clasificación de riesgo en renal metastásico
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Mauricio Lema Medina MD – Clínica de oncología Astorga, Clínica SOMA, Medellín
Clasificación del riesgo renal metastásico
51 Congreso Internacional de Urología, Medellín, Agosto 11, 2016
BHD=Birt-Hogg-Dubé; FH=fumarate hydratase; VHL=von Hippel-Lindau.Modified from Linehan WM et al. J Urol. 2003;170:2163-2172.
Histological Classificationof Human Renal Epithelial Neoplasms
RCC
Clear cell75%
Type
Incidence (%)
Associated mutations VHL
Papillary type 1
5%
c-Met
Papillary type 2
10%
FH
Chromophobe
5%
BHD
Oncocytoma
5%
BHD
CJ Creighton et al. Nature 000, 1-7 (2013) doi:10.1038/nature12222
Somatic alterations in ccRCC.
CJ Creighton et al. Nature 000, 1-7 (2013) doi:10.1038/nature12222
DNA methylation and ccRCC
CJ Creighton et al. Nature 000, 1-7 (2013) doi:10.1038/nature12222
mRNA and miRNA patterns reflect molecular subtypes of ccRCC.
CJ Creighton et al. Nature 000, 1-7 (2013) doi:10.1038/nature12222
mRNA and miRNA patterns reflect molecular subtypes of ccRCC.
RCC Therapy: Targeting VEGF at Multiple Levels
AKT
mTOR HIFɑVHL
PI3K
Cell stimuli(eg, growth factors)
Cell growthsurvival
HIFɑHIFɑ
HIFɑ
Inactivated VHL tumor suppressor gene
Hypoxia
VEGF
PDGF
VEGFR
PDGFR
TemsirolimusEverolimus
SunitinibSorafenibPazopanib
AxitinibCabozantinib
Bevacizumab
HIFɑ
Adapted from Rini BI, et al. Lancet. In press.
Tumor
EndothelialCell
Cabozantinib
For researchFor predictionFor clinical decision-making
Risk stratification
Relevant
Accepted
Practical
Relevant
Accepted
PracticalSimple
AgeMotzer score
LDHHbCa++Prior history of nephrectomyECOG status
Nuclear grade 1 through 4 tumoursStageHistology
Motzer RJ, et al J Clin Oncol 1999;17:2530–2540
mRCC: prognostic factors1.0
0.8
0.6
0.4
0.2
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Years following systemic therapy
Prop
ortio
n su
rviv
ing All (670 patients, 57 alive)
Median survival: 10 monthsCI: (9, 11)
MSKCC risk factor model
22
53
25
Patients (%)
≥3
1–2
0
Number of poor prognostic features
Poor
Intermediate
Favourable
MSKCCrisk group
4
10
20
Median OS (months)
Motzer RJ et al. J Clin Oncol. 2002;20:289-296.
MSKCC Risk Factor Model in mRCC
0 risk factors (n=80 patients)1 or 2 risk factors (n=269 patients)3, 4, or 5 risk factors (n=88 patients)
Risk factors associated with worse prognosis• KPS <80• Low serum hemoglobin (13 g/dL/11.5 g/dL: M/F) • High corrected calcium (10 mg/dL)• High LDH (300 U/L)• Time from Dx to IFN- <1 yr
Time From Start of IFN- (years)
Prop
ortio
n Su
rviv
ing
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 2 1614131195436 151210876
MS:20 mo10 mo4 mo
Comparison of Risk Factor Criteria for RCC:Memorial Sloan-Kettering Cancer Center (MSKCC) and Cleveland Clinic
Foundation (CCF)
Motzer RJ, et al. J Clin Oncol. 2002; 20:289-296. Mekhail TM, et al. J Clin Oncol. 2005;23:832-841.
Risk groups are defined as follows:Favorable: 0 risk factors present Intermediate: 1 or 2 risk factorsPoor: 3,4, or 5 risk factors
MSKCC Criteria 2002Factor Poor Prognostic
FactorTime from diagnosis totreatment with IFN-alfa
< 12 months
Hemoglobin < lower limit of laboratory’s reference range
Lactate dehydrogenase > 1.5 X the upper limit of laboratory’s range
Corrected serum calcium
> 10.0 mg/dL
Karnofsky Performance Status
< 80
CCF Criteria 2005
Factor Poor Prognostic Factor
Time from diagnosis totreatment with IFN-alfa
<12 months
Hemoglobin < lower limit of laboratory’s reference range
Lactate dehydrogenase > 1.5 X the upper limit of laboratory’s range
Corrected serum calcium
> 10.0 mg/dL
Prior radiotherapy Yes
Presence of hepatic, lung, or retroperitoneal node metastases
Yes (2 or 3)
Comparison of Risk Factor Criteria for RCC:Memorial Sloan-Kettering Cancer Center (MSKCC) and Cleveland Clinic
Foundation (CCF)
Motzer RJ, et al. J Clin Oncol. 2002; 20:289-296. Heng DYC, et al. The Lancet Oncology 2013 (14):141-148.
Risk groups are defined as follows:Favorable: 0 risk factors present Intermediate: 1 or 2 risk factorsPoor: 3,4, or 5 risk factors
mRCC Database Consortium 2013
Factor Poor Prognostic Factor
Karnofsky Performance Status
<80
Time from diagnosis toTreatment
< 12 months
Anemia Hb below normal
Hypercalcemia Corrected serum Ca above normal
Neutrophilia ANC above normal
Thrombocytosis Platelet count above normal
MSKCC Criteria 2002Factor Poor Prognostic
FactorTime from diagnosis totreatment with IFN-alfa
< 12 months
Hemoglobin < lower limit of laboratory’s reference range
Lactate dehydrogenase > 1.5 X the upper limit of laboratory’s range
Corrected serum calcium
> 10.0 mg/dL
Karnofsky Performance Status
< 80
Figure 1
The Lancet Oncology 2013 14, 141-148DOI: (10.1016/S1470-2045(12)70559-4) Heng DYC, et al. The Lancet Oncology 2013 (14):141-148.
External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study
Figure 2 External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study
Heng DYC, et al. The Lancet Oncology 2013 (14):141-148.
Figure 2 External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study
Heng DYC, et al. The Lancet Oncology 2013 (14):141-148.
Figure 2 The International Metastatic Renal Cell Carcinoma Database Consortium model as a prognostic tool in patients with metastatic renal cell carcinoma previously treated with
first-line targeted therapy: a population-based study
Ko JJ et al. The Lancet Oncology 2015 (16): 293-300.
Figure 2 The International Metastatic Renal Cell Carcinoma Database Consortium model as a prognostic tool in patients with metastatic renal cell carcinoma previously treated with
first-line targeted therapy: a population-based study
Ko JJ et al. The Lancet Oncology 2015 (16): 293-300.
MSKCC is king
Sunitinib improves PFS in 1st-line mRCC
0 3 6 9 120
0.5
1.0
15
PFS in 750 patients
Time (months)
PFS
prob
abilit
y
Hazard ratio = 0.415(95% CI: 0.32–0.54)p<0.000001
SunitinibMedian PFS = 11 monthsIFN-Median PFS = 5 months
Motzer R, et al. NEJM 2007
1.0
0.8
0.6
0.4
0.2
0Surv
ival
Dist
ributi
on F
uncti
on
0 5 10 15 20 25 30 35Time to Death (Mos)
Arm 3: IFN + Tem
Arm 2: TemArm 1: IFN
*Modified MSKCC poor risk. †Stratified by country and nephrectomy status. ‡SD 24 wks.Hudes G, et al. N Engl J Med. 2007;356:2271-2281.
RANDOMIZATION†
IFN-α 3 MU-18 MU (n = 207)CR + PR: 4.8%
CR + PR + SD‡: 15.5%
Tem 25 mg QW (n = 209)CR + PR: 8.6%
CR + PR + SD: 32.1%
3/6 Poor-Risk Features:LDH > 1.5 x ULNHb < LLNCa++ (corrected) > 10 mg/dLKPS 60-70Initial diag to random < 1 yr
Multiple sites of metastases mRCC (N = 626)
IFN-α 3 MU-6 MU + Tem 15 mg QW (n = 210) CR + PR: 8.1%
CR + PR + SD: 28.1%
Parameter IFN Arm 1
(n = 207)
TemArm 2
(n = 209)
Tem + IFN Arm 3
(n = 210)
Median survival, Mos
7.3 10.9 8.4
Comparisons Arm 2 toArm 1
Arm 3 to Arm 1
Stratified log-rank P
.008 .70
Temsirolimus Phase III Trial in Poor-Risk RCC*: Tem ± IFN-α; OS by Treatment
Phase III COMPARZ: First-line Pazopanib vs Sunitinib for Clear-Cell mRCC
• Primary endpoint: PFS • Secondary endpoints: OS, ORR, time to response, safety, QoL,
medical resource utilization
Pts with mRCC clear-cell histology and no previous
systemic therapy(N = 1110)
Motzer RJ, et al. N Engl J Med. 2013;369:722-731.
Pazopanib 800 mg/day
Sunitinib50 mg/day
(schedule 4/2)
60
COMPARZ: Efficacy Outcomes
• Mean change from baseline in 11 of 14 health-related QoL during first 6 mos of treatment favored pazopanib (P < .05 for all 11 comparisons)
– Significantly less fatigue and foot soreness with pazopanib than with sunitinib
NMedian PFS, Mos (95% CI)
Pazopanib 557 8.4 (8.3-10.9)
Sunitinib 553 9.5 (8.3-11.1)
HR: 1.05 (95% CI: 0.90-1.22)
Motzer RJ, et al. N Engl J Med. 2013;369:722-731. Motzer RJ, et al. N Engl J Med. 2014;370:1769-1770.
PazopanibSunitinib
0O
S (%
)
Mos Since Randomization
NMedian OS, Mos (95% CI)
Pazopanib 557 28.3 (26.0-35.5)
Sunitinib 553 29.1 (25.4-33.1)
HR: 0.92 (95% CI: 0.79-1.06);P = .24
20
40
60
80
100
0 8 16 24 32 40 48 56 640 4 8 12 16 20 24 28 32 36 40
PazopanibSunitinib
100
PFS
(%)
Mos
80
40
20
0
Motzer R et al. N Engl J Med. 2007; 356:115-24
MSKCC risk in relevant clinical trials in mRCCMSKCC factor No. (%) Sunitinib Interferon-alpha
0 (favorable) 143(38) 121(34)
1-2 (intermediate) 209(56) 212(59)
>=3 (poor) 23(6) 25(7)
COMPARZ: Motzer R et al. N Engl J. 2013 Aug 22;369(8):722-31 (Appendix)
Favors Pazopanib Favors Sunitinib
Global ARCC: Hudes G et al. N Engl J Med. 2007; 356:2271-2281
MSKCC factor No. (%) Temsirolimus Interferon-alpha
1-2 (intermediate) 50(24) 64(31)
>=3 (poor) 157(76) 145(64)
100
80
60
40
20
00 2 4 6 8 10 16 24
Mos
Everolimus vs Placebo: Survival Outcomes of RECORD-1
Patients at Risk, n
Everolimus 277 192 115 51 26 10 1 0
Placebo 139 47 15 6 2 0 0 0
Patients at Risk, n
Everolimus 277 267 240 204 164 155 131 101 61 30 6 0 0
Placebo 139 131 117 100 88 74 56 43 27 13 3 0 0
Prob
abili
ty (%
)
HR: 0.87 (95% CI: 0.65-1.17)
Kaplan-Meier Median, MosEverolimus : 14.78Placebo: 14.39Log-rank P = .162
HR: 0.33 (95% CI: 0.25-0.43)
Median PFS, MosEverolimus : 4.90Placebo: 1.87Log-rank P < .001
Everolimus (n = 277)Placebo (n = 139)
PFSCentral Radiology Review
OS
Everolimus (n = 277)Placebo (n = 139)
Motzer RJ, et al. Cancer. 2010;116:4256-4265.
100
80
60
40
20
00 2 4 6 8 10 12 14
Mos12 14 18 20 22
361 256 202 145 96 64 38 20 10 1 0362 224 157 100 51 28 12 6 3 1 0
Patients at Risk, nAxitinibSorafenib
1.00.9
0.80.70.60.50.40.30.20.1
00 2 4 6 8 10
Mos
Stratified HR: 0.665(95% CI: 0.544-0.812;log-rank P < .0001)
12 14 16 18 20
AxitinibSorafenib
mPFS, Mos6.74.7
95% CI6.3-8.64.6-5.6
Prob
abili
ty o
f PFS
Rini BI, et al. Lancet. 2011;378:1931-1939.
AXIS Trial: PFS (IRC Assessment)
Phase III METEOR: PFS of Cabozantinib vs Everolimus After VEGFR TKI
Choueiri T, et al. N Engl J Med. 2015.
100
80
60
40
20
00 3 6 9 12 15 18
Mos
PFS
(%)
Cabozantinib
Everolimus
CabozantinibEverolimus
187188
7.4 (5.6-9.1)3.8 (3.7-5.4)
121126
Events, n
Median PFS,Mos (95% CI)
Pts, n
HR: 0.58 (95% CI: 0.45-0.75); P < .001
MSKCC risk, No. (%)4 Everolimus + BSC, n=277 Placebo + BSC, n=139 Favorable 81 (29) 39 (28)
Intermediate 156 (56) 79 (57)
Poor 40 (14) 21 (15)
RECORD-1: Motzer RJ, et al. Cancer. 2010;116:4256-4265.
Beyond first-line mRCC
MSKCC risk, No. (%)4 Axitinib, n=192 Sorafenib, n=96 Favorable 94(49%) 53(55%)
Intermediate 84(44%) 40(42%)
Poor 7(4%) 2(2%
AXIS: Rini BI, et al. Lancet. 2011;378:1931-1939.
METEOR: Choueiri T, et al. N Engl J Med. 2015].
MSKCC risk, No. (%)4 Cabozantinib, n=187 Everolimus, n=188 Favorable 80(43%) 83(44%)
Intermediate 80(43%) 75(40%)
Poor 27(14%) 30(16%)
CheckMate 025: Efficacy of Nivolumab vs Everolimus in Advanced RCC
Motzer RJ, et al. N Engl J Med. 2015
1.0
0.8
0.6
0.4
0.2
00 333 6 9 12 15 18 21 24 27 30
Mos
NivolumabEverolimus
410411
25.0 (21.8-NE)19.6 (17.6-23.1)
183215
Deaths, n
Median OS,Mos (95% CI)
Pts,n
4.6 (3.7-5.4)4.4 (3.7-5.5)
318322
Progression, n
Median PFS,Mos (95% CI)
Prob
abili
ty o
f PFS
HR: 0.88 (95% CI: 0.75-1.03; P = .11)1.0
0.8
0.6
0.4
0.2
00 333 6 9 12 15 18 21 24 27 30
Mos
HR: 0.73 (98.5% CI: 0.57-0.93; P < .002)
Prob
abili
ty o
f OS
CheckMate 025: Efficacy of Nivolumab vs Everolimus in Advanced RCC
Motzer RJ, et al. N Engl J Med. 2015.
MSKCC risk, No. (%)4 Nivolumab, n=410 Everolimus, n=411 Favorable 145(35) 148(36)
Intermediate 201(49) 203(49)
Poor 64(16) 60(15)
Metastasectomy in Renal Cell Carcinoma
• Characteristics associated with improved survival in patients undergoing metastasectomy for first recurrence– Disease-free interval > 1 yr– Single site of metastasis
• Lung better than brain
• 5-yr survival of 44%– Similar 5-yr survival rates with curative resection
upon second and third recurrence
Kavolius JP, et al. J Clin Oncol. 1998;16:2261-2266.
Observation Before Systemic Therapy Safe for a Subset of Pts With mRCC
Phase II study of pts with mRCC and no previous systemic therapy– Observation with periodic CT assessment; initiation of systemic treatment per discretion of physician and
pt
– Unaffected by IMDC risk group (P = .57), location or number of metastases
Median mos of observation until start of systemic therapy: 14.1 mos
Rini B, et al. ASCO 2014. Abstract 4520.
100
80
60
40
20
00 6 12 18 24 30 36 42 48
Mos From Study Entry
Pts
Still
Und
er
Obs
erva
tion
(%)
P = .05
Meas. burden ≤ 3.0 cm (n = 19)Meas. burden > 3.0 cm or nontarget lesions only (n = 27)
1. Flanigan RC, et al. N Engl J Med. 2001;345:1655-1659. 2. Mickisch GH, et al. Lancet. 2001;358:966-970.
Cytoreductive Nephrectomy
SWOG[1]Median
Survival, MosIFN- + nephrectomy (n = 120) 11.1
IFN- (n = 121) 8.1
EORTC[2]Median
Survival, MosIFN- + nephrectomy (n = 42) 17.0
IFN- (n = 42) 7.0
Mos
P = .05 P = .03
0
20
40
60
80
100
Surv
ival
(%)
0 24 48 72 960
20
40
60
80
100
Surv
ival
(%)
0 12 24 36Mos
Debulking Nephrectomy in mRCC
Pts most likely to benefit from cytoreduction[1] include those with:
– Good performance status with adequate end-organ function
– Potentially surgically resectable primary tumor mass representing at least 75% of total tumor burden
– Good prognostic features– No central nervous system metastases
Current recommendations based on data from trials incorporating IFN alfa-2b[2]
1. NCCN. Clinical practice guidelines in oncology: kidney cancer. v.3.2015. 2. Flanigan RC, et al. J Urol. 2004;171:1071-1076.
Conclusions
• Risk classification in mRCC is vital for:– Prognostic assessment– Treatment allocation– Expected outcomes– Research
• Although the m RCC MSKCC-risk score may not be the best, it is the most widely used
• We probably should continue to use it as long is the “law of the nation” in clinical research.
Sunitnib vs IFN
COMPARZ
METEOR
CheckMate 25
MSKCC risk-score
RECORD1
Robert Motzer
@onconerd
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