Post-ASCO 2013 Urologische tumoren. Stefan Sleijfer

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1 Post-ASCO 2013 Urologische tumoren Stefan Sleijfer

2 Bekentenis 1 Research funding by: GSK, Pfizer, Roche, J&J, Philips

3 Bekentenis 2: geen rijbewijs Redenen voor mannen om op latere leeftijd rijbewijs te halen: Midlife crisis Mooie auto willen hebben

4 Bekentenis 2: geen rijbewijs Redenen voor mannen om op latere leeftijd rijbewijs te halen: Midlife crisis: Zit ik mijn hele leven al in Mooie auto willen hebben: ASCO Collega De Jong Collega Lolkema

5 Indeling Tumortypes: Kiemceltumoren Urotheelcelcarcinomen Prostaatcarcinomen Niercelcarcinomen

6 Standaardbehandeling stadium I testisca. Seminoma: Adjuvant radiotherapie (20 Gy) 1-malig carboplatin (AUC 7) Wait-and-see Non-seminoma: Wait-and-see Oliver, Lancet 2005 (2x BEP) (Retroperitoneale LK-dissectie, evt gevolgd door 2x BEP)

7 Wait-and-see seminoma stage I Denmark: surveillance standard Vast majority detected by CT-abdomen 1822 pt between pts relapsed (20%): < 2 yrs: 72% 2-5 yrs: 20% >5 yrs: 8% (tot 15 jaar ) Presentation metastatic disease Good prognostic group: 99% Intermediate risk: 1%

8 Wait-and-see seminoma stage I Statistically significant risk factors for relapse: Invasion small vessels: HR 1.82 Tumor size > 4 cm: HR 1.39 hcg>200 U/l: HR 3.58 (rete testis invasion not) Treatment of relapse: Surgery followed by BEP: 3 BEP: 136 Radiotherapy: 216 (24 needed subsequent BEP) Conclusion: Wait-and-see excellent option Spares 80% of pts from treatment Use of these results to adapt FU schemes Median FU of 15 yrs: Cause-specific survival: 99.5%: Death of disease: 6 pts Death from Tx: 4 pts OS: 92%

9 Wait-and-see non-seminoma stage I Surveillance for 1168 pts between ( ) 21% lymphovascular invasion 256 relapses (22%): Median time to relapse 6 mnths (1-75 mnths) 93% within 3 yrs Detection almost always by CT-abdomen and/or tumor markers Presentation metastatic disease: 90% good risk 8% intermediate 2% poor risk

10 Wait-and-see non-seminoma stage I Impact of LVI 117/244 LVI positive relapsed (48%): 93% within 1 yr 129/903 LVI negative relapsed (14%) Excellent long-term outcomes Conclusion: Wait-and-see excellent option Adaption of FU schemes: CT-scans in particular helpfull 0-2 yrs, thereafter in particular tumormarkers

11 Treatment metastatic disease Based on: histology, primary site, tumor markers, site of metastases Good prognosis group (5-yrs OS: 94%): 3x BEP (or 4x EP) Intermediate prognosis (5-yrs OS: 83%): 4x BEP (or 4x VIP) Poor risk (5-yrs OS: 71%): 4x BEP (or 4x VIP) Poor risk group: Those with unfavorable tumor marker decline at day 21 fare worse Fizazi, JCO 2004

12 Unfavorable tumor marker decline: 4 BEP vs dd regimen Phase III in poor risk pts with unfavorable marker decline after 1x BEP: 3x BEP vs 2x T-BEP/oxaliplatin + 2x BIP (dose-dense regimen) End point 3-yrs PFS: improvement from 46% to 66% (α=.05; 80% power: 196 randomised pt with unfavorable decline (80% whole group)

13 Unfavorable tumor marker decline: 4 BEP vs dd regimen Primary endpoint met: No OS difference (underpowered) Further observations: Neutropenic fever: 17 vs 17% Neurotoxicity gr 2: 23% vs 4% Toxic deaths: 1 vs 1% Salvage HDC + transplant: 6 vs 16% Conclusions: New standard?

14 Urotheelcelcarcinomen standaardbehandeling Gelokaliseerde ziekte: Oppervlakkige tumoren: lokale therapie Spierinvasief: (neo-adjuvante chemotherapie +) lokale therapie (chirurgie of (chemo)radiotherapie) Gemetastaseerd: Eerste lijn: MVAC (q 28 d) Dose- dense MVAC (+ G-CSF q 14 d): Gem/cDDP: gem 1,000 mg/m2 d1,8,15; cddp 70 mg/m2 d2 q28 d

15 Bizar weinig No oral presentations A few prognostic models: Impact of high IGF1R expression in localized disease Risk factors for poor outcome to 1 st line treatment (PS 2, anemia, visceral mets (old news..)) Phase II: advanced disease, renal insufficiency (30-60 ml/min): Gemcitabine, paclitaxel, doxorubicine (+ G-CSF) q 2 wks as 1st line RR: 23/40 pts; median OS: 13,8 mnths Toxicity acceptable Conclusion: randomized study needed (vs gem/carbo)

16 Prostate cancer: the new sexy tumor type

17 Prostaatcarcinoom standaardbehandeling Gelokaliseerde ziekte (afh stadium, Gleason etc): Observatie / prostatectomie / radiotherapie / androgeen suppressie Gemetastaseerd: Androgeen suppressie Castratie-resistent prostaatcarcinoom: docetaxel 3 wekelijks + prednison Post-docetaxel: abiraterone / cabazitaxel / enzalutamide: No direct comparisons Sequence probably matters

18 Diet and prostate cancer Pts with low stages, observation Placebo vs Pomi-T: granaatappel, groene thee, broccoli, kurkuma: All components active against cancer cell lines Primary end point: PSA rise: Beneficial effect (also less pts on active treatment) Conclusions: Interesting (caveat intervention group older (so less testosterone)) Further studies needed

19 CRPC: docetaxel +/- strontium/zoledronate Randomized phase III (2x2 design); 4 arms: Docetaxel/prednisone +/- strontium or zoledronate or both End point: clinical bone progression free survival composite (pain progression, SRE or death) No differences in primary endpoint and OS: Secondary end points: zoledronate: clinical SRE free interval better (HR 0.74 (median 13.1 vs 18.1 mnths)), mostly post-progression Conclusion: Role for ZA as maintenance? But what is impact combined with novel agents that are nowadays given post-docetaxel Cost-effectiveness?

20 CRPC: docetaxel +/- aflibercept Aflibercept: VEGF-trap Phase III: Docetaxel +/- aflibercept Primary end point OS Of note: more than 1200 pts Conclusions: Many failed phase III studies for docetaxel +/-: Bevacizumab, aflibercept, strontium, zolendronate, risedronate, calcitriol, GVAX vaccine, atrasentan, lenalidomide, dasatinib

21 Standaardbehandeling niercelcarcinoom (RCC) Gelokaliseerde ziekte: Nefrectomie Gemetastaseerde ziekte: Afhankelijk van: Subtype RCC MSKCC risk score (interval diagnose-start behandeling, PFS, Hb, Ca, LDH)

22 Standaardbehandeling RCC 1 ste lijn heldercellig RCC: Goede en intermediaire prognose: Sunitinib or pazopanib (equivalent, voorkeur pt voor pazopanib) IFN / bevacizumab Slechte prognose: Temsirolimus 2 e lijn heldercellig: Na cytokine: sorafenib/pazopanib/axitinib Na VEGF-R: everolimus Na mtor blokker: geen standaard Andere subtypes: Urotheelcelca: als blaascarcinoom Ander subtypes (papillair, chromofoob): geen standaard

23 Adjuvant cg250 Adjuvant cg250 (Girentuximab) in high-risk clear cell RCC: Ligand carbonix anhydrase IX Expression in >90% of clear cell RCC Placebo-controlled phase III, double blind No impact on DFS or OS: Maybe DFS effect in high expressors DFS OS

24 Everolimus-sunitinib vs sunitinib-everolimus Randomized phase II: everolimus at PD sunitinib vs sunitinib at PD everolimus Metastatic RCC (clear-cell and non-clear cell) Primary end point: PFS, non-inferiority of everolimus vs sunitinib in 1st line : PFS: HR <1.1: non-inferior 460 pts needed Results: PFS 1 st line: 7.8 mnths vs 10.7 mnts (HR 1.43 [ ])

25 Everolimus-sunitinib vs sunitinib-everolimus Other results: Also non-clear: sunitinib better (HR 1.64) RR: Sunitinib 26% vs everolimus 8% Combined PFS: similar OS: trend better OS for sunitinibeverolimus Conclusion: Start with VEGFR-TKI

26 Intermittent sunitinib Metastatic clear-cell RCC, treatment naive Sunitinib 2 cycles standard dose (50 mg 4/2 wks): < 10% tumor shrinkage: continue treatment > 10% tumor shrinkage: stop treatment, restart with 2 cycles at 10% increase Primary endpoint: feasibility 37 pts enrolled 20 pts intermittent treatment arm: Whole group at final PD : 61 cycles (156 with continuous treatment) Conclusion: many potential advantages (QALY, costs): STAR trial (UK): phase II/III: sunitinib/pazopanib: continuous vs intermittent

27 * 1:1 randomisatie gestratificeerd op basis van MSKCC prognostic criteria Ropetar studie (WINO studie) ROPETAR trial

28 Treatment of RCC with sarcomatoid dedifferentiation Found in 15-20% of RCC, associated with poor outcome Phase II: sunitinib 37.5 mg (2/1 wks) + gemcitabine 1000 mg/m2 (d1,8) End point RR 35 pts: RR: 31% PFS 5.3 mnths 8/35 stopped because of toxicity (neutropenia) Conclusion: Interesting, but should have been done in randomized phase II setting Randomized trial needed to put into perspective (vs VEGFR-TKI alone) (ongoing)

29 Conclusies Kiemceltumoren: Wait-and-see wat mij betreft standaard voor zowel seminoma en non-seminoma st I (aanpassen FU schema s) Poor risk with unfavorable marker decline: dose-dense chemo? Blaascarcinomen: Gebeurt erg weinig; grote behoefte aan nieuwe behandelingen (Heldercellig) niercelcarcinoom: Adjuvant cg250 geen toegevoegde waarde 1e lijn: everolimus inferieur t.o.v.sunitinib Intermittent sunitinib aantrekkelijk om verder uit te zoeken vs continu schema Sunitinib/gemcitabine vervolgstudie nodig

30 Conclusies Prostaatcarcinoom: Pomi-T: in lage stadium waarvoor observatie aantrekkelijk om verder uit te zoeken Gemetastaseerde ziekte: Strontium/zoledronate/aflibercept geen toegevoegde waarde aan docetaxel Komende tijd, veel studies: Directe vergelijkingen, optimale sequentie en combinaties in de verschillende settings met: Cabazitaxel Abiraterone Enzalutamide (MDV3100) Predictieve modellen voor de diverse behandelingen

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