title: PAN-EX: a pooled analysis of two trials of neoadjuvant chemotherapy followed by chemoradiotherapy in MRI-defined, locally advanced rectal cancer.
abstract: EXPERT and EXPERT-C were phase II clinical trials of neoadjuvant chemotherapy (NACT) followed by chemoradiotherapy (CRT) in high-risk, locally advanced rectal cancer (LARC).
  
  
  
  We pooled individual patient data from these trials. The primary objective was overall survival (OS) in the intention-to-treat (ITT) population. Prognostic factors were also analysed.
  
  
  
  A total of 269 patients were included. Of these, 91.1% completed NACT, 88.1% completed CRT and 240 (89.2%) underwent curative surgery (R0/R1). After a median follow-up of 71.9 months, 5-year progression-free survival (PFS) and OS were 66.4% and 73.3%, respectively. In the group of R0/R1 resection patients, 5-year relapse-free survival (RFS) and OS were 71.6% and 77.2%, respectively, with local recurrence occurring in 5.5% and distant metastases in 20.6% of cases. Significant prognostic factors after multivariate analyses included age, tumour grade and MRI extramural venous invasion (mrEMVI) at baseline, MRI tumour regression grade (mrTRG) after CRT, ypT stage after surgery and adherence to study treatment. mrTRG after NACT was associated with PFS (P = 0.002) and OS (P = 0.018) and appeared to stratify patients based on the incremental benefit from sequential CRT. Among the outcome measures considered, in the subgroup of R0/R1 resection patients, ypT and ypStage had the highest predictive accuracy for RFS (concordance index: 0.6238 and 0.6252, respectively) and OS (concordance index: 0.6094 and 0.6132, respectively).
  
  
  
  Administering NACT before CRT could be a potential strategy for high-risk LARC. In this setting, mrTRG after CRT is an independent prognostic factor, while mrTRG after NACT should be tested as a parameter for treatment selection in trials of NACT ± CRT. ypT stage may be a valuable surrogate end point for future phase II trials investigating intensified neoadjuvant treatments in similar patient populations.
authors.affiliation: Department of Medicine.
authors.forename: F
authors.initials: F
authors.lastname: Sclafani
authors.affiliation: Department of Radiology.
authors.forename: G
authors.initials: G
authors.lastname: Brown
authors.affiliation: Department of Medicine david.cunningham@rmh.nhs.uk.
authors.forename: D
authors.initials: D
authors.lastname: Cunningham
authors.affiliation: Department of Histopathology.
authors.forename: A
authors.initials: A
authors.lastname: Wotherspoon
authors.affiliation: Department of Medicine.
authors.forename: D
authors.initials: D
authors.lastname: Tait
authors.affiliation: Department of Clinical Research & Development, The Royal Marsden NHS Foundation Trust, London and Surrey, UK.
authors.forename: C
authors.initials: C
authors.lastname: Peckitt
authors.affiliation: Department of Radiology.
authors.forename: J
authors.initials: J
authors.lastname: Evans
authors.affiliation: Department of Radiology.
authors.forename: S
authors.initials: S
authors.lastname: Yu
authors.affiliation: Department of Histopathology.
authors.forename: L
authors.initials: L
authors.lastname: Sena Teixeira Mendes
authors.affiliation: Department of Medical Oncology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Tabernero
authors.affiliation: Department of Immunology, Genetics and Pathology, Section of Experimental and Clinical Oncology, University of Uppsala, Uppsala, Sweden.
authors.forename: B
authors.initials: B
authors.lastname: Glimelius
authors.affiliation: Department of Haematology and Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Cervantes
authors.affiliation: Department of Medicine.
authors.forename: J
authors.initials: J
authors.lastname: Thomas
authors.affiliation: Department of Medicine.
authors.forename: R
authors.initials: R
authors.lastname: Begum
authors.affiliation: Department of Medicine.
authors.forename: J
authors.initials: J
authors.lastname: Oates
authors.affiliation: Department of Medicine.
authors.forename: I
authors.initials: I
authors.lastname: Chau
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D059248:Chemoradiotherapy / Q000009:adverse effects; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009364:Neoplasm Recurrence, Local / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D012004:Rectal Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D016896:Treatment Outcome
keywords: MR tumour regression grade; chemoradiotherapy; locally advanced rectal cancer; neoadjuvant chemotherapy; pooled analysis