Depth of Remission is a Prognostic Factor for Survival in Patients with Metastatic Renal Cell Carcinoma

Abstract

Background Response remains an important endpoint in clinical cancer trials. However, the prognostic utility of best tumor response in metastatic renal cell carcinoma (mRCC) remains vague. Objective To define the prognostic relevance of the depth of remission in mRCC Design, setting, and participants Pooled data of 2,749 patients from phase II and III clinical trials of the Pfizer data-base in mRCC was analyzed. Tumor-shrinkage was categorized by fractions of best percent change in the sum of the largest diameter of target lesions. Outcome was computed by Kaplan-Meier curves and correlation was assessed by Cox regression, including a 6-month landmark. Intervention Sunitinib, sorafenib, axitinib, temsirolimus, temsirolimus and/or IFN-α. Outcome Measurements and Statistical Analysis Categorized tumor-shrinkage, overall survival (OS), progression free survival (PFS). Results and limitations Major tumor shrinkage of 60% or more occurred in about 10% of patients and was associated with a median overall survival (OS) of 54.5 months. With depth of remission, OS expectations declined steadily (26.4, 16.6, 10.4, and 7.3 months). The association was maintained when stratified by type of therapy, line of therapy, and performance status. The 6-month landmark Cox proportional regression analyses confirmed the prognostic relevance of major tumor shrinkage (HR 0.29; CI 95% 0.22–0.39; p<0.001). The major limitation of our study is the variability of imaging intervals among studies. Conclusions This is the first and largest analysis of best tumor response in mRCC. We demonstrate that depth of remission is an independent prognostic factor in mRCC. Patient summary It remains unknown whether tumor shrinkage during therapy is needed to achieve clinical activity in mRCC. Our analysis shows that the magnitude of tumor shrinkage correlates with a better survival in patients. This observation may be used as a clinical research tool in future trials. Trial registration NCT00054886, NCT00077974, NCT00267748, NCT00338884, NCT00137423, NCT00083889, NCT00065468, NCT00678392

Predictive Factors for Second-Line Therapy in Metastatic Renal Cell Carcinoma: A Retrospective Analysis

“…For example, the depth of remission during first-line therapy proved to be an independent prognostic factor. Early tumor shrinkage and the depth of remission were significantly associated with an improved OS (16). However, early progression itself is technically not a baseline parameter, which will generate problems because clinicians cannot base therapeutic decision making on this parameter up front of first-line therapy.…”

Prognostic Significance of Early Tumor Shrinkage Under Second-Line Targeted Therapy for Metastatic Renal Cell Carcinoma: A Retrospective Multi-Institutional Study in Japan

“…Taken together, it may be necessary to identify parameters that help individualize patient prognostication to provide an optimal sequential therapy for mRCC as a post-first-line setting. The significant impact of the tumor response to a targeted agent on the subsequent prognosis in patients with mRCC has been reported [12][13][14][15][16][17][18][19][20]. However, albeit significant antitumor activities from a clinical viewpoint, molecular-targeted agents have been shown to be characterized by a comparatively low level of tumor shrinkage due to the mechanisms mediating their activities against mRCC through the inhibition of angiogenesis rather than that of tumor cell proliferation [1].…”

“…Moreover, this study showed for the first time that the degree of ETS under second-line targeted therapy was proportional to OS among the four subgroups; that is, the median OS stratified according to the degree of ETS, as described above, was 45.8, 30.9, 22.1 and 14.2 months, respectively. To date, there have been several studies demonstrating the significant impact of the level of tumor shrinkage on survival in patients with mRCC receiving first-or second-line targeted therapy [12][13][14][15][16][17][18][19][20]. For example, Seidel et al reported the close correlation between OS and tumor shrinkage early in the course of first-line targeted therapy, which was stratified into the following five groups: tumor remission of -100 to -60 %, -59 to -30 %, -29 to 0 %, or gain of 1 to 19 %, C20 % [12].…”

“…It remains the standard approach for assessing the prognosis of mRCC patients treated with molecular-targeted agents to use the Memorial Sloan-Kettering Cancer Center (MSKCC) and International Renal Cell Carcinoma Database Consortium (IMDC) risk classifications [10,11], while the significant prognostic impact of the objective tumor response to these novel agents in mRCC patients has only recently been documented in various studies [12][13][14][15][16][17][18][19]. We also reported that the overall survival (OS) in patients with mRCC was closely correlated with the degree of tumor shrinkage at 12 weeks after the introduction of firstline TKIs [20].…”

Checkpoint Blockade - a New Treatment Paradigm in Renal Cell Carcinoma

“…Superior outcome was detected in patients with any tumor shrinkage on targeted therapies, with an exceptional response in those with a tumor shrinkage of at least 60% [4]. This paves the way for novel concepts in mRCC trials, indicating that the enlargement of the fraction of patients with deep remission will improve survival.…”