25.03.13 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 25.03.13 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 25.03.13 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 25.03.13 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 25.03.13 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 25.03.13 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 25.03.13 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