Bone sarcoma

Ahmed ZeeneldinAssociate Professor of Medical

Oncology

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)• M1a: lung mets• M1b: non-lung distant mets

• Low grade: G1, 2• High grade: G3,4• Grade cannot be assessed: GX

T1 T2 T3 N1 M1a/b

LG, GX IA IB IB IVB IVA/IVB

HG IIA IIB III IVB IVA/IVB

Surgical Staging system 1980

• T1: intracompartmental• T2: extracompartmental

• N1: regional LN (RARE)• M1: distant mets

• Low grade: G1, 2• High grade: G3,4

T1 T2 N1 M1

LG IA IB III III

HG IIA IIB III III

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

CS OS ES MFH HETHPC

Chordoma

age Middle ageOlder adults

ChildrenYoung adults

ChildrenYoung adults

Origin Cartilage bone ? Fibrous T vascular notochord

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

Workup

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)

Chondrosarcoma (CS)

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

CS treatment

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)

Ewing’s sarcoma (ES)

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

Xray

On imaging, the bone appears mottled. Periostealreaction is classic and it is referred to as “onion skin

Ewing Sarcoma Family of tumorsESFT

• Ewing’s sarcoma,• extraosseous Ewing’s sarcoma • Askin’s tumor,• Primitive neuroectodermal tumor (PNET), • PNET of bone

ES genetics

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

ES IHCstrong expression of cell-surface glycoprotein MIC2 (CD99)

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)

Treatment of ES

Treatment of non-progressive disease

Chemotherapy in ES• Metastatic:

– VDC– Others

• Nonmetastatic : more intensive– Include etoposide– Alternating cycles

• Drugs – V: vincreistine– A: dactinomycin– C: cyclophosphamide– D (A): doxorubicin– I: fosfamide– E: etoposide

• Regimens– VAC vs VACD (IESSI-II)– VACD vs VACD/IE– VAIA vs VACA– VAIA vs EVAIA

VAC vs VACD

VAC (IESS-I) VACD (IESS-II)

RFS 24 60%

OS Better

toxicity More

VACD vs VACD/IE

VACD vs VACDlIE

Non-metastatic disease

VACD VACD/IE P

N ~200 ~200

5- y EFS 55% 70% 0.005

5-y OS 61 72% 0.01

Metastatic disease

VACD VACD/IE P

N ~120 ~120

5- y EFS 22% 22% 0.81

5-y OS 34% 35% 0.43

Figure 1. Event-free Survival According to Study Group and the Presence or Absence of Metastatic Disease.

Figure 2. Event-free Survival According to Study Group and Tumor Site among Patients without Metastases

VACD vs VAIA vs EVAIA

VACA vs VAIA vs EVAIAStandard risk (localized, low volume < 100 ml)VAIA = VAID, VACA= VACD

VAIAàVAIA

VAIAàVACA

P

N 79 76

3- y EFS 74% 73% NS

3-y OS 86 90% NS

Toxicity Less more

High-risk (metastatic, high volume > 100 ml)VAIA = VAID

EVAIA VAIA P

N 252 242

3- y EFS 52% 47% NS

3-y OS 62 59 NS

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

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

Osteosarcoma (OS)

OS

• Commonest bone malig in children and young adults

• Sites of max bone growth (distal femur and prox tibia)

• Types: • Classic: 80%

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)

OS plain x ray

• Plain radiographs show cortical destruction and irregular reactive bone formation

Workup in OS

• Imaging:– For 1ry:

• Plain radiograph• MRI (BEST) and or CT• Bone scan

– For 2ry:• CT chest, bone scan

• Lab: LDH, ALP

Treatment

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

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

Treatment of OS

Adjuvant CT better than observation

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

Short equal to long CT regimens in operable OS

Short Long

Drugs Doxorubicin 25 mg/m2 D1–3cisplatin 100 mg/m2 D1preoperatively (9wks)postoperatively (9 wks)

preoperatively ( 7wks)vincristine, high-dose methotrexate, and doxorubicin; postoperatively (37 wks) bleomycin, cyclophosph, dactinomycin, vincristine, methotrexate, doxorubicin, cisplatin

Cycles/weeks 6 cycles (18 wks) 44 weeks

Results

PFS the same OS the same

Two drugs (Cis-Adria)

Multiagent

Treatment completion

94% 51%

TOXICITY Similar similar

> 90% tumor necrosis

29% 29%

Ifosfamide/etoposide in met OS

Adding ifosfamide to cisplatinEpirubicin in non-met OS

Indirect comparison Cisplatin –adriamycin

Cisplatin –epirubicin –ifosfamide

APx3 àS àAPx3 PEI x 3 àS àPEI x 3

Treatmentcomplateion

94% 84%

Complete R 26%

Good R 29% 37%

5-y DFS 42%

5-y OS 48%

AP vs PEI

Neoadj CT

High dose CT and SCT

• Investigational• High risk metastatic and relapsed • TRM 3%• 3-y DFS: 12%• 3-y OS: 21%

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