Trial Information

Effect of Concurrent Chemoradiation on Circulating Endothelial Progenitor Cells in Cervical Cancer

Invasive carcinoma of the uterine cervix remains the most common invasive cancer in women in
many countries. Concurrent chemoradiotherapy (CCRT) is now recommended as a standard
treatment for locally advanced and high-risk cervical carcinoma (1-3). Although the local
control rate and survival have improved with use of CCRT, the treatment does cause greater
toxicity in the bone marrow and other normal tissues compared with that caused by
conventional RT. Our previous study demonstrated that serial changes in serum cytokines
during chemoradiation correlated with tumor regression and treatment morbidity. The sudden
elevation of serum TGF-beta 1 and VEGF levels after the first fraction of brachytherapy
correlate with the development of greater RT morbidity. Higher pretreatment TGF-beta 1 and
VEGF levels are associated with poor tumor response to chemoradiation (4). It implicates
that angiogenic factor, such as VEGF, may play roles in the toxicity and outcome of CCRT.
However, it still lacks a surrogate marker for prediction of clinical outcome of CCRT.

The most commonly used chemotherapeutic drugs combined with radiation as radiosensitizers
are cis-platinum and 5-fluorouracil. These drugs, especially cis-platinum, are toxic to
kidney, myelosuppressive and prone to cause life-threatening neutropenia, anemia or
thrombocytopenia, which are more severe than those with radiotherapy alone (1-3). To avoid
unnecessary over-treatment, the optimization of CCRT is of critical importance. Herein, the
development of a surrogate marker for monitoring treatment efficacy as well as toxicity 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 cervical cancer (5). Many novel compounds, such as EGCG (6), that potently inhibit
formation of neoplastic blood vessels have been recently developed. There is increasing
interest in developing angiogeneis-suppressive agents for cancer treatment and growing
number of anti-angiogenesis drugs currently being evaluated in clinical trials for various
malignancies. Promising results have been reported include an increase in overall survival
and reduction in the risk of death (Bevacizumab), reversal of cellular drug resistance
(Cetuximab) and activity as second-line therapy in colorectal cancer patients who have
exhausted other available treatment options (Cetuximab, ABX-EGF, PTK-787, Gefitinib,
Erlotinib) (7,8).

Although the therapeutic role of angiogenesis target therapy has been approved in cancer
treatment, 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
(9,10). Growing evidence suggests that the levels of circulating EPC reflect the response to
chemotherapy both in animal model and clinical trial (11-13). Thus, circulating EPC can be
used as a marker for optimizing and monitoring the anti-angiogenesis therapy including
angiogenesis inhibitors and chemotherapy.

Circulating endothelial cells (CEC), especially apoptotic CEC, were observed to increase in
breast cancer patients with a clinical benefit (defined as a clinical response or a stable
disease) after metronomic therapy (14). Preclinical models indicated that the source of
apoptotic CEC was most likely the tumor vasculature (14).

Whether circulating EPC or CEC can be served as markers of CCRT efficacy and toxicity in
cervical cancer or not remains undetermined. Since CCRT is now a standard treatment of
locally advanced and high-risk cervical cancer, the development of the surrogate marker for
monitoring CCRT response and optimize treatment intensity, again, is very important.