journal of the American Society of Clinical Oncology
Vol 10, No 1
January 1992
EDITORIAL
Osteosarcoma: Good News Despite Crude Tools
T
HE SURVIVAL OF patients with osteosarcoma has dramatically improved in the last 2 decades, primarily because effective multiagent chemotherapy regimens have been developed. Many investigators at single institutions and in cooperative group trials here and abroad have played important roles in this progress. The work of clinicians at Memorial Sloan-Kettering Cancer Center (MSKCC) is particularly important. They were among the first to begin chemotherapy adjuvant trials for osteosarcoma, and they have championed several specific approaches: the use of preoperative (neoadjuvant) chemotherapy before surgical ablation of the primary tumor; the use of limb-salvage surgery, which avoided amputation in selected patients; and development of a pathologic assessment of response to chemotherapy (the four-grade histologic assessment of tumor necrosis). Meyers et al' are to be congratulated for reporting the long-term follow-up of patients treated on these sequential therapy outlines (T4, T5, T7, T10, and T12) that have dramatically influenced the direction of clinical investigation of osteosarcoma in the last decade. This information is invaluable. It reconfirms the initial promise that nonmetastatic osteosarcoma is a curable disease for about two thirds of patients. Most importantly, this report reevaluates the conclusions of the earlier reports of these trials that have so greatly influenced the treatment of osteosarcoma around the world. The disease-free survival (DFS) for the 279 patients included in this report is 65%, with a comfortable follow-up period. In an attempt to make comparisons with other published series, the MSKCC investigators analyzed the subset of patients with osteosarcoma of the extremities and age less than 22 years at diagnosis and who had been treated on the T10 protocol (the treatment outline that appeared to be among the best of those analyzed).' The DFS for this subset is 76%. For all 255 patients with extremity tumors, the DFS is 67%.
Although DFS in this study is among the best reported, it is similar to the Multiinstitutional Osteosarcoma Study (MIOS), German Cooperative Osteosarcoma Studies (COSS), and some single-institution protocol results. In addition, the single-institution MSKCC experience has not been easily reproduced, with inferior results in the cooperative Childrens Cancer Study Group (CCSG) 782 trial. The authors suggest that this may be due to the method of administration of high-dose methotrexate. However, it is also likely that significant variations in the treatment actually received by each patient have made duplication of results impossible. As they state, "treatment did not strictly follow protocol guidelines; rather patient treatment was individualized using a variety of indicators of patient response to therapy." Although investigators from MSKCC claimed in an earlier report2 that the excellent survival of their patients is the result of "an investigative method" where "dose schedules must be precise with little variation ... ", it is now clear that patients treated on these successive treatment outlines "received different sequences and doses of chemotherapy . .." based, in part, on ". . . the treating physician's judgment." This will make confirmatory studies very difficult. The MSKCC trials provided the first demonstration that response to therapy could be gauged by the histologic assessment of tumor necrosis.3 Because osteosarcoma produces extensive extracellular matrix that does not consistently disappear after effective therapy, an accurate evaluation of response clinically and radiographically is difficult. Thus, the "gold standard" for the assessment of response is a histologic determination of tumor necrosis. How much necrosis is needed to define a responsive tumor has been a controversial issue, varying in different studies. The MSKCC trials have defined good histologic response as grades III (only scattered foci of viable tumor) and IV (no viable tumor or complete necrosis); the present review continues to use
Journal of Clinical Oncology, Vol 10, No 1 (January), 1992: pp 1-2
Downloaded from ascopubs.org by UNIVERSITY LIVERPOOL on April 20, 2019 from 154.059.124.102 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
1
2
SIMONE, MEYER, AND LINK
this definition.' However, the data show that only the grade IV response predicted an excellent outcome, with no difference in outcome for patients whose tumors had grade II and grade III responses. In addition, the data suggest that as preoperative therapy becomes more intensive, uses most or all active agents, and is prolonged, the correlation of tumor necrosis with DFS decreases, as also reported by others.4'5 Also, the authors previously reported that assessment of tumor necrosis after preoperative chemotherapy allowed them to change postoperative therapy for poor responders and improve their outcome.6 However, others could not confirm this finding and now, with longer follow-up, the authors report no improvement for histologic poor responders after modification of postoperative therapy to include cisplatin. The authors raise several crucial questions. What factors best predict outcome for patients with osteosarcoma? From this report and others, the serum lactate dehydrogenase (LDH) and alkaline phosphatase, the primary site of tumor, and the degree of histologic response appear important, although therapy remains the single most important factor by far. What is the optimal chemotherapy for osteosarcoma? Although the long-term outcome for the group of patients treated at MSKCC rivals any other published result, the optimal therapy is still undetermined. At least one third of patients with osteosarcoma still die of disease. Is a period of chemotherapy before definitive surgery superior to immediate surgery followed by adjuvant chemotherapy? The authors report no difference in outcome whether chemotherapy or surgery comes first. This
question is being investigated prospectively in a current Pediatric Oncology Group study. If histologic response to preoperative chemotherapy predicts outcome, is it possible to alter therapy for poor responders to improve their prognosis? Unfortunately, the present report and work from several other investigators suggest that this is not currently possible. Finally, we offer two sober observations. First, this and most reported studies of osteosarcoma consider only patients with single-focus, resectable, nonmetastatic, primary tumors, usually involving an extremity. Although a minority, at least 20% of patients have flat-bone or axial tumors or metastatic disease at diagnosis. These patients have a very poor prognosis because chemotherapy alone is rarely curative. Second, the impressive incremental success since the 1970s has been accomplished by empirical, often flawed clinical trials using chemotherapy agents that singly range in effectiveness from fair to mediocre. Remember, with surgery alone only 10% to 15% of these patients are cured. This speaks well for the perseverance and inventiveness of the clinical investigators who are responsible for this remarkable success. Joseph V. Simone William H. Meyer St Jude Children'sResearch Hospital Memphis, TN Michael P. Link Stanford University School of Medicine Stanford, CA
REFERENCES 1. Meyers PA, Heller G, Healey J, et al: Chemotherapy for nonmetastatic osteogenic sarcoma: The Memorial Sloan-Kettering experience. J Clin Oncol 10:5-15, 1992 2. Rosen G, Nirenberg A: Chemotherapy for osteogenic sarcoma: An investigative method, not a recipe. Cancer Treat Rep 66:1687-1697, 1982 3. Rosen G, Marcove RC, Caparros B, et al: Primary osteogenic sarcoma: The rationale for preoperative chemotherapy and delayed surgery. Cancer 43:2163-2177, 1979 4. Jaffe N, Raymond AK, Ayala A, et al: Effect of cumulative
courses of intraarterial cisdiamminedichloroplatin-II on the primary tumor in osteosarcoma. Cancer 63:63-67, 1989 5. Weiner MA, Harris MB, Lewis M, et al: Neoadjuvant high-dose methotrexate, cisplatin, and doxorubicin for the management of patients with nonmetastatic osteosarcoma. Cancer Treat Rep 70:1431-1432, 1986 6. Rosen G, Caparros B, Huvos AG, 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
Downloaded from ascopubs.org by UNIVERSITY LIVERPOOL on April 20, 2019 from 154.059.124.102 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
Vol 10, No 1
January 1992
EDITORIAL
Osteosarcoma: Good News Despite Crude Tools
T
HE SURVIVAL OF patients with osteosarcoma has dramatically improved in the last 2 decades, primarily because effective multiagent chemotherapy regimens have been developed. Many investigators at single institutions and in cooperative group trials here and abroad have played important roles in this progress. The work of clinicians at Memorial Sloan-Kettering Cancer Center (MSKCC) is particularly important. They were among the first to begin chemotherapy adjuvant trials for osteosarcoma, and they have championed several specific approaches: the use of preoperative (neoadjuvant) chemotherapy before surgical ablation of the primary tumor; the use of limb-salvage surgery, which avoided amputation in selected patients; and development of a pathologic assessment of response to chemotherapy (the four-grade histologic assessment of tumor necrosis). Meyers et al' are to be congratulated for reporting the long-term follow-up of patients treated on these sequential therapy outlines (T4, T5, T7, T10, and T12) that have dramatically influenced the direction of clinical investigation of osteosarcoma in the last decade. This information is invaluable. It reconfirms the initial promise that nonmetastatic osteosarcoma is a curable disease for about two thirds of patients. Most importantly, this report reevaluates the conclusions of the earlier reports of these trials that have so greatly influenced the treatment of osteosarcoma around the world. The disease-free survival (DFS) for the 279 patients included in this report is 65%, with a comfortable follow-up period. In an attempt to make comparisons with other published series, the MSKCC investigators analyzed the subset of patients with osteosarcoma of the extremities and age less than 22 years at diagnosis and who had been treated on the T10 protocol (the treatment outline that appeared to be among the best of those analyzed).' The DFS for this subset is 76%. For all 255 patients with extremity tumors, the DFS is 67%.
Although DFS in this study is among the best reported, it is similar to the Multiinstitutional Osteosarcoma Study (MIOS), German Cooperative Osteosarcoma Studies (COSS), and some single-institution protocol results. In addition, the single-institution MSKCC experience has not been easily reproduced, with inferior results in the cooperative Childrens Cancer Study Group (CCSG) 782 trial. The authors suggest that this may be due to the method of administration of high-dose methotrexate. However, it is also likely that significant variations in the treatment actually received by each patient have made duplication of results impossible. As they state, "treatment did not strictly follow protocol guidelines; rather patient treatment was individualized using a variety of indicators of patient response to therapy." Although investigators from MSKCC claimed in an earlier report2 that the excellent survival of their patients is the result of "an investigative method" where "dose schedules must be precise with little variation ... ", it is now clear that patients treated on these successive treatment outlines "received different sequences and doses of chemotherapy . .." based, in part, on ". . . the treating physician's judgment." This will make confirmatory studies very difficult. The MSKCC trials provided the first demonstration that response to therapy could be gauged by the histologic assessment of tumor necrosis.3 Because osteosarcoma produces extensive extracellular matrix that does not consistently disappear after effective therapy, an accurate evaluation of response clinically and radiographically is difficult. Thus, the "gold standard" for the assessment of response is a histologic determination of tumor necrosis. How much necrosis is needed to define a responsive tumor has been a controversial issue, varying in different studies. The MSKCC trials have defined good histologic response as grades III (only scattered foci of viable tumor) and IV (no viable tumor or complete necrosis); the present review continues to use
Journal of Clinical Oncology, Vol 10, No 1 (January), 1992: pp 1-2
Downloaded from ascopubs.org by UNIVERSITY LIVERPOOL on April 20, 2019 from 154.059.124.102 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
1
2
SIMONE, MEYER, AND LINK
this definition.' However, the data show that only the grade IV response predicted an excellent outcome, with no difference in outcome for patients whose tumors had grade II and grade III responses. In addition, the data suggest that as preoperative therapy becomes more intensive, uses most or all active agents, and is prolonged, the correlation of tumor necrosis with DFS decreases, as also reported by others.4'5 Also, the authors previously reported that assessment of tumor necrosis after preoperative chemotherapy allowed them to change postoperative therapy for poor responders and improve their outcome.6 However, others could not confirm this finding and now, with longer follow-up, the authors report no improvement for histologic poor responders after modification of postoperative therapy to include cisplatin. The authors raise several crucial questions. What factors best predict outcome for patients with osteosarcoma? From this report and others, the serum lactate dehydrogenase (LDH) and alkaline phosphatase, the primary site of tumor, and the degree of histologic response appear important, although therapy remains the single most important factor by far. What is the optimal chemotherapy for osteosarcoma? Although the long-term outcome for the group of patients treated at MSKCC rivals any other published result, the optimal therapy is still undetermined. At least one third of patients with osteosarcoma still die of disease. Is a period of chemotherapy before definitive surgery superior to immediate surgery followed by adjuvant chemotherapy? The authors report no difference in outcome whether chemotherapy or surgery comes first. This
question is being investigated prospectively in a current Pediatric Oncology Group study. If histologic response to preoperative chemotherapy predicts outcome, is it possible to alter therapy for poor responders to improve their prognosis? Unfortunately, the present report and work from several other investigators suggest that this is not currently possible. Finally, we offer two sober observations. First, this and most reported studies of osteosarcoma consider only patients with single-focus, resectable, nonmetastatic, primary tumors, usually involving an extremity. Although a minority, at least 20% of patients have flat-bone or axial tumors or metastatic disease at diagnosis. These patients have a very poor prognosis because chemotherapy alone is rarely curative. Second, the impressive incremental success since the 1970s has been accomplished by empirical, often flawed clinical trials using chemotherapy agents that singly range in effectiveness from fair to mediocre. Remember, with surgery alone only 10% to 15% of these patients are cured. This speaks well for the perseverance and inventiveness of the clinical investigators who are responsible for this remarkable success. Joseph V. Simone William H. Meyer St Jude Children'sResearch Hospital Memphis, TN Michael P. Link Stanford University School of Medicine Stanford, CA
REFERENCES 1. Meyers PA, Heller G, Healey J, et al: Chemotherapy for nonmetastatic osteogenic sarcoma: The Memorial Sloan-Kettering experience. J Clin Oncol 10:5-15, 1992 2. Rosen G, Nirenberg A: Chemotherapy for osteogenic sarcoma: An investigative method, not a recipe. Cancer Treat Rep 66:1687-1697, 1982 3. Rosen G, Marcove RC, Caparros B, et al: Primary osteogenic sarcoma: The rationale for preoperative chemotherapy and delayed surgery. Cancer 43:2163-2177, 1979 4. Jaffe N, Raymond AK, Ayala A, et al: Effect of cumulative
courses of intraarterial cisdiamminedichloroplatin-II on the primary tumor in osteosarcoma. Cancer 63:63-67, 1989 5. Weiner MA, Harris MB, Lewis M, et al: Neoadjuvant high-dose methotrexate, cisplatin, and doxorubicin for the management of patients with nonmetastatic osteosarcoma. Cancer Treat Rep 70:1431-1432, 1986 6. Rosen G, Caparros B, Huvos AG, 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
Downloaded from ascopubs.org by UNIVERSITY LIVERPOOL on April 20, 2019 from 154.059.124.102 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
