Adjuvant Capecitabine vs Gemcitabine Plus Cisplatin in Resected Extrahepatic Cholangiocarcinoma

Overview

There is no proven adjuvant treatment after curative surgical resection in patients with cholangiocarcinoma, although previous meta-analysis suggested potential survival benefit of adjuvant chemotherapy or radiotherapy in patients with lymph node-positive resected cholangiocarcinoma. Despite of lack of level 1 evidence and no data which regimen is optimal, adjuvant chemotherapy is widely used in daily practice setting. Based on this background, the investigators designed the randomized phase 2 trial comparing capecitabine and gemcitabine plus cisplatin in patients with resected lymph node-positive extrahepatic cholangiocarcinoma.

Full Title of Study: “Randomized Phase 2 Study of Capecitabine vs Gemcistabine Plus Cisplatin in Patients With Resected Extrahepatic Cholangiocarcinoma With Regional Lymph Node Metastasis”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: April 2021

Interventions

  • Drug: Gemcitabine plus cisplatin
    • Gemcitabine 1,000 mg/m2 and cisplatin 25 mg/m2 Day 1 and 8, every 3 weeks
  • Drug: Capecitabine
    • Capecitabine 1,250 mg/m2 Day 1 to 14, every 3 weeks

Arms, Groups and Cohorts

  • Active Comparator: Capecitabine
    • Adjuvant Capecitabine
  • Experimental: Gemcitabine plus cisplatin
    • Adjuvant Gemcitabine plus Cisplatin

Clinical Trial Outcome Measures

Primary Measures

  • 2-year disease-free survival
    • Time Frame: 2 years
    • Proportion of patients without disease recurrence after 2 years

Secondary Measures

  • Disease-free survival
    • Time Frame: 4 years
    • Median time point that 50% of study patients recur
  • Toxicities (Adverse events related with chemotherapy)
    • Time Frame: 4 years
    • Adverse events related with chemotherapy
  • Overall survival
    • Time Frame: 4 years
    • Median time point that 50% of study patients is alive

Participating in This Clinical Trial

Inclusion Criteria

  • Patients aged 19 years and older
  • Histologically documented extrahepatic cholangiocarcinoma (perihilar or distal bile duct tumor)
  • Microscopic or macroscopic surgical resection (ie., R0 or R1 resection)
  • Regional lymph node metastasis according to the American Joint Committee on Cancer (AJCC) 7th edition
  • No distant metastasis
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 ~ 1
  • No prior chemotherapy or radiotherapy
  • Serum CA 19-9 < 100 U/mL at the time of enrollment
  • Adequate bone marrow function as defined by platelets ≥ 100 x 109/L and neutrophils ≥ 1.5 x 109/L
  • Adequate renal function, with serum creatinine < 1.5 x upper limit of normal (ULN)
  • Adequate hepatic function with serum total bilirubin < 2 mg/dL, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) < 2.5 x ULN
  • No other malignant disease apart from non-melanotic skin cancer or carcinoma in situ of the uterine cervix or any other non life-threatening cancer (i.e., prostate or thyroid cancer) except where treated with curative intent > 5 years previously without evidence of relapse Written informed consent to the study

Exclusion Criteria

  • Medical or psychiatric conditions that compromise the patient's ability to give informed consent or to complete the protocol or a history of non-compliance
  • Histologies other than adenocarcinoma such as mixed hepatocellular carcinoma/cholangiocarcinoma, adenosquamous carcinoma or mixed adenocarcinoma/neuroendocrine carcinoma
  • Intrahepatic cholangiocarcinoma or gallbladder cancer
  • Obstruction of gastrointestinal tract
  • Active gastrointestinal bleeding
  • Myocardial infarction within 6 months prior to the study medication, and other clinically significant heart disease (e.g., unstable angina, congestive heart failure or uncontrolled hypertension)
  • Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the investigator's opinion makes it undesirable for the patient to participate in the study or which would jeopardise compliance with the protocol
  • Female subjects who are pregnant or lactating, or males and females of reproductive potential not willing or not able to employ a highly effective method of birth control/contraception to prevent pregnancy from 2 weeks before receiving study drug until 3 months after receiving the last dose of study drug. A highly effective method of contraception is defined as having a low failure rate (< 1% per year) when used consistently and correctly.

Gender Eligibility: All

Minimum Age: 19 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Asan Medical Center
  • Provider of Information About this Clinical Study
    • Principal Investigator: Baek-Yeol Ryoo, Professor – Asan Medical Center
  • Overall Official(s)
    • Baek-Yeol Ryoo, MD, Principal Investigator, Asan Medical Center
  • Overall Contact(s)
    • Chanhoon Yoo, MD, +82-2-3010-1727, yooc@amc.seoul.kr

References

Horgan AM, Amir E, Walter T, Knox JJ. Adjuvant therapy in the treatment of biliary tract cancer: a systematic review and meta-analysis. J Clin Oncol. 2012 Jun 1;30(16):1934-40. doi: 10.1200/JCO.2011.40.5381. Epub 2012 Apr 23. Review.

Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan S, Iveson T, Hughes S, Pereira SP, Roughton M, Bridgewater J; ABC-02 Trial Investigators. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010 Apr 8;362(14):1273-81. doi: 10.1056/NEJMoa0908721.

Ramírez-Merino N, Aix SP, Cortés-Funes H. Chemotherapy for cholangiocarcinoma: An update. World J Gastrointest Oncol. 2013 Jul 15;5(7):171-6. doi: 10.4251/wjgo.v5.i7.171.

Neoptolemos JP, Moore MJ, Cox TF, Valle JW, Palmer DH, McDonald AC, Carter R, Tebbutt NC, Dervenis C, Smith D, Glimelius B, Charnley RM, Lacaine F, Scarfe AG, Middleton MR, Anthoney A, Ghaneh P, Halloran CM, Lerch MM, Oláh A, Rawcliffe CL, Verbeke CS, Campbell F, Büchler MW; European Study Group for Pancreatic Cancer. Effect of adjuvant chemotherapy with fluorouracil plus folinic acid or gemcitabine vs observation on survival in patients with resected periampullary adenocarcinoma: the ESPAC-3 periampullary cancer randomized trial. JAMA. 2012 Jul 11;308(2):147-56. doi: 10.1001/jama.2012.7352. Erratum in: JAMA. 2012 Nov 14;308(18):1861.

Patt YZ, Hassan MM, Aguayo A, Nooka AK, Lozano RD, Curley SA, Vauthey JN, Ellis LM, Schnirer II, Wolff RA, Charnsangavej C, Brown TD. Oral capecitabine for the treatment of hepatocellular carcinoma, cholangiocarcinoma, and gallbladder carcinoma. Cancer. 2004 Aug 1;101(3):578-86.

Petekkaya I, Gezgen G, Roach EC, Solak M, Gullu I. Long-term advanced cholangiocarcinoma survivor with single-agent capecitabine. J BUON. 2012 Oct-Dec;17(4):796.

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