Researchers who studied apopulation-based cohort of patientswith metastatic renal cell carcinoma (mRCC) found a trend towardimproved survival with the shift fromthe cytokine to the targeted therapy era.The degree of improvement, however,was slightly less than that observed inclinical trials of targeted therapies.

For non-clear-cell mRCC, the limitedtherapeutic options translatedinto modest survival gains in the targetedtherapy era, according to theinvestigators. 

“These data permit accurate counselingof a heterogeneous, ‘real world’ populationof mRCC patients seeking care,especially in the setting of late presentationand unclear histology,” a researchteam led by Liam C. Macleod, MD, ofthe University of Washington in Seattle,concluded. “We are hopeful this workmay serve as an impetus to systematicallyimprove implementation of histologicallyguided care for mRCC.” 

Using the Surveillance, Epidemiology,and End Results (SEER) database, Dr.Macleod’s group identified 14,521patients diagnosed with mRCC from1990 to 2009. They analyzed survivalby treatment era (cytokine era,1990–2005; targeted therapy era,2006–2009). Prior to the mid-2000s,the authors noted, mRCC treatmentsincluded the cytokines interferon alfaand interleukin-2. As a result of studieselucidating the molecular biologyof kidney cancer, researchers developedagents targeting the vascularendothelial growth factor pathway(such as sunitinib, sorafenib, and bevacizumab)and the mammalian target ofrapamycinpathway (such as temsirolimusand everolimus). 

Results showed that median survivalamong the 4,149 patients with clear cellmRCC improved significantly from11 to 14 months before and after thedebut of targeted therapy, the researchersreported online ahead of print inUrology. Median survival improvedsignificantly from 7 to 9 months amongthe 904 patients with non-clear-cellmRCC. Median survival did not changesignificantly among the 608 patientswho had mRCC with sarcomatoid featuresand the 8,860 patients with RCCnot otherwise specified. 

Factors influencing survival 

On multivariate analysis, treatment inthe targeted era was associated witha 13% decreased risk of death comparedwith treatment in the cytokineera. Clear-cell histology was associatedwith a 24% decreased risk of deathcompared with other histologic subtypes.Patients who underwent cytoreductivenephrectomy had a 57%decreased risk of death compared withthose who did not. 

The researchers acknowledged somestudy limitations. For example, theydid not have available granular information,which portends mRCC prognosis.“Therefore, we cannot accountfor performance status, key laboratoryvalues, or sites and burden of metastaticdisease volume.” 

In addition, as a result of increaseduse of imaging during the targetedtherapy era, patients treated in this eramay have been diagnosed earlier inthe course of their disease than thosetreated in the cytokine era. 

The researchers said the differencein overall survival between their studyand trial data may relate to the morestringent selection criteria for inclusionin clinical trials compared with population-based SEER data. 

“SEER captures a heterogeneoushealth care delivery system and patientswith disparate access to new agents anddecision making,” they wrote. “Manycases may be treated without histologicinformation, predisposing patients tocare with less beneficial agents.” 

Eric A. Singer, MD, MA, assistantprofessor of surgery and director of theKidney Cancer Program at the RutgersCancer Institute of New Jersey in NewBrunswick, who was not involved inthe new study, commented that thatinvestigation by Dr. Macleod’s groupis important but has some weaknesses,such as the exclusion of the 2 mostrecently approved drugs for treatingmRCC (pazopanib in 2009 and axitinibin 2012). “It illustrates that this study islimited by the time period it is examining,”Dr. Singer said, adding that pazopaniboften is used as first-line therapy.“However, I suspect even with the inclusionof pazopanib and axitinib in thestudy, if we could examine data through2015, we would still see shorter survivalcompared to the published clinical trials.”This most likely would be due todifferences between the study populationsand the general population. 

Off protocol patients differ 

“Off protocol, oncologists are able totreat many more patients,” Dr. Singertold Renal & Urology News. “However,many of these patients may be sickeror have non-clear-cell histologies thatwere not included in the original pivotaltrials.” All of the targeted therapiesapproved by the FDA have beentested predominantly in patients withclear-cell mRCC, he said, adding thatapproximately 25% of mRCC patientshave non-clear-cell histology. 

“We must continue to study nonclear-cell tumors … if we are going tobe able to make significant progressagainst mRCC,” he said. 

Dr. Singer was part of a research teamthat recently published study findingsshowing that high-dose interleukin-2therapy is now used infrequently formRCC in the United States and thatits use has decreased with the uptakeof targeted therapy. The study evaluatedtrends in high-dose interleukin-2therapy use from 2004 to 2012. The usedecreased from 444 patients in 2004 to135 in 2008, than increased to 230 in2012, the researchers reported onlineahead of print in Urologic Oncology:Seminars and Original Investigations

The findings of this study are inline with those reported recently byanother research team in we(2015;85:1399-1403). In a study of25,186 mRCC patients, Elizabeth K.Ferry, MD, of University HospitalsCase Medical Center in Cleveland,and colleagues found that the useof immunotherapy decreased from30.3% of patients in 1998 to 3.8% in2011, whereas the use of chemotherapyincreased from 16.2% to 54% duringthe same period.