Osteosarcoma:-DIAGNOSIS AND TREATMENTpptx

Osteosarcoma is a primary malignant bone tumor, most common in adolescents and young adults. Its treatment requires a multimodal approach involving surgery, chemotherapy, and, in select cases, radiotherapy. Here is a concise overview of its management:

1. Diagnosis and Staging
Imaging: X-rays, MRI (local extent), CT chest (metastasis), and bone scan/PET-CT.
Biopsy: Core needle biopsy confirms diagnosis.
Staging: Enneking staging and AJCC TNM classification are used to determine disease extent.
2. Treatment Approach
A. Neoadjuvant Chemotherapy
Purpose: Shrink tumor size, address micrometastases, and facilitate limb-sparing surgery.
Regimen:
High-dose Methotrexate
Doxorubicin
Cisplatin
Optional: Ifosfamide (for resistant cases).
B. Surgery
Goal: Achieve wide margins for local tumor control.
Options:
Limb-Sparing Surgery (preferred when possible): Removes tumor with reconstruction (prosthesis or bone graft).
Amputation: Reserved for extensive local disease, neurovascular involvement, or infection risk.
C. Adjuvant Chemotherapy
Post-surgery, chemotherapy continues to eradicate residual microscopic disease.
Standard regimens include the same agents as neoadjuvant therapy (MAP: Methotrexate, Adriamycin/Doxorubicin, and Cisplatin).
3. Role of Radiotherapy
Indications:
Unresectable tumors.
Poor surgical candidates.
Palliation of metastases (e.g., lung, bones).
Radiotherapy is less effective in osteosarcoma due to its relative radioresistance but can still provide local control.
4. Metastatic Disease
Lungs: Pulmonary metastasectomy (surgical removal of lung nodules) improves survival when feasible.
Systemic Therapy: Chemotherapy continues for widespread metastases.
5. Prognosis and Follow-up
Prognostic Factors:
Response to chemotherapy (<90% necrosis is poor prognosis).
Stage at diagnosis.
Tumor size and location.
Surveillance: Regular imaging (MRI, CT chest) every 3-6 months for 2-3 years, then annually.
6. Emerging Therapies
Targeted Therapy: Investigating drugs targeting pathways like mTOR and VEGF.
Immunotherapy: Role of immune checkpoint inhibitors is being explored.
Bone-seeking agents: Trials with bisphosphonates or radionuclides are ongoing.
Summary
The standard treatment for osteosarcoma involves neoadjuvant chemotherapy, followed by surgery (preferably limb-sparing), and adjuvant chemotherapy. Multidisciplinary care is essential for optimizing outcomes. Advances in targeted therapy and immunotherapy hold promise for refractory or metastatic disease.

1. OSTEOSARCOMA DR SUMIT KUMAR Assistant professor I ECMO NEIGRIHMS, Shillong

2. INTRODUCTION Osteosarcoma is a highly malignant bone cancer, most common in adolescents and young adults aged 15-25. It is the most frequent primary malignant bone tumor, with an incidence of 1–5 cases per million. The tumor is aggressive, with early metastasis, especially to the lungs and bones. Males are more commonly affected, but both genders can be diagnosed. Prognosis varies; some studies suggest better outcomes in adolescents, while others favour younger children.

3. Extremity osteosarcomas have a better prognosis than axial ones. Treatment includes surgery, chemotherapy, and sometimes radiation, with a 60% 5-year survival rate. Many patients still face fatal outcomes due to metastasis or recurrence. Key prognostic factors include tumor size, metastasis, and chemotherapy response. Identifying low-cost, accessible markers is crucial for improving survival through early intervention INTRODUCTION

4. Epidemiology

5. Risk Factors

6. Pathogenesis Origin : Osteosarcoma likely arises from bone-forming stem or progenitor cells in the skeleton. Molecular Alterations : Tumors exhibit complex karyotypes due to chromothripsis , leading to chromosomal rearrangements and amplifications/deletions. Key Genetic Regions : Deletions in 3q, 13q (RB gene), 17p (TP53 gene), and 18q (Paget disease) are common. Pathway Inactivation : Combined inactivation of RB and TP53 pathways frequently occurs.

7. Pathogenesis Genetic Amplifications : MYC (8q) amplification occurs in 50% of cases, associated with poor prognosis, and alterations in FGFR1 and IGF1R pathways are observed. Other Genetic Alterations : IDH1 and IDH2) for conventional ς h ο ո ԁ r ο ѕа r со m а; MDM2 in parosteal and low-grade central ο ѕ t е ο ѕа r с ο m а; DLG2, ATRX, CDK4, and VEGFR and involvement of Wnt /Notch/IGF pathways contribute to pathogenesis. Rapid Bone Growth : The disease peaks during the adolescent growth spurt, especially in rapidly growing bones like the femur, tibia, and humerus.

8. Histology Histology Main Points Prognosis Conventional osteosarcoma Most common (90%), arises in the metaphysis of long bones, with subtypes like osteoblastic, chondroblastic , and fibroblastic. Moderate prognosis, depending on subtype. Osteoblastic osteosarcoma Abundant osteoid production with woven bone matrix, variable mineralization. Moderate prognosis. Fibroblastic osteosarcoma High-grade spindle cell stroma with focal bone production, often resembling high-grade sarcoma. Moderate to poor prognosis. Chondroblastic osteosarcoma Cartilage matrix production, lower grade but can contain atypical cells. Moderate prognosis. Telangiectatic osteosarcoma High-grade vascular tumor with minimal osteoid, can be confused with aneurysmal bone cysts or giant cell tumors . Better prognosis than conventional osteosarcoma. Small cell osteosarcoma Small cells with scant cytoplasm and round nuclei, osteoid production, can resemble Ewing sarcoma. Poor prognosis, requires differentiation from Ewing's sarcoma. Osteosarcoma NOS Includes conventional, telangiectatic, and small cell osteosarcoma, with similar treatment and age distribution. Varies by subtype.

9. Parosteal osteosarcoma Surface lesion, low-grade fibroblastic cells, affects older age group (20-40 years). Good prognosis with surgery alone (~90% survival). Dedifferentiated parosteal osteosarcoma High-grade sarcoma component with parosteal osteosarcoma. Poor prognosis, requires surgery and chemotherapy. Periosteal osteosarcoma Intermediate-grade chondroblastic surface osteosarcoma, usually in proximal tibia. Better prognosis than conventional osteosarcoma (~84% 10-year survival). High-grade surface osteosarcoma High-grade, may be confused with parosteal or periosteal osteosarcoma, treated like conventional osteosarcoma. Poor prognosis, similar to conventional osteosarcoma. Secondary osteosarcoma Develops after radiation or chemotherapy, or in conditions like Paget's disease. Worse prognosis than conventional osteosarcoma. Multifocal osteosarcoma Rare, multiple synchronous or metachronous lesions, challenging to distinguish from metastases. Poor prognosis, though some patients may achieve life prolongation. Craniofacial osteosarcoma Occurs in older patients, more likely to have local recurrence, often involves mandible and maxilla. Moderate to poor prognosis, surgery is primary treatment. Low-grade central osteosarcoma Slow-growing, occurs in young adults, low mitotic activity, can progress to high-grade sarcoma. Good prognosis with surgical resection (~90% survival). Histology

10. Clinical feature Category Details Primary vs. Secondary - Primary : Most common in children, adolescents, and AYAs; sporadic. - Secondary : Seen in adults, linked to Paget's disease, radiation, or chemotherapy. Tumor Location - Children : Metaphyses of long bones. Common sites: Distal femur (32%), Proximal tibia (19%), Proximal humerus (10%), Middle/proximal femur (10%). - Adults : Axial and craniofacial bones; areas previously treated with radiation or with bone abnormalities. Distant Metastases - Present in 10–20% of patients at diagnosis. - Lungs are the most common site, followed by bones. - Skip metastases : Found in 1–6% of patients, can worsen prognosis. Symptoms - Localized pain : Common at the primary tumor site, lasting weeks. - Pain may be triggered by an injury or pathologic fractures (in 12% of cases). - Systemic symptoms (fever, weight loss) are generally absent. Physical Exam - Soft tissue mass : Large, tender, increased vascularity of the skin. - Decreased range of motion or limp in lower extremity tumors . - Pelvic tumors : More difficult to detect. - Regional lymphadenopathy may be presen

11. Diagnostic Evaluation Modality Purpose Key Features Plain Radiograph Initial imaging test for suspected osteosarcoma Destruction of normal bone trabeculae, indistinct margins, Codman triangle, sunburst periosteal pattern. MRI (Magnetic Resonance Imaging) Detailed imaging for soft tissue, marrow, joint involvement, and skip metastases T1 coronal sequence for tumor extent; with contrast to identify hypervascular and necrotic regions. Laboratory Tests Supportive evaluation Alkaline phosphatase and lactate dehydrogenase may be elevated; not routinely used for management. Diagnostic Biopsy Definitive diagnosis through tissue sampling Core needle or open biopsy, ideally performed at specialized centers for accurate sampling.

12. Differential Diagnosis Category Conditions Key Distinctions Other Malignant Bone Tumors Ewing sarcoma, Lymphoma, Metastatic bone tumors Ewing sarcoma often affects diaphysis; lymphoma shows diffuse bone destruction. Benign Bone Tumors Aneurysmal bone cyst, Chondroblastoma Osteoblastoma, Giant cell tumor of bone Radiolucent areas; aneurysmal bone cysts resemble telangiectatic osteosarcoma. Nonneoplastic Conditions Osteomyelitis, Chronic nonbacterial osteomyelitis, Langerhans cell histiocytosis Non-malignant lytic bone lesions with systemic signs like fever (osteomyelitis) or unique markers (LCH).

13. Post-Diagnostic Evaluation Step Purpose Details Primary Tumor Staging Assess tumor extent, surgical planning MRI of primary tumor (if not done earlier) for detailed evaluation. Systemic Disease Evaluation Identify metastases and guide prognosis Chest CT (preferred for lungs), PET-CT or bone scan for extrapulmonary metastases, whole-body MRI as alternative. Histological Confirmation Confirm suspected metastatic lesions Lung metastases: Video-assisted thoracoscopy or open thoracotomy for tissue biopsy.

14. STAGING

15. Management: ESMO

16. Management: NCCN

17. Management: NCCN

18. Management: NCCN

19. Management: NCCN

20. Management: Option

21. Surgical Treatment for Osteosarcoma : Primary Approach : Surgery plays a critical role in the management of osteosarcoma, aiming to remove the tumor completely and preserve function. Limb Salvage Surgery: Eligibility : 70-80% of patients with non-metastatic osteosarcoma are eligible. Indication : High-grade tumors with good response to NACT . Achievable wide surgical margins . Favorable anatomical location (e.g., distal femur, proximal tibia). Outcome : Similar survival rates to amputation, with better functional outcomes . Amputation: Eligibility : 20-30% of patients require amputation. Indication : Unfavorable tumor location or poor NACT response . Inadequate surgical margins after attempted limb-sparing. Outcome : Good survival, but loss of limb function.

22. Study Characteristics Retrospective cohort study 63 patients with high-grade, non-metastatic distal tibia osteosarcoma (32 in limb salvage, 31 in amputation group) Survival Data Overall Survival Rate : 88% (56 out of 63) Median Overall Survival : Similar between groups Functional Outcomes Limb Salvage Surgery : 85% had good functional outcomes Amputation : 61% had good functional outcomes Quality of Life Limb Salvage Surgery : 80% had higher quality of life Amputation : 58% had higher quality of life Complications Limb Salvage Surgery : 15% with complications (e.g., infection, non-union) Amputation : 29% with complications (e.g., stump infection, prosthetic issues) LIMB Sparing Surgery vs. Amputation for Distal Tibia Osteosarcoma : Conclusion :-- Limb salvage surgery offers similar survival with better functional outcomes and quality of life compared to amputation

23. Chemotherapy in Osteosarcoma Historically, >80% of osteosarcoma patients treated with surgery alone developed metastatic disease, highlighting the need for systemic chemotherapy. Adjuvant chemotherapy is a standard of care, significantly improving survival compared to surgery alone. Neoadjuvant chemotherapy is often preferred for limb-sparing procedures, though no survival advantage over adjuvant chemotherapy is proven. The standard regimen is MAP (Methotrexate, Doxorubicin, Cisplatin), with 10 weeks preoperatively and 29 weeks postoperatively. Response to neoadjuvant chemotherapy is a key prognostic factor but does not alter postoperative therapy. For patients over 40, a simplified regimen of Doxorubicin + Cisplatin is commonly used.

24. Neoadjuvant Chemotherapy Initial trials in the 1970s improved 5-year survival rates from <20% to 40-60% with adjuvant chemotherapy. Neoadjuvant chemotherapy evolved with limb-sparing surgery, facilitating prosthesis fabrication and reducing tumor size for better resectability . Functions as an in vivo drug trial to assess tumor sensitivity and customize postoperative therapy. Tumor necrosis >90% (good response) correlates with improved survival (71-80% vs. 45-60% for poor responders).

25. Enables evaluation of chemotherapy efficacy to determine tumor response before surgery. Can eliminate micrometastases , improving long-term survival outcomes. Subtypes show varying response rates: Fibroblastic: 83% (good response), 5-year survival: 83%. Telangiectatic: 80%, survival: 75%. Osteoblastic: 58%, survival: 62%. Chondroblastic : 43%, survival: 60%. Neoadjuvant Chemotherapy Histologic response remains a critical prognostic factor, though less predictive in chondroblastic subtypes

26. Changing Systemic Therapy After Neoadjuvant Chemotherapy Patients with less than 10% viable tumor cells after neoadjuvant therapy benefit from continuing the same regimen post-surgery. Outcomes are worse for patients with 10% or more viable tumor cells. The T10 protocol showed initial benefits of changing chemotherapy but failed in long-term follow-up. The EURAMOS-1 trial found no survival benefit in switching to ifosfamide and etoposide for poor responders. Postoperative chemotherapy improves outcomes even for poor responders compared to no chemotherapy. Routine changes to postoperative regimens based on histologic response are not recommended.

27. Neoadjuvant vs. Adjuvant Chemotherapy The POG 8651 trial showed similar five-year survival rates for neoadjuvant and adjuvant chemotherapy (65% vs. 61%). Limb-salvage rates were also comparable (55% vs. 50%). Proper patient selection is critical; poor surgical decisions can harm outcomes. Neoadjuvant therapy supports surgery but cannot replace sound surgical principles. Neoadjuvant chemotherapy increases limb-salvage eligibility but reflects surgical advances more than chemotherapy benefits

28. Study Aspect Details Study Overview UCLA prospective trial (1981–1984), comparing Adj. CT vs. obs. in 59 patients with high-grade, localized osteosarcoma. Key Outcomes - DFS : 28% (CT) vs. 15% (obs.), - OS : 38% (CT) vs. 15% (obs.), Predictive Marker Tumor necrosis >90% after one chemotherapy cycle significantly predicted better OS (164 mths vs. 65 mths ,) and DFS (141 mths vs. 14 mths ,). Bernthal NM, Federman N, Eilber FR, Nelson SD, Eckardt JJ, Eilber FC, Tap WD. Long-term results (>25 years) of a randomized, prospective clinical trial evaluating chemotherapy in patients with high-grade, operable osteosarcoma. Cancer. 2012 Dec Adjuvant Chemotherapy Conclusion :- Adj. CT improved long-term survival, with tumor necrosis being a key predictor of outcomes.

29. Study Overview A 10-year experience (1973–1983) with 208 patients treated with preoperative chemotherapy for osteogenic sarcoma of the extremity. Treatment Protocols Four successive chemotherapy protocols were used, with refinements based on tumor response. Disease-Free Survival - Minimum follow-up : 36 months for 87 patients on the T-10 protocol. - 87 patients (T-10 protocol) : 67 (77%) remained disease-free. - Overall group (208 patients) : 150 (72%) remained disease-free. Complete Response Rate 49% CRR of the primary tumor to preoperative chemotherapy. Relapse Rates Relapses occurred in 19 patients with tumors near the knee due to local recurrences after en bloc resection. Amputation Outcome 58 patients had amputation, with 46 (79.3%) remaining disease-free. Proximal Humerus Resection Outcome 25 patients had humeral resections, with 23 (92%) remaining disease-free and no local recurrences. Rosen G. Preoperative (neoadjuvant) chemotherapy for osteogenic sarcoma: a ten year experience. Orthopedics . 1985 May ; NeoAdjuvant Chemotherapy Conclusion :---- Neo Adj. CT improved survival rates, CT regimens, and helped select the best postoperative therapy.

30. Objective Assess impact of preoperative chemotherapy response on postoperative treatment. Methods 57 patients received NACT (HDMTX, Adriamycin, BCD). Response determined postoperative regimen. Histologic Response >90% tumor necrosis: regimen B; poor response: regimen A. Regimens Regimen A: Cisplatinum , Adriamycin, BCD; Regimen B : continued HDMTX, Adriamycin, BCD. Results 93% DFS(6-35 months). 91% (regimen A), 95% (regimen B) remained disease-free. Rosen G, Caparros B, Huvos AG, Kosloff C, Nirenberg A, Cacavio A, Marcove RC, Lane JM, Mehta B, Urban C. Preoperative chemotherapy for osteogenic sarcoma: selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy. Cancer. 1982 Mar NeoAdjuvant Chemotherapy Conclusion :-- Histologic response predicts survival; tailored postoperative regimens improve outcomes.

31. Duration 75 months (Commenced March 2005) Participants 2260 patients from 326 centers across 17 countries Randomization 59% (1334 patients) Pre-operative Chemotherapy Completed by 94% of patients Complications - Grade 3–4 neutropenia: 83% of cycles - Infections: 59% of cycles Mortality from Chemotherapy 0.13% (3 deaths) Surgical Outcomes 50% of patients had ≥90% tumor necrosis Conclusion Large-scale trials are feasible but require overcoming significant barriers

32. Study Design Open-label, international, phase 3 randomised controlled trial Eligibility Criteria Patients aged ≤40 years with newly diagnosed, resectable, high-grade osteosarcoma Randomisation 1:1 to either MAP or MAPIE Primary Outcome EFS (intention-to-treat population)

33. Category MAP MAPIE Median Follow-Up 62.3 months 61.1 months Event-Free Survival Events 153 154 Deaths 101 92 Grade 3–4 Neutropenia 89% 90% Thrombocytopenia 78% 83% Febrile Neutropenia 50% 73% Non- Hematological Toxicity 12% 24% Outcome Details Treatment-Related Deaths 1 in MAP (infection), 1 in MAPIE (cardiac dysfunction) Serious Adverse Reaction 1 case of bone marrow infarction (MAP, methotrexate-related) Interpretation:-- Adding ifosfamide and etoposide (MAPIE) increased toxicity without improving event-free survival. MAP remains the standard of care for poorly responding osteosarcoma.

34. Study Design Randomized clinical trial (1986–1993) by Pediatric Oncology Group (POG) trial 8651 Population 100 patients under 30 years with nonmetastatic high-grade osteosarcoma Comparison Immediate surgery + postoperative chemotherapy vs. 10 weeks neoadjuvant chemotherapy + surgery Chemotherapy Regimen HDMTX with leucovorin rescue, cisplatin, doxorubicin, bleomycin, cyclophosphamide, and dactinomycin (BCD) Survival Benefit Both presurgical and postsurgical chemotherapy similarly improved survival. Limb-Sparing Surgery Increased with neoadjuvant chemotherapy but also attributed to advancements in surgical techniques and expertise. Concerns Neoadjuvant chemotherapy does not replace sound surgical principles; inappropriate selection may harm patients.

35. Issue Details Low Limb-Sparing Surgery Rates By modern standards, both groups had low rates of limb-salvage surgery. Use of BCD Regimen Contribution to efficacy unclear; associated with long-term bleomycin-related pulmonary toxicity. Outcome Immediate Surgery (Adjuvant) Neoadjuvant Chemotherapy Five-Year Relapse-Free Survival 65% 61% Limb-Salvage Rate 55% 50% Conclusion:-- Neoadjuvant chemotherapy improves the feasibility of limb-salvage surgery and serves as an established approach for osteosarcoma management. However, careful surgical decision-making remains crucial.

36. Background - L-MTP-PE (Liposomal Muramyl Tripeptide Phosphatidylethanolamine) improves overall survival in non-metastatic osteosarcoma (OS) . - This study evaluates L-MTP-PE addition to chemotherapy for patients with metastatic OS . Methods - Trial Name : Intergroup-0133 (INT-0133) - Design : Prospective, randomized, phase III trial. - Population : Newly diagnosed patients with OS. - Chemotherapy Regimens : - Regimen A : Cisplatin + Doxorubicin + High-dose Methotrexate. - Regimen B : Regimen A + Ifosfamide . - Intervention : Addition of L-MTP-PE to chemotherapy. - Outcomes Evaluated : - 5-year Event-Free Survival (EFS). - 5-year Overall Survival (OS).

37. Results 1. L-MTP-PE Addition : - 5-year EFS : - L-MTP-PE: 42% (n=46). - No L-MTP-PE: 26% (n=45). - Relative Risk (RR): 0.72, p=0.23 , 95% CI: 0.42–1.2. - 5-year Overall Survival : - L-MTP-PE: 53%. - No L-MTP-PE: 40%. - Relative Risk (RR): 0.72, p=0.27 , 95% CI: 0.40–1.3. 2. Regimen A vs. Regimen B : - 5-year EFS : - Regimen A: 35%. - Regimen B: 34%. - Relative Risk (RR): 1.07, p=0.79 , 95% CI: 0.62–1.8. - 5-year Overall Survival : - Regimen A: 52%. - Regimen B: 43%. - Relative Risk (RR): 1.1, p=0.75 , 95% CI: 0.61–2.0. Conclusions - In metastatic osteosarcoma patients, the addition of L-MTP-PE to chemotherapy did not achieve statistical significance for improved outcomes. - However, the outcome trends with L-MTP-PE in metastatic OS patients are similar to those observed in non-metastatic OS patients.

38. Role of High-Dose Methotrexate in Osteosarcoma Phase II Trials : Most trials showing benefit for HDMTX are phase II and conducted primarily in children, with patients up to 40 years included. Randomized Trials : Studies comparing HDMTX + doxorubicin/cisplatin vs. doxorubicin/cisplatin alone showed no survival advantage for the three-drug regimen. Higher vs. Intermediate Doses : A trial comparing higher vs. intermediate doses of methotrexate showed no survival benefit for higher doses. Supporting Evidence : Some phase II trials showed better outcomes with high-dose methotrexate in multi-agent regimens. Correlation between peak serum levels of methotrexate and tumor response has been observed. Systematic Review : Multi-drug regimens (including MAP) significantly improved EFS and OS over two-drug regimens, though most trials included were not randomized. Conclusion:--- HDMTX shows potential benefits in osteosarcoma treatment, especially in multi-agent regimens, but its role remains unclear due to mixed trial results. Further research is needed.

39. Chemotherapy in Adults with Osteosarcoma Treatment in Adults : Intensive chemotherapy and resection are essential in adults, as osteosarcoma is potentially curable. A poor response to neoadjuvant chemotherapy is a bad prognosis indicator. Chemotherapy Regimen : Standard Regimen : Doxorubicin + cisplatin for fit adults. Older Adults : High-dose methotrexate (HDMTX) may be included if tolerated. Monitoring : Close monitoring of renal function is essential to minimize toxicity, especially in older adults. Prognosis : Adults generally have worse outcomes than children. Based on SEER data (1973-2004): Age 0-24 : 62% 5-year survival Age 25-59 : 59% 5-year survival Age 60+ : 24% 5-year survival, with even worse rates in older age groups (50s: 50%, 60s: 17%, 80s: 11%).

40. Role of Radiation in Osteosarcoma Primary Osteosarcoma : Typically resistant to radiation. Surgery is preferred for local control. Indications Non-Surgical Candidates : Radiation may be used when surgery is not possible, especially for tumors that respond to chemotherapy. Axial Tumors : In cases of tumors located in challenging areas (skull base, spine, sacrum), radiation can offer local control when surgery is not feasible. Adjuvant Radiation : Considered in cases of incomplete resection or unresectable tumors . Dose Primary RT for Extremity Tumors : Standard dose is 60-70 Gy . Axial Tumors : Proton beam or carbon ion therapy used for localized control, typically with doses of around 68-70 Gy . Adjuvant RT : Incomplete resections or high-risk cases may receive additional radiation after surgery . Results Extremity Tumors : Local control rates of 56% in non-surgical patients treated with RT (60 Gy ). Axial Tumors : Proton and carbon ion therapy show local control rates of 62-72%. Adjuvant RT : Does not improve survival if systemic chemotherapy and effective surgery are done. Increases secondary cancer risk .

41. Management of Resectable Metastases in Osteosarcoma Preoperative chemotherapy, wide excision of the primary tumor, metastasectomy , and Stereotactic Radiation Therapy (SRT) for non-resectable pulmonary metastases. Treatment & Dose : SRT : 36–54 Gy in 3–5 fractions. Results : Study 1 (UCLA): 4-year overall survival (OS) of 78% for 16 patients with lung metastases. Study 2 : Local control of 94% at 12 months, 86% at 24 months, with OS of 76% at 12 months, 43% at 24 months. Conclusion : SRT is a promising alternative to surgery for pulmonary metastases in osteosarcoma.

42. 27 metastatic lesions (21 osseous, 6 pulmonary) in 14 patients with osteosarcoma (19) or Ewing sarcoma (8). Treated with curative or palliative intent. Dose : Curative : 40 Gy (range 30–60 Gy ), 3–10 fractions. Palliative : 40 Gy (range 16–50 Gy ), 1–10 fractions. Osseous Lesions : CTV =GTV) by 1 cm within the bone. If the tumor extended into soft tissue, expansion into the surrounding soft tissue by 5 mm was performed to account for possible microscopic disease. No extraosseous expansion was applied if there was no soft tissue extension. Pulmonary Lesions : 4D CT simulation CTV was not defined separately; ITV) was delineated, PTV was created by expanding the ITV by 5 mm Results : Curative : 85% 2-year local control. One failure after 30 Gy in 3 fractions. Palliative : Pain improvement despite progression in some cases. Conclusion : SBRT shows high local control for curative intent and effective pain relief for palliative care

43. Number of Studies : 14 studies included in the review. Number of Patients : 640 patients. Acute Toxicity (Grade ≥3) : Ranged from 0.0% to 12.2%, with 1.8% experiencing severe pneumonitis. Late Toxicity (Grade ≥2) : More common in patients who had prior thoracic surgery, chemotherapy, or boost irradiation. Overall Survival (OS) : No significant impact seen in comparative studies, though some individual studies indicated improved survival with WLI. Conclusion : Despite low severe toxicity, the impact of WLI on outcomes remains unclear, and new treatment strategies should be tested.

44. Management of Metastatic Osteosarcoma: Prognosis : Long-term survival: 10-50% with metastatic disease. Lung-only metastasis offers better survival (20-30% EFS), while bone metastasis has poorer prognosis. Treatment : Surgery : Essential for controlling macroscopic disease, especially for lung metastases. Chemotherapy : Regimen with HDMTX, doxorubicin, cisplatin, and ifosfamide . Radiotherapy (RT) : Used in some cases for local control.

45. Management of Metastatic Osteosarcoma Innovative Approaches : Therapeutic Window : Use of novel agents before standard chemotherapy improves outcomes. Induction Therapy : Ifosfamide and etoposide show a 59% overall response rate, especially in bone metastasis . Chemotherapy Response : Combination Therapy : Multi-agent regimens yield higher response rates. Surgical Considerations : Pulmonary metastases have better outcomes with aggressive surgery and chemotherapy. Bone metastasis requires aggressive treatment but with limited long-term survival Standard Regimen (MAP) : High-dose Methotrexate, Doxorubicin, Cisplatin (MAP) is first-line treatment, with lower response rates in metastatic cases. Alternative Options : Etoposide & Ifosfamide (with or without carboplatin), High-dose ifosfamide , Cyclophosphamide + etoposide, or gemcitabine-based regimens. Bone Metastases : Samarium-153 used for palliation in bone metastases but with bone marrow toxicity risk.

46. Treatment of Recurrent Osteosarcoma Prognosis After Recurrence : Salvage is possible with surgery and chemotherapy but survival is worse than initial treatment. Long-term survival higher for patients with longer relapse-free intervals. Five-year survival post-relapse: 35% for those with >2-year relapse-free interval vs. 14% for those with shorter intervals. Favorable Prognostic Factors : Fewer than two pulmonary nodules, unilateral involvement, no pleural disruption, and successful second surgical remission . Relapse Patterns : Pulmonary relapse is most common, but increasing adjuvant therapy may lead to distant bony relapses instead of pulmonary ones .

47. Therapeutic Approach : Resection : Initial treatment for late relapse (e.g., >1 year after treatment) with resectable pulmonary nodules. Multiple Relapses : Survival rates decrease with each recurrence, but surgical remission can prolong survival. Early Relapse : Poor prognosis, especially with nonpulmonary or unresectable lesions. Unresectable Disease : Incurable in most cases; consider clinical trials or palliative chemotherapy/radiotherapy. Pre-surgery Chemotherapy : May help make previously unresectable metastases resectable , especially in the lungs or rare bone metastases. Post-surgical Chemotherapy : Chemotherapy after resection of multiple lesions may delay recurrence but is unlikely to improve long-term survival rates. Treatment of Recurrent Osteosarcoma

48. Multitargeted Kinase Inhibitors in Osteosarcoma Treatment Agents : Regorafenib, Cabozantinib , Sorafenib, Lenvatinib (with Etoposide and Ifosfamide ). Mechanism : These tyrosine kinase inhibitors target VEGFR and other kinases. Activity : Limited efficacy in advanced osteosarcoma, with relatively short time to disease progression when used as subsequent therapy. Need for Further Research : More data are needed to assess their role in osteosarcoma treatment.

49. Objective Assess efficacy and safety of regorafenib in progressive metastatic osteosarcoma. Study Design Phase 2, double-blind, placebo-controlled, randomized (2:1). Participants 43 adults (≥10 years old), histologically confirmed osteosarcoma, progressive disease post 1–2 chemotherapy lines. Primary Endpoint Non-progression at 8 weeks. Treatment Groups Regorafenib (160 mg/day for 21 of 28 days) vs placebo + best supportive care. Metric Regorafenib Placebo Non-Progression (8 wks) 65% (17/26 patients) 0% PFS (months) Median 3.6 Median 1.7 Serious Adverse Events 24% (e.g., hypertension, fatigue) None Treatment-Related Deaths None None Conclusion Regorafenib delayed disease progression and showed manageable toxicity. Recommended for advanced disease and potential earlier use in high-risk relapse cases.

50. Purpose Evaluate regorafenib’s effect on progression-free survival (PFS) in metastatic osteosarcoma. Study Design Phase II, randomized (1:1), placebo-controlled, crossover allowed post-progression. Participants 42 patients, median age: 37 years (range: 18–76 years), ≥1 prior therapy line, ECOG 0-1. Key Outcomes PFS: 3.6 months (regorafenib) vs. 1.7 months (placebo); HR: 0.42, P = 0.017. Adverse Events Grade 3-4 Events: 64% in regorafenib group; 1 case of grade 4 colonic perforation. SARC024 Trial Summary: Regorafenib in Metastatic Osteosarcoma Conclusion :- Regorafenib significantly improved PFS; no new safety signals; recommended for relapsed cases.

51. Parameter SARC024 (Regorafenib) CABONE ( Cabozantinib ) Sorafenib Lenvatinib (ITCC-050) Purpose Evaluate regorafenib for progressive metastatic osteosarcoma. Assess cabozantinib in recurrent osteosarcoma. Investigate sorafenib in relapsed/unresectable osteosarcoma. Assess lenvatinib with etoposide/ifosfamide in relapsed osteosarcoma. Study Design Phase II, randomized, placebo-controlled. Phase II, single-arm. Phase II, single-arm. Phase I/II, nonrandomized. Participants 42 patients, ≥1 prior therapy line. 42 patients with recurrent measurable disease. 35 patients with relapsed/unresectable disease. 35 patients with relapsed/refractory osteosarcoma. Primary Endpoint PFS improvement. PFS and partial responses (PR). PFS at 4 months. PFS at 4 months, objective responses. Key Outcomes PFS: 3.6 months (regorafenib) vs. 1.7 months (placebo). PFS at 4 months: 71%; PR: 12%. PFS at 4 months: 46%. PFS at 4 months: 51%; PR: 9%. Adverse Events Grade 3-4 in 64% (e.g., hypertension, colonic perforation). - - - Conclusion Improved PFS; supports use in advanced cases. Demonstrates activity; supports use in recurrence. Promising activity; potential treatment option. Promising combination; further evaluation needed. Targeted Therapies in Osteosarcoma: Comparative Summary

52. Osteosarcoma :--Other Agents Limited activity observed with: mTOR inhibitors. Eribulin . Bisphosphonates. Checkpoint inhibitors (e.g., pembrolizumab). Bacille Calmette-Guerin (BCG) + interferon. Aerosolized GM-CSF. Anti-GD2 antibodies.

53. Purpose Evaluate Disease Control Rate (DCR) in recurrent osteosarcoma treated with dinutuximab and GM-CSF Study Design Phase 2, single-arm (AOST1421) 39 Patients with recurrent pulmonary osteosarcoma in complete surgical remission Treatment Up to 5 cycles of dinutuximab (70 mg/m²) with GM-CSF Primary Endpoint DCR (event-free at 12 months) Benchmark DCR 20% (historical) Dinutuximab Schedules 35 mg/m²/day for 2 days vs 17.5 mg/m²/day for 4 days Event-free at 12 months (DCR) 28.2% (11/39) Toxicity One death, ≥ Grade 3 events (pain, diarrhea, hypoxia, hypotension) Pharmacokinetics Similar across both schedules Conclusions :- Dinutuximab did not significantly improve DCR in recurrent osteosarcoma; other GD2-targeting strategies being explored

54. undifferentiated pleomorphic sarcoma (UPS), dedifferentiated liposarcoma (DDLPS), synovial sarcoma (SS) and leiomyosarcoma (LMS). The BS arm included 40 pts with osteosarcoma (OGS), Ewing sarcoma (ES) or dedifferentiated chondrosarcoma (CS) Study Type Phase 2, open-label, non-randomized Patients 86 patients with STS and BS Primary Endpoint Objective Response Rate (ORR) Treatment Pembrolizumab 200 mg IV every 3 weeks STS ORR 18% (UPS 40%, LPS 20%, SS 10%, LMS 0%) BS ORR 5% (OGS 5%, CS 20%, ES 0%) Adverse Events Fatigue, anemia, lymphopenia, immune-related events Conclusion Activity in UPS and LPS, ongoing expansion in these subtypes

55. The OS2006 trial was a phase 3 study evaluating whether adding zoledronate to chemotherapy improves event-free survival (EFS) in patients with high-grade osteosarcoma. It enrolled 318 patients aged 5 to 50 years across 40 French centers . The trial was stopped for futility after an interim analysis, as zoledronate did not improve EFS . Key Results: ---3-year EFS : 63.4% (control group) vs. 57.1% (zoledronate group) – no significant difference (HR 1.36, p=0.094). Zoledronate side effects : Higher rates of hypocalcaemia and hypophosphataemia . No difference in orthopaedic complications between groups. Conclusion:- The study does not recommend zoledronate for osteosarcoma. Further research is needed to understand why these results contradict preclinical data.

56. Summary Treatment Approach Surgical Management: Limb-salvage surgery preferred; amputation if needed. Chemotherapy: Neoadjuvant (MAP regimen: Methotrexate, Doxorubicin, Cisplatin) to shrink tumors . Adjuvant chemotherapy post-surgery to target micrometastasis . Radiotherapy: Limited role, for unresectable tumors or palliation. Prognosis & Follow-Up Prognosis based on tumor response, size, metastasis. Regular follow-up with imaging for recurrence/metastasis.