Primary Tumor Response to Targeted Agents in Patients with Metastatic Renal Cell Carcinoma

Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
European Urology (Impact Factor: 13.94). 10/2010; 59(1):10-5. DOI: 10.1016/j.eururo.2010.09.034
Source: PubMed


The recent development of multiple targeted agents for metastatic renal cell carcinoma (mRCC) has changed the treatment paradigm; hence the benefit and optimal timing of cytoreductive nephrectomy is being reevaluated.
To determine primary tumor response to treatment with targeted agents in patients with mRCC.
We reviewed the clinical and radiographic data of all mRCC patients seen at our institution between November 2004 and December 2009 without prior systemic treatment who received targeted therapy with their primary tumor in situ.
Two independent reviewers measured the diameter of primary and metastatic tumors at baseline and subsequent scans, using Response Evaluation Criteria Solid Tumors (RECIST) v.1.1 to assess disease response.
We identified 168 consecutive patients with a median 15 mo of follow-up and a median maximum tumor diameter of 9.6 cm. Median maximum primary tumor response was -7.1% (interquartile range: -14.0 to -0.1). A total of 61 patients had multiple studies available for evaluation. In 43 patients with <10% decrease in primary tumor within in the first 60 d, median maximum response was -7.2% at 154 d versus -24.5% maximum response at 174.5 d for 18 patients with ≥10% decrease in primary tumor during the initial 60 d.
Decrease in primary tumor diameter >30% while on targeted therapy for mRCC is rare, with most patients demonstrating minimal or no decrease in primary tumor diameter. Early response predicts a better overall primary tumor response.

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Available from: Stephen Culp, Dec 12, 2013
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    • "Eighty percent of patients demonstrated variable primary tumor shrinkage, with a median of 1.6 cm (range 0.4- 5.1) [38,39]. A larger study of 168 mRCC patients who received targeted therapy with their primary tumors in situ found noted negligible decreases in the size of the primary tumors [25]. Although contradictory, these studies do suggest discordant responses to drugs in primary and metastatic tumors. "
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    ABSTRACT: Background Targeted therapies in renal cell carcinoma can have different effects on primary and metastatic tumors. To pave the way for predictive biomarker development, we assessed differences in expression of targets of currently approved drugs in matched primary and metastatic specimens from 34 patients. Methods Four cores from each site were embedded in tissue microarray blocks. Expression of B-Raf, C-Raf, cKIT, FGF-R1, HIF-2α, mTOR, PDGF-Rβ, VEGF-R1, VEGF-R2, VEGF-R3, VEGF, VEGF-B, VEGF-C, VEGF-D, MEK1, and ERK1/2 was studied using a quantitative immunofluorescence method. Results No significant differences were observed in global expression levels in primary and metastatic renal cell carcinoma tumors, with the exception of MEK, which had higher expression in metastatic than primary specimens. Similarly, more ki67 positive cells were seen in metastatic specimens. Correlations between marker expression in primary and metastatic specimens were variable, with the lowest correlation seen for FGF-R1 and VEGF-D. There were no significant differences in the degree of heterogeneity in primary versus metastatic tumors. Conclusions Expression of most of the studied markers was similar in primary and metastatic renal cell carcinoma tumors, suggesting that predictive biomarker testing for these markers can be conducted on either the primary or metastatic tumors for most markers.
    Full-text · Article · Feb 2013 · BMC Clinical Pathology
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    • "Several groups have reported significant primary tumor debulking with pre-nephrectomy anti-angiogenic therapy in metastatic RCC patients [13-16]. However, a recent retrospective review showed less decrease in primary tumor diameter in metastatic RCC patients than in metastatic sites [17]. It is unclear whether there are differences in vessel density in primary and metastatic RCC tumors, and whether this may be the cause of possible discordant response in primary and metastatic sites. "
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    ABSTRACT: Purpose Anti-angiogenic therapies are among the most commonly used drugs in renal cell carcinoma. Tumor vascularity, defined by microvessel area, may be associated with response to these drugs. Clinical studies suggest that metastatic sites are more responsive than primary tumors. Our purpose was to characterize microvessel area (MVA) in matched primary and metastatic samples and in samples of different histologies. Methods We employed a method of automated, quantitative analysis of in situ tumor components to identify the area of CD-34 staining endothelial cells within renal cell carcinoma tumors. MVA was assessed in corresponding primary and metastatic samples from 34 patients, as well as in 334 primary nephrectomy specimens with variable histologies. Results MVA measurements from different parts of the same tumor correlated well (R = 0.75), indicating that MVA was fairly uniform within a tumor. While MVA was slightly higher in primary tumors than corresponding metastatic sites, the difference was not statistically significant (P = 0.1). MVA in paired primary and metastatic samples correlated moderately well (R = 0.36). MVA was higher in clear cell than papillary histology and oncocytomas (P < 0.0001 and P = 0.018, respectively). Conclusions Lack of significant differences MVA in matched primary and metastatic samples suggests that both types of tumors should respond to anti-angiogenic drugs. This should be confirmed on additional cohorts. Given the small cohort, future predictive biomarker studies entailing MVA measurements should include specimens from both sites. Clear cell carcinomas are more vascular than other histologic subtypes, which may explain the higher response rates to anti-angiogenic therapies in clear cell tumors.
    Full-text · Article · Jan 2013 · Journal of Translational Medicine
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    • "Recently, new prognostic markers for bladder cancer have been validated in prospectively collected data sets, including a 20-gene model that predicts pathologic nodal involvement at cystectomy [3]. Discovery of predictive markers is also advancing , including the use of the coexpression extrapolation, or COXEN, approach [4], which rapidly develops predictive "

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