Bony Sarcomas Flashcards
What is the distribution of osteosarcoma?
8% mandible
10% humerus
15% hip/femur
60% knee
What is identified on the pathology of osteosarcoma?
Malignant osteoblasts and osteoid
Pink amorphous intercellular material
+/- Collagen (Complix Dx)
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
Is osteosarcoma radiation sensitive?
NO
What are the surgical options for osteosarcoma?
1) Amputation
2) Wide excision +/- megaprosthesis
3) Rotationplasty
What is the survival rate of osteosarcoma with surgery alone?
20%
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
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
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
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
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
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
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%
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]
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
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
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]
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
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
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
What is the 5y OS for 5th Recurrence of osteosarcoma?
20%
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)
What is the most common bony sarcoma of adulthood?
Chondrosarcoma
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
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
Which part of the bone does osteosarcoma usually arise from?
Metaphysis of a long bone
Most commonly around the knee.
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
Which osteosarcomas have a lower metastatic potential?
Low-grade central osteosarcoma
Paraosteal osteosarcoma
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)
What are the 6 most active chemotherapeutic agents in the treatment of Ewing’s sarcoma?
Cyclophosphamide Doxorubicin Vincristine Ifosfamide Etoposide Dactinomycin
What are the types of chondrosarcoma that you know of?
1) Intramedullary
- Conventional (Hyaline/myxoid)
- cc
- De-differentiated
- Mesenchymal
2) Juxtacortical
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
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
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
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%
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
List in order of most frequent to least frequent:
Chondrosarcoma, osteosarcoma, Ewing’s
1) Osteosarcoma
- 55%
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
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
Which part of the bone does chondrosarcoma usually arise from?
Metaphyseal region of long bones
Where do Chordoma arise from?
From embryonic remnants of the notochord
More common in older adults
Where are chordomas found?
Axial skeleton
Skull base
Sacrum
Spine
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
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)
