title: Adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with rectal cancer: a systematic review and meta-analysis of individual patient data.
abstract: BACKGROUND
  The role of adjuvant chemotherapy for patients with rectal cancer after preoperative (chemo)radiotherapy and surgery is uncertain. We did a meta-analysis of individual patient data to compare adjuvant chemotherapy with observation for patients with rectal cancer.
  
  
  METHODS
  We searched PubMed, Medline, Embase, Web of Science, the Cochrane Library, CENTRAL, and conference abstracts to identify European randomised, controlled, phase 3 trials comparing observation with adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with non-metastatic rectal cancer. The primary endpoint of interest was overall survival.
  
  
  RESULTS
  We analysed data from four eligible trials, including data from 1196 patients with (y)pTNM stage II or III disease, who had an R0 resection, had a low anterior resection or an abdominoperineal resection, and had a tumour located within 15 cm of the anal verge. We found no significant differences in overall survival between patients who received adjuvant chemotherapy and those who underwent observation (hazard ratio [HR] 0.97, 95% CI 0.81-1.17; p=0.775); there were no significant differences in overall survival in subgroup analyses. Overall, adjuvant chemotherapy did not significantly improve disease-free survival (HR 0.91, 95% CI 0.77-1.07; p=0.230) or distant recurrences (0.94, 0.78-1.14; p=0.523) compared with observation. However, in subgroup analyses, patients with a tumour 10-15 cm from the anal verge had improved disease-free survival (0.59, 0.40-0.85; p=0.005, p(interaction)=0.107) and fewer distant recurrences (0.61, 0.40-0.94; p=0.025, p(interaction)=0.126) when treated with adjuvant chemotherapy compared with patients undergoing observation.
  
  
  CONCLUSIONS
  Overall, adjuvant fluorouracil-based chemotherapy did not improve overall survival, disease-free survival, or distant recurrences. However, adjuvant chemotherapy might benefit patients with a tumour 10-15 cm from the anal verge in terms of disease-free survival and distant recurrence. Further studies of preoperative and postoperative treatment for this subgroup of patients are warranted.
  
  
  BACKGROUND
  None.
authors.affiliation: Department of Surgery, Leiden University Medical Centre, Leiden, Netherlands.
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Breugom
authors.affiliation: Department of Surgery, Leiden University Medical Centre, Leiden, Netherlands.
authors.forename: Marloes
authors.initials: M
authors.lastname: Swets
authors.affiliation: Department of Radiation Oncology, Besançon University Hospital J Minjoz, Besançon, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Bosset
authors.affiliation: Department of Statistics, European Organisation for Research and Treatment of Cancer, Brussels, Belgium.
authors.forename: Laurence
authors.initials: L
authors.lastname: Collette
authors.affiliation: Department of Radiotherapy, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Sainato
authors.affiliation: Department of Radiotherapy, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Cionini
authors.affiliation: Department of Medical Oncology, Mount Vernon Centre for Cancer Treatment, London, UK.
authors.forename: Rob
authors.initials: R
authors.lastname: Glynne-Jones
authors.affiliation: CRUK & UCL Cancer Trials Centre, London, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Counsell
authors.affiliation: Department of Surgery, Leiden University Medical Centre, Leiden, Netherlands; Department of Gerontology and Geriatrics, Leiden University Medical Centre, Leiden, Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: Bastiaannet
authors.affiliation: Department of Surgery, Leiden University Medical Centre, Leiden, Netherlands.
authors.forename: Colette B M
authors.initials: CB
authors.lastname: van den Broek
authors.affiliation: Department of Surgery, Leiden University Medical Centre, Leiden, Netherlands.
authors.forename: Gerrit-Jan
authors.initials: GJ
authors.lastname: Liefers
authors.affiliation: Department of Medical Statistics and Bio-informatics, Leiden University Medical Centre, Leiden, Netherlands.
authors.forename: Hein
authors.initials: H
authors.lastname: Putter
authors.affiliation: Department of Surgery, Leiden University Medical Centre, Leiden, Netherlands. Electronic address: C.J.H.van_de_Velde@lumc.nl.
authors.forename: Cornelis J H
authors.initials: CJ
authors.lastname: van de Velde
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D002986:Clinical Trials as Topic; D003131:Combined Modality Therapy; D013505:Digestive System Surgical Procedures; D006801:Humans; D011379:Prognosis; D018714:Radiotherapy, Adjuvant; D012004:Rectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000628:therapy; D015996:Survival Rate