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Chemoradiation and Endothelial Progenitor Cells in Colorectal Cancer

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ClinicalTrials.gov Identifier: NCT00325871
Recruitment Status : Completed
First Posted : May 15, 2006
Last Update Posted : March 22, 2017
Sponsor:
Information provided by (Responsible Party):
Yu-Jen Chen, Mackay Memorial Hospital

Tracking Information
First Submitted Date May 12, 2006
First Posted Date May 15, 2006
Last Update Posted Date March 22, 2017
Study Start Date April 2006
Actual Primary Completion Date March 2009   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures Not Provided
Original Primary Outcome Measures Not Provided
Change History
Current Secondary Outcome Measures Not Provided
Original Secondary Outcome Measures Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Chemoradiation and Endothelial Progenitor Cells in Colorectal Cancer
Official Title The Effect of Concurrent Chemoradiation on Circulating Endothelial Progenitor Cells in Colorectal Cancer
Brief 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
Study Type Observational
Study Design Observational Model: Case-Control
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Not Provided
Sampling Method Probability Sample
Study Population Rectal cancer post-op with CCRT
Condition Colorectal Cancer
Intervention Procedure: concurrent chemoradiation
Study Groups/Cohorts Not Provided
Publications * Lin CC, Liu CY, Chen MJ, Wang TE, Chu CH, Wang HY, Shih SC, Hsu ML, Hsu TC, Chen YJ. Profiles of circulating endothelial cells and serum cytokines during adjuvant chemoradiation in rectal cancer patients. Clin Transl Oncol. 2013 Oct;15(10):855-60. doi: 10.1007/s12094-013-1004-6. Epub 2013 Feb 12.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Completed
Actual Enrollment
 (submitted: May 12, 2006)
30
Original Enrollment Same as current
Actual Study Completion Date April 2009
Actual Primary Completion Date March 2009   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion Criteria:

  • Colorectal cancer patients indicated for chemoradiation

Exclusion Criteria:

  • With major systemic disease including other cancer, diabetes, cardiovacular disease.
  • Received prior chemotherapy or radiotherapy within 1 month
  • Receiving immunosuppressants
Sex/Gender
Sexes Eligible for Study: All
Ages 30 Years to 60 Years   (Adult)
Accepts Healthy Volunteers No
Contacts Contact information is only displayed when the study is recruiting subjects
Listed Location Countries Taiwan
Removed Location Countries  
 
Administrative Information
NCT Number NCT00325871
Other Study ID Numbers MMH-I-S-243
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement
Plan to Share IPD: No
Responsible Party Yu-Jen Chen, Mackay Memorial Hospital
Study Sponsor Mackay Memorial Hospital
Collaborators Not Provided
Investigators
Principal Investigator: Yu-Jen Chen, MD, PhD Department of Radiation Oncology, Mackay Memorial Hospital
PRS Account Mackay Memorial Hospital
Verification Date March 2017