(O)varia
Liesbeth de Vries UMCG
Opbouw
• • • •
Vulvacarcinoom Endometriumcarcinoom Cervixcarcinoom Ovariumcarcinoom
Vulvacarcinoom • 330 nieuwe tumoren/jaar • Inguinale lymfekliermetastasen negatieve prognostische factor • Behandeling: – Lymphadenectomy als positieve klieren – Adjuvante regionale bestraling • na klierdebulking • na standaard inguino femorale klierdissectie indien: – >1 positieve klier – klinisch N1,2 klieren die ook pathologisch blijken te zijn aangedaan – extra-nodale groei
• Internationaal onduidelijkheid over nut adjuvante therapie – Radiotherapie – Chemotherapie • Kleine studies
Retrospectieve Duitse vulvastudie in 29 centra 1998-2008 1637 patients with vulvar cancer 245 patients with unknown LN status (15%)
497 patients with LN metastases
910 node-negative patients 26 patients with unknown Tx status (5%)
243 patients with adjuvant Tx 209 patients with adjuvant RT 86%
288 patients without adjuvant Tx 34 patients with adjuvant RCT 14%
AGO-CaRe-1: node positieve vulvacarcinoompatienten
GROINSS-V2 observational trial + stopping rules ongoing • Therapie:
– Tumoren <4 cm – Sentinel node negatief: geen lymfadenectomy – Positieve liesklieren (20%): gerichte bestraling
• On hold Sept 2010: – want liesrecidief 10% – > 2 mm recidief 20%
• Nu weer accrual – < 2 mm radiotherapie (50% sentinel nodes) – > 2 mm lymfadenectomie, afhankelijk uitslag +/- rad ther (extranodaal enzo)
• Nu n=756, totaal aantal gepland 1500 (150 sentinel node < 2 mm)
Stadium 1 endometriumcarcinoom Adjuvante radiotherapie – Laag stadium (FIGO 1988 stadium I-IIA; FIGO 2009 stadium I) met laag of laag-intermediair risicoprofiel alleen chirurgie. – Laag stadium (FIGO 1988 stadium I-IIA; FIGO 2008 stadium I) met hoog-intermediair risicoprofiel radiotherapie. • Vaginale brachytherapie voorkeur boven uitwendige radiotherapie.
– Stadium I (FIGO 1988 stadium I-IIA; FIGO 2008 stadium I) met hoog risicoprofiel, stadium II (FIGO 1988 stadium IIB; FIGO 2008 stadium II) en stadium III • Uitwendige radiotherapie.
Klassieke studie 1980: Lindeman et al
TAH-BSO 540 patients
Conclusion: Only patients with poorly differentiated tumors (grade 3), which infiltrate more than half the myometrial thickness, might benefit from additional external radiotherapy
Vaginal IRCT
No further treatment: 277
Pelvic RT: 263
Update: Follow up endometriumcarcinoom Registry of Statistics Norway Survival Study population
Individual linkage
Causes of Death Registry
Cancer Registry of Norway
Median follow-up 20.5 (0-43.4 years)
Incident secondary cancers
Survival endometriumcarcinoom 568 patienten behandeld 1968-1974 mediane follow-up 20,5 jaar
Relapse free survival
Overall survival
<60 jaar bij diagnose endometriumcarcinoom Overall survival
Overall
Risk secondary cancer
2de tumoren <60 jaar Localization
EBRT (n=150)
Control (n=145)
n
%
n
%
Vulva/vagina
1
0,7
0
0
Bladder
6
4,0
1
0,7
Other urological cancer
1
0,7
1
0,7
Colorectal/anus
14
9,3
9
6,2
Skin
9
6,0
2
1,4
Small bowel
0
0
0
0
Gastric, pancreas, gallbladder
6
4,0
6
4,1
Breast
8
5,3
9
6,2
Lung
2
1,3
1
0,7
Leukemia/Lymphoma
3
2,0
3
2,1
Sarcoma
0
0
0
0
Other
4
2,7
2
1,4
Total
54
36,0
34
23,4
Toekomst • Steeds minder radiotherapie • Brachy minder belastend dan externe radiotherapie • Rol chemotherapie
Medicamenteuze behandelopties vergevorderd endometriumcarcinoom • 1ste lijn: o Hormonale therapie: progestagenen o Chemotherapie: slecht gedifferentieerde en/of ER/PgR neg. tumor of als ongevoelig geworden voor hormoontherapie. • 2de lijn: – Geen standaard • Oncoline: bv tamoxifen
Molecular determinants van effect mTOR inhibitie in 3 studies in endometriumcarcinoompatienten PI3K-AKT-mTOR pathways
PTEN mutaties 30-70%
Celcylcus Angiogenese etc
Moleculaire resultaten versus best response 73 tumoren:238 mutations in 19 oncogenes
Perfect man easier to find than perfect biomarker
Gemetastaseerd cervixcarcinoom • Patienten vaak eerder cisplatin & radiotherapie gehad • Behandeling – Bij afstandsmetastasen: • carboplatine + paclitaxel – vertaling: Phase 3 study of cisplatin with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: a GOG study. Moore DH et al J Clin Oncol 2004;22:3113-9.
– Cie Bom: cisplatine met topotecan kan als goed nierfunctie
Fase 3 paclitaxel + carboplatin vs paclitaxel + cisplatin in stage IVb cervixcarcinoom: JCOG0505.
PFS
Overall Survival cisplatine met topotecan
Prognose ovariumcarcinoom
2011
Dose-dense weekly paclitaxel in Stage II-IV ovarian cancer: JGOG Carboplatin AUC 6
Paclitaxel 180 mg/m2
x 6-9
R Carboplatin AUC 6
Paclitaxel 80 mg/m2/wk x 3
x 6-9
Dose-dense paclitaxel > hematologic toxicity, and < patients completed all protocol therapy. Accrual 637 patients (631 intent to treat) Katsumata N, et al. Lancet. 2009;374:1331-1338
Update progressie vrije overleving JGOG trial
Overall survival JGOG trial in relatie tot residuale ziekte
histologisch subtype geen effect clear cell & mucineus
Conclusies
• Dose dense paclitaxel beter – Al onderdeel NCCN guidelines
• Speciaal voor Japanners? – Dose dense paclitaxel ook superieur bij borstkanker
• Confirmatory studies ongoing
Ovaria: targeted agents
1. 2.
3.
Erlotinib: EGFR1 tyrosine kinase remmer: 1ste lijn: Olaparib: PARP remmer: gerandomiseerde fase 2: recidief platinum sensitief Bevacizumab: Platina resistent recidief fase 3
Randomised trial erlotinib vs observatie in 1ste lijn ovariumcarcinoom Ovarian, tubal or peritoneal cancer FIGO stage high-risk I or II-IV (n=835) 6-9 courses platin-based chemotherapy No progression at the end of chemotherapy Randomisation
Erlotinib 150mg daily orally 2 years
Observation
Erlotinib study
PFS
Overall survival
Olaparib plus paclitaxel & carboplatin followed by olaparib maintenance in platinum-sensitive recurrent serous ovarian cancer patients. Phase 2
Patients with: • • • • •
Platinum-sensitive A serous histology or serous component Measurable disease ≤ 3 previous platinum-containing regimens Progression free ≥ 6 months following completion of last platinum-containing regimen
Olaparib 200 mg bid (d1-10 every 21 days) n=81 + paclitaxel 175 mg/m2 (iv, d1) + carboplatin AUC4 (iv, d1)
R 1:1 n=81
n=66 Maintenance phase
Olaparib 400 mg bid continuously
Completion of 4-6 x 21-day cycles of chemotherapy
Paclitaxel 175 mg/m2 (iv, d1) + carboplatin AUC6 (iv, d1)
All patients followed for objective radiologic progression and survival
n=55 Maintenance phase No further study treatment
Progression free survival
Fase 2 gerandomiseerde studie: olaparib in patiënten met response op platinum voor recidief sereus ovariumcarcinoom Platinum-sensitive high grade serous ovarian cancer •≥ 2 previous platinum regimens •Last chemotherapy: platinumbased with a maintained response •Stable CA125 at trial entry •Randomization stratification factors: • Time to diseasse progression on penultimate platinum therapy • Objective response to last platinum therapy • Ethnic descent
Olaparib 400 mg po bid
R
1:1
Treatment until disease progression
Placebo po bid
Multinational study; 82 sites in 16 countries
Ledermann et al, NEJM 2012
Progression free & overall survival
AURELIA trial in platinum resistente ovariumtumoren
Platinum-resistant OC • ≤ 2 prior anticancer regimens • No history of bowel obstruction/ abdominal fistula, or clinical/ radiological evidence of rectosigmoid involvement
Chemotherapy
Treat to PD/toxicity
Optional BEV monotherapy
R 1:1 BEV 15 mg/kg q3w + chemotherapy
Treat to PD/toxicity
Investigators choice (without BEV)
Progression free survival Aurelia & Oceans (platinum sensitive recurrent disease) Aurelia
Oceans
Aghajanian C et al. J Clin Oncol 2012;30:2039-2045
De biologie van kanker • Oncogenes activatie – Mutaties, amplificaties of translocaties in een nieuw eiwit – Meest belangrijke • Amplificaties: – HER2-neu
• Translocaties: – ALk, BCR-Abl, RAR-PML
• Mutaties – B-RAF, EGFR, c-Kit, Jak, Patch
• Tumor suppressors verlies – VHL-angiogenese inhibitors – BRCA1,2-PARP inhibitors
Genetica gynecologische tumoren
• Cervix en endometriumcarcinoom – 1/3 drugable target
• Ovariumcarcinoom – 160 mutaties in 15 drugable genes – Nauwelijks afwijkingen
– Sereuze ovariumcarcinoom mn loss van tumorsuppressors • Mn P53, BRCA loss
CGH analyse: serous ovariumcarcinoomThe Cancer Genome Atlas. • Ziekte van genome instabiliteit • Amplificaties en deleties
Somatische mutaties 2 ovariumcarcinomen
Conclusies discussiant • Stop targeted therapy studies in sereus ovariumcarcinoom • Sequence 10000 ovariumcarcinomen • Gebruik nieuwe strategieën – (Maak gebruik van genoominstabiliteit) – ADC – Immunotherapie
Low grade sereus ovariumcarcinoom PI3K and MEK inhibitor combinations Receptor tyrosine kinase
• •
Vaak K-Ras, B-Raf mutatie A phase 1 studie oraal BKM120 + GSK1120212 in patients with selected advanced solid tumors: Philippe Bedard et al PTEN
Pan-PI3K
BKM120
RAS
PI3K
AKT
RAF
Crosstalk
MEK
GSK112 MEK 1/2
FOXO
ERK mTORC1
Cell survival
Cell growth, metabolism
Cell proliferation angiogenesis
= frequently mutated in cancers
Best % change from baseline and best overall response: by treatment
* * *
* Denotes partial response
Take home messages • Vulva- en endometriumcarcinoom: – Rol radiotherapie aan het verschuiven
• (Sereus) Ovariumcarcinoom – Weinig drugable targeted options – Standaard: • Carboplatin met (wekelijks) paclitaxel
• Low grade sereus ovariumcarcinoom – Andere tumor met drugable targets
• Toekomst
Planning
The perfect biomarker and man?
