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Title: Matrix metalloproteinase-9 expression correlated with tumor response in patients with locally advanced rectal cancer undergoing preoperative chemoradiotherapy

Abstract

Purpose: To analyze whether the expression of matrix metalloproteinases (MMPs) and their tissue inhibitors are associated with tumor response to preoperative chemoradiotherapy in rectal cancer patients. Methods and Materials: Forty-four patients who had undergone preoperative chemoradiotherapy were evaluated retrospectively. Treatment consisted of pelvic radiotherapy and two cycles of 5-fluorouracil plus leucovorin. Surgery was performed 6-8 weeks later. MMP-2, MMP-9, and tissue inhibitors of metalloproteinase-1 and -2 expression was analyzed by immunohistochemistry of the preradiation biopsy and surgical specimens. The intensity and extent of staining were evaluated separately, and a final score was calculated by multiplying the two scores. The primary endpoint was the correlation of expression with tumor response, with the secondary endpoint the effect of chemoradiotherapy on the expression. Results: Preoperative treatment resulted in downstaging in 20 patients (45%) and no clinical response in 24 (55%). The pathologic tumor response was complete in 11 patients (25%), partial in 23 (52%), and none in 10 (23%). Positive MMP-9 staining was observed in 20 tumors (45%) and was associated with the clinical nodal stage (p = 0.035) and the pathologic and clinical response (p < 0.0001). The staining status of the other markers was associated with neither stage nor response. Themore » overall pathologic response rate was 25% in MMP-9-positive patients vs. 52% in MMP-9-negative patients (p = 0.001). None of the 11 patients with pathologic complete remission was MMP-9 positive. Conclusions: Matrix metalloproteinase-9 expression correlated with a poor tumor response to preoperative chemoradiotherapy in rectal carcinoma patients.« less

Authors:
 [1];  [2];  [3];  [4];  [3];  [4]
  1. Department of Radiation Oncology, Gazi University Faculty of Medicine, Ankara (Turkey). E-mail: diclehan@yahoo.com
  2. Department of Medical Oncology, Gazi University Faculty of Medicine, Ankara (Turkey)
  3. Department of Pathology, Gazi University Faculty of Medicine, Ankara (Turkey)
  4. Department of Radiation Oncology, Gazi University Faculty of Medicine, Ankara (Turkey)
Publication Date:
OSTI Identifier:
20850314
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; Journal Volume: 67; Journal Issue: 1; Other Information: DOI: 10.1016/j.ijrobp.2006.08.010; PII: S0360-3016(06)02732-5; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; BIOPSY; CARCINOMAS; CITROVORUM FACTOR; COMBINED THERAPY; CORRELATIONS; PATIENTS; RADIOTHERAPY; SURGERY; URACILS

Citation Formats

Unsal, Diclehan, Uner, Aytug, Akyurek, Nalan, Erpolat, Petek, Dursun, Ayse, and Pak, Yucel. Matrix metalloproteinase-9 expression correlated with tumor response in patients with locally advanced rectal cancer undergoing preoperative chemoradiotherapy. United States: N. p., 2007. Web. doi:10.1016/j.ijrobp.2006.08.010.
Unsal, Diclehan, Uner, Aytug, Akyurek, Nalan, Erpolat, Petek, Dursun, Ayse, & Pak, Yucel. Matrix metalloproteinase-9 expression correlated with tumor response in patients with locally advanced rectal cancer undergoing preoperative chemoradiotherapy. United States. doi:10.1016/j.ijrobp.2006.08.010.
Unsal, Diclehan, Uner, Aytug, Akyurek, Nalan, Erpolat, Petek, Dursun, Ayse, and Pak, Yucel. Mon . "Matrix metalloproteinase-9 expression correlated with tumor response in patients with locally advanced rectal cancer undergoing preoperative chemoradiotherapy". United States. doi:10.1016/j.ijrobp.2006.08.010.
@article{osti_20850314,
title = {Matrix metalloproteinase-9 expression correlated with tumor response in patients with locally advanced rectal cancer undergoing preoperative chemoradiotherapy},
author = {Unsal, Diclehan and Uner, Aytug and Akyurek, Nalan and Erpolat, Petek and Dursun, Ayse and Pak, Yucel},
abstractNote = {Purpose: To analyze whether the expression of matrix metalloproteinases (MMPs) and their tissue inhibitors are associated with tumor response to preoperative chemoradiotherapy in rectal cancer patients. Methods and Materials: Forty-four patients who had undergone preoperative chemoradiotherapy were evaluated retrospectively. Treatment consisted of pelvic radiotherapy and two cycles of 5-fluorouracil plus leucovorin. Surgery was performed 6-8 weeks later. MMP-2, MMP-9, and tissue inhibitors of metalloproteinase-1 and -2 expression was analyzed by immunohistochemistry of the preradiation biopsy and surgical specimens. The intensity and extent of staining were evaluated separately, and a final score was calculated by multiplying the two scores. The primary endpoint was the correlation of expression with tumor response, with the secondary endpoint the effect of chemoradiotherapy on the expression. Results: Preoperative treatment resulted in downstaging in 20 patients (45%) and no clinical response in 24 (55%). The pathologic tumor response was complete in 11 patients (25%), partial in 23 (52%), and none in 10 (23%). Positive MMP-9 staining was observed in 20 tumors (45%) and was associated with the clinical nodal stage (p = 0.035) and the pathologic and clinical response (p < 0.0001). The staining status of the other markers was associated with neither stage nor response. The overall pathologic response rate was 25% in MMP-9-positive patients vs. 52% in MMP-9-negative patients (p = 0.001). None of the 11 patients with pathologic complete remission was MMP-9 positive. Conclusions: Matrix metalloproteinase-9 expression correlated with a poor tumor response to preoperative chemoradiotherapy in rectal carcinoma patients.},
doi = {10.1016/j.ijrobp.2006.08.010},
journal = {International Journal of Radiation Oncology, Biology and Physics},
number = 1,
volume = 67,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}
  • Purpose: To examine retrospectively whether levels of epidermal growth factor receptor (EGFR) expression can predict tumor downstaging after preoperative chemoradiotherapy in patients with locally advanced rectal cancer. Methods and Materials: A total of 183 patients with rectal cancer (cT3-T4 or N+) were enrolled in this study. Preoperative chemoradiotherapy consisted of 50.4 Gy of pelvic radiation with concurrent 5-fluorouracil and leucovorin bolus intravenous chemotherapy in 94 patients or oral capecitabine and leucovorin in 89 patients. EGFR expression in pretreatment paraffin-embedded tumor biopsy specimens was assessed by immunohistochemistry. EGFR expression was determined from the intensity and extent of staining. Tumor downstaging wasmore » defined as a reduction of at least one T-stage level. Results: Tumor downstaging occurred in 97 patients (53%), and the tumors showed a pathologic complete response in 27 patients (15%). Positive EGFR expression was observed in 140 (76%) of 183 patients. EGFR expression levels were low in 113 patients (62%) and high in 70 patients (38%). On logistic regression analysis, the significant predictive factor for increased tumor downstaging was a low level of EGFR expression and preoperative chemotherapy using oral capecitabine (odds ratio, 0.437; p 0.012 vs. odds ratio, 3.235; p < 0.001, respectively). Conclusion: A high level of EGFR expression may be a significant predictive molecular marker for decreased tumor downstaging after preoperative chemoradiotherapy in locally advanced rectal cancer.« less
  • Purpose: To evaluate the role of serum carcinoembryonic antigen (CEA) as a predictor of response to preoperative chemoradiotherapy (CRT) and prognostic factor for rectal cancer. Materials and Methods: The study retrospectively evaluated 352 locally advanced rectal cancer patients who underwent preoperative CRT followed by surgery. Serum CEA levels were determined before CRT administration (pre-CRT CEA) and before surgery (post-CRT CEA). Correlations between pre-CRT CEA levels and rates of good response (Tumor regression grade 3/4) were explored. Patients were categorized into three CEA groups according to their pre-/post-CRT CEA levels (ng/mL) (Group A: pre-CRT CEA {<=} 3; B: pre-CRT CEA >3,more » post-CRT CEA {<=}3; C: pre- and post-CRT CEA >3 ng/mL), and their oncologic outcomes were compared. Results: Of 352 patients, good responses were achieved in 94 patients (26.7%). The rates of good response decreased significantly as the pre-CRT CEA levels became more elevated (CEA [ng/mL]: {<=}3, 36.4%; 3-6, 23.6%; 6-9, 15.6%; >9, 7.8%; p < 0.001). The rates of good response were significantly higher in Group A than in Groups B and C (36.4% vs. 17.3% and 14.3%, respectively; p < 0.001). The 3-year disease-free survival rate was significantly better in Groups A and B than in Group C (82% and 79% vs. 57%, respectively; p = 0.005); the CEA grouping was identified as an independent prognostic factor (p = 0.025). Conclusions: In locally advanced rectal cancer patients, CEA levels could be of clinical value as a predictor of response to preoperative CRT and as an independent prognostic factor after preoperative CRT and curative surgery.« less
  • Purpose: We aimed to validate our hypothesis that a preoperative chemoradiotherapy regimen with S-1 plus irinotecan is feasible, safe, and active for the management of locally advanced rectal cancer in a single-arm Phase II setting. Methods and Materials: Eligible patients had previously untreated, locally advanced rectal adenocarcinoma. Radiotherapy was administered in fractions of 1.8Gy/d for 25 days. S-1 was administered orally in a fixed daily dose of 80mg/m{sup 2} on Days 1 to 5, 8 to 12, 22 to 26, and 29 to 33. Irinotecan (80mg/m{sup 2}) was infused on Days 1, 8, 22, and 29. Four or more weeksmore » after the completion of the treatment, total mesorectal excision with lateral lymph node dissection was performed. The primary endpoint was the rate of completing treatment in terms of feasibility. The secondary endpoints were the response rate and safety. Results: We enrolled 43 men and 24 women in the study. The number of patients who completed treatment was 58 (86.6%). Overall, 46 patients (68.7%) responded to treatment and 24 (34.7%) had a complete histopathologic response. Three patients had Grade 3 leukopenia, and another three patients had Grade 3 neutropenia. Diarrhea was the most common type of nonhematologic toxicity: 3 patients had Grade 3 diarrhea. Conclusions: A preoperative regimen of S-1, irinotecan, and radiotherapy to the rectum was feasible, and it appeared safe and effective in this nonrandomized Phase II setting. It exhibited a low incidence of adverse events, a high rate of completion of treatment, and an extremely high rate of pathologic complete response.« less
  • Purpose: To determine whether the tumor volume reduction rate (TVRR) measured using three-dimensional region-of-interest magnetic resonance volumetry correlates with the pathologic tumor response after preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer. Methods and Materials: The study included 405 patients with locally advanced rectal cancer (cT3-T4) who had undergone preoperative CRT and radical proctectomy. The tumor volume was measured using three-dimensional region-of-interest magnetic resonance volumetry before and after CRT but before surgery. We analyzed the correlation between the TVRR and the pathologic tumor response in terms of downstaging and tumor regression grade (TRG). Downstaging was defined as ypStage 0-I (ypT0-T2N0M0),more » and the TRG proposed by Dworak et al. was used. Results: The mean TVRR was 65.0% {+-} 22.3%. Downstaging and complete regression occurred in 167 (41.2%) and 58 (14.3%) patients, respectively. The TVRRs according to ypT classification (ypT0-T2 vs. ypT3-T4), ypN classification (ypN0 vs. ypN1-N2), downstaging (ypStage 0-I vs. ypStage II-III), good regression (TRG 3-4 vs. TRG 1-2), and complete regression (TRG 4 vs. TRG 1-3) were all significantly different (p <.05). When the TVRR was categorized into three groups (<60%, 60-80%, and >80%), the rates of ypT0-T2, ypN0, downstaging, and good regression were all significantly greater for patients with a TVRR of {>=}60%, as was the complete regression rate for patients with a TVRR >80% (p <.05). Conclusion: The TVRR measured using three-dimensional region-of-interest magnetic resonance volumetry correlated significantly with the pathologic tumor response in terms of downstaging and TRG after preoperative CRT for locally advanced rectal cancer.« less
  • Purpose: To investigate the prognostic significance of tumor volume reduction rate (TVRR) after preoperative chemoradiotherapy (CRT) in locally advanced rectal cancer (LARC). Methods and Materials: In total, 430 primary LARC (cT3-4) patients who were treated with preoperative CRT and curative radical surgery between May 2002 and March 2008 were analyzed retrospectively. Pre- and post-CRT tumor volumes were measured using three-dimensional region-of-interest MR volumetry. Tumor volume reduction rate was determined using the equation TVRR (%) = (pre-CRT tumor volume - post-CRT tumor volume) Multiplication-Sign 100/pre-CRT tumor volume. The median follow-up period was 64 months (range, 27-99 months) for survivors. Endpoints weremore » disease-free survival (DFS) and overall survival (OS). Results: The median TVRR was 70.2% (mean, 64.7% {+-} 22.6%; range, 0-100%). Downstaging (ypT0-2N0M0) occurred in 183 patients (42.6%). The 5-year DFS and OS rates were 77.7% and 86.3%, respectively. In the analysis that included pre-CRT and post-CRT tumor volumes and TVRR as continuous variables, only TVRR was an independent prognostic factor. Tumor volume reduction rate was categorized according to a cutoff value of 45% and included with clinicopathologic factors in the multivariate analysis; ypN status, circumferential resection margin, and TVRR were significant prognostic factors for both DFS and OS. Conclusions: Tumor volume reduction rate was a significant prognostic factor in LARC patients receiving preoperative CRT. Tumor volume reduction rate data may be useful for tailoring surgery and postoperative adjuvant therapy after preoperative CRT.« less