Antiangiogenic therapy: impact on invasion, disease progression, and metastasis

Abstract

Antiangiogenic drugs targeting the VEGF pathway have slowed metastatic disease progression in some patients, leading to progression-free survival (PFS) and overall survival benefits compared with controls. However, the results are more modest than predicted by most preclinical testing and benefits in PFS are frequently not accompanied by overall survival improvements. Questions have emerged about the basis of drug resistance and the limitations of predictive preclinical models, and also about whether the nature of disease progression following antiangiogenic therapy is different to classic cytotoxic therapies-in particular whether therapy may lead to more invasive or metastatic behavior. In addition, because of recent clinical trial failures of antiangiogenic therapy in patients with early-stage disease, and the fact that there are hundreds of trials underway in perioperative neoadjuvant and adjuvant settings, there is now greater awareness about the lack of appropriate preclinical testing that preceded these studies. Improved preclinical assessment of all stages of metastatic disease should be a priority for future antiangiogenic drug discovery and development.

Figure 1

Clinical results of combinations of PFS and overall survival. There are several different combinations of PFS and overall survival, including no change in either (not shown here). a | Improvement in PFS translates into improved overall survival. In completed phase III trials with anti-VEGF-pathway therapy (Tables 1 and 2), two additional scenarios have occurred: b | PFS benefit does not translate into improved overall survival, and c | reduced PFS (Table 2). Worse overall survival has not been shown in a phase III trial though a recent interim analysis of the AVANT trial indicated that this trend is possible. It is possible that response to anti-VEGF therapy (even if leading to improved PFS) can change the natural history of disease progression to include a more aggressive phenotype—possibly explaining lack of changes in overall survival. This figure is based on conceptual ideas outlined by David Reardon. Abbreviation: PFS, progression-free survival.

Figure 2

Variable efficacy of VEGF pathway-targeted therapies: exposing the gap between preclinical and clinical testing. The number of studies that have been completed in the clinic in each setting are inversely correlated with the number of preclinical publications that model each setting. *See Supplementary Table 2 online. ^‡See Table 3. ^§See Table 1. Abbreviations: CRC, colorectal cancer; GBM, glioblastoma muliforme; GIST, gastrointestional stromal tumors; HCC, hepatocellular carcinoma; MBC, metastatic breast cancer; NSCLC, non-small-cell lung cancer; RCC, renal cell carcinoma.