Chapter 080. Cancer Cell Biology and Angiogenesis (Part 19) Several general principles have arisen from these studies. Bevacizumab appears to potentiate the effects of many different types of active chemotherapeutic regimens used to treat a variety of different tumor types. No phase III trials have demonstrated single-agent activity for bevacizumab; colon and lung cancer trials have demonstrated a lack of activity when used alone. An exception may be renal cell cancer (RCC), a tumor that is specifically dependent upon VEGF as the result of deletion of the VHL tumor suppressor and activation of the HIF-1α transcription factor (see above). A randomized phase II study of single-agent bevacizumab given at low or high dose compared to placebo in patients with advanced RCC demonstrated a significant prolongation of time to disease progression, a finding that merits further study. The mechanisms by which bevacizumab enhances the activity of chemotherapy and possibly radiotherapy have been studied (Table 80-4). Inhibition of VEGF, especially in the early stages of treatment, has been postulated to result in the normalization of blood flow in tumors (Fig. 80-10). When given in combination with chemotherapy, this may enhance the delivery of cytotoxic agents to the tumor, where death of tumor cells and proliferating endothelial cells may result. As antiangiogenic therapy continues, growth of new tumor vessels is inhibited, leading to nutritional deprivation and death of tumor cells. Table 80-4 Mechanisms of Bevacizumab Action 1. Inhibition of VEGF- dependent signaling pathways required for the proliferation and survival of endothelial cells within the tumor vasculature. This may enhance the direct toxic effects of chemotherapy on tumor endothelial cells. 2. Inhibiti on of vascular permeability, decreasing interstitial pressure in tumors, and promoting delivery of therapeutic drugs and oxygen (a process termed vessel normalization). 3. Prevention of neoangiogenesis between cycles of chemotherapy, blocking tumor regrowth. 4. Inhibition of the recruitment of proangiogenic bone marrow– derived cells (including circulating endothelial precursors and monocytes) to the tumor vasculature. 5. Blocking potential direct effects of VEGF on tumors that have been reported to express VEGFR2, e.g., colon and pancreatic cancer cells. 6. Reversing the inhibitory activity of VEGF on dendritic cells, thereby promoting antitumor immunity. Note: VEGF(R), vascular endothelial growth factor (receptor). Bevacizumab is administered IV every 2–3 weeks (its half-life is nearly 20 days) and is generally well tolerated. Hypertension has been noted in most trials that utilize inhibitors of VEGF receptors, but only 10% of patients require treatment with anti-hypertensive agents and this rarely requires discontinuation of therapy. A mechanism for the hypertension may be a bevacizumab-induced decrease in vessel production of nitric oxide, resulting in vasoconstriction and increased blood pressure. Rare but serious side effects of bevacizumab include an increased risk of arterial thromboembolic events including stroke and myocardial infarction, usually in patients over the age of 65 with a history of cardiovascular disease. An increased risk of hemorrhage was noted in lung cancer patients with a squamous histology and large central tumors near the major mediastinal blood vessels. Cavitation of the tumor with vessel rupture and massive hemoptysis lead to the exclusion of squamous cell cancers from treatment with bevacizumab. This potentially fatal side effect may actually reflect an increased activity of bevacizumab plus chemotherapy in squamous cell cancers. Other serious complications include bowel perforations that have been observed in 1–3% of patients (mainly those with colon and ovarian cancers). Important questions remain concerning the clinical use of bevacizumab. Do patients develop resistance to this agent? Although patients with advanced colon, lung, and breast cancers benefit from treatment with bevacizumab-containing regiments, few patients are cured and most will relapse and die of their disease. While resistance of cancer cells to chemotherapeutic agents is expected, it is unclear to what extent the relapses reflect resistance to bevacizumab (if at all). Preclinical studies have demonstrated that inhibition of VEGF-mediated angiogenic pathways can select for tumor variants that utilize other angiogenic mechanisms, such as the secretion of the proangiogenic chemokine IL-8, which is a downstream mediator of the EGFR pathway. This has led to studies in which bevacizumab has been combined with cetuximab or erlotinib (inhibitors of EGFR signaling), and preliminary phase II studies have shown efficacy of these combinations in heavily pretreated patients with colon and lung cancers. . Chapter 080. Cancer Cell Biology and Angiogenesis (Part 19) Several general principles have arisen from these studies. Bevacizumab appears to potentiate the effects. cells and proliferating endothelial cells may result. As antiangiogenic therapy continues, growth of new tumor vessels is inhibited, leading to nutritional deprivation and death of tumor cells squamous cell cancers from treatment with bevacizumab. This potentially fatal side effect may actually reflect an increased activity of bevacizumab plus chemotherapy in squamous cell cancers.