title: Caspase-3 activity predicts local recurrence in rectal cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Nonirradiated freshly frozen tissue samples from 117 stage III rectal cancer patients were collected from a randomized clinical trial that evaluated preoperative radiotherapy 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, and T status (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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Surgery, Leiden University Medical Centre, the Netherlands.
authors.forename: Pieter
authors.initials: P
authors.lastname: de Heer
authors.forename: Elza C
authors.initials: EC
authors.lastname: de Bruin
authors.forename: Elma
authors.initials: E
authors.lastname: Klein-Kranenbarg
authors.forename: Remco I J M
authors.initials: RI
authors.lastname: Aalbers
authors.forename: Corrie A M
authors.initials: CA
authors.lastname: Marijnen
authors.forename: Hein
authors.initials: H
authors.lastname: Putter
authors.forename: Hans J
authors.initials: HJ
authors.lastname: de Bont
authors.forename: J Fred
authors.initials: JF
authors.lastname: Nagelkerke
authors.forename: J Han J M
authors.initials: JH
authors.lastname: van Krieken
authors.forename: Hein W
authors.initials: HW
authors.lastname: Verspaget
authors.forename: Cornelis J H
authors.initials: CJ
authors.lastname: van de Velde
authors.forename: Peter J K
authors.initials: PJ
authors.lastname: Kuppen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D012004:Rectal Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology*; D012008:Recurrence
chemical_list: D053148:Caspase 3