The Effect of Concurrent Chemoradiation on Circulating Endothelial Progenitor Cells in Colorectal Cancer
Colorectal cancer (CRC) is one of the common malignancies worldwide, accounting for a
significant percentage of cancer mortality. The incidence in both developing and developed
countries has been increasing over the past few decades (1). Radiation therapy, either as
post-operative adjuvant treatment for resectable disease or definitive treatment along with
chemotherapy for unresectable disease, has an important role in management of this cancer
Concurrent chemoradiation (CCRT) is now a standard treatment for cervical cancer (bulky and
locally advanced lesions) (5) and unresectable malignancies of gastrointestinal system
origin (esophagus, stomach, pancreas and anorectum) (6−9). To improve quality of life, CCRT
is also commonly applied in treatment of lower rectal and anal canal cancer to preserve anal
sphincter function (9). The most commonly used chemotherapeutic drugs combined with
radiation as radiosensitizers are cis-platinum, 5-fluorouracil (5-FU) and mitomycin C (6−9).
These drugs are myelosuppressive and prone to cause life-threatening neutropenia, anemia or
thrombocytopenia, which are more severe than those with radiotherapy alone (5−9). To avoid
unnecessary over-treatment in CRC, the optimization of CCRT is of critical importance.
Herein, the development of a surrogate marker for monitoring treatment efficacy is pivotal
to optimize CCRT.
Angiogenesis is a heavily regulated process, which is involved by complex interactions
between inhibitory and stimulatory angiogenic factors. It is essential for tumor growth,
progression and metastasis and is correlated with poor prognosis in cancer patients
including CRC. Many novel compounds that potently inhibit formation of neoplastic blood
vessels have been recently developed. There is increasing interest in developing
angiogeneis-suppressive agents for colorectal cancer treatment and growing number of
anti-angiogenesis drugs currently being evaluated in clinical trials for CRC. Promising
results have been reported include an increase in overall survival and reduction in the risk
of death (Bevacizumab), reversal of cellular resistance (Cetuximab) and activity as
second-line therapy in patients who have exhausted other available treatment options
(Cetuximab, ABX-EGF, PTK-787, Gefitinib, Erlotinib) (10,11).
Although the therapeutic role of angiogenesis target therapy has been approved in cancer
treatment including CRC, the way to optimize the dose of angiogenesis inhibitors remains to
be determined because of the lack of reliable surrogate markers of tumor angiogenesis.
Shaked et al. reported that the levels of circulating endothelial progenitor cells (EPC),
which contribute to the tumor vessel formation, reflect the anti-tumor efficacy of
anti-angiogenesis regimens (12). Growing evidence suggests that the levels of circulating
EPC reflect the response to chemotherapy both in animal model and clinical trial (13,14).
Thus, circulating EPC can be used as a marker for optimizing and monitoring the
anti-angiogenesis therapy including angiogenesis inhibitors and chemotherapy.
Whether circulating EPC can be served as a marker of CCRT efficacy or not remains
undetermined. Since CCRT is now a standard treatment of locally advanced and high-risk CRC,
the development of a surrogate marker for monitoring CCRT response and optimize treatment
intensity, again, is very important.
In this grant we intent to monitor the levels of circulating EPC in locally advanced and
high-risk CRC patients before, during and after CCRT. To further characterize the changes in
function and biology of EPC caused by CCRT, a syngeneic animal model will be also used to
evaluate the clonogenecity and specific gene expression of EPC in tumor-bearing mice
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Observational Model: Case Control, Time Perspective: Longitudinal, Time Perspective: Prospective
Yu-Jen Chen, MD, PhD
Department of Radiation Oncology, Mackay Memorial Hospital
Taiwan: Department of Health