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Prognostic Factors for mRCC:Relevance in Clinical Practice
Daniel Heng MD MPH FRCPCChair, GU Tumor Group
Tom Baker Cancer CenterUniversity of Calgary
Prognostic FactorsPatient Factors
Performance StatusSymptoms
ProinflammatoryMarkers
IL-6ESR
NeutrophiliaThrombocytosis
C-reactive proteinTumor Burden
Prior nephrectomySites of metastasesBone / Liver MetastasesLDHAnemiaCalciumSodium
Treatment-relatedFactors
Prior therapyPrior radiotherapy
Disease-free intervalDiagnosis to treatment interval
Patient X
Patient Y
Patient Z
MSKCC Prognostic Profiles
Motzer et al JCO 2002
IKCWG Prognostic Criteria
Manola et al Clin Cancer Res 2011
International mRCC Database ConsortiumCurrently includes 3700 patients from 25 institutions
Int’l mRCC Database Consortium Prognostic Factors
AnemiaHypercalcemia
NeutrophiliaThrombocytosis
KPS < 80%Dx to Tx Interval <1yr
Heng et al J Clin Oncol 2009
Prognostic Factors
If patient has 0 factors: Favorable Prognosis
If patient has 1-2 factors: Intermediate Prognosis
If patient has 3-6 factors: Poor Prognosis
Heng et al Lancet Oncology 2013
Prognostic Factors: Targeted Therapy Era
43 months
8 months
23 months
Benchmarks from IMDCPopulation (Data from IMDC) PFS (mon)
(95% CI)OS (mon) (95%CI)
1st line therapy (all pts) 7.2 (6.7-7.7)n=2659
20.9 (19.6-22.5)n=2705
1st line therapy in intermediate/poor risk patients & diagnosis to treatment interval < 1 year (similar to ADAPT (AGS003) pts)
5.6 (5.3-6.1)n=1174
14.7 (13.3-16.5)n=1189
1st line therapy in patients with prior nephrectomy (similar to TIVO-1 (Tivozanib) pt)
8.2 (7.8-8.6)n=2080
24.8 (23.1-27.3)n=2117
2nd line therapy (similar to INTORSECT patients)
3.9 (3.6-4.3)n=1151
13.0 (12.2-14.7)n=1157
3rd line therapy (all pts) 4.0 (3.4-4.5)n=425
12.1 (10.7-13.9)n=455
3rd line therapy in patients with 1 prior VEGF and 1 prior mTOR inhibitor (similar to GOLD (dovitinib) pts) 4.4 (3.3-5.2)
n=14018.0 (11.8-24.0)
n=147Ko et al BJC 2014
Conditional Survival Our prognostic criteria are used at the
initiation of treatment How does survival change as you survive
longer? How does survival change as you survive
past the median in your risk group?
Harshman et al Lancet Oncol 2012
Survival of each risk group over time survived already
Harshman et al Lancet Oncol 2012
Conditional Survival in SEER
Bianchi et al BJU 2013
The future of prognostication Reached the ceiling of clinical variables Need biologic markers to add to the
accuracy of existing models IMDC model + X + Y to improve
accuracy
Cancer Genome Atlas Research Network Nature 2013
Why are Prognostic Factors Important?
Prognostic Factors Important for patient counseling
Will you live < 1 year or > 1 year? Important for clinical trial risk
stratification and retrospective study adjustment methods
Italian Database 281/2065 had 3 lines of
targeted therapy VEGF VEGF mTOR vs
VEGF mTOR VEGF HR 2.59 (1.59-4.22)
after adjusting for prognostic criteria
Assumes patients make it to three lines of therapy
No axitinib in study
Iacovelli et al EJC 2013
Prognostic Factors Important for planning therapy
We use temsirolimus for poor risk patients Is active surveillance appropriate for small
bulk, not growing, favorable risk, highly selected patients
Is cytoreductive nephrectomy appropriate?
Cytoreductive Nephrectomy3245 mRCC patients
982/1658 (59%) CytoreductiveNephrectomy
676/1658 (41%)No nephrectomy
EXCLUDED 1587 (49%) w/ nephrectomy
prior to metastases
2569 (79%) patients with nephrectomy
FINAL NUMBERS
Overall Survival
Cytoreductive nephrectomy
No Cytoreductive nephrectomy
Median OS 20.6 vs 9.5 months (p<0.0001)Adjusted HR 0.60 (95%CI 0.52-0.69, p<0.0001)
Ove
rall
Sur
viva
l
Months Since Initiation of Targeted Therapy
HR adjusted for IMDC criteria:0.60 (95%CI 0.52-0.69, p<0.0001)
Incremental BenefitOverall Survival (Months)
No CN OS (Months)
CN OS (Months)
P-value
< 24 7.1n=456
12.3n=480
<0.0001
<18 6.7n=430
10.0n=395
<0.0001
<12 5.5n=366
7.3n=290
<0.0001
<9 4.5n=303
5.5n=218
0.0027
<6 3.2n=230
4.0n=151
0.0084
<3 2.1n=118
2.2n=71
0.9429
Incremental BenefitOverall Survival (Months)
No CN OS (Months)
CN OS (Months)
P-value Incremental Benefit
(Months)< 24 7.1
n=45612.3
n=480<0.0001 +5.2
<18 6.7n=430
10.0n=395
<0.0001 +3.3
<12 5.5n=366
7.3n=290
<0.0001 +2.2
<9 4.5n=303
5.5n=218
0.0027 +1.0
<6 3.2n=230
4.0n=151
0.0084 +0.8
<3 2.1n=118
2.2n=71
0.9429 +0.1
Incremental BenefitOverall Survival (Months)
No CN OS (Months)
CN OS (Months)
P-value Incremental Benefit
(Months)
Hazard Ratio Adjusted for IMDC Criteria
< 24 7.1n=456
12.3n=480
<0.0001 +5.2 0.72 (0.62-0.85) p<0.0001
<18 6.7n=430
10.0n=395
<0.0001 +3.3 0.85 (0.72-1.00) p=0.0498
<12 5.5n=366
7.3n=290
<0.0001 +2.2 0.97 (0.81-1.17) p=0.7614
<9 4.5n=303
5.5n=218
0.0027 +1.0 0.98 (0.79-1.20) p=0.8108
<6 3.2n=230
4.0n=151
0.0084 +0.8 1.02 (0.80-1.31) p=0.8561
<3 2.1n=118
2.2n=71
0.9429 +0.1 1.03 (0.72-1.46)p=0.8782
Using IMDC Prognostic Factors# of IMDC Criteria
MetNo CN OS months
(N)CN OS months
(N)P value
0 92% (65/71) patients had CN, insufficient number to compare
1 22.5 (n=72) 30.4 (n=178) 0.0024
2 10.2 (n=143) 20.2 (n=253) <0.0001
3 10.0 (n=113) 15.9 (n=106) <0.0001
4 5.4 (n=103) 6.0 (n=67) 0.1664
5 3.6 (n=36) 2.8 (n=14) 0.5044
6 25% (3/12) patients had CN, insufficient number to compare
Cytoreductive Nephrectomy Perhaps not appropriate in patients with
survival estimated to be < 1 year Perhaps not appropriate in patients with
4 or more adverse prognostic factors
Prognosis Is important for patient counseling, study
design, and planning therapy Prognosis is dynamic Prognosis needs to be improved with
biomarkersTHANK YOU!
daniel.heng@albertahealthservices.ca
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