Preoperative serum markers for individual patient prognosis in stage I-III colon cancer.

Carcinoembryonic antigen (CEA) remains the only recommended biomarker for follow-up care of colorectal cancer (CRC), but besides CEA, several other serological parameters have been proposed as prognostic markers for CRC. The present retrospective analysis investigates a comprehensive set of serum markers with regard to cancer-specific survival (CSS) and disease-free survival (DFS). A total of 472 patients with colon cancer underwent surgery for curative intent between January 1988 and June 2007. Preoperative serum was analyzed for the following parameters: albumin, alkaline phosphatase (aP), beta-human chorionic gonadotropin (ßhCG), bilirubin, cancer antigen 125 (CA 125), cancer antigen 19-9 (CA 19-9), CA 72-4, CEA, C-reactive protein (CRP), cytokeratin-19 soluble fragment (CYFRA 21-1), ferritin, gamma-glutamyltransferase (γGT), glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), hemoglobin, haptoglobin, interleukin-6, interleukin-8, creatinine, lactate dehydrogenase (LDH), serum amyloid A (SAA), and 25-hydroxyvitamin D. After a median follow-up period of 5.9 years, the overall 3- and 5-year CSS was 91.7 and 84.9 % and DFS rates were 82.7 % (3 years) and 77.6 % (5 years). Multivariate analyses confirmed preoperative CEA as an independent prognostic factor with regard to CSS and DFS. CA 19-9 and γGT also provided prognostic value for CSS and DFS, respectively. Younger age was negatively associated with DFS. According to UICC stage, CEA provided significant prognostic value with regard to CSS and DFS, while CA 19-9 was only prognostic for CSS. Combined analysis is able to identify patients with favorable prognosis. In addition to tumor baseline parameters, preoperative CEA could be confirmed as prognostic marker in colon cancer. CA 19-9 and γGT also provide additional prognostic value with regard to survival and recurrence in stage III and stage I disease, respectively. The combined use of CEA together with CA 19-9 and γGT improve risk-adapted post-op surveillance.

Evaluation of preoperative serum markers for individual patient prognosis in stage I-III rectal cancer.

Several independent serum biomarkers have been proposed as prognostic and/or predictive markers for colorectal cancer (CRC). To this date, carcinoembryonic antigen (CEA) remains the only recommended serological CRC biomarker. The present retrospective analysis investigates the prognostic value of several serum markers. A total of 256 patients with rectal cancer underwent surgery for curative intent in a university cancer center between January 1988 and June 2007. Preoperative serum was retrospectively analyzed for albumin, alkaline phosphatase (aP), beta-human chorionic gonadotropin, bilirubin, CA 125, cancer antigen 19-9, cancer antigen 72-4 (CA 72-4), CEA, CRP, CYFRA 21-1, ferritin, gamma-glutamyl transpeptidase, glutamate oxaloacetate transanunase, glutamate pyruvate transaminase, hemoglobin, haptoglobin, interleukin-6, interleukin-8, creatinine, lactate-dehydrogenase, serum amyloid A (SAA), and 25-hydroxyvitamin D. Cancer-specific survival (CSS) and disease-free survival (DFS) were estimated. Median follow-up time was 8.4 years. Overall 3- and 5-year CSS was 88.6 and 78.9 %, respectively. DFS rates were 72.8 % (3 years) and 67.5 % (5 years). Univariate analysis of CSS indicated aP, CA 72-4, CEA, and SAA as prognostic factors, while aP, CEA, and SAA were also prognostic with regard to DFS. Multivariate analysis confirmed SAA together with T and N stage as prognostic factors. According to UICC stage, CEA and SAA add prognostic value in stages II and III with regard to DFS and CSS, respectively. The combined use of CEA and SAA is able to identify patients with favorable and poor prognosis. In addition to tumor baseline parameters, routine analysis of SAA together with CEA provided markedly improved prognostic value on CSS and DFS in resected rectal cancer.

Analysis of specific transcriptional regulators as early predictors of independent prognostic relevance in resected colorectal cancer.

PURPOSE: Prognostic studies on transcription factors acting at specific promoter elements have never been done so far. However, in tumors with long necessary follow-up, such as colorectal cancer, early-risk predictors would be needed. The invasion-related gene u-PAR is regulated via an activator protein 2 (AP-2)/Sp1 (-152/-135) and an AP-1 binding promoter motif (-190/-171), mediating u-PAR induction by K-Ras and Src. The present study was done to give first evidence for early prognostic relevance of transcription factors differentially bound to the u-PAR promoter, and their molecular inducers, in colorectal cancer. EXPERIMENTAL DESIGN: Tumor/normal tissues of 92 prospectively followed (median = 26.3 months) patients were analyzed for Src activity/protein, K-ras mutations, and transcription factor binding to both u-PAR promoter motifs (in vivo gel shift, kinase assay, and PCR). RESULTS: Kaplan-Meier/Mantel-Cox analysis showed a significant correlation among elevated Sp1/Sp3 binding to region -152/-135 (P = 0.002 and P = 0.006), the combinations of Sp1/AP-2 and Sp1/AP-1 binding to both motifs (P = 0.010 and P = 0.005), and Sp1 binding/high Src protein in tumors (P < 0.001), with poor survival. Survival decreased with the number of bound transcription factors to both motifs, with binding of three factors defining a high-risk group (P = 0.021). In multivariate analysis, elevated Sp1 binding, combinations of Sp1/AP-2 binding and Sp1/AP-1 binding, or Sp1 binding/high Src were independent prognostic variables; u-PAR expression itself being not yet prognostic. A first molecular staging model (CART) was defined, providing novel early high-risk groups (mean survival time as low as for non-curatively resected patients) from these variables. CONCLUSIONS: This study defines transcription factors acting at specific promoter elements of an invasion-related gene, mediating specific signaling, as novel, independent, early predictors of prognosis in colorectal cancer.

Results of long-term follow-up after curative resection of Dukes A colorectal cancer.

Patients with Dukes A (UICC I) colorectal cancer have a good prognosis after curative resection. It is not known, however, if the outcome is significantly different for UICC Ia and Ib patients or if patients with reduced risks of recurrences can be identified early after surgery. This is of interest, as it would permit a more cost-effective, patient-oriented, and tumor stage-oriented follow-up program. To study these questions, a prospective follow-up database, including 1375 patients after curative resection of colorectal cancer, was analyzed. A total of 296 patients with Dukes A colorectal cancer with a median follow-up of 44 months were studied. Perioperative and follow-up mortality rates were 3% and 14%, respectively. Recurrent disease developed in 10% of Dukes A patients after a disease-free interval of 16 months. Significantly more patients suffering from pT2 (UICC Ib) cancer had recurrent disease than patients with pT1 (UICC Ia) cancer (13% vs. 4%; p <0.05). Preoperative CEA levels in patients with recurrent disease were significantly higher than in long-term disease-free patients (5.3 +/- 1.8 vs. 3.5 +/- 0.6 ng/ml; p <0.05). Curative resection of recurrent disease was achieved in 38% of the patients with recurrences (4% of all patients). Survival analysis showed significantly better survival in patients with Dukes A cancer than in those at higher tumor stages (log rank, <0.0001), and only 39% of all Dukes A patients who died during follow-up had recurrent disease. Dukes A (UICC Ia and Ib) colorectal cancer was diagnosed in 22% of our patients treated for cure, and long-term survival was 86%. There were significantly fewer cases of recurrent disease after curative resection of UICC Ia (pT1N0M0) cancer, so we propose a novel, less intensive follow-up regimen for these patients, leading to a more cost-effective, patient-oriented, and tumor stage-oriented follow-up program.

Effect of preoperative radiochemotherapy on lymph node retrieval after resection of rectal cancer.

HYPOTHESIS: Preoperative radiochemotherapy for advanced rectal cancer results in fewer lymph nodes detected in the tumor-bearing specimen. DESIGN: Nonrandomized control trial with analysis of a prospective perioperative database. SETTING: Department of Surgery of a large-volume university hospital. PATIENTS: All patients who underwent conventional open surgery to cure rectal cancer between January 1, 1996, and March 31, 2001. INTERVENTIONS: During the study period 184 patients (81%, control group) underwent surgery without receiving preoperative radiochemotherapy. Forty-two patients (19%, study group) who had advanced rectal cancer (modified Dukes stages B [tumors that have penetrated the muscle layer of the bowel wall or have gone through the bowel] or C [tumors that have spread to the lymph nodes in the same region]) received preoperative radiochemotherapy (2 cycles of fluorouracil, 4500 rad) during this period. Most patients underwent anterior rectal resection in both groups (77.7% of those who did not receive preoperative radiochemotherapy and 71.8% of those who did), the remaining patients were treated with abdominoperineal resection. RESULTS: A mean (SEM) of 19 (1) lymph nodes per specimen were detected in the control patients, while significantly fewer lymph nodes were detected in study patients (13 [1]; P<.05). The rate of inadequate lymph node staging (pNx) increased from 7% in the control group to 12% in the study group (P =.06). Pathological lymph node staging disclosed that significantly more study patients who received preoperative radiochemotherapy had modified Dukes stage A (tumors that are found only in the inner wall or rectum) cancer when compared with the control group (17% vs 0%, respectively; P<.05). CONCLUSIONS: Preoperative radiochemotherapy for advanced rectal cancer results in a significant decrease of lymph nodes detected within the tumor-bearing specimen. Preoperative radiochemotherapy induces significant downstaging with fewer positive lymph nodes and more patients presenting with Dukes stage A rectal cancer. Great care must be taken to remove an adequate number of lymph nodes and more sophisticated pathological techniques of lymph node detection are required since the tumors of ever-increasing numbers of patients are inadequately classified.