Prognostic Value of Apoptosis in Rectal Cancer Patients of the Dutch Total Mesorectal Excision Trial: Radiotherapy Is Redundant in Intrinsically High-Apoptotic Tumors

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Purpose: Radiotherapy followed by total mesorectal excision surgery has been shown to significantly reduce local recurrence rates in rectal cancer patients. Radiotherapy, however, is associated with considerable morbidity.The present study evaluated the use of biochemical detection of enzymatic caspase-3 activity as preoperative marker for apoptosis to preselect patients that are unlikely to develop a local recurrence to spare these patients from overtreatment and the negative side effects of radiotherapy. Experimental Design: Nonirradiated freshly frozen tissue samples from 117 stage III rectal cancerpatientswere collectedfromarandomizedclinicaltrialthatevaluatedpreoperativeradiotherapy in total mesorectal excision surgery. Additional frozen archival tissues from 47 preoperative biopsies and corresponding resected colorectal tumors were collected. Level of apoptosis was determined by measuring the enzymatic activity of caspase-3 in a biochemical assay. Results: In tumor tissue, caspase-3 activity lower than the median was predictive of 5-year local recurrence (hazard ratio,7.4; 95% confidence interval,1.7-32.8; P = 0.008), which was unaffected by adjustment for type of resection, tumor location, andTstatus (adjusted hazard ratio, 7.5; 95% confidence interval, 1.7-34.1; P = 0.009). Caspase-3 activity in preoperative biopsies was significantly correlated with caspase-3 activity in corresponding resected tumors (r = 0.56; P <0.0001).Conclusion: Detection of tumor apoptosis levels by measuring caspase-3 activity, for which a preoperative biopsy can be used, accurately predicted local recurrence in rectal cancer patients. These findings indicate that caspase-3 activity is an important denominator of local recurrence and should be evaluated prospectively to be added to the criteria to select rectal cancer patients in which radiotherapy is redundant.

Section: Discussionmentioning

confidence: 48%

Section: Discussionmentioning

confidence: 80%

Caspase-3 Activity Predicts Local Recurrence in Rectal Cancer

Heer¹,

Bruin²,

Klein-Kranenbarg³

et al. 2007

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“…Tissue microarrays from formalinfixed, paraffin-embedded tumors included in the Dutch TME trial were constructed with a custom-built precision tissue arrayer (Beecher Instruments) using a 2-mm-diameter punch as described previously (20).…”

Section: Methodsmentioning

confidence: 99%

Cyclooxygenase 2 Expression in Rectal Cancer Is of Prognostic Significance in Patients Receiving Preoperative Radiotherapy

Heer

Gosens²,

Bruin³

et al. 2007

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Purpose: To determine the effect of cyclooxygenase (COX)-2 expression on clinical behavior in irradiated and nonirradiated rectal carcinomas. Experimental Design:Tumor samples were collected from 1,231patients of the DutchTME trial, in which rectal cancer patients were treated with standardized surgery and randomized for preoperative short-term (5 Â 5 Gy) radiotherapy or no preoperative radiotherapy. Tissue microarrays were constructed from primary tumor material, and COX-2 expression was assessed by immunohistochemistry. Tumor cell apoptosis was determined by M30 immunostaining. Results: A high level of COX-2 expression after radiotherapy was associated with low levels of tumor cell apoptosis (P = 0.001). COX-2 expression had no significant effect on patient survival or tumor recurrence in nonirradiated tumors. However, in patients receiving preoperative radiotherapy, high level of COX-2 expression was associated with higher incidence of distant recurrences [P = 0.003; hazard ratio (HR), 1.7; 95% confidence interval (95% CI), 1.2-2.5] and shorter disease-free survival (P = 0.002; HR, 1.8; 95% CI, 1.2-2.5) and overall survival (P = 0.009; HR, 1.5; 95% CI, 1.1-2.0), independent of patient age, tumor stage, tumor location, or the presence of tumor cells in the circumferential resection margin. Conclusions: A high level of COX-2 expression after preoperative radiotherapy in resection specimens is associated with apoptosis resistance, high distant recurrence rates, and a poor prognosis in rectal cancer.In recent years, the role of a key enzyme in prostaglandin synthesis, cyclooxygenase (COX)-2, has been appreciated in cancer development and progression. COX-2 is responsible for the conversion of arachidonic acid to prostaglandins and other eicosanoids. In addition to its well-known role in inflammatory reactions, COX-2 plays a role in tumor progression, angiogenesis, metastatis, and abrogation of the antitumor immune response (1 -4). COX-2 prevents apoptosis by generation of antiapoptotic PGE 2 (5) and PGI 2 (6) and by removal of the proapoptotic substrate arachidonic acid (7). PGE 2 induces transformations that result in increased Bcl-2 expression and prolong the cell cycle G 1 phase with increased cyclin D1 expression (8). Numerous epidemiologic studies have indicated that the use of nonsteroidal antiinflammatory drugs, and COX-2 inhibitors is associated with a significant decreased incidence and mortality rate in colorectal cancer (9 -12). In addition, selective COX-2 inhibitors have been shown to decrease COX-2 expression and COX-2 activity in gastrointestinal malignancies (13). The clinical effect of COX-2 expression has been evaluated in a large number of studies in colorectal cancer and results have not been consistent (9,14,15). Considering the distinct differences in tumor biology (16), treatment, recurrence rates, and metastatic behavior, it is regrettable that most studies make no distinction between rectal and colon cancer.The purpose of the current study was to obtain a conclusive answer of the...

“…Tumor staging was determined with the tumor-node-metastasis (TNM) classification (15). Paraffin-embedded tumors (1,047) were available in tissue microarray format, as previously described (16). Patients who were ineligible (n = 25) or TNM stage 0 (n = 6) were excluded from the analyses, leaving 1,016 patients for evaluation of the prognostic value of HLA-DR expression.…”

Section: Methodsmentioning

confidence: 99%

Epithelial Human Leukocyte Antigen-DR Expression Predicts Reduced Recurrence Rates and Prolonged Survival in Rectal Cancer Patients

Bruin

Velde

Krieken

et al. 2008

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Purpose: The development of local and distant recurrences is a major problem in the treatment of rectal cancer patients. In this study, we investigated whether epithelial human leukocyte antigen-DR (HLA-DR) expression allowed discrimination between high and low tumor recurrence rates, and analyzed the mechanism behind its expression. Experimental Design: The role of IFNg in HLA-DR expression was studied in rectal cancer cell lines and tumors by promoter-specific analyses of class II transactivator (CIITA). The predictive value of epithelial HLA-DR expression was investigated by immunohistochemical evaluation of 1,016 rectal tumors, obtained from a large prospective trial. Associations with recurrences and survival were determined by univariate and multivariate log-rank testing. Results: HLA-DR was induced by IFNg in rectal cancer cell lines. Activity of the IFNg-inducible pIV-CIITA promoter correlated with epithelial HLA-DR expression in rectal tumors. Patients with HLA-DR^positive tumors developed less frequent local and distant recurrences [1.6% versus 9.1% (P = 0.0015) and 15.3% versus 29.9% (P < 0.0001), respectively, after 5 years of followup] and had better survival (78.6% versus 61.3%; P < 0.0001) than patients with HLA-DRn egative tumors. Epithelial HLA-DR was more often found in lower tumor-node-metastasis (TNM) stages. Next to TNM and circumferential resection margin, HLA-DR expression was independently associated with lower distant recurrence rates and prolonged survival. Conclusions: Epithelial HLA-DR expression can be used as a marker to discriminate patients with high or low risk of developing recurrences.The possible involvement of IFNg, the relationship with lowerTNM stages, and the independent effect on recurrence development together suggest that the host immune response plays an important role in controlling tumor cells.In the treatment of rectal cancer patients, local and distant recurrences are a major problem because these are associated with both high mortality and morbidity. The introduction of total mesorectal excision (TME) surgery in combination with preoperative radiotherapy has been shown to be useful in reducing local recurrences. However, more than 25% of the patients develop metastases within 5 years after surgical treatment with curative intent (1, 2).We and others have shown that (colo)rectal cancer patients develop less frequent recurrences when high numbers of infiltrating immune cells are present in the tumor (3 -6). An optimal antitumor immune response usually requires activation of CD4 + and CD8 + T lymphocytes with a tumor-associated antigen. CD8 + T cells are activated by antigen presented by human leukocyte antigen (HLA) class I molecules whereas CD4 + T cells are activated by antigen presented by HLA class II molecules, normally expressed on professional antigen-presenting cells such as dendritic cells and macrophages. We have recently shown that a subgroup of tumors expressed high levels of HLA classes I and II and several other immune-related genes. Important...