Capecitabine and Oxaliplatin or Standard Follow-Up Care in Treating Patients Who Have Undergone Surgery for Locally Advanced Rectal Cancer

Chemotherapy or No Chemotherapy in Clear Margins After Neoadjuvant Chemoradiation in Locally Advanced Rectal Cancer. A Randomised Phase III Trial of Control Vs Capecitabine Plus Oxaliplatin [CHRONICLE]

RATIONALE: Drugs used in chemotherapy, such as capecitabine and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving combination chemotherapy after surgery may kill any tumor cells that remain after surgery. It is not yet known whether giving capecitabine together with oxaliplatin is more effective than standard follow-up care in treating rectal cancer that was removed by surgery.

PURPOSE: This randomized phase III trial is studying capecitabine and oxaliplatin to see how well they work compared with standard follow-up care in treating patients who have undergone surgery for locally advanced rectal cancer.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer
• Intervention / Treatment: Procedure: adjuvant therapy; Drug: oxaliplatin; Drug: capecitabine; Procedure: standard follow-up care

Detailed Description

OBJECTIVES:

• Compare the efficacy of adjuvant chemotherapy comprising capecitabine and oxaliplatin vs standard follow-up care, in terms of disease-free and overall survival, in patients with clear margins after complete resection of locally advanced rectal cancer.

OUTLINE: This is an open-label, randomized, controlled, prospective, multicenter study. Patients are stratified according to surgeon and nodal status (node positive vs node negative vs unknown). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients undergo standard follow up.
• Arm II: Patients receive oral capecitabine twice daily on days 1-14 and oxaliplatin IV over 2 hours on day 1. Treatment repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 3 months for 2 years, every 6 months for 5 years, and then annually thereafter.

Peer Reviewed and Funded or Endorsed by Cancer Research UK

PROJECTED ACCRUAL: A total of 800 patients will be accrued for this study.

• Study Type: Interventional
• Enrollment (Anticipated): 800
• Phase: Phase 3

Contacts and Locations

Study Locations

• United Kingdom
  • Hereford, United Kingdom, HR1 2ER
    • Hereford Hospitals
  • Scarborough, United Kingdom, YO12 6QL
    • Scarborough General Hospital
  • England
    • Ashington, England, United Kingdom, NE63 9JJ
      • Wansbeck General Hospital
    • Barnstaple, England, United Kingdom, EX31 4JB
      • North Devon District Hospital
    • Barrow in Furness, England, United Kingdom, LA14 4LF
      • Furness General Hospital
    • Birmingham, England, United Kingdom, B9 5SS
      • Birmingham Heartlands Hospital
    • Birmingham, England, United Kingdom, B15 2TH
      • Queen Elizabeth Hospital at University Hospital of Birmingham NHS Trust
    • Birmingham, England, United Kingdom, B75 7RR
      • Good Hope Hospital
    • Blackpool, England, United Kingdom, FY3 8NR
      • Blackpool Victoria Hospital
    • Boston, England, United Kingdom, PE21 9QT
      • Pilgrim Hospital
    • Bristol, England, United Kingdom, BS2 8ED
      • Bristol Haematology and Oncology centre
    • Burton-upon-Trent, England, United Kingdom, DE13 0RB
      • Queen's Hospital
    • Carlisle, England, United Kingdom, CA2 7HY
      • Cumberland Infirmary
    • Chelmsford, Essex, England, United Kingdom, CM1 7ET
      • Broomfield Hospital
    • Cheltenham, England, United Kingdom, GL53 7AN
      • Gloucestershire Oncology Centre at Cheltenham General Hospital
    • Cottingham, England, United Kingdom, HU16 5JQ
      • Castle Hill Hospital
    • Coventry, England, United Kingdom, CV2 2DX
      • Walsgrave Hospital
    • Derby, England, United Kingdom, DE1 2QY
      • Derbyshire Royal Infirmary
    • Doncaster, England, United Kingdom, DN2 5LT
      • Doncaster Royal Infirmary
    • Durham, England, United Kingdom, DH1 5TW
      • University Hospital of North Durham
    • Essex, England, United Kingdom, CM20 1QX
      • Princess Alexandra Hospital
    • Exeter, England, United Kingdom, EX2 5DW
      • Royal Devon and Exeter Hospital
    • Farnworth, England, United Kingdom, BL4 0JR
      • Royal Bolton Hospital
    • Gateshead, England, United Kingdom, NE9 6SX
      • Queen Elizabeth Hospital
    • Gloucester, England, United Kingdom, GL1 3NN
      • Gloucestershire Royal Hospital
    • Guildford, England, United Kingdom, GU2 7XX
      • St. Luke's Cancer Centre at Royal Surrey County Hospital
    • High Wycombe, England, United Kingdom
      • Wycombe General Hospital
    • Hull, England, United Kingdom, HU8 9HE
      • Princess Royal Hospital at Hull and East Yorkshire NHS Trust
    • Ilford, Essex, England, United Kingdom, IG3 8YB
      • King George Hospital
    • Ipswich, England, United Kingdom, IP4 5PD
      • Ipswich Hospital
    • Isleworth, England, United Kingdom, TW7 6AF
      • West Middlesex University Hospital
    • Kidderminster Worcestershire, England, United Kingdom, DY11 6RJ
      • Kidderminster Hospital
    • Lancanshire, England, United Kingdom, WN1 2NN
      • Royal Albert Edward Infirmary
    • Lancaster, England, United Kingdom, LA1 4RP
      • Royal Lancaster Infirmary
    • Leeds, England, United Kingdom, LS16 6QB
      • Cookridge Hospital
    • Lincoln, England, United Kingdom, LN2 5QY
      • Lincoln County Hospital
    • Liverpool, England, United Kingdom, L9 7AL
      • Aintree University Hospital
    • London, England, United Kingdom, SW17 0QT
      • St. George's Hospital
    • London, England, United Kingdom, EC1A 7BE
      • Saint Bartholomew's Hospital
    • London, England, United Kingdom, W6 8RF
      • Charing Cross Hospital
    • London, England, United Kingdom, NW1 2PG
      • University College of London Hospitals
    • London, England, United Kingdom, N18 1QX
      • Helen Rollason Cancer Care Centre at North Middlesex Hospital
    • London, England, United Kingdom, NW1 2QG
      • UCL Cancer Institute
    • London, England, United Kingdom, N19 5NF
      • Whittington Hospital
    • Macclesfield, England, United Kingdom, SK10 3BL
      • Macclesfield District General Hospital
    • Manchester, England, United Kingdom, M20 4BX
      • Christie Hospital
    • Merseyside, England, United Kingdom, CH63 4JY
      • Clatterbridge Centre for Oncology
    • Middlesbrough, England, United Kingdom, TS4 3BW
      • James Cook University Hospital
    • Newport, England, United Kingdom, PO30 5TG
      • St. Mary's Hospital
    • Northampton, England, United Kingdom, NN1 5BD
      • Northampton General Hospital
    • Northwood, England, United Kingdom, HA6 2RN
      • Mount Vernon Cancer Centre at Mount Vernon Hospital
    • Oxford, England, United Kingdom, OX3 7LJ
      • Churchill Hospital
    • Preston, England, United Kingdom, PR2 9HT
      • Rosemere Cancer Centre at Royal Preston Hospital
    • Romford, England, United Kingdom, RM7 OBE
      • Oldchurch Hospital
    • Salford, England, United Kingdom, M6 8HD
      • Hope Hospital
    • Scunthorpe, England, United Kingdom, DN15 7BH
      • Scunthorpe General Hospital
    • Sheffield, England, United Kingdom, S10 2SJ
      • Cancer Research Centre at Weston Park Hospital
    • Shrewsbury, England, United Kingdom, SY3 8XQ
      • Royal Shrewsbury Hospital
    • Southampton, England, United Kingdom, SO16 6YD
      • Southampton General Hospital
    • Southport, England, United Kingdom, PR8 6PN
      • Southport and Formby District General Hospital
    • Sunderland, England, United Kingdom, SR4 7TP
      • Sunderland Royal Hospital
    • Surrey, England, United Kingdom, KT2 7QB
      • Kingston Hospital
    • Walsall, England, United Kingdom, WS2 9PS
      • Walsall Manor Hospital
    • West Bromwich, England, United Kingdom, B71 4HJ
      • Sandwell General Hospital
    • Westcliff-On-Sea, England, United Kingdom, SS0 0RY
      • Southend University Hospital NHS Foundation Trust
    • Worcester, England, United Kingdom, WR5 1DD
      • Worcester Royal Hospital
    • Yeovil, England, United Kingdom, BA21 4AT
      • Yeovil District Hospital
  • Scotland
    • Aberdeen, Scotland, United Kingdom, AB25 2ZN
      • Aberdeen Royal Infirmary
    • Edinburgh, Scotland, United Kingdom, EH4 2XU
      • Edinburgh Cancer Centre at Western General Hospital
    • Glasgow, Scotland, United Kingdom, G11 6NT
      • Beatson West of Scotland Cancer Centre
  • Wales
    • Cardiff, Wales, United Kingdom, CF14 2TL
      • Velindre Cancer Center at Velindre Hospital
    • Lhantrisant, Wales, United Kingdom, CF72 8XR
      • Royal Glamorgan Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the rectum

  • Within 15 cm of the anal verge
  • Locally advanced disease

• Underwent complete resection of primary tumor within the past 12 weeks

  • ypT0-4, N0-2 with definitive histology at surgery
  • Circumferential resection margin > 1 mm
  • No gross evidence of residual disease

• Received neoadjuvant fluoropyrimidine-based chemoradiotherapy with ≥ 45 Gy planned total radiation dose, given in 1 of the following fashions:

  • Prolonged fluorouracil IV during radiotherapy
  • Low-dose leucovorin calcium and fluorouracil (days 1-5 and 29-33) concurrently with radiotherapy
  • Oral capecitabine concurrently with radiotherapy
• No evidence of metastatic disease

PATIENT CHARACTERISTICS:

• WHO performance status 0-1
• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Creatinine clearance ≥ 50 mL/min
• Bilirubin ≤ 1.25 times upper limit of normal (ULN)
• AST and ALT ≤ 1.25 times ULN
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for ≥ 3 months after completion of study treatment
• No known dihydropyrimidine dehydrogenase deficiency
• No hypersensitivity to platinum compounds
• No preexisting peripheral neuropathy ≥ grade 1
• No lack of physical integrity of the upper gastrointestinal tract
• No malabsorption syndrome

• No other serious uncontrolled medical condition or concurrent medical illness that would compromise life expectancy and/or preclude study compliance, including any of the following:

  • Serious uncontrolled infections
  • Significant cardiac disease (e.g., uncontrolled angina, congestive heart failure, cardiomyopathy, or arrhythmias) or myocardial infarction within the past 12 months
  • Interstitial pneumonia or symptomatic lung fibrosis
• No other malignancies except adequately treated in situ carcinoma of the cervix or basal cell or squamous cell carcinoma of the skin, unless disease-free for ≥ 10 years
• No history of uncontrolled seizures, CNS disorders, or psychiatric disability that would preclude study compliance

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• No prior chemotherapy exceeding 6 weeks in duration

  • Prior chemotherapy given as part of neoadjuvant treatment (i.e., chemoradiotherapy) may last a maximum of 11-12 weeks
• No prior oxaliplatin
• Prior mitomycin C, irinotecan hydrochloride, or cetuximab allowed
• No concurrent warfarin, antiviral agents, or phenytoin

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Disease-free survival at 3 years

Secondary Outcome Measures

Outcome Measure
Toxicity
Overall survival at 5 years

Collaborators and Investigators

• Sponsor: Cancer Research UK
• Investigators: Study Chair: Robert Glynne-Jones, MD, Mount Vernon Cancer Centre at Mount Vernon Hospital

Publications and helpful links

General Publications

• Glynne-Jones R, Counsell N, Quirke P, Mortensen N, Maraveyas A, Meadows HM, Ledermann J, Sebag-Montefiore D. Chronicle: results of a randomised phase III trial in locally advanced rectal cancer after neoadjuvant chemoradiation randomising postoperative adjuvant capecitabine plus oxaliplatin (XELOX) versus control. Ann Oncol. 2014 Jul;25(7):1356-1362. doi: 10.1093/annonc/mdu147. Epub 2014 Apr 8.

Study record dates

Study Major Dates

• Study Start: November 1, 2004
• Primary Completion (Actual): March 1, 2008

Study Registration Dates

• First Submitted: January 25, 2007
• First Submitted That Met QC Criteria: January 25, 2007
• First Posted (Estimate): January 29, 2007

Study Record Updates

• Last Update Posted (Estimate): August 26, 2013
• Last Update Submitted That Met QC Criteria: August 23, 2013
• Last Verified: June 1, 2007

More Information

Terms related to this study

• Keywords: adenocarcinoma of the rectum; stage II rectal cancer; stage III rectal cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Capecitabine; Oxaliplatin
• Other Study ID Numbers: CDR0000526299; CRUK-CHRONICLE; CRUK-BRD/05/132; EU-20679; ISRCTN59865116; CTA21106/0016/001; EUDRACT-2004-001484-21