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Flashcards in Bony Sarcomas Deck (44):
1

What is the distribution of osteosarcoma?

8% mandible
10% humerus
15% hip/femur
60% knee

2

What is identified on the pathology of osteosarcoma?

Malignant osteoblasts and osteoid
Pink amorphous intercellular material
+/- Collagen (Complix Dx)

3

What are the Primary osteosarcoma subtypes?

G.P. CTSP

Grade
- Low Grade central
- High Grade surface
Periosteal

Conventional
- Osteoblastic
- chondroblastic
- Fibroblastic
Telengiectatic
Small Cell
Paraosteal

4

Is osteosarcoma radiation sensitive?

NO

5

What are the surgical options for osteosarcoma?

1) Amputation
2) Wide excision +/- megaprosthesis
3) Rotationplasty

6

What is the survival rate of osteosarcoma with surgery alone?

20%

7

What are the more recent historical trials showing benefit of adjuvant chemotherapy

1) Link et al NEJM 1986
- 2y RFS 20% (observation) vs 65% (Adj chemo)
2) Eliber et al
- 2y RFS 20% vs 55% (Adj chemo)
- 2y OS 50% vs 80% (adj chemo)
*Adj chemo used = HD MTX, Doxorubicin, Bleomycin, Cyclophosphamide, Dactinomycin

8

What are the theoretical advantages of pre-op chemo?

S.P.O.R.T

Salvage of limb
Prosthesis modeling
O -micrO-met management
Response to chemo for prognostication
Tailor post-op treatment

9

Tell me about POG-8651 study

Goorin JCO 2003

Aim: Comparing pre-op chemo vs postop chemo in non metastatic osteosarcoma

N=100
Surgery

RESULTS:
5y EFS:
- preop = 60%
- postop = 70% [trend]
5y OS:
- preop = 76%
- postop = 79% [trend]
Limb salvage:
- preop = 50%
- postop = 55%
Risk of PD during chemo 13%

Criticisms:
- low rate of limb-sparing surgery in both groups
- inclusion of BCD

10

What prognostic factors of osteosarcoma do you know?

H.H.E.A.L

1) Histological response
- Good vs poor responders
>> Good LTS 80%, Poor LTS 50%
- PD during induction chemo do the worst. ~10%

2) Histo Subtype (COFT)
- Chondroblastic

11

Tell me briefly about the EOI studies

EOI = European Osteosarcoma Intergroup

EOI-1 = Randomized Phase II exploring benefits of HD MTX + AP

EOI-2 = Standard AP vs T-10 protocol

EOI-3 = Standard 3-weekly AP vs 2-weekly interval

12

Tell me about EOI-1

Bramwell JCO 1992
Aim: investigating benefits of adding HD MTX to AP

N=200, classical HG osteosarcoma

2 arms:
1) 6# Doxo (75) + CDDP (100) Q3w
2) 4# HD MTX (8g/m2) --> 6# Doxo (75) + CDDP (100)
- HD MTX given 10 days before AP

EOI-1 had surgery sandwiched inbetween
3#AP/2# HDMTX --> Surgery --> 3# AP/2# HDMTX

RESULTS:
5y DFS 60% (AP) vs 40% (MAP) [sig]
5y OS 65% vs 50% (MAP) [not sig]

CONCLUSION:
- no added benefit to HD MTX

13

Tell me about EOI-2

Link and Eliber

N=400
Operable, non-metastatic osteosarcoma

2 arms:
1) AP
2) T-10

T-10 protocol, alternating chemo
- HD MTX (8-12 g/m2)
- Doxorubicin (30mg/m2/day)
- Bleomycin (15 mg/m2/day)
- Cyclophosphamide (600 mg/m2/day)
- Dactinomycin (600 mcg/m2/day)

In the T-10 protocol, resection/amputation to be done ~4 weeks, after 4 doses of HDMTX
- Endoprosthetic replacement to be done ~16 weeks

RESULTS:
5y PFS 40%
3y OS 65%
5y OS 55%
Path CR 30%

14

Tell me about EOI-3

Aim: To evaluate if there is benefit in intensifying AP by giving it 2-weekly instead of 3-weekly

N=500

2 arms:
1) 6# AP Q3w
2) 6# AP Q2w
Surgery to be done Week 6 in both arms

RESULTS:
Good histo response (I.e.>90% necrosis): 35% vs 50% (q2w)
OS HR 0.94 [trend]
PFS HR 0.98 [trend]

15

What s the conclusion of EOI 1/2/3?

Standard of care in Europe is:
1) Doxo (75) + CDDP (100)
2) Q3w dosing
3) 6 cycles
4) 3# before surgery, 3# after surgery

16

What do you know about the COG MAP protocol?

Uses:
- Doxorubicin (75)
- CDDP (120)
- MTX (12g/m2) - max dose 20 mg

Surgery to be done week 10 after 2# of MAP
Week 0 AP
Week 3 M
Week 4 M
Q5weekly
No break in between except surgery week 10, rest week 11
Resume week 12: AP
Week 15 M
Week 16 M
Week 17 AP

Total 31 weeks

17

Tell me about the EURAMOS 1

Aim:
1) To evaluate the role of Alpha IFN in good responders
2) To evaluate the role of IE in poor responders


Biopsy-proven resectable osteosarcoma
N=2200

Treated with induction MAP, followed by surgery
We then assess the histology and divide into 2 arms:
1) Good responders
2) Poor responders

Good responders further randomize to:
1) MAP
2) MAP + alpha IFN

Poor responders further randomize to:
1) MAP
2) MAP + IE
====================
Good responders:
Result reported 2015 June JCO, not statistically different from MAP
- 3y EFS 74% (MAP) vs 77% (MAP-IFN) [trend]

18

Tell me what you know about Muramyl Tripeptide

MTP = Muramyl Tripeptide

Immune stimulant
Component of BCG Cell wall

Delivered to monocytes + Macrophages and becomes activated.
When activated, becomes tumoricidal

19

Any RCTs that you know about that used Muramyl Tripeptide?

Yes, Meyers JCO 2005

N=650
Prospective phase III study
Newly Dx osteosarcoma

Aim: evaluate benefit of Ifosfamide and/or MTP when added to MAP

4 arm study:
1) MAP + Ifosfamide --> Sx --> Maintenance MAP
2) MAP + MTP --> Sx --> Maintenance MAP/MTP
3) MA + Ifosfamide --> Sx--> Maintenance MD/Ifosfamide/CDDP
4) MA + Ifosfamide + MTP --> Surgery --> Maintenance MAP/Ifosfamide/MTP

RESULTS:
- MTP Trend towards better EFS HR 0.8
- MTP Improves OS HR 0.71

CONCLUSION: No benefit to addition of IE

20

What percentage of patients with 1st osteosarcoma relapse are long-term survivors?

15-20%

Remaining:
1/2 do not achieve CR
1/2 achieve CR and relapse further

21

What is the 5y OS for 5th Recurrence of osteosarcoma?

20%

22

What are the risk factors for osteosarcoma so?

Previous RT
Pages disease of bone
Germline abnormalities (eg Li-Fraumeni, Werner, Rothmund-Thomson, loom, Hereditary retinoblastoma)

23

What is the most common bony sarcoma of adulthood?

Chondrosarcoma

24

What is the most likely bone tumor in the following age groups:
(A) 5 yo
(C) >40yo

(A) 5 yo
- Primary bone sarcoma

(C) >40yo
- metastasis
- myeloma

25

Why is internal fixation contraindicated in a case of pathological fracture when bony tumors are suspected?

This will result in dissemination of tumor further into the bone and soft tissue, and will increase the risk of local recurrence.

External splintage is recommended + adequate pain control

26

Which part of the bone does osteosarcoma usually arise from?

Metaphysis of a long bone
Most commonly around the knee.

27

What are the adverse prognostic or predictive factors of osteosarcoma?

Detectable primary mets
Axial or proximal extremity tumor site
Large tumor size
Elevated serum ALP or LDH
Older age

28

Which osteosarcomas have a lower metastatic potential?

Low-grade central osteosarcoma
Paraosteal osteosarcoma

29

Describe the molecular biology of Ewing sarcoma

Almost all share a common gene rearrangement involving:
- reciprocal translocation t(11;22)(q24;q12)

Other translocation so include:
- t(21;22)(q22;q12)
- t(7;22)
- t(17;22)
- t(2;22)
- inv (22)

30

What are the 6 most active chemotherapeutic agents in the treatment of Ewing's sarcoma?

Cyclophosphamide
Doxorubicin
Vincristine
Ifosfamide
Etoposide
Dactinomycin

31

What are the types of chondrosarcoma that you know of?

1) Intramedullary
- Conventional (Hyaline/myxoid)
- cc
- De-differentiated
- Mesenchymal
2) Juxtacortical

32

What is condrosarcoma?

Rare bone sarcoma

Characterized by the production of cartilage by neoplastic cells

5 main types:
1) Conventional
- Primary central chondrosarcoma
- secondary peripheral chondrosarcoma
2) cc
3) De-differentiated
4) Mesenchymal

33

What is the general treatment outline for chondrosarcoma?

Relatively chemo and radio-resistant

Conventional/cc = surgery
De-differentiated = treat as for Osteosarcoma with Adjuvant AP
Mesenchymal - treat as for Ewing's

34

What is the general treatment outline for Ewing's sarcoma?

Induction chemo - 4 to 6 cycles
Local therapy - Surgery vs radiation
Adjuvant chemo - total 14#

Choice of chemo - Alternating CAV-IE

Grier NEJM 2003

35

What is the evidence for CAV-IE in the treatment of Ewing's sarcoma and primitive neuroectodermal tumor of bone?

NCI protocol INT-0091
Grier NEJM 2003

30 yo or younger, n=500
2 arms:
1) 49w of CAV alone
2) CAV alternating with IE

Chemo Q3weekly X 17 courses = 49 weeks
Dactinomycin substituted for Doxorubcin when dose >375mg/m2

RESULTS:
5y EFS 55% vs 70%
5y OS 60% vs 70%

36

What is the evidence for using did CAV-IE in Ewing's ?

Womer JCO 2008
Sensitivity of ESFT (Ewing sarcoma family tumors) to alkylating agents with a steep dose response curve

37

List in order of most frequent to least frequent:
Chondrosarcoma, osteosarcoma, Ewing's

1) Osteosarcoma
- 55%

38

Tell me about the COSS study

Cooperative Osteosarcoma Study Group (COSS) analysis

1700 patients
Time to relapse 18m, with subsequent relapses shorter
1st relapse usually distant (87%), of which 3/4 lung only

1st Osteosarcoma relapse:
- 20% are long-term survivors
- 40% achieve CR and relapse further
- 40% never achieve CR

39

What is Giant Cell Tumor?

Aggressive, locally recurrent tumor of low malignant potential

Histo; unknown origin
Sites: Long bone, vertebra, sacrum

20% become malignant after local recurrence

Resection provides 90% cure
Currettage provides 50% recurrence

Adjuvant RT has a role as:
- GCT is radio-sensitive
- local control rate 80%
- consider for Unresectable cases

40

Which part of the bone does chondrosarcoma usually arise from?

Metaphyseal region of long bones

41

Where do Chordoma arise from?

From embryonic remnants of the notochord
More common in older adults

42

Where are chordomas found?

Axial skeleton
Skull base
Sacrum
Spine

43

What makes up the Ewing's Sarcoma Family of Tumors? (ESFTs)

ESFTs are a group of small round-cell neoplasms.

They include:
1) Ewing' sarcoma
2) PNET (Primitive neuroectodermal tumor)
3) Askin's tumor
4) PNET of bone
5) Extra-osseous Ewing's sarcoma

44

What characterizes Ewing's

Fusion of EWS gene with various members of the ETS gene family

EWS gene = EWSR1
- on chromosome 22q12
ETS Gene family include:
- FLI1
- ERG
- ETV1
- ETV4
- FEV

EWS-FLI1 fusion transcript results from fusion of EWS and FLI1
- FLI1 is located on chromosome 11
- t(11;22)(q24;12)
- identified in 85% of pts Ewing's

Ewing's is also characterized by strong expression of cell surface glycoproteins MIC2 (CD99)