Combined Vascular Endothelial Growth Factor–Targeted Therapy and Radiotherapy for Rectal Cancer: Theory and Clinical Practice

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Despite the routine use of adjuvant and neoadjuvant chemoradiotherapy, patients with advanced rectal tumors experience significant rates of treatment failure and disease recurrence. Resistance to radiation is a particular problem. Adding a vascular endothelial growth factor (VEGF)–targeted therapy may improve outcomes in these patients. Epidemiologic studies have shown that tumor expression of VEGF predicts disease recurrence and lower overall survival in patients treated with radiation. In tumor xenograft models in mice, VEGF-targeted agents increase the response to radiation, with a greater probability of tumor control and a greater delay in tumor growth. In addition to killing cancer cells indirectly by damaging tumor blood vessels (antivascular effect), VEGF-targeted therapy may sensitize tumors to radiation through two mechanisms: by normalizing the tumor vasculature, leading to greater tumor oxygenation, and thereby increasing the cytotoxicity of radiation to cancer cells, and by increasing the radiosensitivity of tumor-associated endothelial cells. In addition, anti-VEGF agents may inhibit the regrowth of tumors after radiation by decreasing the number of circulating endothelial cells and endothelial progenitor cells. A phase I dose-escalation study has shown the safety of bevacizumab at a dose of 5 mg/kg in combination with 5-fluorouracil and radiation in patients with rectal carcinoma, and has provided evidence of both vascular normalization and antivascular mechanisms. Phase II evaluation of bevacizumab in this setting is under way.

Section snippets

VEGF-Targeted Agents and Radiation in Experimental Tumor Models

Some of the early preclinical studies that used non–VEGF-targeted antiangiogenic agents combined with radiation found that the combination induced greater delays in the growth of tumors than did either modality alone.11, 12 Other studies showed that adding antiangiogenic agents could compromise the response to radiation.13 However, preclinical studies using selective inhibitors of VEGF combined with ionizing radiation have shown good tumor control. For example, the growth of various xenografted

Mechanisms of Action and Schedule Optimization of Anti-VEGF Therapy With Radiotherapy

The mechanisms of action by which anti-VEGF agents increase the efficacy of radiotherapy are not completely understood.20, 21 Three potential mechanisms have been reported.9, 10, 20 First, the inhibition of VEGF–VEGFR-2 signaling can radiosensitize tumor-associated endothelial cells, thereby reducing vascular density and inhibiting the formation of new vessels. Impaired vascular delivery of nutrients and oxygen may result in cancer cell death.22 Second, anti-VEGF agents can normalize the tumor

Multitargeted Agents That Target VEGF Receptors

In addition to antibodies that specifically inhibit VEGF or its main receptor, VEGFR-2, there are also a number of small molecules (receptor tyrosine kinase inhibitors) that inhibit VEGFR-2 in parallel with inhibition of other pathways.20 Some of these agents (eg, SU5416, PTK787/ZK 222584) inhibit primarily VEGF receptors, and others (eg, ZD6474, SU11248) inhibit the activity of several receptor tyrosine kinases in various stromal and cancer cells. Multitargeted inhibitors given as monotherapy

Clinical Trials

Chemoradiotherapy is a standard treatment for patients with locally advanced rectal cancer. To test the hypothesis that adding an anti-VEGF agent to a chemoradiotherapy protocol is safe, we conducted a phase I/II trial of neoadjuvant bevacizumab in combination with 5-FU and radiation therapy in patients with T3 or T4 rectal cancer (Fig 2).23, 24 Patients were given bevacizumab monotherapy in cycle 1 (2 weeks) and bevacizumab plus 5-FU and radiation therapy in cycles 2 to 4. Bevacizumab was

Summary

The successful clinical use of anti-VEGF agents, alone (multitargeted tyrosine kinase inhibitors) and in combination with chemotherapy (bevacizumab), raises important questions about their use in combination with radiation. VEGF plays an important role in the resistance of tumors to radiation. In tumor xenograft models, VEGF-targeted agents are known to sensitize tumors to radiation, increasing the delay of tumor growth and the probability of local control. The radiation-enhancing effects of

References (26)

  • R. Sauer et al.

    Preoperative versus postoperative chemoradiotherapy for rectal cancer

    N Engl J Med

    (2004)
  • N. Wolmark et al.

    Randomized trial of postoperative adjuvant chemotherapy with or without radiotherapy for carcinoma of the rectum: National Surgical Adjuvant Breast and Bowel Project Protocol R-02

    J Natl Cancer Inst

    (2000)
  • P. Wachsberger et al.

    Tumor response to ionizing radiation combined with antiangiogenesis or vascular targeting agents: Exploring mechanisms of interaction

    Clin Cancer Res

    (2003)
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    This work was supported by grants from the National Institutes of Health-National Cancer Institute (R21-CA 99237 to C.G.W. and P01-CA80124 and R01-CA115767 to R.K.J.), the National Foundation for Cancer Research (to R.K.J. and C.G.W.), and the American Association for Cancer Research (to D.G.D.).

    1

    Dr Jain is a consultant to AstraZeneca Pharmaceuticals, GLG, Nektar Therapeutics, and ThromboGenics.

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