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Behandlingsprinsipper Osteosarkom-­‐Ewings sarkom/PNET • Multimodal
Cytostatikabehandling
ved sarkomer
• Preoperativ cytostikabehandling
• Mutilerende kirurgi/svært toksisk cytostatika
• Total behandlingsperiode: 6-9 mnd
Kirsten Sundby Hall
Sarkomprogrammet
Radiumhospitalet
• Behandlingsprotokollene: 4 - 40 år
Forskjeller
Metotrexat ikke effektive ved ES
ES: strålefølsom tumor –
Strålebehandling viktig behandling ved ES
Histoteknikerforeningenes seminar 22.3. 2013
CT=chemotherapy Surg=surgery RT=radiotherapy
Overlevelse - osteosarkom
og Ewing sarkom
OS
EWS
* Historiske data
15-20%
5-10%
I dag lokalisert tumor 70%
60%
Ved metastaser
15-20%
Metastases-free
Survival
Osteosarcoma results:
Scandinavian Sarcoma Group
ISG/SSG 1 1997-2000
SSG VIII 1990-97
SSG II (T-10) 1982-89
CAMOS 1975-80 (DnR)
30%
Surgey alone 1965-75 (DnR)
* FØR CYTOSTATIKA
Months
EURAMOS 1
Treatment outline
Good
response
R
MAP
MAP
IFmaintenance
• Pasientbilder MAP
a
n
d
MAP
Poor
response
M A P + IE
Closed: June 2011, 2260 patients
(SSG 119, COG 1164,
COSS 520, EOI 457)
(301 institutions, 18 countries)
1
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Event-free survival according to response to primary chemotherapy and to high-dose
chemotherapy(HDBuM)
VAC
VIA
V
0
VAC
V
1
2
VAC
3
VIA
Surgery
EI
V
4
5
EI
Oncovin
Adriamycin
Actinomycin
Sendoxan
Holoxan
Etoposide
Good responders
6 7
8
VAC
9
10 11Poor
VIA
EI
Good responders
Poor responders receiving HDBuM
Event-free
survival
Ewings/PNET sarkom
ISG/SSG III
Poor responders not receiving HDBuM
responders
VAC
VIA
EI
Good
Progressive disease
Poor
13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37
VAC
CE
VAC
EI
HMAS
RT 1,5 Gy x 2 x 14 (18)
Ferrari S et al. Ann Oncol 2011;22:1221-1227
© The Author 2010. Published by Oxford University Press on behalf of the European Society for
Medical Oncology. All rights reserved. For permissions, please email:
journals.permissions@oxfordjournals.org
Follow-­‐up – Bone sarcoma Serious late effects after cytostatic treatment
myocard:
kidney :
hearing :
infertility:
doxorubicin
cisplatin,ifosfamide
cisplatin
ifosfamide, cyclophosfamide
After radiotherapy
skeletal growth disturbances
hormonal disturbances
skin
secondary cancer
Bruk av cytosta?ka ved bløtvevssarkomer • Primær kjemoterapi-­‐ (f. eks rhabdomyosarkom) • Adjuvant ?l ”høyrisikopas.” (SSG XX) • v/inop. tumor +metastaser når ”kura?v” intensjon • Pallia?v behandling Cont. follow-­‐up “ Health in long-­‐term side survivors of bone sarcomas”(Scandinavian sarcoma group, MD,PhD, Liv Hege Aksnes, DissertaAon April 2009) -­‐ Most survivors manage well -­‐ Long term effects may present many years a<er treatment -­‐ Survivors have poorer health status compared to controls Rhabdomyosarkom Før vs eQer kjemoterapi tumor
06.09.12
væske
20.11.12
2
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Risk factors – former adjuvant study SSG XIII STS of histologically high-­‐grade malignancy SSG XX Adjuvant therapy arm
for high-risk STS in extremities and trunk wall
with primary surgery Metastases free survival
Surgery
Wide margin for subcutaneous tumor or wide margin for radically amputated patients regardless of tumour depth.
Arm 1
Max 12 weeks
CT1
0
CT2
1
2
CT3
3
4
5
CT4
6
7
8
9
Surgery
Margina l margin for sucutaneous or deep tumor, wide margin for deep tumor
RT 36 Gy
Arm 2
CT1
CT2
CT3 (1.8 x 2/d x 10d)
Max 12 weeks
0
1
2
3
4
5
6
7
8
CT5
10
11
12
CT4
9
10
CT6
13
14
15
16 weeks
CT5
11
12
13
0/1 factor
CT6
14
15
0
2
3
• Tumor size (>10cm) • Vascular invasion • Tumor necrosis 2/3 factors
CT2
1
SIN-­‐factors 16 weeks
Surgery
Intralesional margin, regardless of tumor depth
Arm 3
CT1
Max 12 weeks
PrognosIc system CT3
4
5
6
RT 45Gy
(1.8 x 2/d x 12.5d)
7
8
9
CT4
10
11
CT5
12
13
14
CT6
15
16
SSG XIII
CT regimen Doxorubicin: 60 mg/m2 as a 4 hours infusion Ifosfamide: 2 g/m2 as a 2 hours infusion (with Mesna) on 3 consecu?ve days G-­‐CSF rou?nely P. Gustafson 1994
Adjuvant cytostaIka SSG XX Metastases-free survival
Int J Radiation Oncol Biol Phys Jebsen et al.
2010
Risikofaktorer-­‐Inklusjonskriterier Malignitetsgrad III eller IV • Vaskulær invasion (definert mikroskopisk av patolog) og/eller 2 eller 3 av følgende kriterier • Størrelse ≥ 8.0 cm • Infiltra?v perifer tumorvekst (patolog) • Tumornekrose (patolog) Months
INOPERABEL TUMOR, KURATIV INTENSJON
Kvinne, fysioterapeut f. 57: Bløtdelstumor h. Lår. Almensymptomer-B
Hist: Høygradig malignt fibrøst histiocytom
Multimodal beh: cytostatika+RT+kirurgi
Før kirurgi: cytostatika+ RT
high risk STS
17 weeks
GIST • Stromal tumor som oppstår i gastrointes?naltraktus • GIST ble ?dligere diagnos?sert som leiomyom, leiomyoblastom eller leiomyosarkom • Metastaserer ?l lever og peritoneum – sjelden ?l lunge og lymfeknuter Etter kirurgi: cytostatika + RT:
ET
3
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From “Diagnosis and Management of Soft Tissue Sarcoma” (by
Brennan and Lewis 2002)
Metasta?sk GIST • Strålebehandling sjelden aktuelt • Konvensjonell kjemoterapi brukes svært sjelden (responsrate ca 5-­‐10%) • Første pasient behandlet med Glivec 2000 Long-­‐term results from a randomized phase III trial of standard-­‐versus higher dose Ima?nib for pts with unresectable or metasta?c GIST ……. J Clin Oncol 2008; 26: 620-­‐625 147 pts • Pasientbilder Normal KIT Signaling
The KIT kinase (receptor)
domain activates a
substrate protein, eg,
PI3 kinase, by
phosphorylation
This activated substrate
initiates a signaling
cascade culminating in
cell proliferation and
survival
Time to progression
Substrate
ADP
P
PPP
ATP
PPP
Overall survival
Conclusion: Nearly 50% of patients with advanced GIST who were treated with imatinib
survived for more than 5 years, regardless of a 400mg or 600mg/d starting dose
Effector
Kinase
domains
90% of GISTs: overexpression of KIT receptor=CD117 receptor
Savage and Antman. N Engl J Med. 2002;346:683.
=stem
cell factor receptor
Scheijen and Griffin. Oncogene. 2002;21:3314.
SIGNALING
4
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Mutasjoner c-­‐KIT eller PDGFRA -­‐ GIST Mutasjonsstatus er vik?g fordi det rela?vt godt predikerer behandlingsrespons Imatinib Mesylate- (GlivecR)
Mechanism of Action
Imatinib mesylate occupies
the ATP binding pocket
of the KIT kinase
domain
This prevents substrate
phosphorylation and
signaling
A lack of signaling inhibits
proliferation and survival
KIT
Overall mutation
frequency: 87.4%
Kinase
domains
Exon 9 (11%)
Exon 11 (67.5%)
Exon 13 (0.9%)
Exon 12 (0.9%)
Exon 14 (0.3%)
Exon 17 (0.5%)
Cytoplasm
Exon 18 (6.3%)
PPP
Registrert i Norge : 2002
Imatinib
mesylate
• Kronisk myelogen leukemi
• GIST: inoperabel og/eller metastaserende
SIGNALING
Savage and Antman. N Engl J Med. 2002;346:683.
Scheijen and Griffin. Oncogene. 2002;21:3314.
Novartis
KIT and PDGFRA Mutations Predict Overall
Survival in GIST patients taking Glivec
Overall survival (%)
Wild-type= no
mutations
Membrane
P
ATP
100
90
80
70
60
50
40
30
20
10
0
PDGFRA
KIT exon 11 (n=85)
Heinrich et al. Hum Pathol. 2002;33:484.
Corless et al. Proc Am Assoc Cancer Res. 2003;44. Abstract R4447.
Suni?nib eQer progresjon på ima?nib SuniInib (Sutent) 2.linje ved met. GIST (AcIvity against: c-­‐kit, PDGFR, VEGFR) Indikasjon: manglende effekt eller bivirkninger av Glivec KIT exon 9 (n=23)
No kinase mutation (n=9)
0
100 200 300 400 500 600 700 800
Days
Heinrich et al 2003
Heinrich et al. J Clin Oncol. 2003;21:4342. Reprinted with permission from the American Society of Clinical Oncology.
Adjuvant behandling • I og med at ima?nib hadde en imponerende effekt ved metasta?sk sykdom ble adjuvante studier selvfølgelig igangsaQ SSGXVIII/AIO study design
An open label, multicenter Phase III study. 400pts
Random
assignment
1:1
Imatinib for 12
months
Imatinib for 36 months
Adjuvant imatinib
as treatment of operable GIST
with a high risk of recurrence
Follow-up
Follow-up
ASCO 2011
5
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Overall survival (ITT)
%
96.3%
100
Risikovurdering 92.0%
94.0%
80
81.7%
60
36 Months of imatinib
12 Months of imatinib
40
– vik?ge faktorer: Hazard ratio 0.45 (95% CI, 0.22-0.89)
20
P = .019
0
0
1
36 Months of imatinib
12 Months of imatinib
2
3
4
5
6
7
Years since randomization
No. at risk
198
199
192
188
184
176
152
140
100
88
56
46
13
20
• Man gjør ingen malignitetsgradering av GIST, men en risikovurdering av svulsten • Ulike risikostra?fiseringer • størrelse • mito?sk index • tumorruptur • lokalisasjon 0
0
JAMA 2012 Joensuu H et al
(Human pathology 2002; 33:459-65).
Prognostic factors in primary GIST
GIST Goals 2009
+ Tumor rupture
SSG/ESMO guidelines for Adjuvant Glivec in GIST • Patients: histopathologically proven GIST
(c-kit or DOG-1 +, or typical mutation) with
>= 50% risk for relapse according to NIH
classification + rupture
• - 3 year of treatment
• - 400 mg daily (for exon 9 : 800 mg could
be considered)
• - Exceptions: exon 18 D842V, WT
Neoadjuvant Glivec
Neoadjuvant Glivec Biopsi
Mutasjonsanalyse
Kvinne f.1948
6
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Bivirkninger av ima?nib(Glivec) Generelt godt tolerert • Ødemer • Kvalme • Diare • Derma?Q • Fa?gue • Levertoksisitet • Blødning fra tumor • Interaksjoner med medikamenter som metaboliseres via CYP3A4 er kjent, og man bør være forsik?g med sam?dig bruk av f.eks. paracetamol og warfarin Oppsummering GIST • Kura?v behandling innebærer all?d kirurgi (ved et sarkomsenter) • Ima?nib har revolusjonert den onkologiske behandlingen • Nye medikamenter kommer : Regorafenib, Pazopanib • Mul?modal –tverrfaglig vurdering-­‐ som ved andre sarkomer Bensarkomer • nye medikamenter trengs Bløtvevssarkomer • histologiske undergrupper styrer valg av cytosta?ka • målsøkende medikamenter 7
