Randomized Phase III Trial of Adjuvant Chemotherapy or Chemoradiotherapy in Resectable Gastric Cancer (CRITICS)

• ClinicalTrials.gov Identifier: NCT00407186
• Recruitment Status: Active, not recruiting
• First Posted: December 4, 2006
• Last Update Posted: October 10, 2017
• Sponsor: Dutch Colorectal Cancer Group
• Collaborators: The Netherlands Cancer Institute; Roche Pharma AG
• Information provided by (Responsible Party): Dutch Colorectal Cancer Group

Tracking Information

• First Submitted Date: December 1, 2006
• First Posted Date: December 4, 2006
• Last Update Posted Date: October 10, 2017
• Actual Study Start Date: January 11, 2007
• Estimated Primary Completion Date: December 2018 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: September 5, 2008): overall survival [ Time Frame: study duration ]
• Original Primary Outcome Measures (submitted: December 1, 2006): overall survival

Current Secondary Outcome Measures (submitted: September 5, 2008)

• disease-free survival [ Time Frame: study duration ]
• toxicity [ Time Frame: study duration ]
• health-related quality of life [ Time Frame: study duration ]

Original Secondary Outcome Measures (submitted: December 1, 2006)

• disease-free survival
• toxicity
• health-related quality of life

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Randomized Phase III Trial of Adjuvant Chemotherapy or Chemoradiotherapy in Resectable Gastric Cancer (CRITICS)
• Official Title: A Multicenter Randomized Phase III Trial of Neo-adjuvant Chemotherapy Followed by Surgery and Chemotherapy or by Surgery and Chemoradiotherapy in Resectable Gastric Cancer (CRITICS Study)
• Brief Summary: The purpose of this study is to evaluate the efficacy and safety of combined chemotherapy and radiotherapy (in comparison to chemotherapy alone) as adjuvant treatment after surgery for gastric cancer. Prior to surgery all patients will receive neo-adjuvant chemotherapy as well.

Detailed Description

The mainstay of curative treatment of gastric cancer is radical surgical dissection. Because most patients in the Western world present with advanced stages long term survival is found in about 25%, with local recurrences as part of treatment failure in up to 80% of cases. Studies examining the role of more extended lymph node dissections (D1 vs. D2), adjuvant radiotherapy or adjuvant chemotherapy did not result in a clinical relevant improvement of survival. In 2001 results of a South West Oncology group (SWOG) trial that randomized between surgery and surgery with chemoradiotherapy were published. This trial, that was hampered by suboptimal surgery (less than D1 in majority of patients) and radiotherapy (2D radiotherapy; 35% protocol deviations) showed an absolute increase in median survival of 9 months. More recently results of the MAGIC study, which randomized between surgery and surgery plus 6 perioperative courses of ECF chemotherapy, were presented. This regimen resulted in an absolute 5-year survival benefit of 13% and in a 10% higher resectability rate.

This phase III prospectively randomized study investigates whether chemoradiotherapy (45 Gy in 5 weeks with daily cisplatin and capecitabine) after preoperative chemotherapy (3x ECC (epirubicin, cisplatin, capecitabine)) and adequate (D1+) surgery leads to improved survival in comparison with postoperative chemotherapy (3x ECC). Furthermore, toxicity of both treatment regimens will be explored.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Gastric Cancer

Intervention

• Drug: cisplatin+capecitabine
  cisplatin 20 mg/m2 (i.v., q 1 w, 5 weeks), capecitabine 575 mg/m2 (b.i.d., oral, on radiotherapy days.
• Radiation: radiotherapy
  45 Gy in 25 fracions (5 days/week)
• Drug: epirubicin+cisplatin+capecitabine
  3 courses q 3 w: epirubicin 50 mg/m2 (i.v., day 1), cisplatin 60 mg/m2 (i.v., day 1), capecitabine 1000 mg/m2 (b.i.d., oral, day 1-14)

Study Arms

• Experimental: 1chemoradiotherapy
  5 weeksadjuvant treatment; radiotherapy and concomitant chemotherapy with cisplatin and capecitabine.
  Interventions:

  • Drug: cisplatin+capecitabine
  • Radiation: radiotherapy
• Active Comparator: 2chemotherapy
  3 adjuvant courses epirubicin, cisplatin, capecitabine.
  Intervention: Drug: epirubicin+cisplatin+capecitabine

Publications *

• Quaas A, Biesma HD, Wagner AD, Verheij M, van Berge Henegouwen MI, Schoemig-Markiefka B, Pamuk A, Zander T, Siemanowski J, Sikorska K, Egthuijsen JMP, Meershoek-Klein Kranenbarg EM, van de Velde CJH, Buettner R, Alakus H, Cats A, Ylstra B, van Laarhoven HWM, van Grieken NCT. Microsatellite instability and sex differences in resectable gastric cancer - A pooled analysis of three European cohorts. Eur J Cancer. 2022 Sep;173:95-104. doi: 10.1016/j.ejca.2022.06.025. Epub 2022 Jul 18.
• Slagter AE, Vollebergh MA, Caspers IA, van Sandick JW, Sikorska K, Lind P, Nordsmark M, Putter H, Braak JPBM, Meershoek-Klein Kranenbarg E, van de Velde CJH, Jansen EPM, Cats A, van Laarhoven HWM, van Grieken NCT, Verheij M. Prognostic value of tumor markers and ctDNA in patients with resectable gastric cancer receiving perioperative treatment: results from the CRITICS trial. Gastric Cancer. 2022 Mar;25(2):401-410. doi: 10.1007/s10120-021-01258-6. Epub 2021 Oct 29.
• de Steur WO, van Amelsfoort RM, Hartgrink HH, Putter H, Meershoek-Klein Kranenbarg E, van Grieken NCT, van Sandick JW, Claassen YHM, Braak JPBM, Jansen EPM, Sikorska K, van Tinteren H, Walraven I, Lind P, Nordsmark M, van Berge Henegouwen MI, van Laarhoven HWM, Cats A, Verheij M, van de Velde CJH; CRITICS investigators. Adjuvant chemotherapy is superior to chemoradiation after D2 surgery for gastric cancer in the per-protocol analysis of the randomized CRITICS trial. Ann Oncol. 2021 Mar;32(3):360-367. doi: 10.1016/j.annonc.2020.11.004. Epub 2020 Nov 20.
• Slagter AE, Sikorska K, Grootscholten C, van Laarhoven HWM, Lind P, Nordsmark M, Meershoek-Klein Kranenbarg E, van de Velde CJH, van Grieken NCT, van Sandick JW, Jansen EPM, Verheij M, Cats A. Venous thromboembolism during preoperative chemotherapy in the CRITICS gastric cancer trial. Cancer Med. 2020 Sep;9(18):6609-6616. doi: 10.1002/cam4.3118. Epub 2020 Jul 31.
• Slagter AE, Tudela B, van Amelsfoort RM, Sikorska K, van Sandick JW, van de Velde CJH, van Grieken NCT, Lind P, Nordsmark M, Putter H, Hulshof MCCM, van Laarhoven HWM, Grootscholten C, Braak JPBM, Meershoek-Klein Kranenbarg E, Jansen EPM, Cats A, Verheij M. Older versus younger adults with gastric cancer receiving perioperative treatment: Results from the CRITICS trial. Eur J Cancer. 2020 May;130:146-154. doi: 10.1016/j.ejca.2020.02.008. Epub 2020 Mar 21.
• Cats A, Jansen EPM, van Grieken NCT, Sikorska K, Lind P, Nordsmark M, Meershoek-Klein Kranenbarg E, Boot H, Trip AK, Swellengrebel HAM, van Laarhoven HWM, Putter H, van Sandick JW, van Berge Henegouwen MI, Hartgrink HH, van Tinteren H, van de Velde CJH, Verheij M; CRITICS investigators. Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial. Lancet Oncol. 2018 May;19(5):616-628. doi: 10.1016/S1470-2045(18)30132-3. Epub 2018 Apr 9.
• Dikken JL, van Sandick JW, Maurits Swellengrebel HA, Lind PA, Putter H, Jansen EP, Boot H, van Grieken NC, van de Velde CJ, Verheij M, Cats A. Neo-adjuvant chemotherapy followed by surgery and chemotherapy or by surgery and chemoradiotherapy for patients with resectable gastric cancer (CRITICS). BMC Cancer. 2011 Aug 2;11:329. doi: 10.1186/1471-2407-11-329.
• Jansen EPM, Boot H, Dubbelman R, Verheij M, Cats A. Postoperative chemoradiotherapy in gastric cancer--a phase I-II study of radiotherapy with dose escalation of weekly cisplatin and daily capecitabine chemotherapy. Ann Oncol. 2010 Mar;21(3):530-534. doi: 10.1093/annonc/mdp345. Epub 2009 Aug 18.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: December 1, 2006): 788
• Original Enrollment: Same as current
• Estimated Study Completion Date: December 2025
• Estimated Primary Completion Date: December 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Ib-IVa (no distant metastases) gastric cancer (histologically proven); tumor bulk in the stomach
• WHO < 2
• Age ≥18 yrs
• Operable gastric cancer
• No prior abdominal radiotherapy or chemotherapy
• Tumornegative laparoscopy when CT suggests peritoneal carcinomatosis
• Start treatment within 10 working days after registration
• Written informed consent

Exclusion Criteria:

• T1N0 disease (endoscopic ultrasound)
• Distant metastases
• Inoperable patients; due to technical surgery-related factors or general condition
• Previous malignancy, except adequately treated non-melanoma skin cancer or in-situ cancer of the cervix uteri.
• Solitary functioning kidney that will be within the radiation field
• Major surgery within 4 weeks prior to study treatment start, or lack of complete recovery from the effects of major surgery
• Uncontrolled (bacterial) infections
• Significant cardiac disorders
• Continuous use of immunosuppressive agents
• Concurrent use of the antiviral agent sorivudine or chemically related analogues
• Hearing loss > CTC grade 1
• Neurotoxicity > CTC grade 1

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Netherlands

Administrative Information

• NCT Number: NCT00407186
• Other Study ID Numbers: CRITICS
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Dutch Colorectal Cancer Group
• Original Responsible Party: Not Provided
• Current Study Sponsor: Dutch Colorectal Cancer Group
• Original Study Sponsor: Same as current

Collaborators

• The Netherlands Cancer Institute
• Roche Pharma AG

Investigators

• Principal Investigator: Marcel Verheij, MD PhD; Nederlands Kanker Insituut/Antoni van Leeuwenhoek Ziekenhuis

• PRS Account: Dutch Colorectal Cancer Group
• Verification Date: October 2017