Post-ASCO 2013 Urologische tumoren. Stefan Sleijfer

Post-ASCO 2013 Urologische tumoren

Stefan Sleijfer

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

Bekentenis 2: geen rijbewijs  Redenen voor mannen om op latere leeftijd rijbewijs te halen:  Midlife crisis

 Mooie auto willen hebben

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:

Collega De Jong  ASCO

Collega Lolkema

Indeling  Tumortypes:

• Kiemceltumoren • Urotheelcelcarcinomen • Prostaatcarcinomen • Niercelcarcinomen

Standaardbehandeling stadium I testisca.  Seminoma:  Adjuvant radiotherapie (20 Gy)  1-malig carboplatin (AUC 7)  Wait-and-see

 Non-seminoma:  Wait-and-see  (2x BEP)  (Retroperitoneale LK-dissectie, evt gevolgd door 2x BEP)

Oliver, Lancet 2005

Wait-and-see seminoma stage I  Denmark: surveillance standard Vast majority detected by CT-abdomen  1822 pt between 1984-2007

 355 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%

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)

Median FU of 15 yrs:  Conclusion:

•Cause-specific survival: 99.5%:



Wait-and-see excellent option

•Death of disease: 6 pts



Spares 80% of pts from treatment

•Death from Tx: 4 pts



Use of these results to adapt FU schemes

•OS: 92%

Wait-and-see non-seminoma stage I  Surveillance for 1168 pts between (1999-2009)  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

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

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

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)

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?

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

Bizar weinig  No oral presentations  A few prognostic models:  Impact of high IGF1R expression in localized disease  Risk factors for poor outcome to 1st 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)

Prostate cancer: the new sexy tumor type

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

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

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?

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

Standaardbehandeling niercelcarcinoom (RCC)  Gelokaliseerde ziekte:

• Nefrectomie

 Gemetastaseerde ziekte: • Afhankelijk van:

• Subtype RCC • MSKCC risk score (interval diagnose-start behandeling, PFS, Hb, Ca, LDH)

Standaardbehandeling RCC  1ste lijn heldercellig RCC:  Goede en intermediaire prognose: • Sunitinib or pazopanib (equivalent, voorkeur pt voor pazopanib) • IFN / bevacizumab  Slechte prognose: • Temsirolimus

 2e 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

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

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 [1.15-1.77])

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

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

Ropetar studie (WINO studie) ROPETAR trial

* 1:1 randomisatie gestratificeerd op basis van MSKCC prognostic criteria

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)

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

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