title: Multicenter validation study of pathologic response and tumor thickness at the tumor-normal liver interface as independent predictors of disease-free survival after preoperative chemotherapy and surgery for colorectal liver metastases.
abstract: BACKGROUND
  To validate pathologic markers of response to preoperative chemotherapy as predictors of disease-free survival (DFS) after resection of colorectal liver metastases (CLM).
  
  
  METHODS
  One hundred seventy-one patients who underwent resection of CLM after preoperative chemotherapy at 4 centers were studied. Pathologic response-defined as the proportion of tumor cells remaining (complete, 0%; major, <50%; minor, ≥50%) and tumor thickness at the tumor-normal liver interface (TNI) (<0.5 mm, 0.5 to <5 mm, ≥5 mm)-was assessed by a central pathology reviewer and local pathologists.
  
  
  RESULTS
  Pathologic response was complete in 8% of patients, major in 49% of patients, and minor in 43% of patients. Tumor thickness at the TNI was <0.5 mm in 21% of patients, 0.5 to <5 mm in 56% of patients, and ≥5 mm in 23% of patients. On multivariate analyses, using either pathologic response or tumor thickness at TNI, pathologic response (P = .002, .009), tumor thickness at TNI (P = 0.015, <.001), duration of preoperative chemotherapy (P = .028, .043), number of CLM (P = .038, . 037), and margin (P = .011, .016) were associated with DFS. In a multivariate analysis using both parameters, tumor thickness at TNI (P = .004, .015), duration of preoperative chemotherapy (P = .025), number of nodules (P = .027), and margin (P = .014) were associated with DFS. Tumor size by pathology examination was the predictor of pathologic response. Predictors of tumor thickness at the TNI were tumor size and chemotherapy regimen. There was near perfect agreement for pathologic response (κ = .82) and substantial agreement (κ = .76) for tumor thickness between the central reviewer and local pathologists.
  
  
  CONCLUSIONS
  Pathologic response and tumor thickness at the TNI are valid predictors of DFS after preoperative chemotherapy and surgery for CLM.
authors.affiliation: Department of Digestive Surgery and Surgical Oncology, Ambroise Paré Hospital, Boulogne-Billancourt, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Brouquet
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zimmitti
authors.forename: Scott
authors.initials: S
authors.lastname: Kopetz
authors.forename: Judith
authors.initials: J
authors.lastname: Stift
authors.forename: Catherine
authors.initials: C
authors.lastname: Julié
authors.forename: Anne-Isabelle
authors.initials: AI
authors.lastname: Lemaistre
authors.forename: Atin
authors.initials: A
authors.lastname: Agarwal
authors.forename: Viren
authors.initials: V
authors.lastname: Patel
authors.forename: Stephane
authors.initials: S
authors.lastname: Benoist
authors.forename: Bernard
authors.initials: B
authors.lastname: Nordlinger
authors.forename: Alessandro
authors.initials: A
authors.lastname: Gandini
authors.forename: Michel
authors.initials: M
authors.lastname: Rivoire
authors.forename: Stefan
authors.initials: S
authors.lastname: Stremitzer
authors.forename: Thomas
authors.initials: T
authors.lastname: Gruenberger
authors.forename: Jean-Nicolas
authors.initials: JN
authors.lastname: Vauthey
authors.forename: Dipen M
authors.initials: DM
authors.lastname: Maru
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000473:pathology* / Q000601:surgery / Q000628:therapy*; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000556:secondary* / Q000601:surgery / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D012189:Retrospective Studies
keywords: colorectal liver metastases; preoperative chemotherapy; Avastin; survival; pathology response; validation; multicenter study; tumor regression; tumor-normal liver interface