What is the purpose of Neoadjuvant Chemotherapy (NACT) in bone cancers?

Purpose of Neoadjuvant Chemotherapy (NACT) in Bone Cancers

Neoadjuvant chemotherapy is strongly recommended for high-grade osteosarcoma (category 1 evidence) to improve survival outcomes, facilitate limb-sparing surgery, and provide prognostic information through assessment of tumor response. 1

Primary Purposes of NACT in Bone Cancers

1. Improved Survival Outcomes

• NACT combined with surgery has dramatically improved survival rates in high-grade osteosarcomas
• The Multi-Institutional Osteosarcoma Study (MIOS) demonstrated that 6-year event-free survival was significantly higher with adjuvant chemotherapy compared to surgery alone (61% vs 11%) 1
• Modern protocols using NACT and surgery have improved survival rates to nearly 80% for patients with localized disease 2

2. Facilitation of Surgical Resection

• Reduces tumor size and extent, making surgical excision easier and less extensive 3
• Enables limb-sparing surgery in 90-95% of patients who would otherwise require amputation 2
• Creates a reactive zone around the tumor that facilitates surgical margins 1
• Allows for better functional outcomes compared to amputation 1

3. Assessment of Chemotherapy Response

• Provides critical prognostic information through histologic evaluation of tumor necrosis 1
• Good histologic response (>90% tumor necrosis) strongly correlates with improved survival 1
• The 5-year disease-free survival rates are significantly better in good responders: 67.9% vs 51.3% in poor responders (p<0.0001) 1
• The 5-year overall survival rates are 78.4% vs 63.7% for good vs poor responders (p<0.0001) 1
• Allows for potential modification of post-operative chemotherapy based on response 3

4. Treatment of Micrometastatic Disease

• Addresses subclinical metastases that are present but undetectable at diagnosis 4
• Prevents or delays development of distant metastases, particularly to the lungs 3

Treatment Approach Based on Bone Cancer Type

High-Grade Osteosarcoma

• NACT is standard of care (category 1 recommendation) 1
• Common regimens include combinations of:
  • Doxorubicin, cisplatin, and high-dose methotrexate (most frequently used) 1
  • May also include ifosfamide and etoposide 1
• After surgery, continue same chemotherapy if good response (<10% viable tumor) 1
• For poor responders (≥10% viable tumor), continuing with the same regimen or switching to a different regimen are both options, though studies show no clear benefit to changing regimens 1

Low-Grade Osteosarcoma

• NACT is not indicated; wide surgical excision alone is the standard treatment 1
• This includes low-grade intramedullary and surface osteosarcomas 1

Periosteal Osteosarcoma

• Evidence is mixed regarding benefit of NACT
• A systematic review of 291 patients found no statistically significant improvement in mortality with (neo)adjuvant chemotherapy 1
• Wide excision is the primary treatment, with chemotherapy considered if high-grade elements are found on pathology 1

Chondrosarcoma

• Generally chemoresistant; NACT is rarely used 3
• Surgical excision is the primary treatment 2

Important Considerations and Caveats

1. Response Assessment:

   • Histologic response to NACT is one of the strongest prognostic factors 1
   • Repeat imaging should be performed after NACT to reassess tumor resectability 1

2. Patient Selection:

   • Selected elderly patients may benefit from immediate surgery rather than NACT 1
   • Patients with metastatic disease at presentation have poorer outcomes with NACT compared to those with localized disease 1

3. Treatment Limitations:

   • Increasing doses of preoperative chemotherapy does not improve the rate of good histologic response or survival 5
   • Attempts to improve outcomes in poor responders by modifying adjuvant chemotherapy have been unsuccessful 1

4. Multidisciplinary Approach:

   • Treatment should be administered by experienced oncologists in reference institutions with appropriate infrastructure 1
   • Close monitoring for toxicity is essential, with appropriate supportive care 1

NACT has transformed the treatment landscape for bone cancers, particularly high-grade osteosarcoma, by improving survival, enabling limb preservation, and providing valuable prognostic information through assessment of tumor response.