Behandlingsprinsipper Osteosarkom- Ewings sarkom/pnet. Cytostatikabehandling ved sarkomer M A P. Overlevelse - osteosarkom og Ewing sarkom

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1 Behandlingsprinsipper Osteosarkom- Ewings sarkom/pnet Cytostatikabehandling ved sarkomer Kirsten Sundby Hall Sarkomprogrammet Radiumhospitalet Histoteknikerforeningenes seminar Multimodal Preoperativ cytostikabehandling Mutilerende kirurgi/svært toksisk cytostatika Total behandlingsperiode: 6-9 mnd Behandlingsprotokollene: 4-40 år Forskjeller Metotrexat ikke effektive ved ES ES: strålefølsom tumor Strålebehandling viktig behandling ved ES CT=chemotherapy Surg=surgery RT=radiotherapy Overlevelse - osteosarkom og Ewing sarkom Metastases-free Survival Osteosarcoma results: Scandinavian Sarcoma Group OS EWS * Historiske data 15-20% 5-10% I dag lokalisert tumor 70% 60% ISG/SSG SSG VIII SSG II (T-10) Ved metastaser 15-20% 30% * FØR CYTOSTATIKA Months CAMOS (DnR) Surgey alone (DnR) EURAMOS 1 Treatment outline Good response IFmaintenance Pasientbilder R a n d Closed: June 2011, 2260 patients (SSG 119, COG 1164, COSS 520, EOI 457) (301 institutions, 18 countries) Poor response + IE 1

2 VAC VIA VAC EI V V Ewings/PNET sarkom ISG/SSG III V Good responders Poor responders Oncovin Adriamycin Actinomycin Sendoxan Holoxan Etoposide Event-free survival according to response to primary chemotherapy and to high-dose chemotherapy(hdbum) Event-free survival Good responders Poor responders receiving HDBuM Poor responders not receiving HDBuM Good Poor VAC VIA EI VAC VIA EI VAC VIA EI VAC CE VAC EI HMAS RT 1,5 Gy x 2 x 14 (18) Progressive disease Ferrari S et al. Ann Oncol 2011;22: The Author Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please journals.permissions@oxfordjournals.org Follow- up Bone sarcoma Cont. follow- up Serious late effects after cytostatic treatment myocard: doxorubicin kidney : cisplatin,ifosfamide hearing : cisplatin infertility: ifosfamide, cyclophosfamide After radiotherapy skeletal growth disturbances hormonal disturbances skin secondary cancer 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 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 Rhabdomyosarkom Før vs eqer kjemoterapi tumor væske

3 SSG XX Adjuvant therapy arm for high-risk STS in extremities and trunk wall with primary surgery Wide margin for subcutaneous tumor or wide margin for radically amputated patients regardless of tumour depth. Arm 1 CT1 CT2 CT3 CT4 CT5 CT6 Max 12 weeks weeks Marginal 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) CT4 CT5 CT6 Max 12 weeks Risk factors former adjuvant study SSG XIII STS of histologically high- grade malignancy Metastases free survival 0/1 factor PrognosIc system SIN- factors Tumor size (>10cm) Vascular invasion Tumor necrosis weeks Intralesional margin, regardless of tumor depth RT 45Gy Arm 3 CT1 CT2 CT3 (1.8 x 2/d x 12.5d) CT4 CT5 CT6 Max 12 weeks 2/3 factors high risk STS weeks CT regimen Doxorubicin: 60 mg/m 2 as a 4 hours infusion Ifosfamide: 2 g/m 2 as a 2 hours infusion (with Mesna) on 3 consecu?ve days G- CSF rou?nely P. Gustafson 1994 SSG XIII Metastases-free survival Int J Radiation Oncol Biol Phys Jebsen et al Adjuvant cytostaika SSG XX Months 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) INOPERABEL TUMOR, KURATIV INTENSJON Kvinne, fysioterapeut f. 57: Bløtdelstumor h. Lår. Almensymptomer-B Hist: Høygradig malignt fibrøst histiocytom Multimodal beh: cytostatika+rt+kirurgi GIST Før kirurgi: cytostatika+ RT Etter kirurgi: cytostatika + RT: 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 ET 3

4 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 Pasientbilder 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: pts Normal KIT Signaling Time to progression Overall survival 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 Kinase domains ADP P P P P ATP Substrate P P P Effector 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 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

5 Imatinib Mesylate- (Glivec R ) 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 Registrert i Norge : 2002 Kronisk myelogen leukemi GIST: inoperabel og/eller metastaserende Savage and Antman. N Engl J Med. 2002;346:683. Scheijen and Griffin. Oncogene. 2002;21:3314. Kinase domains Imatinib mesylate P ATP P P P SIGNALING Novartis Mutasjoner c- KIT eller PDGFRA - GIST Mutasjonsstatus er vik?g fordi det rela?vt godt predikerer behandlingsrespons KIT Exon 9 (11%) Exon 11 (67.5%) Exon 13 (0.9%) Exon 17 (0.5%) Heinrich et al. Hum Pathol. 2002;33:484. Corless et al. Proc Am Assoc Cancer Res. 2003;44. Abstract R4447. PDGFRA Overall mutation frequency: 87.4% Wild-type= no mutations Exon 12 (0.9%) Exon 14 (0.3%) Membrane Cytoplasm Exon 18 (6.3%) KIT and PDGFRA Mutations Predict Overall Survival in GIST patients taking Glivec Overall survival (%) 100 KIT exon 11 (n=85) KIT exon 9 (n=23) No kinase mutation (n=9) Days Heinrich et al 2003 Heinrich et al. J Clin Oncol. 2003;21:4342. Reprinted with permission from the American Society of Clinical Oncology. 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 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 Follow-up Imatinib for 36 months Adjuvant imatinib as treatment of operable GIST with a high risk of recurrence ASCO 2011 Follow-up 5

6 % Overall survival (ITT) Hazard ratio 0.45 (95% CI, ) P = % 94.0% 92.0% 81.7% 36 Months of imatinib 12 Months of imatinib Years since randomization No. at risk 36 Months of imatinib Months of imatinib JAMA 2012 Joensuu H et al Risikovurdering Man gjør ingen malignitetsgradering av GIST, men en risikovurdering av svulsten Ulike risikostra?fiseringer vik?ge faktorer: størrelse mito?sk index tumorruptur lokalisasjon (Human pathology 2002; 33:459-65). Prognostic factors in primary GIST GIST Goals Tumor rupture SSG/ESMO guidelines for Adjuvant Glivec in GIST Neoadjuvant Glivec Biopsi Mutasjonsanalyse Neoadjuvant Kvinne f.1948 Glivec 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 mg daily (for exon 9 : 800 mg could be considered) - Exceptions: exon 18 D842V, WT 6

7 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