Standard Treatment Options
Treatment Options Under Clinical Evaluation
Current Clinical Trials

Complete surgical resection is crucial for patients with localized osteosarcoma; however, at least 80% of patients treated with surgery alone will develop metastatic disease.[1,2] Randomized clinical trials have established that adjuvant chemotherapy is effective in preventing relapse or recurrence in patients with localized resectable primary tumors.[1,3] Older reports suggested that osteosarcoma arising following therapeutic radiation had a uniformly poor prognosis. A single-institution retrospective review reported that patients with osteosarcoma arising following radiation therapy treated with multiagent chemotherapy and surgical resection have a prognosis similar to patients with osteosarcoma arising de novo.[4]

A number of single-arm trials evaluated the role of chemotherapy administered both preoperatively and postoperatively. Some of these trials evaluated the necrosis of the primary tumor following chemotherapy and used this information to determine subsequent therapy.[5,6] Current chemotherapy protocols include combinations of the following agents: high-dose methotrexate, doxorubicin, cyclophosphamide, cisplatin, ifosfamide, etoposide, and carboplatin.[6-16] Overall, relapse-free survival ranges from 50% to 75% in these trials.[5,14] One randomized trial found no difference in survival between two drugs given for a shorter duration and multiagent regimens, though event-free survival (EFS) in both arms was less than 50%.[17] In a large Cooperative Osteosarcoma Study Group trial, higher chemotherapy dose intensity did not correlate with improved outcome.[18]

All patients with osteosarcoma should undergo surgical resection of the primary tumor if possible. The type of surgery required for complete ablation of the primary tumor depends on a number of factors that must be evaluated on an individual basis.[19] If limb-sparing (removal of the malignant bone tumor without amputation and replacement of bones or joints with allografts or prosthetic devices) is contemplated, the biopsy should be performed by the surgeon who will do the definitive operation, since incision placement is crucial. While a needle biopsy can often confirm the diagnosis, participation in some clinical trials requires collection of material for biologic studies that can only be obtained via an open biopsy or multiple needle biopsies. Rotationplasty and limb-sparing procedures have been evaluated for both their functional result and their effect on survival.[20] There is no difference in overall survival (OS) between patients initially treated by amputation and those treated with a limb-sparing procedure.[21] One randomized trial noted no difference in disease-free survival (DFS) with preoperative chemotherapy compared with immediate surgery followed by adjuvant chemotherapy.[22] Limb-sparing procedures should be planned only when the preoperative staging indicates that it is possible to achieve wide surgical margins. A pathologic fracture noted at diagnosis or during preoperative chemotherapy does not preclude limb-salvage surgery if wide surgical margins can be achieved.[23] In one series, patients presenting with a pathologic fracture at diagnosis had similar outcomes to those without pathologic fractures at diagnosis, while in a second series, pathologic fracture at diagnosis was associated with a worse overall outcome.[24,25] If the pathologic examination of the surgical specimen shows inadequate margins, an immediate amputation should be considered, especially if the histologic necrosis following preoperative chemotherapy was poor.[21] In one study, patients undergoing limb-salvage procedures who had poor histologic response and close surgical margins had a high rate of local recurrence.[26] For patients who receive chemotherapy prior to surgery, the degree of tumor necrosis observed postoperatively is highly predictive of DFS, local recurrence, and OS.[8,9,27] Increasing the intensity of preoperative chemotherapy raised the proportion of patients with good histologic response in two studies [28,29] but not in another.[30] A European Consortium conducted a large randomized trial comparing doxorubicin and cisplatin courses every 2 or 3 weeks for six courses. Surgery was done at week 6 in both groups. Although the group randomized to every 2 week courses of therapy had a higher rate of good histologic response, there was no difference in survival.[29] Results from both arms of the study were inferior to those achieved in other large cooperative studies that used more than two drugs.[29]

The Children's Oncology Group (COG) performed a prospective randomized trial in newly diagnosed children and young adults with localized osteosarcoma. All patients received cisplatin, doxorubicin, and high-dose methotrexate. One-half of the patients were randomly assigned to receive ifosfamide. In a second randomization, one-half of the patients were assigned to receive the biological compound muramyl tripeptide-phosphatidyl ethanolamine encapsulated in liposomes (L-MTP-PE) beginning after definitive surgical resection. Neither the addition of ifosfamide alone nor L-MTP-PE alone to three standard chemotherapy agents improved EFS. The addition of both agents achieved the best EFS in this study, but the difference was not statistically significant when compared with the outcome of the three standard chemotherapy agents alone.[16] A joint Scandinavian/Italian study compared standard-dose ifosfamide (9 g/m²/course) with high-dose ifosfamide (15 g/m²/course). All patients received methotrexate, cisplatin, doxorubicin, and ifosfamide. High-dose ifosfamide did not improve EFS but was associated with increased renal and hematologic toxicity.[14]

Patients with primary tumors of the femur have a higher local recurrence rate than do patients with primary tumors of the tibia/fibula. Not surprisingly, patients who undergo amputation have lower local recurrence rates than patients undergoing limb-sparing procedures.[27] In general, more than 80% of patients with extremity osteosarcoma can be treated by a limb-sparing operation and do not require amputation.[5] While limb-sparing tumor resection is the current practice for local control at most pediatric institutions, there are few data to indicate that limb-salvage of the lower limb is substantially superior to amputation with regard to patient quality of life.[31] Patients with osteosarcoma may benefit from radiation therapy if surgical margins are inadequate.[32,33] Information about ongoing clinical trials is available from the NCI Web site.

Localized, completely resectable high-grade osteosarcoma

• Most patients receive preoperative (neoadjuvant) chemotherapy followed by extirpative surgery (amputation, limb preservation, or rotationplasty) [20] and postoperative adjuvant chemotherapy. Limb length inequality is a major potential problem for young children. Treatment options include extensible prostheses, amputation, and rotationplasty for these children.



• Preoperative chemotherapy (either systemically or intra-arterially) followed by extirpative surgery (amputation, limb preservation, or rotationplasty).[10,20,34] After surgery, tumor necrosis is used to determine degree of response to the initial chemotherapy. If tumor necrosis exceeds a preset level (90%–95%), the preoperative chemotherapy regimen is continued; however, if necrosis is inferior, some groups have used alternative regimens that have not been examined in randomized studies.[5,35]



• Surgical resection of the primary tumor with adequate margins is an essential component of the curative strategy for patients with localized osteosarcoma. Reconstruction after surgery can be accomplished with many options, including metallic endoprosthesis, allograft, vascularized autologous bone graft, and rotationplasty. The choice of optimal surgical reconstruction involves many factors, including the site and size of the primary tumor, the ability to preserve the neurovascular supply of the distal extremity, the age of the patient and potential for additional growth, and the needs and desires of the patient and family for specific function, such as sports participation. Cure of the patient remains the primary objective. If a complicated reconstruction delays or prohibits the resumption of needed systemic chemotherapy, limb preservation may endanger the chance for cure. For some patients, amputation remains the optimal choice for management of the primary tumor.



• For lesions that cannot be removed, some data from retrospective nonrandomized studies suggest that high-dose radiation therapy may improve local control, especially when there is only microscopic or minimal residual disease.[32,33] Clinical studies are now being conducted using a phase II/III approach or using intensive combination chemotherapy and high-dose, very well-collimated and localized radiation.

For patients with malignant fibrous histiocytoma (MFH) of bone, wide local excision is recommended regardless of tumor grade. Most patients with MFH will need preoperative chemotherapy to achieve a wide local excision.[36]

Patients who develop osteosarcoma following radiation therapy should receive chemotherapy and undergo surgical resection. Outcome for patients with radiation-induced osteosarcoma who receive chemotherapy is similar to that of patients with conventional high-grade osteosarcoma.[37] Patients with Rothmund-Thomson syndrome, and RECQL4 gene mutations, who develop osteosarcoma tend to be younger than patients with conventional osteosarcoma, however, the clinical behavior is similar and should be treated in the same manner.[38]

The COG, in collaboration with several European groups, has opened a trial in which all patients receive preoperative therapy with doxorubicin, cisplatin, and high-dose methotrexate. Patients are then divided into the following two strata on the basis of histologic necrosis in the resected primary tumor:

• Favorable histologic response (<10% viable tumor): All patients receive postoperative therapy with the same drugs as those given preoperatively. Patients will be randomly assigned to receive additional therapy with pegylated interferon-alpha-2b.[39]



• Standard histologic response (10%–100% viable tumor): Patients will be randomly assigned to receive postoperative chemotherapy with the same drugs as those given preoperatively plus or minus additional courses of ifosfamide/etoposide.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with localized osteosarcoma and localized childhood malignant fibrous histiocytoma of bone. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

1. Link MP, Goorin AM, Miser AW, et al.: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med 314 (25): 1600-6, 1986.  [PUBMED Abstract]
   
   
2. Hosalkar HS, Dormans JP: Limb sparing surgery for pediatric musculoskeletal tumors. Pediatr Blood Cancer 42 (4): 295-310, 2004.  [PUBMED Abstract]
   
   
3. Eilber F, Giuliano A, Eckardt J, et al.: Adjuvant chemotherapy for osteosarcoma: a randomized prospective trial. J Clin Oncol 5 (1): 21-6, 1987.  [PUBMED Abstract]
   
   
4. Shaheen M, Deheshi BM, Riad S, et al.: Prognosis of radiation-induced bone sarcoma is similar to primary osteosarcoma. Clin Orthop Relat Res 450: 76-81, 2006.  [PUBMED Abstract]
   
   
5. Bacci G, Ferrari S, Bertoni F, et al.: Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the istituto ortopedico rizzoli according to the istituto ortopedico rizzoli/osteosarcoma-2 protocol: an updated report. J Clin Oncol 18 (24): 4016-27, 2000.  [PUBMED Abstract]
   
   
6. Fuchs N, Bielack SS, Epler D, et al.: Long-term results of the co-operative German-Austrian-Swiss osteosarcoma study group's protocol COSS-86 of intensive multidrug chemotherapy and surgery for osteosarcoma of the limbs. Ann Oncol 9 (8): 893-9, 1998.  [PUBMED Abstract]
   
   
7. Meyer WH, Pratt CB, Poquette CA, et al.: Carboplatin/ifosfamide window therapy for osteosarcoma: results of the St Jude Children's Research Hospital OS-91 trial. J Clin Oncol 19 (1): 171-82, 2001.  [PUBMED Abstract]
   
   
8. Davis AM, Bell RS, Goodwin PJ: Prognostic factors in osteosarcoma: a critical review. J Clin Oncol 12 (2): 423-31, 1994.  [PUBMED Abstract]
   
   
9. Provisor AJ, Ettinger LJ, Nachman JB, et al.: Treatment of nonmetastatic osteosarcoma of the extremity with preoperative and postoperative chemotherapy: a report from the Children's Cancer Group. J Clin Oncol 15 (1): 76-84, 1997.  [PUBMED Abstract]
   
   
10. Bacci G, Picci P, Avella M, et al.: Effect of intra-arterial versus intravenous cisplatin in addition to systemic adriamycin and high-dose methotrexate on histologic tumor response of osteosarcoma of the extremities. J Chemother 4 (3): 189-95, 1992.  [PUBMED Abstract]
    
    
11. Cassano WF, Graham-Pole J, Dickson N: Etoposide, cyclophosphamide, cisplatin, and doxorubicin as neoadjuvant chemotherapy for osteosarcoma. Cancer 68 (9): 1899-902, 1991.  [PUBMED Abstract]
    
    
12. Voûte PA, Souhami RL, Nooij M, et al.: A phase II study of cisplatin, ifosfamide and doxorubicin in operable primary, axial skeletal and metastatic osteosarcoma. European Osteosarcoma Intergroup (EOI). Ann Oncol 10 (10): 1211-8, 1999.  [PUBMED Abstract]
    
    
13. Ferguson WS, Harris MB, Goorin AM, et al.: Presurgical window of carboplatin and surgery and multidrug chemotherapy for the treatment of newly diagnosed metastatic or unresectable osteosarcoma: Pediatric Oncology Group Trial. J Pediatr Hematol Oncol 23 (6): 340-8, 2001 Aug-Sep.  [PUBMED Abstract]
    
    
14. Ferrari S, Smeland S, Mercuri M, et al.: Neoadjuvant chemotherapy with high-dose Ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: a joint study by the Italian and Scandinavian Sarcoma Groups. J Clin Oncol 23 (34): 8845-52, 2005.  [PUBMED Abstract]
    
    
15. Zalupski MM, Rankin C, Ryan JR, et al.: Adjuvant therapy of osteosarcoma--A Phase II trial: Southwest Oncology Group study 9139. Cancer 100 (4): 818-25, 2004.  [PUBMED Abstract]
    
    
16. Meyers PA, Schwartz CL, Krailo M, et al.: Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate. J Clin Oncol 23 (9): 2004-11, 2005.  [PUBMED Abstract]
    
    
17. Souhami RL, Craft AW, Van der Eijken JW, et al.: Randomised trial of two regimens of chemotherapy in operable osteosarcoma: a study of the European Osteosarcoma Intergroup. Lancet 350 (9082): 911-7, 1997.  [PUBMED Abstract]
    
    
18. Eselgrim M, Grunert H, Kühne T, et al.: Dose intensity of chemotherapy for osteosarcoma and outcome in the Cooperative Osteosarcoma Study Group (COSS) trials. Pediatr Blood Cancer 47 (1): 42-50, 2006.  [PUBMED Abstract]
    
    
19. Grimer RJ: Surgical options for children with osteosarcoma. Lancet Oncol 6 (2): 85-92, 2005.  [PUBMED Abstract]
    
    
20. Hillmann A, Hoffmann C, Gosheger G, et al.: Malignant tumor of the distal part of the femur or the proximal part of the tibia: endoprosthetic replacement or rotationplasty. Functional outcome and quality-of-life measurements. J Bone Joint Surg Am 81 (4): 462-8, 1999.  [PUBMED Abstract]
    
    
21. Bacci G, Ferrari S, Lari S, et al.: Osteosarcoma of the limb. Amputation or limb salvage in patients treated by neoadjuvant chemotherapy. J Bone Joint Surg Br 84 (1): 88-92, 2002.  [PUBMED Abstract]
    
    
22. Goorin AM, Schwartzentruber DJ, Devidas M, et al.: Presurgical chemotherapy compared with immediate surgery and adjuvant chemotherapy for nonmetastatic osteosarcoma: Pediatric Oncology Group Study POG-8651. J Clin Oncol 21 (8): 1574-80, 2003.  [PUBMED Abstract]
    
    
23. Scully SP, Ghert MA, Zurakowski D, et al.: Pathologic fracture in osteosarcoma : prognostic importance and treatment implications. J Bone Joint Surg Am 84-A (1): 49-57, 2002.  [PUBMED Abstract]
    
    
24. Bacci G, Ferrari S, Longhi A, et al.: Nonmetastatic osteosarcoma of the extremity with pathologic fracture at presentation: local and systemic control by amputation or limb salvage after preoperative chemotherapy. Acta Orthop Scand 74 (4): 449-54, 2003.  [PUBMED Abstract]
    
    
25. Bramer JA, Abudu AA, Grimer RJ, et al.: Do pathological fractures influence survival and local recurrence rate in bony sarcomas? Eur J Cancer 43 (13): 1944-51, 2007.  [PUBMED Abstract]
    
    
26. Grimer RJ, Taminiau AM, Cannon SR, et al.: Surgical outcomes in osteosarcoma. J Bone Joint Surg Br 84 (3): 395-400, 2002.  [PUBMED Abstract]
    
    
27. Weeden S, Grimer RJ, Cannon SR, et al.: The effect of local recurrence on survival in resected osteosarcoma. Eur J Cancer 37 (1): 39-46, 2001.  [PUBMED Abstract]
    
    
28. Meyers PA, Gorlick R, Heller G, et al.: Intensification of preoperative chemotherapy for osteogenic sarcoma: results of the Memorial Sloan-Kettering (T12) protocol. J Clin Oncol 16 (7): 2452-8, 1998.  [PUBMED Abstract]
    
    
29. Lewis IJ, Nooij MA, Whelan J, et al.: Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy: a randomized phase III trial of the European Osteosarcoma Intergroup. J Natl Cancer Inst 99 (2): 112-28, 2007.  [PUBMED Abstract]
    
    
30. Bacci G, Forni C, Ferrari S, et al.: Neoadjuvant chemotherapy for osteosarcoma of the extremity: intensification of preoperative treatment does not increase the rate of good histologic response to the primary tumor or improve the final outcome. J Pediatr Hematol Oncol 25 (11): 845-53, 2003.  [PUBMED Abstract]
    
    
31. Nagarajan R, Neglia JP, Clohisy DR, et al.: Limb salvage and amputation in survivors of pediatric lower-extremity bone tumors: what are the long-term implications? J Clin Oncol 20 (22): 4493-501, 2002.  [PUBMED Abstract]
    
    
32. Ozaki T, Flege S, Kevric M, et al.: Osteosarcoma of the pelvis: experience of the Cooperative Osteosarcoma Study Group. J Clin Oncol 21 (2): 334-41, 2003.  [PUBMED Abstract]
    
    
33. DeLaney TF, Park L, Goldberg SI, et al.: Radiotherapy for local control of osteosarcoma. Int J Radiat Oncol Biol Phys 61 (2): 492-8, 2005.  [PUBMED Abstract]
    
    
34. Wilkins RM, Cullen JW, Camozzi AB, et al.: Improved survival in primary nonmetastatic pediatric osteosarcoma of the extremity. Clin Orthop Relat Res 438: 128-36, 2005.  [PUBMED Abstract]
    
    
35. Meyers PA, Heller G, Healey J, et al.: Chemotherapy for nonmetastatic osteogenic sarcoma: the Memorial Sloan-Kettering experience. J Clin Oncol 10 (1): 5-15, 1992.  [PUBMED Abstract]
    
    
36. Daw NC, Billups CA, Pappo AS, et al.: Malignant fibrous histiocytoma and other fibrohistiocytic tumors in pediatric patients: the St. Jude Children's Research Hospital experience. Cancer 97 (11): 2839-47, 2003.  [PUBMED Abstract]
    
    
37. Bacci G, Longhi A, Forni C, et al.: Neoadjuvant chemotherapy for radioinduced osteosarcoma of the extremity: The Rizzoli experience in 20 cases. Int J Radiat Oncol Biol Phys 67 (2): 505-11, 2007.  [PUBMED Abstract]
    
    
38. Hicks MJ, Roth JR, Kozinetz CA, et al.: Clinicopathologic features of osteosarcoma in patients with Rothmund-Thomson syndrome. J Clin Oncol 25 (4): 370-5, 2007.  [PUBMED Abstract]
    
    
39. Müller CR, Smeland S, Bauer HC, et al.: Interferon-alpha as the only adjuvant treatment in high-grade osteosarcoma: long term results of the Karolinska Hospital series. Acta Oncol 44 (5): 475-80, 2005.  [PUBMED Abstract]
    
    

Back to Top

< Previous Section  |  Next Section >