Osteosarcoma ppt

RADIATION ONCOLOGY

1. INDICATION,EVIDENCES AND RT TECHNIQUES IN OSTEOSARCOMA DR.SHUCHITA DNB RESIDENT

2. Classification PRIMARY or SECONDARY PRIMARY OSTEOSARCOMAS are Conventional /classic osteosarcoma (high grade, intra medullar y) Low-grade intramedullary osteosarcoma Parosteal osteosarcoma Periosteal osteosarcoma High-grade surface osteosarcoma Telangiectatic osteosarcoma , and Small cell osteosarcoma . 3

3. Classification SECONDARY OSTEOSARCOMAS Osteosarcomas occurring at the site of another disease process. more common in >50 years of age The most common causes are Paget disease Previous radiation treatment Other associated conditions are Fibrous dysplasia Bone infarcts Osteochondromas Chronic osteomyelitis Dedifferentiated chondrosarcomas Osteogenesis imperfecta 4

4. INTRODUCTION Osteosarcoma is most common primary bone cancer (35%). Osteosarcoma has a bimodal distribution with cases arising during the teenage years as well as cases associated with other conditions (Paget Disease, fibrous dysplasia) that arise in an older (age >65 yrs) population . Osteosarcoma is more common in boys (> girls) and in blacks (> whites ). Highly malignant tumor of mesenchymal origin. Incidence – 1 to 3 per million per year

5. INTRODUCTION Osteosarcoma arises most frequently in the appendicular skeleton (80% of cases) at the metaphyseal portions of the distal femur, tibia, and humerus . Osteosarcoma spreads hematogenously , with the lung being most common metastatic site. Osteosarcoma is associated with Li- Fraumeni syndrome (germline inactivation of p53) as well as retinoblastoma.

6. DISTRIBUTION OF PRIMARY & SECONDARIES

7. Classic High Grade Osteosarcoma These aggressive, high-grade tumors begin in an intramedullary location, but may break through the cortex and form a soft-tissue mass. The histologic hallmark - malignant osteoblastic spindle cells producing osteoid , presence of woven bone with malignant appearing stromal cells subtypes - osteoblastic , chondroblastic fibroblastic 8

8. Clinical Presentation Pain – Progresssive pain due to microinfarction night pain in 25 % Swelling - Palpable mass is noted in up to 1/3 of patients at the first visit Fever, malaise or other constitutional symptoms are not typical of osteosarcoma 9

9. Plain X-ray Lesions are usually permeative Associated with destruction of the cancellous and cortical elements of the bone Ossification within the soft tissue component, if tumour has broken through cortex Borders are ill defined 10 INVESTIGATIONS:-

10. Plain X-ray Periosteal reaction may appear as the characteristic Codman triangle . Extension of the tumor through the periosteum may result in a so-called “ sunburst ” appearance. 11

11. Other investigations MRI CT Angiogram Bone scan Laboratory studies Biopsy 12

12. MRI Best modality for documenting the extent of a primary bone and soft tissue mass is an MR scan Should include the entire involved bone so as to make sure that skip metastases are not present Specialized cross-sectional studies, including MR neurograms , MR angiograms, and CT angiograms are important to assist with surgical planning. 13

13. CT-scan A dedicated chest CT scan is perhaps the most sensitive way to exclude distant disease in the lungs (Lung mets at presentation 10%) CT scanning also has proven utility in studying axial primary sites, as well as in predicting pathologic fracture risk 14

14. Angiogram Determine vascularity of the tumour Detect vascular displacement Relationship of vessels to the tumour Not of much use after CT or MR angiography, only used when embolization is required 15

15. Bone scan Bone mets <5% Helps to determine polyostotic (multifocal) involvement and metastatic disease 16

16. PET  PET or PET/CT scan quantifies metabolic activity in the primary site and helps to exclude occult metastases. The utility of [F-18]-FDG PET/CT scanning in the management of patients with bone sarcoma is well established

17. Laboratory studies Full blood count, ESR, CRP. LDH (elevated level is associated with poor prognosis) ALP (highly osteogenic ) Platelet count Electrolyte levels Liver function tests Renal function tests Urinalysis 18

18. Biopsy Supreme caution must be taken to avoid contamination Guided FNA or core procedures- These method has the advantage maximizing sampling throughout the mass while minimizing contamination Whenever an open biopsy procedure is chosen, careful attention must be paid to incisional length (short) and placement (in line with the definitive resection procedure)

19. Treatment Current standard of care Radiological staging Biopsy to confirm diagnosis Preoperative chemotherapy Repeat radiological staging (access chemo response, finalize surgical treatment plan) Surgical resection with wide margin Reconstruction using one of many techniques Post op chemo based on preop response 23

20. TREATMENT OF OSTEOSARCOMA SURGERY The main goal of surgery is to safely and completely remove the tumor. Historically – amputation. Over the past few years - limb-sparing procedures have become the standard, mainly due to advances in chemotherapy and sophisticated imaging techniques Limb salvage procedures now can provide rates of local control and long-term survival equal to amputation. 24

21. SURGERY Pelvic tumors require a hemipelvectomy for en bloc resection. Adjuvant radiation has been used to improve outcomes in patients with incomplete resections of pelvic tumors . Spinal tumors are difficult to resect with negative margins. Typically, an en bloc resection with vertebrectomy is performed, combined with mechanical stabilization. Postoperative radiation therapy used when negative margins cannot be obtained, particularly when there is microscopic dural involvement.

22. Amputation Amputation involves removal of the limb with a safe margin It should not be viewed as a failure of treatment, but rather as the first step towards patient’s return to a more comfortable and productive life 26

23. Amputation Indication 1. Grossly displaced pathologic fracture 2. Encasement of neurovascular bundle 3. Tumor that enlarges during preop chemo and is adjacent to neurovascular bundle 4. Palliative measure in metastatic disease 5. If the tumor has caused massive necrosis, fungation, infection, or vascular compromise. 27

24. Limb salvage surgery Removing the tumor with a normal cuff of tissue surrounding it while preserving vascular and nerve supply to the extremity. 28

25. Limb salvage surgery Surgical guidelines- No major neurovascular involvement En block removal of all previous biopsy site and potentially contaminated tissues with wide margins Resection of bone 3 to 4 cm beyond abnormal uptake, as determined by CT, MR and bone scan Adequate motor reconstration

26. Limb salvage surgery Skeletal defect must be reconstructed by Endoprosthesis (most common) – replacing the removed bone with a metal implant Allograft (cadaveric) bone Vascularized bone acquired from the patient Allograft-prosthetic composite constructions 30

27. Rotationplasty Compromise between amputation and limb salvage most commonly used for osteosarcomas of the distal femur in skeletally immature patients It is a procedure where the neurovascular structures and distal aspect of the limb (leg) are retained, and re-attached to the proximal portion after the tumor has been removed. 31

28. Rotationplasty For functional purposes, the distal segment is turned 180 degrees so that the ankle joint functions as a knee joint, thus converting an above-knee to a below-knee amputation in order for prosthetic use to be maximized 32

29. CHEMOTHERAPY Before routine use of CT, 5 year survival was <20% 50% patient developed metastasis (lung) within 6 month Advantages of neoadjuvant chemotherapy - Regression of the primary tumor, making a limb salvage operation easier. M ay decrease the spread of tumor cells at the time of surgery Effectively treating micrometastases at the earliest time possible.

30. It avoid tumor progression, which may occur during any delay before surgery. Given for about 3-4 weeks before definitive procedure Chemotherapy plays an important role for all patients with intermediate- and high-grade tumors .

31. Chemotherapy The drugs used most often to treat osteosarcoma HD- Methotrexate Doxorubicin ( Adriamycin ) Cisplatin or carboplatin Ifosfamide Bleomycin Cyclophosphamide Actinomycin -D 35

32. CHEMOTHERAPY Eilber et al .:- 59 patients with nonmetastatic osteosarcoma randomized to surgery followed by observation versus adjuvant chemotherapy. DFS at 2 years was 55% with chemotherapy and 20% with observation (p < .01). OS was also superior at 2 years: 80% versus 48% with and without chemotherapy, respectively (p < .01).

33. CHEMOTHERAPY Link et al.:- 36 patients with nonmetastatic , high-grade osteosarcoma randomized to observation versus adjuvant chemotherapy after primary surgery. DFS at 2 years was 66% with chemotherapy and 17% with observation (p < .001).

34. CHEMOTHERAPY POG 8651 randomized patients with nonmetastatic , high-grade osteosarcoma to neoadjuvant chemotherapy followed by surgery or surgery followed by the same chemotherapy. 5-year relapse-free survival was not statistically different between the two groups (65% vs. 61%, respectively), nor was the rate of limb salvage (55% vs. 50%, respectively). This trial did not show improved outcomes with neoadjuvant chemotherapy, it did show equivalence and established a benchmark for comparison with future trials.

35. EURAMOS I (AOST 0331):- This ongoing trial is evaluating the benefit of additional chemotherapy after preoperative and postoperative chemotherapy consisting of methotrexate, doxorubicin, and cisplatin. Patients with a poor response to preoperative chemotherapy are randomized to the addition of ifosfamide and etoposide , whereas those with a good response to preoperative chemotherapy are randomized to the addition of interferon. In the past 20 years, standard treatment has evolved to the routine use of NACT and adjuvant CT.

36. RADIATION THERAPY Highly radioresistent tumor Radiation therapy has very limited role in Ostesarcoma INDICATION Unresectable primary tumors Incompletely resected tumors with positive margins Patients who refuse surgery For palliation of symptomatic metastases

37. Radiation Therapy Techniques SIMULATION AND FIELD DESIGN:- 3-D treatment planning with the aid of presurgical and postsurgical imaging is used to define gross tumor volumes and areas of subclinical disease. Typically, a 2-cm margin is used for axial tumors , which can be extended to 4 to 5 cm for extremity tumors . Spare 1.5-2cm strip of skin in extremity,to prevent edema

38. Radiation Therapy Techniques Try to exclude the skin over anterior tibia, due to poor vascularity . The radiation technique used, either 3D-CRT or IMRT, should be tailored to the individual patient. Dose to uninvolved organs should be minimized to prevent late organ dysfunction, as should the integral dose to minimize risk of secondary malignancy.

39. Intraoperative radiation therapy has been used to deliver dose directly to close or involved surgical margins Proton particle therapy has been used in an attempt to escalate radiation dose, particularly in unresectable tumors Radionuclide therapy- Rhenium Strontium samarium Used for palliation of extensive bone metastases with good effects

40. DOSE 60 Gy in 2-Gy fractions used for microscopically involved margins 66 Gy is used for macroscopic residual disease and 70 Gy is used for inoperable tumors . Radiation can be given concurrently but is usually delivered after chemotherapy due to increased acute toxicity with concurrent administration.

41. Cooperative Osteosarcoma Study Group (COSS) Total of 175 pts with histologically proven osteosarcoma irradiated over the period of 1980−2007. 100 pts were eligible for analysis . Indication for RT was :- a primary tumor in 66, a local recurrence in 11, and metastases in 23 pts. 94 pts got external photon therapy ; 2 pts, proton therapy; 2 pts, neutron therapy; and 2 pts, intraoperative RT . The median dose for external RT was 55.8 Gy (30–120). All the pts received chemotherapy in accordance with different COSS-protocols. The median follow-up :- 1.5 (0.2–23) years.

42. Cooperative Osteosarcoma Study Group ( COSS) Survival and local control rates at 5 years were calculated. The overall survival rate after biopsy was 41% at 5 years, while the overall survival rates after RT for the whole group, for treatment of primary tumors , local recurrence, and metastases were 36%, 55%, 15 %,0% respectively. Local control for the whole group was 30%. Local control rates for combined surgery and RT were significantly better than those for RT alone (48% vs. 22%, p = 0.002). Local control for treatment of primary tumors , local recurrence, and metastases were 40%, 17%, and 0% respectively .

43. Schwarz et al. Reported on an analysis of 100 patients treated with radiation therapy in the COSS registry. Local control and overall survival for the whole group were 30% and 36%, respectively, at 5 years. Local control was significantly better when surgery was combined with radiation compared to radiation alone: 48% vs. 22%, respectively (p = .002)

44. Machak et al. Reported on a series of 187 patients with nonmetastatic osteosarcoma treated with induction chemotherapy. 31 patients with non-metastatic osteosarcoma who refused surgery and were treated with induction chemotherapy f/b radiation to a mean dose of 60 Gy . OS,PFS,MFS(Metastasis free survival) at 5 yr were mean of 61%,56%,62% respectively. Patient who were responder had OS and MFS at 5 yrs of 90% and 91% respectively v/s non-responders 35% and 42% respectively(p=0.005, and p=0.005respectively) However, local progression-free survival was 31% at 3 years and 0% at 5 years for nonresponders .

45. De Laney et al. Reported on 41 pts with osteosarcoma who were either not resected or were excised with close or positive margins and who underwent RT with external beam photons (median dose of 66 Gy ) No definitive dose response, although dose>55Gy had higher local control(p=0.11) RT is more effective for patients with microscopic and minimal residual disease

46. COMPLICATIONS Permanent weakening of affected bone Scoliosis Decreased range of movement due to fibrosis or joint involvement Vascular changes resulting in greater sensitivity to infection Lymphedema Osteoradionecrosis

47. EXTRACORPOREAL IRRADIATION ( ECI) It consists of en ‑bloc removal of the tumor bearing bone segment, removal of the tumor from the bone ,irradiation, and re‑implantation back in the body. First reported by Spira et al in 1968 ECI has several potential advantages.:- The affected bone segment is removed from the body and irradiated and therefore, avoidance of radiation injury to the un‑irradiated bone, muscles, joint, and other healthy tissues of the body. The delivery of very high doses of radiation to tumor bearing bone by ECI, which is otherwise not possible in the intact bone. These higher doses in the range of 50‑300 Gy , are lethal to the remaining tumor cells and therefore, reduce the risk of recurrence. It provides an anatomically size‑matched graft for biological reconstruction. It is cost effective as compared to the prosthetic devices. It has psychological advantage as patients feel that their own bone is being used as prosthesis.

48. Extra corporeal Irradiation Several case series from India (DN Sharma,AIIMS ) and outside world showed excellent long term local control in Osteosarcoma , Ewings sarcoma and chondrosarcoma 50 Gy in single fraction is used

49. Davidson et al (2005) Reported a series of 50 patients with different malignant bone tumor mainly ESFT (21 patients) and OS (16 patients) using en bloc resection and ECI (50 Gy ). The mean time of ECI process was 35 min . With a mean follow‑up of 38 months (range 12‑92), 84% patients were alive without any disease and only 8% developed LR.

50. Poffyn et al (2011) Recently published a retrospective analysis of 107 patients with 108 malignant or locally aggressive bone tumors treated by ECI with 300 Gy , and re‑implantation of the bone as an orthotopic autograft . At 5 year follow‑up, there was no LR and 64% of patients had well healed graft. The 0 % LR rate could be due to relatively very high dose of ECI (300 Gy ) used in their study .

51. Conclusion Radioresistant Surgery is main stay of treatment NACT improved the respectability without compromising the Survival Radiation has role in margin positive, unresectable and palliative settings

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