title: Biopsy specimens obtained 7 days after starting chemoradiotherapy (CRT) provide reliable predictors of response to CRT for rectal cancer.
abstract: OBJECTIVE
  Preoperative chemoradiation therapy (CRT) significantly decreases local recurrence in locally advanced rectal cancer. Various biomarkers in biopsy specimens obtained before CRT have been proposed as predictors of response. However, reliable biomarkers remain to be established.
  
  
  METHODS
  The study group comprised 101 consecutive patients with locally advanced rectal cancer who received preoperative CRT with oral uracil/tegafur (UFT) or S-1. We evaluated histologic findings on hematoxylin and eosin (H&E) staining and immunohistochemical expressions of Ki67, p53, p21, and apoptosis in biopsy specimens obtained before CRT and 7 days after starting CRT. These findings were contrasted with the histologic response and the degree of tumor shrinkage.
  
  
  RESULTS
  In biopsy specimens obtained before CRT, histologic marked regression according to the Japanese Classification of Colorectal Carcinoma (JCCC) criteria and the degree of tumor shrinkage on barium enema examination (BE) were significantly greater in patients with p21-positive tumors than in those with p21-negative tumors (P=.04 and P<.01, respectively). In biopsy specimens obtained 7 days after starting CRT, pathologic complete response, histologic marked regression according to both the tumor regression criteria and JCCC criteria, and T downstaging were significantly greater in patients with apoptosis-positive and p21-positive tumors than in those with apoptosis-negative (P<.01, P=.02, P=.01, and P<.01, respectively) or p21-negative tumors (P=.03, P<.01, P<.01, and P=.02, respectively). The degree of tumor shrinkage on both BE as well as MRI was significantly greater in patients with apoptosis-positive and with p21-positive tumors than in those with apoptosis-negative or p21-negative tumors, respectively. Histologic changes in H&E-stained biopsy specimens 7 days after starting CRT significantly correlated with pathologic complete response and marked regression on both JCCC and tumor regression criteria, as well as with tumor shrinkage on BE and MRI (P<.01, P<.01, P<.01, P<.01, and P=.03, respectively).
  
  
  CONCLUSIONS
  Immunohistochemical expressions of p21 and apoptosis together with histologic changes on H&E-stained biopsy specimens obtained 7 days after starting CRT are strong predictors of the response to CRT.
authors.affiliation: Department of Surgery, Tokai University School of Medicine, Kanagawa, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Suzuki
authors.forename: Sotaro
authors.initials: S
authors.lastname: Sadahiro
authors.forename: Akira
authors.initials: A
authors.lastname: Tanaka
authors.forename: Kazutake
authors.initials: K
authors.lastname: Okada
authors.forename: Hiroko
authors.initials: H
authors.lastname: Kamata
authors.forename: Akemi
authors.initials: A
authors.lastname: Kamijo
authors.forename: Chieko
authors.initials: C
authors.lastname: Murayama
authors.forename: Takeshi
authors.initials: T
authors.lastname: Akiba
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kawada
mesh_terms: D000230:Adenocarcinoma / Q000737:chemistry / Q000473:pathology* / Q000628:therapy*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000032:analysis; D001706:Biopsy; D059248:Chemoradiotherapy; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis; D004338:Drug Combinations; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D008875:Middle Aged; D010094:Oxonic Acid / Q000627:therapeutic use; D012004:Rectal Neoplasms / Q000737:chemistry / Q000473:pathology* / Q000628:therapy*; D012007:Rectum / Q000737:chemistry / Q000473:pathology*; D005641:Tegafur / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004338:Drug Combinations; D019394:Ki-67 Antigen; D016159:Tumor Suppressor Protein p53; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid