What is the standard multimodal treatment approach for osteosarcoma, including chemotherapy regimen, surgery, and radiotherapy?

Treatment of Osteosarcoma

High-grade osteosarcoma requires multimodal treatment with neoadjuvant chemotherapy (MAP regimen: methotrexate, doxorubicin, cisplatin), followed by wide surgical resection with negative margins, and then adjuvant chemotherapy—this approach increases 5-year survival from 10-20% with surgery alone to over 60%. 1

Chemotherapy Regimen

Neoadjuvant (Preoperative) Chemotherapy

• Administer MAP chemotherapy as the standard backbone: high-dose methotrexate with leucovorin rescue, doxorubicin, and cisplatin 1
• Typically give 2-3 cycles preoperatively over 8-12 weeks before surgical resection 1, 2
• Ifosfamide can be added to the regimen (creating a 4-drug protocol), though evidence for additional benefit over MAP alone remains debated 1
• Baseline testing is mandatory: renal function, cardiac function (echocardiogram/MUGA), and audiogram before initiating platinum-based therapy 1
• Sperm banking should be offered to males of reproductive age; fertility consultation for females 1

Adjuvant (Postoperative) Chemotherapy

• For good histologic responders (<10% viable tumor): continue the same preoperative MAP regimen for total treatment duration of 6-12 months 1
• For poor histologic responders (≥10% viable tumor): options include continuing MAP or switching to alternative agents (ifosfamide, etoposide), though switching has NOT been proven to improve outcomes in multiple trials including EURAMOS-1 1
• The addition of muramyl tripeptide (L-MTP-PE/mifamurtide) to postoperative chemotherapy showed statistically significant improvement in 10-year overall survival in one large randomized trial and is approved in Europe for patients <30 years with completely resected localized disease 1, 2

Surgical Management

Principles of Resection

• Wide surgical margins (Enneking definition) are mandatory: complete tumor removal including biopsy tract, surrounded by unviolated cuff of normal tissue 1, 3
• Narrower margins significantly increase local recurrence risk and reduce overall survival 1
• Limb salvage is appropriate for most patients (approximately 70% of cases) and is as safe as amputation when adequate margins are achieved 1, 4
• Pathological fracture does NOT automatically require amputation—neoadjuvant chemotherapy can allow fracture hematoma contraction in chemosensitive tumors, permitting subsequent limb-sparing resection 1

Timing and Re-assessment

• Repeat imaging with the same modalities used for initial staging after neoadjuvant chemotherapy to reassess resectability 1
• Histologic response evaluation in the resection specimen provides critical prognostic information: good response (>90% necrosis) predicts 5-year disease-free survival of 67% versus 10% at 45 months for poor responders 1, 4

Radiotherapy

Radiotherapy has a very limited role in extremity osteosarcoma and should be reserved for specific situations 1:

• Inoperable tumors or axial/craniofacial locations where radical surgery is not feasible 1
• Positive or uncertain surgical margins after resection—combined surgery and radiotherapy improves local control and overall survival compared to surgery alone in this setting 1
• Proton beam or combined photon/proton therapy can achieve effective local control for unresectable or incompletely resected disease 1, 5

Treatment by Disease Stage

Localized Disease

• Standard approach: neoadjuvant chemotherapy → surgery → adjuvant chemotherapy as detailed above 1
• Treatment should occur at specialized reference centers with multidisciplinary teams experienced in sarcoma management 1

Metastatic Disease (Primary)

• Same chemotherapy and surgical approach as localized disease, PLUS mandatory surgical removal of ALL metastatic deposits 1
• Bilateral exploratory thoracotomy with manual palpation of both lungs is recommended, as CT scans underestimate pulmonary metastases and may miss contralateral involvement 1
• Approximately 30% of primary metastatic patients and >40% achieving complete surgical remission become long-term survivors 1

Recurrent Disease

• Surgery is the primary treatment for recurrence—complete removal of all metastases must be attempted, as disease is otherwise almost universally fatal 1
• More than one-third of patients achieving second surgical remission survive >5 years 1
• Repeated thoracotomies are warranted even for multiple recurrences if lesions remain resectable 1
• Second-line chemotherapy role is poorly defined with no standard regimen; it provides only limited survival prolongation in inoperable cases 1

Special Variants

Low-Grade Osteosarcoma

• Low-grade central and parosteal osteosarcoma are treated by surgery ALONE—no chemotherapy indicated 1

Periosteal Osteosarcoma

• Intermediate-grade variant with unclear chemotherapy benefit—retrospective analyses show no survival advantage from chemotherapy 1
• Surgery remains the primary treatment 1

Craniofacial Osteosarcoma

• Treatment approach depends on grade: low-grade treated surgically, high-grade receives multimodal therapy 1

Critical Caveats

• Adverse prognostic factors include: detectable metastases at presentation, axial or proximal extremity location, large tumor size, elevated alkaline phosphatase or LDH, and older age 1, 3
• High-dose methotrexate requires meticulous adherence to protocol-specific recommendations due to significant toxicity risk 1
• Growth factor support should be used appropriately but does NOT improve survival when used for dose escalation or intensity 1
• Multimodal therapy carries risk of permanent cardiac, renal, auditory, and reproductive dysfunction, plus secondary malignancies—appropriate surveillance during follow-up is essential 1
• The EURAMOS-1 trial definitively showed that adding interferon-α-2b to MAP for good responders and adding ifosfamide/etoposide to MAP for poor responders both failed to improve outcomes 1