Trial Information

Association of MSI, TS, DPD, MVD and EGFR With Chemosensitivity in Stage IV in Colorectal Cancer

Stage IV disease represented approximately 25% of all colorectal cancer (CRC) cases. The
mainstay treatment for stage IV CRC is chemotherapy and surgery is only for palliation of
symptoms including colorectal bleeding and obstruction. If patients with stage IV CRC were
not treated, the average survival time was 6 months. Recently, with the progress of
chemotherapeutic agents, such as oxaliplatin and irinotecan, the stage IV patients’ average
survival time considerably increased to 18 months. However, the currently utilized
chemotherapeutic regimens, including FOLFOX (Folinic acid ＋ 5-Fu ＋oxaliplatin) and FOLFIRI
(Folinic acid ＋ 5-Fu ＋ irinotecan), their response rate was only around 50-60%. Moreover,
these agents had several severe side-effects, such as neurotoxicity and diarrhea. Therefore,
it is mandatory for us to seek clinicopathogical parameters or novel molecular markers that
predicted chemosensitivity, in terms of increase of response rate and avoidance of
side-effects. Recently, the carcinogenesis of CRC was better clarified than before. Some
molecular markers, such as p53, K-ras, microsatellite instability (MSI), microvessel
density（MVD）, and epidermal growth factor receptor（EGFR）, and their relation to survival of
colorectal cancer patients have become the focus of research.

The present project basically follows our previous study that p53 overexpression predict
poorer chemosensitivity（Liang et al. Int. J. Cancer 2002; 97: 451-457）, and we plan to
further explore the association between chemosensitivity with MSI-H, MVD, and EGFR. In fact,
in either FOLFOX or FOLFIRI, they all belong to 5-Fu-based therapy. Therefore, the tumor
expression of enzymes related to the metabolism of 5-Fu, such as thymidylate synthase（TS）and
dipyrimidine dehydrogenase（DPD）, have also become the hot issue of research. In this
project, we will explore the clinical implications of MSI, TS, DPD, MVD, and EGFR. This is
because our previous study has indicated that MSI-H is a marker of mutator phenotype of
colorectal cancer, i.e., colorectal cancers with MSI-H tend to have multiple mutations of
downstream genes, especially those with repetitive microsatellite sequences within the
genes. Our previous study has shown MSI-H predicted better chemosensitivity（Liang et al.
Int. J. Cancer 2002; 101: 519-525）. Therefore, we are curious to know that if MSI-H is
related to the alterations of TS and DPD in the tumor, i.e., if the alterations for the
tumor levels of TS and DPD is one of the mechanisms for the better chemosensitivity in
tumors with MSI-H. On the other hand, it has been known that EGFR is related to tumor
growth, invasion, angiogenesis, and metastasis of colorectal cancers. Therefore, it is
mandatory to further dissect the correlation between EGFR and MVD. To the best of our
knowledge, this has not been published before.

The present project will follow our previous phaseⅡ study of FOLFOX regimens for the
treatment of stage Ⅳ colorectal cancer. We will recruit at least 200 patients for this
study. The selection of patients will be based on rigorous eligibility criteria. The
patients will be allocated based on the expression of each molecular marker and the
implementation of chemotherapy. For example, in the examination for the clinical
implications of EGFR, the patients will be classified into four groups: EGFR（＋）
chemotherapy（＋）; EGFR（＋） chemotherapy（－）; EGFR（－） chemotherapy（＋）; EGFR（－） chemotherapy（－）.
Base on the analysis of this 2×2 table, we will clarify the prognostic significance of a
specific molecular marker is due to whether the specific molecular marker predicts
biological invasiveness and/or chemosensitivity. After the analysis of prognostic
significance of each molecular marker, we will explore the interrelationship between these
molecular markers. Also, all these 5 molecular markers and various clinicopathological
factors will be subjected to multivariate analysis. Because the survival of stage Ⅳ CRC
patients will generally not exceed 30 months, the patients study will not have to be
followed up for a long time before the final study result appears. We believe the present
study will have the following significance: （1）To further clarify the mechanisms for the
carcinogenesis and progression of CRC; （2）To facilitate the development of novel
chemotherapeutic agents; and （3） To gain the experience for the practice of evidence-based
medicine.