Comprehensive overview of bone sarcoma: staging, diagnosis, risk stratification and treatment

1. Bone sarcoma
Ahmed Zeeneldin
Associate Professor of Medical
Oncology

2. GTNM Staging BS, 2010
• T1: <= 8 cm
• T2: > 8 cm
• T3: Discontinuous tumors in the primary bone site
• No T4 like ovaries
• N1: regional LN (RARE) T1 T2 T3 N1 M1a/b
• M1a: lung mets LG, GX IA IB IB IVB IVA/IVB
• M1b: non-lung distant mets HG IIA IIB III IVB IVA/IVB
• Low grade: G1, 2
• High grade: G3,4
• Grade cannot be assessed: GX

3. Surgical Staging system 1980
• T1: intracompartmental
• T2: extracompartmental
T1 T2 N1 M1
• N1: regional LN (RARE) LG IA IB III III
• M1: distant mets HG IIA IIB III III
• Low grade: G1, 2
• High grade: G3,4

4. Incidence
• Rare: 0.2% of all cancers
• Often curable
• Common forms:
– Osteosarcoma (35%), OS
– Chondrosarcoma (30%), CS
– Ewing’s sarcoma (16%), ES
– Malignant fibrous histiocytoma (MFH) and
fibrosarcoma (FS) (<1%)
– Others hemangioendothelioma (HET) and
hemangiopericytoma (HPC), and chordoma: very rare

5. CS OS ES MFH HET Chor
HPC doma
age Middle age Children Children
Older adults Young adults Young adults
Origin Cartilage bone ? Fibrous T vascular notochord

6. Multidisciplinary Team
• Core group
– Bone pathologist
– Musculoskeletal radiologist
– Orthopaedic oncologist
– Medical/pediatric oncologist
– Radiation oncologist
• Specialists critical in certain cases
– Thoracic surgeon
– Plastic surgeon
– Interventional radiologist
– Physiatrist
– Vascular surgeon
– Additional surgical subspecialties

7. Workup

8. Workup
• Radiology:
– Primary site:
• Plain film, MRI and or CT, bone scan
– Exclude mets and other lesions:
• Chest x-ray or CT
• Bone scan, PET
• Lab:
– CBC, LDH, Alk Phos, Ca
– Biopsy: Core needle or surgical (better at treating
center)

9. Chondrosarcoma (CS)

10. CS
• Produce cartilage matrix without bone
• Occur at any age, but more common in older
adults
• Types:
– Conventional CS: 85%
• 1ry or central: from normal bone
• 2ry or peripheral: from preexisting lesion
– Other types CS: 10-15%
• Clear cell
• Dedifferentiated
• Myxoid and mesenchymal

11. CS treatment

12. Chemotherapy in CS
• Not sensitive to chemo especially
conventional
• Dedifferentiated and mesenchymal are more
sensitive
– Dedifferentiated: treat as OS (cisplatin doxo)
– Mesenchymal: treat as ES (VACD, VAIA, EVIAI)

13. Ewing’s sarcoma (ES)

14. ES
• adolescents and young adults
• All ES are undifferentiated
• Common sites: femur, pelvic bones, and the
bones of chest wall, but any bone can be
affected
• Diaphysis is the commonest area
• Symptoms:
– Pain and swelling
– Constitutional: fever, weight loss, and fatigue

15. Xray
On imaging, the
bone appears
mottled.
Periosteal
reaction is
classic and it is
referred to as
“onion skin

16. Ewing Sarcoma Family of tumors
ESFT
• Ewing’s sarcoma,
• extraosseous Ewing’s sarcoma
• Askin’s tumor,
• Primitive neuroectodermal tumor (PNET),
• PNET of bone

17. ES genetics
- fusion of EWS
gene on chr 22q
WITH
ETS gene family
(FLI1) on chr 11
- Found in 85%
of ES

18. ES IHC
strong expression of cell-surface
glycoprotein MIC2 (CD99)

19. Prognostic factors
• Good
– Distal site
– Absence of mets
– Normal LDH
• Risk stratification:
– High risk: mets, high disease volume (< 100 ml)
– Low/standard risk: no mets, low disease vol(> 100
ml)

20. Treatment of ES

21. Treatment of non-progressive disease

22. Chemotherapy in ES
• Drugs • Metastatic:
– V: vincreistine – VDC
– A: dactinomycin – Others
– C: cyclophosphamide • Nonmetastatic : more
– D (A): doxorubicin intensive
– I: fosfamide – Include etoposide
– E: etoposide – Alternating cycles
• Regimens
– VAC vs VACD (IESSI-II)
– VACD vs VACD/IE
– VAIA vs VACA
– VAIA vs EVAIA

23. VAC vs VACD
VAC (IESS-I) VACD (IESS-II)
RFS 24 60%
OS Better
toxicity More

24. VACD vs VACD/IE

25. VACD vs VACDlIE
Non-metastatic disease Metastatic disease
VACD VACD/IE P VACD VACD/IE P
N ~200 ~200 N ~120 ~120
5- y EFS 55% 70% 0.005 5- y EFS 22% 22% 0.81
5-y OS 61 72% 0.01 5-y OS 34% 35% 0.43

26. Figure 1. Event-free Survival According to Study Group Figure 2. Event-free Survival According to Study Group
and the Presence or Absence of Metastatic Disease. and Tumor Site among Patients without Metastases

27. VACD vs VAIA vs EVAIA

28. VACA vs VAIA vs EVAIA
Standard risk (localized, low volume < 100 ml) High-risk (metastatic, high volume > 100 ml)
VAIA = VAID, VACA= VACD VAIA = VAID
VAIAà VAIAà P EVAIA VAIA P
VAIA VACA
N 79 76 N 252 242
3- y EFS 74% 73% NS 3- y EFS 52% 47% NS
3-y OS 86 90% NS 3-y OS 62 59 NS
Toxicity Less more

29. Relapsed or Refractory ES
• Good Prognostic factors:
– Time to Rec => 2years
– Local recurrence treatable by surgery and
intensive chemo
– Lug only mets
– Non-elevated LDH

30. Treatment of relapsed or refractory ES
• Relapse => 2years:
– the same initial therapy can be used
• Relapse < 2 years:
– Cyclophosphamide and topotecan
– Temozolomide and irinotecan
– Ifosfamide and etoposide
– Ifosfamide, carboplatin and etoposide
– Docetaxel and gemcitabine

31. Osteosarcoma (OS)

32. OS
• Commonest bone malig in children and young
adults
• Sites of max bone growth (distal femur and
prox tibia)
• Types:
• Classic: 80%

33. Prognostic factors
• Tumor site (distal vs prox)
• Tumor size (small vs large)
• Metastases (no vs yes)
• Metastatic site (lung vs non-lung)
• Number of lung mets (few/resectable vs
many/iresectable)
• Response to chemotherapy ( good vs poor)
• Resection (R0 vs R1)
• LDH (normal vs elevated)

34. OS plain x ray
• Plain radiographs show
cortical destruction and
irregular reactive bone
formation

35. Workup in OS
• Imaging:
– For 1ry:
• Plain radiograph
• MRI (BEST) and or CT
• Bone scan
– For 2ry:
• CT chest, bone scan
• Lab: LDH, ALP

36. Treatment
• Surgery (limb sparing or amputation) AND
• Adjuvant or neoadjuvant chemotherapy

37. Chemotherapy regimens
• First line (adj/neoadj/primary)
– Cisplatin and doxorubicin
– MAP (High-dose methotrexate, cisplatin and doxorubicin)
– Doxorubicin, cisplatin, ifosfamide and high-dose methotrexate
– Ifosfamide and etoposide
– Ifosfamide, cisplatin and epirubicin
• Second line (relapsed and refractory)
– Docetaxel and gemcitabine
– Cyclophosphamide and etoposide
– Cyclophosphamide and topotecan
– Gemcitabine Ifosfamide and etoposide
– Ifosfamide, carboplatin and etoposide
– High-dose methotrexate, etoposide and ifosfamide
• Third line
– Resection
– RT
– Samarium

38. Treatment of OS

39. Adjuvant CT better than observation

40. As in the historical experience,
50% of the patients suffered relapse within six months of diagnosis, and
overall, more than 80% developed recurrent disease.
Fewer than 20% of patients treated only with surgery of the primary tumor can be expected to survive free of recurrent disease.
Thus adjuvant chemotherapy should be recommended to all patients with high-grade osteosarcoma of the extremity

41. Short equal to long CT regimens in operable OS
Short Long
Drugs Doxorubicin 25 mg/m2 D1–3 preoperatively ( 7wks)
cisplatin 100 mg/m2 D1 vincristine, high-dose methotrexate,
preoperatively (9wks) and doxorubicin;
postoperatively (9 wks) postoperatively (37 wks) bleomycin,
cyclophosph, dactinomycin,
vincristine, methotrexate, doxorubicin,
cisplatin
Cycles/weeks 6 cycles (18 wks) 44 weeks

42. Results
PFS the same OS the same

43. Two drugs Multiagent
(Cis-Adria)
Treatment 94% 51%
completion
TOXICITY Similar similar
> 90% tumor 29% 29%
necrosis

44. Ifosfamide/etoposide in met OS

46. Adding ifosfamide to cisplatin
Epirubicin in non-met OS

47. Indirect comparison
Cisplatin – Cisplatin –
adriamycin epirubicin –
ifosfamide
APx3 àS àAPx3 PEI x 3 àS àPEI x 3
Treatment 94% 84%
complateion
Complete R 26%
Good R 29% 37%
5-y DFS 42%
5-y OS 48%

48. AP vs PEI

50. Neoadj CT

51. High dose CT and SCT
• Investigational
• High risk metastatic and relapsed
• TRM 3%
• 3-y DFS: 12%
• 3-y OS: 21%

53. Good response (>90% necrosis) to Neoadj chemo is a
good prognostic factor