Prognostic and Predictive Factors in the Targeted Therapy Era: Filling in the Blanks

Abstract

Renal cell carcinoma (RCC) is a clinically heterogeneous disease, and analyses of clinical and laboratory factors in patients provide us a prognostic framework to categorize patients. Motzer et al. [1, 2] described clinical characteristics associated with overall survival (OS) in patients with metastatic RCC (mRCC) in several articles. In their 1999 paper [1], which analyzed 670 patients with mRCC treated at the Memorial Sloan-Kettering Cancer Center (MSKCC), anemia, lactate dehydrogenase (LDH) greater than 1.5 times the upper limit of normal (ULN), hypercalcemia, Karnofsky performance score less than 80, and absence of prior nephrectomy were independently associated with OS. An updated publication, which concentrated on patients who received immunotherapy as first-line therapy in clinical trials conducted at MSKCC, maintained four of the five factors [2]. Absence of prior nephrectomy fell out of the analysis, and was replaced with time of less than 1 year from diagnosis to initiation of systemic therapy. These analyses revealed that common clinical and laboratory factors were associated with survival in patients with mRCC. The clinical factors, which include a poor performance status and a shorter time to initiation of systemic therapy, imply the presence of more aggressive tumor biology. A poor performance status can be a result of aggressive tumor growth resulting in pain or specific organ dysfunction, or because fatigue or malaise-inducing cytokines or other circulating factors are produced or induced by the tumor. The need to initiate systemic therapy earlier suggests a more rapid tumor growth rate. The laboratory values tell a similar story. Anemia may be due to direct tumor-induced blood loss, or to an endocrine effect on bone marrow homeostasis by the tumor. Hypercalcemia is due to tumor elaboration of parathyroid-like hormone, or to bone lysis by osseous metastases. Elevated LDH is a general marker of increased tissue turnover, and implies increased tumor metabolism. What is missing from the interpretation of these prognostic factors is their relevance in the context of antiangiogenic therapy, information on whether they are predictive for benefit from one agent over the other, and a mechanistic understanding of these clinical and laboratory phenomena. In an effort to update the MSKCC prognostic criteria, the study by Heng et al. assesses common clinical and laboratory factors in RCC patients who received antiangiogenic therapy.