Prognostic factors in second-line targeted therapy for metastatic clear-cell renal cell carcinoma after progression on an anti-vascular endothelial growth factor receptor tyrosine kinase inhibitor.
BACKGROUND
About 40% of metastatic clear-cell renal cell carcinoma (m-ccRCC) patients receive a second-line targeted therapy after failure of anti-vascular endothelial growth factor receptor tyrosine kinase inhibitors (anti-VEGFR-TKI). Efficacy of second-line therapy is usually limited and prognostic and predictive factors at the start of second-line therapy are lacking. To identify the subgroup of patients that will benefit from such treatment remains a challenge.


METHODS
We performed a multi-institutional, retrospective study of patients who received a second-line therapy after progression on an anti-VEGFR-TKI. Univariate and multivariate analyses were performed in order to identify prognostic factors for progressive disease (PD) as best response, progression-free survival (PFS) and overall survival (OS) on second-line therapy.


RESULTS
For the whole cohort of 108 patients, mOS from the start of second-line therapy was 8.9 months while mPFS on second-line therapy was 2.8 months. A total of 49/105 (47%) patients had PD, 50/105 (48%) stable disease (SD) and 6/105 (6%) a partial response (PR). On multivariate analysis, the following markers were associated with improved outcome on second-line therapy: a PFS on first-line therapy ≥12 months (HR for PFS: 1.961; p = 0.008) (HR for OS: 1.724; p = 0.037) and Fuhrman grade 1-2 tumors (HR for OS: 2.198; p = 0.007). Markers associated with poorer outcome on second-line therapy were: elevated serum lactate dehydrogenase (LDH) levels (HR for PFS: 0.511; p = 0.04) (HR for OS: 0.392; p = 0.017), low albumin (HR for OS: 0.392; p = 0.01) and elevated corrected calcium levels (HR for OS: 0.416; p = 0.01). The impact on OS of the Memorial Sloan Kettering Cancer Centre (MSKCC) and International Renal Cell Carcinoma Database Consortium (IMDC) prognostic scores as calculated at start of second-line therapy was validated in our patient series.


CONCLUSIONS
Duration of first-line PFS, Fuhrman grade, serum LDH levels, albumin levels, corrected calcium levels and the MSKCC and IMDC scores calculated at start of second-line therapy are prognostic factors for m-ccRCC patients treated with second-line targeted therapy.
a Department of General Medical Oncology , University Hospitals Leuven, Leuven Cancer Institute, KU Leuven , Leuven , Belgium .
Anne
A
Sacré
b Department of Medical Oncology , Centre Hospitalier Régional Universitaire , Strasbourg , France .
Philippe
P
Barthélémy
b Department of Medical Oncology , Centre Hospitalier Régional Universitaire , Strasbourg , France .
Clement
C
Korenbaum
b Department of Medical Oncology , Centre Hospitalier Régional Universitaire , Strasbourg , France .
Mickael
M
Burgy
a Department of General Medical Oncology , University Hospitals Leuven, Leuven Cancer Institute, KU Leuven , Leuven , Belgium .|c Laboratory for Experimental Oncology , University Hospitals Leuven, Leuven Cancer Institute, KU Leuven , Leuven , Belgium .
Pascal
P
Wolter
a Department of General Medical Oncology , University Hospitals Leuven, Leuven Cancer Institute, KU Leuven , Leuven , Belgium .|c Laboratory for Experimental Oncology , University Hospitals Leuven, Leuven Cancer Institute, KU Leuven , Leuven , Belgium .
Herlinde
H
Dumez
d Department of Pathology , University Hospitals Leuven, KU Leuven , Leuven , Belgium .
Evelyne
E
Lerut
e Department of Medical Oncology , AZ Groeninge , Kortrijk , Belgium .
Tine
T
Loyson
f Department of Urology , University Hospitals Leuven, KU Leuven , Leuven , Belgium .
Steven
S
Joniau
g Department of Radiology , University Hospitals Leuven, KU Leuven , Leuven , Belgium , and.
Raymond
R
Oyen
e Department of Medical Oncology , AZ Groeninge , Kortrijk , Belgium .|h Ageing & Cancer Research Cluster, Centre for Positive Ageing, University of Greenwich , London , UK.
Philip R
PR
Debruyne
a Department of General Medical Oncology , University Hospitals Leuven, Leuven Cancer Institute, KU Leuven , Leuven , Belgium .|c Laboratory for Experimental Oncology , University Hospitals Leuven, Leuven Cancer Institute, KU Leuven , Leuven , Belgium .
Patrick
P
Schöffski
a Department of General Medical Oncology , University Hospitals Leuven, Leuven Cancer Institute, KU Leuven , Leuven , Belgium .|c Laboratory for Experimental Oncology , University Hospitals Leuven, Leuven Cancer Institute, KU Leuven , Leuven , Belgium .
Benoit
B
Beuselinck
D000328:Adult; D000368:Aged; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000556:secondary*; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000473:pathology*; D009367:Neoplasm Staging; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D012189:Retrospective Studies; D016879:Salvage Therapy; D015996:Survival Rate; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
D047428:Protein Kinase Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A