Comparison of Four Early Posttherapy Imaging Changes (EPTIC; RECIST 1.0, Tumor Shrinkage, Computed Tomography Tumor Density, Choi Criteria) in Assessing Outcome to Vascular Endothelial Growth Factor–Targeted Therapy in Patients With Advanced Renal Cell Carcinoma

doi:10.1016/j.eururo.2011.01.038

European Urology

Volume 59, Issue 5, May 2011, Pages 856-862

https://doi.org/10.1016/j.eururo.2011.01.038 Get rights and content

Abstract

Background

Vascular endothelial growth factor (VEGF)-targeted therapy has become standard treatment for patients with metastatic renal cell cancer (mRCC). Since these therapies can induce tumor necrosis and minimal tumor shrinkage, Response Evaluation Criteria in Solid Tumors (RECIST) may not be optimal for predicting clinical outcome.

Objective

To systematically determine the optimal early posttherapy imaging changes (EPTIC) to separate responders and nonresponders at the first posttreatment follow-up computed tomography (CT).

Design, setting, and participants

Seventy mRCC patients with 155 target lesions treated with first-line sunitinib, sorafenib, or bevacizumab at academic medical centers underwent contrast-enhanced thoracic and abdominal CT at baseline and first follow-up after therapy initiation (median: 78 d after therapy initiation; range: 31–223 d).

Measurements

Evaluations were performed according to (1) RECIST 1.0; (2) Choi criteria; (3) tumor shrinkage (TS) of ≥10% decrease in sum of the longest unidimensional diameter (SLD); and (4) 15% or 20% decrease in mean CT tumor density. Correlation with time to treatment failure (TTF) and overall survival (OS) were compared and stratified by response to each of the radiologic criteria.

Results and limitations

Eleven patients were considered responders by RECIST 1.0; 49 based on Choi criteria; 31 patients had ≥10% decrease in the SLD; and 36 and 32 patients had ≥15% and ≥20% decrease, respectively, in mean tumor density on CT. Only the threshold of 10% decrease in the SLD was statistically significant in predicting TTF (10.4 vs 5.1 mo; p = 0.02) and OS (32.5 vs 15.8 mo; p = 0.002). Receiver operating characteristic analysis yielded a 10% decrease in SLD as the optimal size change threshold for responders. The retrospective nature of the study and measurements by a single oncoradiologist are inherent limitations.

Conclusions

In the retrospectively analyzed study population of mRCC patients receiving VEGF-targeted agents, a 10% reduction in the SLD on the first follow-up CT was an optimal early predictor of outcome.

Introduction

In the past few years, vascular endothelial growth factor (VEGF)–targeted therapies have become standard treatment for patients with metastatic renal cell carcinoma (mRCC). As targeted therapies can induce tumor necrosis and minimal tumor shrinkage [1], [2], the response evaluation criteria in solid tumors (RECIST 1.0), based on computed tomography (CT) tumor-size measurements, may not be optimal to evaluate antitumor activity in this setting. Patients treated with VEGF-targeted therapies often do not achieve the 30% decrease in sum of long-axis diameters (SLD) of target lesions that deems a partial response (PR), yet some stable-disease (SD) patients can remain progression free for extended periods [3], [4], [5], [6]. Therefore, other early, posttherapy imaging changes (EPTIC) may be needed to identify patients earlier who are likely to have a prolonged benefit from the treatment.

Density changes and necrosis have been observed in metastatic lesions of patients treated with antiangiogenic therapies, and several groups have sought to incorporate size and density changes into imaging response criteria. In 2007, Choi response (defined as ≥10% decrease in size or ≥15% decrease in density) was developed for patients with gastrointestinal stromal tumors treated with imatinib [7], [8]. The utility of Choi has been recently evaluated in patients with mRCC [9]. In the radiologic literature, size attenuation CT (SACT) and morphology, attenuation, size, and structure (MASS) criteria have been developed in which a host of radiologic assessments stratify patients into favorable, indeterminate, or unfavorable response groups [10], [11].

Size variation threshold for CT response has been evaluated in patients treated with sunitinib, with a 10% decrease in the SLD of target lesions rapidly identifying patients with treatment benefit [12]. While a 10% decrease in SLD is also a component of Choi criteria, SACT and MASS criteria incorporate a 20% decrease in SLD into the category favorable response. To date, no size threshold has been identified to select responders to VEGF-targeted therapies as a whole, although average long-axis reduction has been described in treatment with a particular agent.

In our report, we compare four EPTIC—RECIST 1.0, Choi, tumor shrinkage (TS), and CT tumor density—in mRCC patients treated with VEGF-targeted therapies. Our goal was to systematically determine the optimal criteria that separate responders from nonresponders at the first posttreatment CT to early identify patients likely to benefit from treatment.

Section snippets

Patients and treatment

Consecutive patients with mRCC of any histology naïve to VEGF-targeted therapy were treated at two large academic institutions (Dana-Farber Cancer Institute [DFCI] and Beth Israel Deaconess Medical Center [BIDMC], Boston, MA, USA) with sunitinib, sorafenib, or bevacizumab. Sunitinib-treated patients (Sutent; Pfizer, New York, NY, USA) were started at a dose of 50 mg orally, daily for 4 wk followed by 2 wk off. Sorafenib-treated patients (Nexavar; Bayer HealthCare, Leverkusen, Germany) were

Patients

Seventy patients with 155 target lesions were evaluated. See Table 1 for patient characteristics. The median age of targeted therapy initiation was 56 yr. Thirty-one patients (44%) were treated with sunitinib, 24 patients (34%) with sorafenib, and 15 patients (22%) with bevacizumab. Median time from baseline CT to drug initiation was 10 d and median time from baseline to first posttreatment CT was 78 d. While the range from baseline to first follow-up CT was 31–223 d, all patients except one

Discussion

We evaluated RECIST, Choi response, TS, and CT tumor density changes as independent imaging predictors of benefit from VEGF-targeted therapy in mRCC patients. In our study of 70 patients, a relatively large cohort with respect to similar literature, a 10% decrease in target SLD was the best predictor of outcome on first follow-up CT, including TTF and OS. EPTIC that can early distinguish those patients destined to achieve benefit aid in patient management, allowing those unlikely to benefit to

Conclusions

In the retrospectively analyzed study population, a reduction of 10% in the SLD at first follow-up CT was the best early predictor of outcome in mRCC patients receiving VEGF-targeted therapies, while RECIST 1.0 and Choi criteria were not predictive of TTF. ROC analysis identified the 10% decrease in SLD as the best size predictor of TTF, while no change in CT tumor density threshold was a good predictor of TTF. Prospective analysis and/or confirmation in an independent population would lend

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Citation Excerpt :
Accordingly, continuous time-to-event end points, such as progression-free survival (PFS) and OS, are frequently evaluated in clinical studies of targeted therapies [3]. Nevertheless, tumour shrinkage following medical treatment with antitumour agents has been shown to be a predictive and/or prognostic factor for OS and PFS in patients with mRCC [4–8]. In retrospective [5] and validation studies [6] in two small cohorts of patients with mRCC (n = 70 and n = 66, respectively), early tumour shrinkage (eTS)—defined as ≥10% decrease in the sum of the longest diameters (SLD) of target lesions at the first scan after initiating VEGF-targeted therapy—correlated with time to treatment failure and OS, whereas objective response per RECIST did not.
The predictive role of objective remission remains undefined for targeted agents in metastatic renal cell carcinoma (mRCC); however, early tumour shrinkage (eTS) was shown to be predictive and/or prognostic for overall survival (OS) and progression-free survival (PFS) in mRCC in several small studies.
To evaluate the degree of eTS following systemic therapy that may predict survival in mRCC.
Data from 4334 patients with mRCC in phase 2 and 3 clinical trials between 2003 and 2013 were pooled for analyses. Early tumour shrinkage was assessed based on percentage change in sum of the longest diameters of target lesions at first postbaseline scan. Patients were categorised by a more or equal versus less optimal threshold of eTS, assessed using receiver operating characteristic (ROC) analysis. OS and PFS in patients with eTS were summarised using the Kaplan-Meier method.
Axitinib, bevacizumab, interferon α, sorafenib, sunitinib, or temsirolimus.
We measured optimal thresholds of eTS and eTS as a predictor of OS or PFS.
Optimal threshold of eTS for the prediction of OS and PFS was determined to be approximately 10%. In Cox proportional hazards models, compared with patients without eTS, those with eTS had significantly longer OS (hazard ratio [HR]: 0.615; p < 0.0001; median: 28.5 vs 16.0 mo) and PFS (HR: 0.628; p < 0.0001; median: 10.5 vs 5.3 mo). The major limitation was the retrospective nature of our analysis, including different lines and types of therapy, although subset analyses detected a similar predictive pattern for eTS across all lines and types of therapy.
Early tumour shrinkage ≥10% at first postbaseline assessment could serve as a putative early end point in patients with mRCC. A prospective evaluation of eTS in clinical trials is warranted.
Early tumour shrinkage may be used to identify patients with metastatic renal cell carcinoma who would benefit from treatment with antitumour agents.
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Kidney CancerComparison of Four Early Posttherapy Imaging Changes (EPTIC; RECIST 1.0, Tumor Shrinkage, Computed Tomography Tumor Density, Choi Criteria) in Assessing Outcome to Vascular Endothelial Growth Factor–Targeted Therapy in Patients With Advanced Renal Cell Carcinoma

Abstract

Background

Objective

Design, setting, and participants

Measurements

Results and limitations

Conclusions

Introduction

Section snippets

Patients and treatment

Patients

Discussion

Conclusions

J Urol

Ann Oncol

Pathological evidence of necrosis in recurrent renal mass following treatment with sunitinib

Int J Urol

The loss of radiographic enhancement in primary renal cell carcinoma tumors following multitargeted receptor tyrosine kinase therapy is an additional indicator of response

Urol

A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cell carcinoma

N Engl J Med

Sunitinib versus interferon alfa in metastatic renal-cell carcinoma

N Engl J Med

Sorafenib in advanced renal cell carcinoma

N Engl J Med

We should desist using RECIST, at least in GIST

J Clin Oncol

Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria

J Clin Oncol

Kidney Cancer
Comparison of Four Early Posttherapy Imaging Changes (EPTIC; RECIST 1.0, Tumor Shrinkage, Computed Tomography Tumor Density, Choi Criteria) in Assessing Outcome to Vascular Endothelial Growth Factor–Targeted Therapy in Patients With Advanced Renal Cell Carcinoma