Targeted therapy in rectal cancer

Abstract

Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) are often overexpressed in colorectal cancer and are associated with inferior outcomes. Based on successful randomized phase III trials, anti-EGFR and anti-VEGF therapeutics have entered clinical practice. Cetuximab (Erbitux), an EGFR-specific antibody, is currently approved in the United States in combination with irinotecan (Camptosar) for patients with metastatic colorectal cancer refractory to irinotecan or as a single agent for patients unable to tolerate irinotecan-based therapy. In retrospective analyses, patients with EGFR-expressing rectal cancer undergoing neoadjuvant radiation therapy had a significantly inferior disease-free survival and lower rates of achieving pathologic complete response. Based on the positive data in metastatic colorectal cancer and synergy with radiation therapy seen in preclinical models, there is a strong rationale to combine cetuximab with neoadjuvant radiation therapy and chemotherapy in rectal cancer. Bevacizumab (Avastin), a VEGF-specific antibody, was the first antiangiogenic agent to be approved in the United States for use in combination with standard chemotherapy in the first- and second-line of treatment in metastatic colorectal cancer. VEGF-targeted therapy may lead to indirect killing of cancer cells by damaging tumor blood vessels, and may increase the radiosensitivity of tumor-associated endothelial cells. VEGF blockade can also "normalize" tumor vasculature, thereby leading to greater tumor oxygenation and drug penetration. This review will address completed and ongoing trials that have established and continue to clarify the effects of these agents in rectal cancer.

Figure 1. Clinical Trial of Rectal Cancer Treatment

Schema of protocol employing bevacizumab with radiation therapy and fluorouracil. IFP = interstitial fluid pressure.

Figure 2. Tumor Interstitial Pressure

Endoscopic image showing the interstitial fluid pressure (IFP) measurement in a rectal cancer using the wick-in-needle technique with changes in IFP, which drops at 12 days after bevacizumab infusion alone. Note the consistent decrease in IFP, particularly in patients with high baseline values. Adapted, with permission, from Willett et al.[58,59]

Figure 3. Tumor Microvascular Density

Tumor microvascular density (MVD) and smooth muscle actin (SMA) staining measured in serial biopsies before and after bevacizumab infusion. At day 12, bevacizumab alone reduced MVD approximately by half in all analyzable rectal carcinoma biopsies. Researchers found increased smooth muscle actin staining in tumor vessels demonstrating increased pericyte coverage of remaining vessels. Reproduced, with permission, from Willett et al.[58]

Figure 4. FDG Uptake

Tumor ¹⁸F-fluorodeoxyglucose (FDG) uptake before treatment, after bevacizumab alone, and after completion of neoadjuvant treatment in the first six patients enrolled in the phase I trial. Bevacizumab alone did not significantly reduce FDG uptake, but the combined treatment produced significant reductions in FDG uptake prior to surgery. PET = positron-emission tomography; SUV = standardized uptake value. Reproduced, with permission, from Willett et al.[58]

Figure 5. Response to Treatment

Tumor response to bevacizumab alone and to combination of bevacizumab with chemoradiotherapy. Reproduced, with permission, from Willett et al.[58]