The role of cytoreductive nephrectomy for mRCC in 2020 - Maarten Albersen Dept. of Urology UZ Leuven with assistance of
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The role of cytoreductive
nephrectomy for mRCC in 2020
Maarten Albersen
Dept. of Urology
UZ Leuven
with assistance of:
Eduard Roussel
Alessandro Larcher
CASE Male, 55 YO Medical history: 2002 pneumonia & TB pleuritis No meds • Presents with macroscopic hematuria / cloth retention in 04/2019 > large tumor Rt kidney with Mayo level 1 thrombus. • Embolisation same night. • Free of symptoms. • CT thorax: multiple pulmonary and pleural mets, bilateral. • IMDC: (before bleeding: 0 risk factors) • What would be your advice on MDT?
CASE 1. AS 2. CN + AS 3. Nivolumab (+- deferred CN) 4. Nivolumab + Ipilimumab (+- deferred CN) 5. Sunitinib (+- deferred CN) 6. Axitinib + Pembrolizumab(+- deferred CN)
What is cytoreductive nephrectomy?
Non-curative nephrectomy in mRCC with the goal of
decreasing total tumorload.
• Often + abdominal metastasectomy/LND
• Upfront or delayed.
• Goals:
• Tumor self-seeding principle: volume reduction
• “abscopal effect” in 2% with metastatic reduction (due to relief of
immune-surpressive effects of primary: immunologic sink)
• Better response with systemic therapy
• Palliation (symptoms/paraneoplastic s)
Setting: mRCC
MSKCC-Motzer criteria IMDC-Heng criteria
Diagnosis-systemic therapy < 1 year Diagnosis-systemic therapy < 1 year
PS ULN
LDH > 1.5x ULN Neutrophils > ULN
Platelets > ULN
0 points: favorable OS = 20 months 0 points: favorable OS = 43,2 months
Heng J Clin Oncol 2009 1 or 2 points = intermediate OS = 10 months 1 or 2 points = intermediate OS = 22,5 months
Motzer J Clin Oncol 2002 >2 points = high risk = 4 months >2 points = high risk = 7,8 months
Historical perspective: IFN era
Prospective RCT
Low metastatic load
PS: ECOG 0
Flanigan et al. NEJM 2001
Mickisch et al. Lancet 2001
> Flanigan et al. J Urol 2004
TKI era
Choueiri 2011 Heng 2014 Hanna 2016
Retrospective
Inherent selection bias with CN
Choueiri et al. J Urol 2011
Heng et al. Eur Urol 2014
Hanna et al. JCO 2016
TKI era
Only CN for patients with
life expectancy >12 months
Max 3 IMDC criteria
Heng et al. Eur Urol 2014
EAU guidelines 2018
CARMENA
3-6
N=226 weeks Subitinib
CN
N=450 50 mg QD 4/2
Key eligibility Criteria
mCCRCC Tx naive Randomization
MSKCC int/poor risk 1:1 Stable disease: 18%
ECOG PS 0-1
Stratification Sunitinib
MSKCC risk groups CN
50 mg QD 4/2
Primary endpoint: OS Centre N=224
Design: non inferiority (HR OSCARMENA Major adverse events in favour of CN + Sunitinib
(net reduction -10%, p=0.04)
Mejean et al - NEJM 2018CARMENA: limitations
Population at high risk:
Survival rates poorer than expected (14-18 mos vs 21.8-
26 mos in Motzer & Chouieri. 43% poor-risk
Slow accrual:
• N= 450/576, accrual 0.7 pts/site/yr
• Need to open UK centres: after accrual open in 26
sites around UK, only 14 patients were enrolled
• Ideal patients for CN did not consent, underwent CN
outside of study, exlucions at investigators discretion
Sunitinib arm:
11/224 (5%) did not recieve Sunitinib
38/213 (18%) underwent CN (median 11 months)
CN+ Sunitinib arm
40/226 (18%) did not receive sunitinib
Mejean et al - NEJM 2018 / Stewart et al. Eur Urol – 2017 / Motzer NEJM 2018 / Chouieri JCO 2017
16/186 (9%) did not receive CNCARMENA: is this the patient we
would typically do CN on?
Arora et al. Eur Urol - 2018CARMENA No survival advantage retrospective 5 - 18 months survival advantage following CN Larcher et al - Eur Urol Oncol 2019
CARMENA in current literature
ccRCC
nccRCC
Bhindi et al - Eur Urol 2019CARMENA: subanalyses: delayed CN (OS)
Response as a Litmus test
SURTIME
15.7 mo 48.5 mo
Mejean et al ASCO 2019SURTIME
N=50
CN Subitinib
N=99 50 mg QD 4/2
Key eligibility Criteria
mCCRCC Tx naive Randomization
ECOG PS 0-1 1:1
Stratification Sunitinib Sunitinib
WHO performance status 50 mg QD 4/2 CN
Primary endpoint: PFS ITT (sec:OS) N=49 3 cycles
50 mg QD 4/2
N (powercalc): 458
PI: Axel Bex
Sponsor: EORTC
Not eligble for CN due to
progression: 29%
Bex et al. Jama Oncology 2018SURTIME
Patients who:
Progress
under TKI
Do not benefit
from CN
Safety: no increase of peri-operative outcomes in deferred CN
Bex et al. Jama Oncology 2018Safety of CN: YAU and Leuven cohorts
Postoperative complications CDC (1-5): 29,5% Postoperative complications CDC (1-5): 42%
• High-grade postoperative complications CDC (3-5): 6,1% • High-grade postoperative complications CDC (3-5): 2,3%
• Surgery-related mortality: 1,4% • Surgery-related mortality: 0%
YAU (n=736) Leuven (n=86)
Cardiopulmonary: 5,3% Neurologic: 3,4%
Neurologic: 1,0% Cardiopulmonary: 4,7%
Vascular/Lymphatic: 9,1% Vascular/Lymphatic: 16,3%
Wound/Skin: 1,8% Wound/Skin: 3,4%
Infectious/Metabolic: 8,8% Infectious/Metabolic: 17,4%
Gastrointestinal: 4,5% Gastrointestinal: 9,3%
Predictors for High-grade postoperative morbidity
• Estimated intraoperative blood loss: HR 2.93 (1.20-7.15)
• CN case load: HR 0.13 (0.03-0.59)CARMENA: subanalyses: 1 IMDC risk factor
Median OS (months) ARM A: CN + Sunitinib ARM B: Sunitinib alone HR (95% CI) P-value
(n=127) (n=139)
IMDC 1 risk factor 31.4 (17.3-45.5) 25.2 (19.6-35.4) 1.29 (0.85-1.98) 0.232
IMDC 2 risk factors 17.6 (13.7-21.5) 31.2 (20.5-40.4) 0.63 (0.44-0.97) 0.033
HR (95% CI) 1.68 (1.10-2.57) 0.88 (0.59-1.30)
P-value 0.015 0.515
Mejean et al ASCO 2019UZ Leuven experience (E. Roussel & A. Verbiest)
CARMENA TKI (26) CARMENA practice changing:
intermediate/poor risk with need for
CARMENA CN-TKI (44)
immediate TKI
TOO GOOD FOR CARMENA There is still a population likely
CN+AS (49) benefitting from CNUZ Leuven experience (E. Roussel & A. Verbiest)
Patients with:
Lung only mets
Single site mets
OligometastasisHowever, all these numbers are
OUTDATED (2020)
New backbone in
all risk groups:
(TKI+) IOIMDC analysis on CN in IO era (ASCO-GU20)
inverse probability treatment weighted propensity scored analysis
Which patients got CN in IO era?IMDC analysis on CN in IO era (ASCO-GU20) inverse probability treatment weighted propensity scored analysis
IMDC analysis on CN in IO era (ASCO-GU20) inverse probability treatment weighted propensity scored analysis
Perspective:
Summary YES, the role of CN has drastically changed after CARMENA • No more upfront CN in intermediate (2 IMDC) and poor risk patients. • Deferred CN has become a valid option with response as litmus test. Upfront CN still is recommended • In symptomatic patients • In IMDC 0-1 favourable/intermediate risk • In oligometastatic patients • In patients in which all tumor can be surgically resected • Probably in the same population combined with IO/IO-TKI
CASE Male, 56 YO Medical history: 2002 pneumonia & TB pleuritis No meds 10 months post-CN: Regression of lung mets (CR)
Primary mCCRCC
Take home: MDT
Requiring and Not immediately requiring
eligible for IO/TKI IO/TKI
IMDC poor IMDC intermediate Oligometastasis
2 factors 1 factor
Ipi-Nivo / Axi-Pembro CN CN
Response
Metastasis
AS
directed Tx
Progressive IMDC
Deferred CN disease favorable
IMDC intermediate / poor Axi-
Pembro
Adapted from: Kuusk et al. Ther Adv Med Oncol 2019You can also read
