Malignant Bone Tumours
Bernadette Brennan
Royal Manchester Children’s
Hospital
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My Brother's Tuna
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The reason I named this piece of art
My Brother's Tuna
is because he said to my mum:
"Why have I got a fish in my leg?“
The reason for this is because he is only five
years old
and he doesn't understand what a tumour is.
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(“Bringing medicine to Life”, by SL, 10 years)
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Numbers
Presentation
? Delay
Osteosarcoma
Ewings
Age distribution of osteosarcoma and Ewing
tumour, national data for England, 1979 - 1997
Percentage Distribution of Cancer Cases
by Age Group (yrs)
Age Group (rank)
15-19
20-24
Lymphoma
27.3 (1)
24.0 (1)
Leukaemia
15.1 (2)
7.7 (5)
Carcinoma
11.3 (3)
21.1 (2)
Malignant Brain Tumours
10.8 (4)
7.7 (5)
Bone Tumours
9.7 (5)
3.4 (8)
Germ Cell Neoplasms
9.6 (6)
16.9 (3)
Soft Tissue Sarcoma
6.3 (7)
4.7 (7)
Malignant Melanoma
5.9 (8)
10.1 (4)
Miscellaneous and Unspecified
4.0
4.4
Bone Tumours
• age
• Limbs common site
• Persistent localised pain-EWING’S
intermittent
• Long history
• Plain x-ray
Goyal et al 2004
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115 patients-Ewing’s Osteosarcoma
1990s
Age 4- 22yrs
Median SI 3.8 months
50 % GP- 36% A&E- 5% specialist
Osteosarcoma
? Outcome after relapse
• Can you be cured
• Prognostic factors
• What systemic treatment
Journal of Clinical Oncology, Vol 21, Issue 4 (February), 2003: 710-715
© 2003 American Society for Clinical Oncology
Postrelapse Survival in Osteosarcoma of the Extremities: Prognostic Factors for
Long-Term Survival
Stefano Ferrari, Antonio Briccoli, Mario Mercuri, Franco Bertoni, Piero Picci,
Amelia Tienghi, Adalberto Brach Del Prever, Franca Fagioli, Alessandro
Comandone, Gaetano Bacci
Ferrari et al, 2003
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5 year PFS 28%
No surgery 0%
Lung>other sites
>24 months better than < 24 months
Chemo prolongs survival in unresectable
disease
Bielack et al., 2009
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5 year OS 16% second relapse
5 year OS third relapse14%
RFI, surgery and number important
No cure without surgery
Systemic Treatment at relapse
• None
• Interferons ?
• Gemcitabine and Docetaxel ?
Interferons in Osteosarcoma
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Cytokine
regulators
Antitumour- direct/indirect
apoptotic
First antiangiogenic regulators
Muller et al., 2005
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89 patients
Non metastatic
Interferon and Surgery only
MFS 63 % after dose increase
Well tolerated
J Clin Onc, 1984;2:617-624
Winkler et al., 1984
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COSS 80 study
Smaller dose
Shorter treatment
No difference in DFS 82%v77%
? Pegylated Interferon the answer
Cancer 2008;113:419-25
Navid et al., 2008
• 17 osteosarcomas
• 3 PR and 1 SD
• Heavily pretreated
Meyer et al., 2008
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662 non metastatic Osteosarcoma
MTP –immune modulator
? Ifosfamide improves OS
? MTP improves OS
Accrual
3000
2500
2000
Safety
Data management / Statistics
Performed/Planned analyses
Accrual in the whole study
30/09/2009
2796 pts
+273 in 1 year
All =>2796
GPOH => 1176
France =>793
UK =>601
EORTC=>149
COG=>77
1500
1000
500
0
sept-99 sept-00 sept-01 sept-02 sept-03 sept-04 sept-05 sept-06 sept-07 sept-08 sept-09
Accrual
3000
2500
2000
Safety
Data management / Statistics
Performed/Planned analyses
Accrual in the whole study and in the sub-trials
30/09/2009
2796 pts
+273 in 1 year
Inclusion => 2796
All R1 => 836 (824 on 01/05/2009)
All R2loc => 189
All R2pulm => 214
1500
30/04/2009
1000
824
500
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sept-99 sept-00 sept-01 sept-02 sept-03 sept-04 sept-05 sept-06 sept-07 sept-08 sept-09
Ewing 2008 Treatment Schema: R1
Disease
evaluation
MRI, CT,
PET +99TC
Register
Disease
evaluation
MRI, CT
PET + 99TC
Primary site
Secondary site(s)
Disease
evaluation
MRI, CT
PET + 99TC
Primary site
Secondary site(s)
Disease
evaluation
Disease
evaluation
Primary site
Secondary site(s)
Primary site
Secondary site(s)
Decision point
for
local therapy
Note: Early
radiotherapy to axial
tumours precludes
busulfan
consolidation!
VIDE INDUCTION
1
2
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harvest PBSC
Quality of Life
assessment
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Y
Quality of Life
assessment
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Zoledronic acid
VAC/VAI
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No add-on
Quality of Life
assessment
K p
a la
nM
- e rie s ru vi a
l se m
it a te s e
p r 0
10
100
% Surviving
75
50
25
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Number at risk
R1 eligible 20
R2 eligible 54
R3 75
1
8
5
4
6
Time in years since relapse
R1 eligible
0
3
1
8
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1
1
R2 eligible
0
0
0
R3
Barker et al., 205
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RFI > 24 months better than < 24 months
Response to second chemo
Metastases at diagnosis
HDT
32% PR
All treatment 50% response
Study rationale :
Phase II : Irino + Temozolomide in Ewing’s S.
Pub 2007
< 2005, dose finding
Irinotecan
temozolomide
< 2005 14 evaluable patients
2006 - 2009 19 evaluable patients
Total
Pub 2009
retrospective
20 mg / m2 / day 5 x 2
100 mg/m2 / day 5
=> 1 CR, 3 PR et 3 minor Resp
=> 5 CR, 7 PR = 63 % responses
33 evaluable patients => 6 CR, 10 PR = 48 % responses
SARC013/NO21158
SARC Global Collaboration: Phase 3 trial of R1507
in combination with cyclophosphamide/topotecan
versus cyclophosphamide/topotecan alone for
treatment of first recurrence Ewing sarcoma
CoPrincipal Investigators
Herbert Juergens
Neyssa Marina
Paul Meyers
Shreyaskumar Patel
Conclusions
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Relapse bad
Need for new therapies
Demonstrate advantage with chemo
Justify cost and QOL