Liver-First Approach for Synchronous Colorectal Metastases: Analysis of 7360 Patients from the LiverMetSurvey Registry

Annals of Surgical Oncology - The liver-first approach in patients with synchronous colorectal liver metastases (CRLM) has gained wide consensus but its role is still to be clarified. We aimed to...     

CA19-9 as the most significant prognostic indicator of metastatic colorectal cancer

BACKGROUND/AIMS: Colorectal cancer is the third leading cause of cancer-related mortality in Taiwan. We became interested in searching for the factors predictive of survival. Serum CA19-9 (carbohydrate antigen 19-9) level has been reported as a factor predictive of survival in patients with colorectal cancer. A few articles have reported that patients with metastatic colorectal cancer who have normal (< or = 37 U/mL) serum CA19-9 levels survived significantly longer than those with higher serum CA19-9 levels. However, these reports are contradictory and lack definite conclusions. This study was carried out in an effort to evaluate the prognostic significance of serum CA19-9 levels in patients with metastatic colorectal cancer in Taiwan. METHODOLOGY: Between 1991 and 1994, a total of 128 patients with histologically confirmed metastatic colorectal cancers were evaluated retrospectively at Veterans General Hospital-Taipei. All patients had measurable metastatic lesions and life expectancies of more than 3 months. 5-Fluorouracil-based chemotherapy, either in a weekly bolus regimen or a monthly 5-day bolus schedule, were administered to all of them. Data on age, sex, performance status, location of primary tumor, extent of metastases, site of metastases, histological differentiation, serum CEA (carcinoembryonic antigen) and CA19-9 levels were analyzed before chemotherapy to determine their association with survival. Blood samples for CEA and CA19-9 measurement were analyzed using the radioimmunoassay method. Multivariate analysis by the Cox's proportional hazards regression model was performed to determine independent prognostic factors among all of the possible variables. RESULTS: By univariate analysis, serum CA19-9 levels (P < 0.001) and performance status of the patients (P = 0.022) were identified as prognostic factors, while age, sex, location of primary tumor, site of metastasis, histological differentiation, and pre-treatment serum CEA levels were not considered significant. By multivariate analysis, serum CA19-9 levels (P < 0.001) and performance status of the patients (P = 0.014) were still found as independent prognostic factors of these patients. CONCLUSIONS: The data from our study indicate that serum CA19-9 level is the most significant prognostic indicator of patients with metastatic colorectal cancer. It is recommended that stratification for further clinical trials for patients with metastatic colorectal cancer should be carried out according to serum CA19-9 levels.     

Circumferential margin plays an independent impact on the outcome of rectal cancer patients receiving curative total mesorectal excision

Background

The aim of this study was to determine the impact of the circumferential resection margin on the outcomes of patients with rectal cancer undergoing total mesorectal excision.

Methods

Medical records from July 2004 to June 2008 were prospectively reviewed, and 348 patients who underwent potentially curative surgery for rectal cancer were identified. The influence of the circumferential resection margin on local recurrence, distant metastasis, and 5-year cancer-specific survival was assessed.

Results

Of 348 patients, 13 (3.7%) had positive circumferential resection margins. During a median follow-up period of 58.0 months, 8 patients (2.3%) had local recurrence and 53 (15.2%) developed distant metastases. Local recurrence rates and distant metastasis rates in patients with positive circumferential resection margins were 15.4% and 61.5%, respectively, significantly higher than in those with negative circumferential resection margins (1.8% and 13.4%, respectively) (P < .001). The 5-year cancer-specific survival rates were 75.8% and 0% for patients with tumors having negative and positive circumferential resection margins, respectively (P < .001).

Conclusions

A circumferential resection margin of ≤1 mm adversely affects cancer-specific survival, local recurrence, and distant metastasis.     

Assessment of the value of carcinoembryonic antigen reduction ratio as a prognosis factor in rectal cancer

Background

Carcinoembryonic antigen (CEA) is the most widely used tumor marker for colorectal cancer. This study aimed to investigate the role of CEA reduction ratio after preoperative chemoradiotherapy (CRT).

Methods

We enrolled 284 patients who underwent preoperative CRT followed by radical surgical resection. Patients were divided into 3 groups: serum CEA levels before CRT (pre-CRT CEA) less than 5 ng/mL (group 1); pre-CRT CEA of 5 ng/mL or more with CEA reduction ratio of 50% or more (group 2); and pre-CRT CEA of 5 ng/mL or more with CEA reduction ratio less than 50% (group 3).

Results

The 5-year disease-free survival (DFS) rate was not different between groups 1 (71.8%) and 2 (69.4%) but was signi?cantly lower in group 3 (49.5%). CEA group, lymph node status after CRT (ypN) stage, and histologic type were independent prognostic factors for DFS on multivariate analysis.

Conclusions

CEA reduction ratio might be an independent prognostic factor for DFS in rectal cancer patients treated with preoperative CRT and radical surgery.     

SDF-1α G801A Polymorphism Predicts Lymph Node Metastasis in Stage T3 Colorectal Cancer

Background  The SDF-1/CXCR4 axis plays an important role in cancer metastasis. SDF1α genetic polymorphisms, including SDF1α-G801A, have been associated with increased cancer risk and may be predictive of distant metastasis. The present study compared the frequency of 6 SDF1α single-nucleotide polymorphisms (SNPs) in patients with colorectal cancer (CRC) with and without lymph node (LN) metastasis and determined whether fibroblasts with different SDF-1α genotypes influenced cancer cell proliferation and migration. Methods  The study enrolled 424 patients with primary T3 stage CRC, with and without lymph node metastasis, and a median follow-up of 48 months. The polymerase chain reaction-sequence specific primers (PCR-SSP) technique was used to identify polymorphisms. Fibroblasts were harvested from 14 patients with stage II CRC and fibroblast-mediated enhancement of cancer cell proliferation and migration was evaluated. Results  Only the SDF1α-G801A polymorphism was associated with LN metastasis. The frequency of GA/AA genotypes was significantly higher in patients with LN metastasis (54.8%) than in patients without LN metastasis (40.7%). In the latter group, disease-free survival was shorter in patients with the GA/AA genotype (74%) than in patients with the GG genotype (87.6%). In patients with LN metastasis, disease-free survival was similar regardless of genotype. Expression of SDF-1α mRNA in GA/AA fibroblasts was three times that in GG fibroblasts. GA/AA (but not GG) fibroblasts enhanced colon cancer cell (HCT116) proliferation and migration. These effects were blocked by an SDF-1α neutralizing antibody. Conclusions  The SDF1α-G801A polymorphism may increase expression of SDF-1α mRNA and be a predictive marker of lymph node metastasis in colorectal cancer.     

Genetic alteration of p53, but not overexpression of intratumoral p53 protein, or serum p53 antibody is a prognostic factor in sporadic colorectal adenocarcinoma

Mutation of p53 is a common event in colorectal cancer and can result in cellular accumulation of p53 protein and induction of p53 antibodies. We investigated the association of colorectal cancer with alterations in p53 DNA, protein and serum antibody levels to determine their prognostic value in colorectal cancer. Colorectal cancer patients (n=167) who underwent surgery in Taipei Veterans General Hospital from January 1999 to December 2000 were enrolled [age 62.91+/-12.61 years (range: 22-85); 111 (66.5%) males]. Of these, 20 were stage I (12%), 54 stage II (32.3%), 58 stage III (34.7%), and 35 stage IV (21%). Median follow-up was 36.3 months (range: 4-58). p53 alteration was detected by DNA sequencing from exon 5 to 9 and loss of heterozygosity (LOH) at two microsatellite markers near p53; and demonstrating intratumoral accumulation of p53 protein and detection of serum p53 antibodies using ELISA. p53 mutation frequency was 41.9% (70/167). Of 127 informative cases for LOH analysis, 73 (57.5%) tumors that had LOH had at least one microsatellite marker. Genetic p53 alterations were found for 56.3% of cases when LOH and DNA sequencing methods were combined. Genetic p53 alterations were associated with advanced tumor stage and tumor differentiation. Overexpression of intratumoral p53 and anti-p53 antibody positivity were 44.9% and 28.1%. The presence of p53-Ab was associated with p53 mutations (chi2 test, 42.9% vs. 17.5%, p=0.001), but not with overexpression of intratumoral p53 protein. The mutations at exon 6 (57.1%) and 7 (53.3%) were associated with presence of serum p53-Ab. Of 132 potentially cured patients, 3-year disease-free survival (DFS) was affected by: advanced TNM stage (I, II, III: 90%, 84%, and 41%), genetic p53 alteration (89% vs. 43%), intratumoral p53 accumulation (71% vs. 56%), and preoperative CEA level >5 ng/ml (74% vs. 58%). In multivariate analysis, genetic alteration of p53 was the most significant independent prognostic factor [hazard ratio (HR) = 6.09; 95% confidence interval (CI): 2.45-15.11], followed by advanced tumor stage (HR = 3.93; 95% CI: 2.14-7.23), and preoperative CEA >5 ng/ml (HR = 1.98; 95% CI: 1.12-3.17). Genetic alterations in p53 but not intratumoral p53 protein accumulation or p53-Ab appear to play a significant role in the progression of colorectal cancer.     

EIA versus RIA in detecting carcinoembryonic antigen level of patients with metastatic colorectal cancer

BACKGROUND/AIMS: Little literature exists comparing the differences between enzyme immunoassay (EIA) and radioimmunoassay (RIA) in the detection of serum carcinoembryonic antigen (CEA) levels of patients with metastatic colorectal cancer. Because EIA has the advantage of avoiding the use of radioisotopes, the potential of using EIA instead of RIA in detecting CEA of patients with colorectal cancer is of interest to us. METHODOLOGY: Between March and August 2001, a total of 120 blood specimens, including 60 specimens from patients with metastatic colorectal cancer and another 60 from patients with non-malignant diseases, were examined in this study. Serum CEA levels were examined by EIA and RIA methods in parallel. The CEA-EIA tests were done using EIA kits manufactured by Abbott Laboratories at Illinois in the United States. Comparison was done with the conventional CEA-RIA tests using RIA kits manufactured by CIS laboratory at France. The blood samples were sent to Veterans General Hospital-Taipei for EIA and RIA determination. The cut-off value for CEA was set at 5.0 ng/mL. RESULTS: The correlation between the Abbott-EIA and the CIS-RIA methods in detecting serum CEA levels was high. The results give a correlation coefficient of 0.992 with a linear regression line y=0.975 x + 0.215 (p<0.0001). Agreement in the Abbott-EIA and CIS-RIA tests in diagnosis was observed in 113 patients (94%), including 53 positive (>5 ng/mL) and 60 negative (<5 ng/mL) in both tests. The sensitivity was similar in both assays (83% vs. 80%) at a cut-off level of 5 ng/mL. The ability to discriminate between colorectal cancer and non-malignant diseases was good in both assays (p<0.001). The specificity and positive predictive value were slightly higher with the Abbott-EIA method compared with CIS-RIA assay (92% vs. 83% and 91% vs. 83%, respectively). The Abbott-EIA method achieved a similar diagnostic accuracy to CIS-RIA method (88% vs. 82%). CONCLUSIONS: These data suggest that the Abbott-EIA has similar diagnostic power to CIS-RIA in the measurement of CEA levels of patients with metastatic colorectal cancer, with an additional advantage of avoiding the use of radioisotopes. We believe that ELA has the potential to replace RIA in the measurement of CEA in clinical practice.     

Sequence-dependent effect of a cyclooxygenase-2 inhibitor on topoisomerase I inhibitor and 5-fluorouracil-induced cytotoxicity of colon cancer cells

Selective cyclooxygenase-2 (COX-2) inhibitors have been found to induce anti-proliferative and apoptotic activity in many cancer cells. However, interaction between COX-2 inhibitors and other chemotherapeutic agents remains to be determined. We investigated the interactive effects of a selective COX-2 inhibitor, etodolac, in combination with 5-fluorouracil (5-FU) or SN-38 (active metabolite of irinotecan) on colon cancer cell lines, HT29 and SW620, in simultaneous and sequential administration schedules. Isobologram analysis demonstrated that etodolac in combination with 5-FU or SN-38 according to a simultaneous schedule resulted in only an additive effect; however, synergism was achieved in a sequential schedule. Apoptosis induction in both cell lines was also significantly increased after sequential treatment with etodolac followed by either 5-FU or SN-38 compared to that after simultaneous treatment with etodolac and either 5-FU or SN-38. Our study suggests apoptosis-inducing synergism resulted from administration of etodolac and either 5-FU or SN-38 sequentially, but not simultaneously.