Chemoradiation and Endothelial Progenitor Cells in Colorectal Cancer
Condition: Colorectal Cancer
MeSH terms: Colorectal Neoplasms
Study type: Observational

Summary: 
      Colorectal cancer (CRC) is one of the common malignancies worldwide, accounting for a
      significant percentage of cancer mortality. Concurrent chemoradiation (CCRT) is now a
      standard treatment for unresectable malignancies of anorectum. To improve quality of life,
      CCRT is also commonly applied in treatment of lower rectal and anal canal cancer to preserve
      anal sphincter function. The most commonly used chemotherapeutic drugs combined with
      radiation as radiosensitizers is 5-fluorouracil (5-FU). Circulating endothelial progenitor
      cells (EPC), which contribute to the tumor vessel formation, reflect the response to
      chemotherapy both in animal model and clinical trial. 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 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
      receiving CCRT.
    

Detailed description: 
      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
      (1-4).

      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
      receiving CCRT.

      References

        1. Midgley R, Kerr D. Colorectal cancer. Lancet 1999;353:391-399.

        2. Fisher B, Wolmark N, Rockette H, et al. Postoperative adjuvant chemotherapy or radiation
           therapy for rectal cancer: results from NSABP protocol R-01. J Natl Cancer Inst
           1988;80:21-29.

        3. O'Connell MJ, Martenson JA, Wieand HS, et al. Improving adjuvant therapy for rectal
           cancer by combining protracted-infusion fluorouracil with radiation therapy after
           curative surgery. New Engl J Med 1994;331:502-507.

        4. Skarlatos J, Kosma L, Koukourakis M, et al. Hypofractionated radiotherapy with
           concurrent 5-fluorouracil radiosensitisation for recurrent or locally advanced
           colorectal cancer. A phase II study. Int J Colore Dis 1996;11:206-210.

        5. Rose PG, Bundy BN, Watkins EB, et al. Concurrent cisplatin-based radiotherapy and
           chemotherapy for locally advanced cervical cancer. New Engl J Med 1999;340:1144-1153.

        6. Cooper JS, Guo MD, Herskovic A, et al. Chemoradiotherapy of locally advanced esophageal
           cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation
           Therapy Oncology Group. J Am Med Assoc 1999;281:1623-1627.

        7. Henning GT, Schild SE, Stafford SL, et al. Results of irradiation or chemoirradiation
           for primary unresectable, locally recurrent, or grossly incomplete resection of gastric
           adenocarcinoma. Int J Radiat Oncol 2000;46:109-118.

        8. Mitchell SE, Mendenhall WM, Zlotecki RA, et al. Squamous cell carcinoma of the anal
           canal. Int J Radiat Oncol 2001;49:1007-1013.

        9. Thomas CR, Weiden PL, Traverso LW, et al. Concomitant intraarterial cisplatin,
           intravenous 5-flourouracil, and split-course radiation therapy for locally advanced
           unresectable pancreatic adenocarcinoma: a phase II study of the Puget Sound Oncology
           Consortium (PSOC-703). Am J Clin Oncol 1997;20:161-165.

       10. Kelly H. Goldberg RM. Systemic therapy for metastatic colorectal cancer: current
           options, current evidence. Journal of Clinical Oncology. 23(20):4553-60, 2005

       11. Mancuso A. Sternberg CN. Colorectal cancer and antiangiogenic therapy: what can be
           expected in clinical practice?. Critical Reviews in Oncology-Hematology. 55(1):67-81,
           2005 Jul.

       12. Schneider M. Tjwa M. Carmeliet P. A surrogate marker to monitor angiogenesis at last.
           Cancer Cell. 7(1):3-4, 2005.

       13. Bertolini F. Paul S. Mancuso P. Monestiroli S. Gobbi A. Shaked Y. Kerbel RS. Maximum
           tolerable dose and low-dose metronomic chemotherapy have opposite effects on the
           mobilization and viability of circulating endothelial progenitor cells. Cancer Research.
           63(15):4342-6, 2003.

       14. Zhang H. Vakil V. Braunstein M. Smith EL. Maroney J. Chen L. Dai K. Berenson JR. Hussain
           MM. Klueppelberg U. Norin AJ. Akman HO. Ozcelik T. Batuman OA. Circulating endothelial
           progenitor cells in multiple myeloma: implications and significance. Blood.
           105(8):3286-94, 2005
    

Intervention name(s): concurrent chemoradiation
Intervention type(s): Procedure
Observational model: Case-Control
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Rectal cancer post-op with CCRT