بسم الله الرحمن الرحيم

1. بسم الله الرحمن الرحيم

2. NEW STANDARD OF NEOADJUVANT AND ADJUVANT CHEMOTHERAPY IN OSTEOGENIC SARCOMA

3. Sarcomas are cancers derived from primitive mesenchymal cells. They can originate from bone or soft tissue and vary in terms of biological behavior, response to different treatment modalities and prognosis. Untreated they run an aggressive course with local & also systemic disease progression.

4. Classification • Current histopathologic classification of bone neoplasms is based on the putative cell of origin. • Malignant tumors may arise from any cellular constituent present in bone. • osteogenic (osteosarcoma) • chondrogenic (chondrosarcoma)

5. Classification • hematopoietic (multiple myeloma, lymphoma) • vascular (angiosarcoma, hemangioendothelioma, leiomyosarcoma) • lipogenic (liposarcoma) • neurogenic (neurofibrosarcoma, chordoma) • and histiocytic and fibrohistiocytic (MFH, Ewing’s sarcoma) elements.

6. Osteosarcoma • Osteosarcomas occur in all age groups but have a bimodal age distribution; 75% occur in patients younger than age 20. • In adolescence, about half of them arise in the metaphysis around the knee, either in the distal femur or proximal tibia. These are the sites of greatest skeletal growth activity. • In persons over age 25, the incidence in flat bones and longbones is almost equal.

7. Pathogenesis • Unknown • Modal incidence correlates with rapid bone growth • Radiation exposure • Cancer survivors • Retinoblastoma

8. Major sites of origin of osteosarcomas. The numbers are approximate percentages.

9. Classification

10. Clinical Presentation • Painful mass arising from bone • Sudden #of the bone • Metastisize early in evolution • 20% clinically detectable mets at dx

11. Osteosarcoma • Grossly, osteosarcomas are bulky tumors that are gritty, gray-white, and often contain areas of hemorrhage and cystic degeneration. The formation of bone by the tumor cells is characteristic of osteosarcoma. Osteosarcoma of the upper end of the tibia. The tan-white tumor fills most of the medullary cavity of the metaphysis and proximal diaphysis. It has infiltrated through the cortex, lifted the periosteum, and formed soft tissue masses on both sides of the bone.

12. Osteosarcoma • Radiographs of the primary tumor usually show a large, destructive, mixed lytic and blastic mass. The tumor frequently breaks through the cortex and lifts the periosteum, resulting in reactive periosteal bone formation. The triangular shadow between the cortex and raised ends of periosteum is known radiographically as Codmantriangle and is characteristic, but not diagnostic of this tumor. Distal femoral osteosarcoma with prominent bone formation extending into the soft tissues. The periosteum, which has been lifted, has laid down a proximal triangular shell of reactive bone known as a Codman triangle (arrow).

13. Differential Diagnosis • Giant Cell Tumor • Aneursymal Bone Cyst • Ewings • Osteoblastoma • Metastasis • Lymphoma

14. The prognosis has improved greatly during the past decades with the use of multiagent chemotherapy, with the improvement of diagnostic technologies such as CT scans and MRI, and with a more aggressive surgical approach. 61 % event free survival at 6 years for adjuvant treated patients and 11 % event free survival at 6 years for patients treated with surgery alone.

15. Although the incidence of local recurrence is low, microscopic dissemination is likely to be present in 80% of patients at the time of diagnosis, leading to distant metastases, mostly in the lungs and bones, within the first 6–12 months.

16. Standard of Care • Surgical excision is the mainstay of treatment for patients with low-grade sarcomas. For high-grade tumors, multimodality therapy is indicated. • For high-grade sarcomas, preoperative multiagent chemotherapy (3 to 4 cycles) is followed by surgical extirpation of the primary tumor

17. Chemotherapy • Best protocol is subject of ongoing trials • Drugs • Doxorubicin • Cisplatin • Ifosfamide • Methotrexate • Cyclophosphamide

18. Induction Chemotherapy • Arose in conjunction with development of limb sparing surgery • Increase survival • prognostic

19. Early trials incorporated high doses of methotrexate, given weekly for 4 weeks with leucovorin rescue, prior to surgery. • Subsequent modifications included the incorporation of bleomycin, dactinomycin (Cosmegen), and cyclophosphamide into the regimen, with the further addition of doxorubicin.

20. Considerations • Surgeon: I got it all • Oncologist: the surgeon got all that he or she could see • Patient: what are my chances?

21. The European Osteosarcoma Intergroup (EOI) reported no difference in histopathologic response to preoperative chemotherapy and overall survival in patients randomized to receive a two-drug regimen with doxorubicin and cisplatin or a complex multidrug protocol containing doxorubicin, cisplatin, and high-dose methotrexate among other agents.

22. Overall Survival DOX/DDP HDMTX/DOX/DDP European Osteosarcoma Intergroup Study I Bramwell et al. JCO 1992.

23. Giving cisplatin intra-arterially did not lead to improved results in a prospective trial of Cooperative Osteosarcoma Study Group. • A recent randomized controlled trial by the European Osteosarcoma Intergroup failed to achieve a survival advantage for adding G-CSF to doxorubicin and cisplatin

24. European Osteosarcoma Intergroup III • No difference in disease-free and overall survival • Higher rate of greater than 90% necrosis in dose intensive arm Lewis et al. JNCI, 2007

25. Poor responders • Patients with poor tumor response may represent 30%–60% of the population with extremity osteosarcoma. For these patients, more effective treatment regimens, such as dose intensification using growth factors and stem-cell support, and newer agents need to be evaluated.

26. Alternative approaches • One alternative approach to neoadjuvant therapy is adjuvant therapy. • A randomized study of the Pediatric Oncology Group (POG) demonstrated no detectable difference in EFS whether chemotherapy was offered before or after surgery.

27. The feasibility of safely performing limb-salvage surgery in these patients, however, has not been studied directly. • Additionally, intra-arterial delivery of cytotoxic agents has shown no specific survival benefit but provides increased concentration of chemotherapy to the primary tumor, which may impact favorably on the extent of the resection for patients undergoing limb-salvage surgery

28. Immunotherapy • A recent investigation found evidence of a survival advantage in osteosarcoma patients who suffer postoperative infections. • The production of tumor-specific humoral & cellular immune responses to osteosarcoma has been previously recognized, prompting interest in the potential role of immunotherapy in osteosarcoma

29. Immunotherapy • Muramyl Tripeptide Phosphatidyl Ethanolamine • Interferons • Inhaled GM-CSF • Trastuzumab • 105AD7 vaccine

30. Background of MTP-PE MTP-PE • Biological response modifier developed by Ciba-Geigy in 1980s • Fully synthetic lipophilic derivative of Mycobacterium cell walls. • Delivered to macrophages stimulates tumoricidal activity • Clinical development for osteosarcoma based on activity in animal models

31. COG Phase III Study Meyers et al. JCO, 2005.

32. GPG Phase III Study Event-free Survival • 3-year EFS • 71% Standard chemotherapy arm • 68% MTP + standard chemotherapy • 61% Ifosfamide + standard chemotherapy • 78% Ifosfamide + MTP + standard chemotherapy Meyers et al. JCO, 2005.

33. Interferons • IFNs exert a direct inhibitory effect against several tumor types in vitro, including osteosarcoma. • The Cooperative German/Austrian Osteosarcoma Study Group (COSS)-80 investigation randomized osteosarcoma patients to either receive or not receive 22 weeks of IFN maintenance therapy after the completion of chemotherapy. Administered twice weekly for 18 weeks and once daily for another 4 weeks, IFN was found to confer no survival advantage.

34. Interferons • Pegylated IFN-α2b is incorporated into the ongoing The European and American Osteosarcoma Study Group (EURAMOS) 1 intergroup study of resectable osteosarcoma tumors. Patients who experience a favorable histological response after neoadjuvant MAP therapy as measured by less than 10% viable tumor will be randomized to receive or not to receive 75 weeks of weekly subcutaneous IFN-α 2b after the completion of adjuvant MAP therapy. Muller et al, Acta Oncol; 2005.

35. Inhaled GM-CSF • GM-CSF is capable of activating numerous components of the immune system including neutrophils, macrophages, lymphocytes, and natural killer cells. • These immunostimulatory effects confer an antitumor effect in numerous cancer types.

36. Inhaled GM-CSF • A Phase II study is being carried out by the Children's Oncology Group (COG), investigating the effect of inhaled GM-CSF in osteosarcoma patients with pulmonary relapse. If favorable therapeutic effects are confirmed, inhaled GM-CSF may be an attractive agent in patients with pulmonary metastasis or as a prophylactic measure in patients at high risk of relapse.

37. Trastuzumab • HER-2 expression has been associated with a poor histologic response to neoadjuvant chemotherapy and decreased EFS in osteosarcoma patients. A study of trastuzumab, a HER-2 monoclonal antibody, in osteosarcoma tumors with HER-2 amplification has recently been completed by the COG, but results from the study have yet to be published

38. Investigational Cytotoxic Chemotherapy • Gemcitabine • Docetaxel • Topotecan • Pemetrexed

39. Investigational Cytotoxic Chemotherapy • Synergistic cytotoxicity with sequential treatment of soft tissue & bone sarcomas with gemcitabine followed by docetaxel has been demonstrated . • This regimen resulted in an overall RR of 43% in multiple types of soft –tissue sarcomas, osteosarcomas & Ewing’s sarcoma at the university of Michigan Comprehensive Cancer center. Leo et al, JCO; 2004.

40. Camptothecins • A Phase II study of topotecan in combination with cyclophosphamide led to a partial response in two of 18 and stable disease in five of 18 relapsed or refractory osteosarcoma patients. All other osteosarcoma patients experienced progressive disease.

41. Pemetrexed • By inhibiting multiple folate-dependent enzymes, the antimetabolite pemetrexed has drawn attention as a promising osteosarcoma therapy. • Pemetrexed has demonstrated synergism with other chemotherapies such as platinum agents and gemcitabine. • However, a recent in vitro study utilizing human osteosarcoma cell lines demonstrated an inferior response to pemetrexed compared to MTX when the agents were used individually.[39] Hence, the value of pemetrexed may be in the context of a multidrug regimen rather than as a monotherapy

42. Bisphosphanates • Many solid tumors, including osteosarcoma, express tumor-specific antigens on their surface, representing targets for immune effector T cells. • At present, a Phase III study is in progress in France, evaluating the impact of zoledronic acid as adjuvant therapy to chemotherapy and surgery on EFS in pediatric and adult patients.

43. Emerging Directed Therapies • An evolving understanding of osteosarcoma biology will likely play a significant role in the development of novel therapeutics. • Promising therapies targeted at molecules critical to the pathogenesis of osteosarcoma tumors are currently under investigation. • These molecular targets include IGF1R, mTOR,, and HSP90 molecular chaperone.

44. Side–effects of chemotherapy • The most frequent chemotherapy related complications include infections,mucositis, impaired renal function(tubular damage due to ifosfamide & glomerular dysfunction caused by cisplatin), hearing loss, neuropathy and cardiomyopathy. • Close monitoring during chemotherapyis mandatotry • Long-term follow up is required not only to monitor remission status but also to screen for and manage late effects

45. Take home message • Osteosarcoma is most commonly observed during the adolescent growth spurt, as well as at the site of pre-existing lesions such as Paget's disease and bone infarcts

46. Take home message • The combination of high-dose methotrexate, doxorubicin, and cisplatin, with or without ifosfamide, is widely used, however, clinical trials remain the standard of care. • Many of the immunotherapy agents currently under investigation are theorized to be the most useful in the setting of minimal residual disease. The impact of these agents in the future remains under investigation

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