A systematic review of sequencing and combinations of systemic therapy in metastatic renal cancer.
BACKGROUND
The introduction of novel molecular-targeted agents has revolutionised the management of patients with metastatic renal cell carcinoma (mRCC). However, uncertainties remain over sequential or simultaneous combination therapies.


OBJECTIVE
To systematically review relevant literature comparing the clinical effectiveness and harms of different sequencing and combinations of systemic targeted therapies for mRCC.


METHODS
Relevant databases (including Medline, Cochrane Library, trial registries, and conference proceedings) were searched (January 2000 to September 2013) including only randomised controlled trials (RCTs). Risk of bias assessment was performed. A qualitative and quantitative synthesis of the evidence was presented.


RESULTS
The literature search identified 5149 articles. A total of 24 studies reporting on 9589 patients were eligible for inclusion; data from four studies were included for meta-analysis. There were generally low risks of bias across studies; however, clinical and methodological heterogeneity prevented pooling of data for most studies. Overall, the data showed several targeted therapies were associated with an improvement in progression-free survival in patients with mRCC. There were limited data from RCTs regarding the issue of sequencing; studies on combination therapies have been hampered by difficulties with tolerability and safety.


CONCLUSIONS
Although the role of vascular endothelial growth factor/vascular endothelial growth factor receptor targeting therapies and mammalian target of rapamycin inhibition in the management of mRCC is now established, limited reliable data are available regarding sequencing and combination therapies. Although data from retrospective cohort studies suggest a potential benefit for sequencing systemic therapies, significant uncertainties remain. Presently, mRCC systemic treatment should follow international guidelines (such as the European Society for Medical Oncology, National Comprehensive Cancer Network, and European Association of Urology) for patients fit to receive several lines of systemic therapies.


RESULTS
We thoroughly examined the literature on the benefits and harms of combining drugs for the treatment of kidney cancer that has spread and on the sequence in which the drugs should be given.
Institut Gustave Roussy, Villejuif, France. Electronic address: laurence.albiges@gustaveroussy.fr.
Laurence
L
Albiges
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Toni
T
Choueiri
Institut Gustave Roussy, Villejuif, France.
Bernard
B
Escudier
The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Matthew
M
Galsky
Duke University Medical Center, Durham, NC, USA.
Dan
D
George
Department of Urology, Sunderby Hospital, Sunderby, Sweden.
Fabian
F
Hofmann
Academic Urology Unit, University of Aberdeen, Aberdeen, UK.
Thomas
T
Lam
Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Robert
R
Motzer
Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands.
Peter
P
Mulders
Medical Oncology, IRCCS San Matteo University Hospital Foundation, Pavia, Italy.
Camillo
C
Porta
Barts Cancer Institute, London, UK.
Thomas
T
Powles
Department of Medical Oncology, San Camillo and Forlanini Hospitals Padiglione Flajani, Rome, Italy.
Cora
C
Sternberg
Division of Surgical Oncology, Department of Urology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Axel
A
Bex
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000556:secondary; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D047428:Protein Kinase Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C546842:MTOR protein, human; D040262:Receptors, Vascular Endothelial Growth Factor; D058570:TOR Serine-Threonine Kinases
Combination of systemic therapies; Renal cell carcinoma; Sequence of systemic therapies; Tyrosine kinase inhibitor