Radiation Therapy vs. Observation Following Gemcitabine and Cisplatin for Inoperable Localized Liver Cancer

Randomized Phase III Study of Focal Radiation Therapy for Unresectable, Localized Intrahepatic Cholangiocarcinoma

This randomized phase III trial studies how well gemcitabine hydrochloride and cisplatin with or without radiation therapy work in treating patients with localized liver cancer that cannot be removed by surgery. Drugs used in chemotherapy, such as gemcitabine hydrochloride and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x rays to kill tumor cells. It is not yet known whether giving gemcitabine and cisplatin is more effective with or without radiation therapy in this patient population. Patients register to this study after receiving gemcitabine and cisplatin.

Study Overview

• Status: Terminated
• Conditions: Stage III Intrahepatic Cholangiocarcinoma; Stage IVA Intrahepatic Cholangiocarcinoma
• Intervention / Treatment: Radiation: Image Guided Radiation Therapy

Detailed Description

PRIMARY OBJECTIVES:

I. To evaluate the addition of liver-directed radiation therapy with respect to overall survival (OS) for patients with unresectable, localized intrahepatic cholangiocarcinoma.

SECONDARY OBJECTIVES:

I. To evaluate the addition of liver-directed radiation therapy with respect to local control for patients with unresectable, localized intrahepatic cholangiocarcinoma.

II. To evaluate the addition of liver-directed radiation therapy with respect to adverse events for patients with unresectable, localized intrahepatic cholangiocarcinoma.

III. To evaluate the addition of liver-directed radiation therapy with respect to regional control for patients with unresectable, localized intrahepatic cholangiocarcinoma.

IV. To evaluate the addition of liver-directed radiation therapy with respect to distant metastases for patients with unresectable, localized intrahepatic cholangiocarcinoma.

V. To evaluate the addition of liver-directed radiation therapy with respect to progression-free survival for patients with unresectable, localized intrahepatic cholangiocarcinoma.

After completion of study treatment, patients are followed up every 3 months for 3 years then every 6 months for 2 years.

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H3H 2R9
      • The Research Institute of the McGill University Health Centre (MUHC)
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham Cancer Center
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences
  • California
    • Sacramento, California, United States, 95816
      • Sutter Medical Center Sacramento
  • Georgia
    • Atlanta, Georgia, United States, 30308
      • Emory University Hospital Midtown
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital/Winship Cancer Institute
    • Atlanta, Georgia, United States, 30309
      • Piedmont Hospital
  • Hawaii
    • Honolulu, Hawaii, United States, 96813
      • Queen's Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Decatur, Illinois, United States, 62526
      • Decatur Memorial Hospital
    • Maywood, Illinois, United States, 60153
      • Loyola University Medical Center
    • Peoria, Illinois, United States, 61637
      • OSF Saint Francis Medical Center
    • Warrenville, Illinois, United States, 60555
      • Northwestern Medicine Cancer Center Warrenville
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University/Melvin and Bren Simon Cancer Center
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Maryland Proton Treatment Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston Medical Center
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Cancer Center
    • Burlington, Massachusetts, United States, 01805
      • Lahey Hospital and Medical Center
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine
    • St Louis, Missouri, United States, 63131
      • Missouri Baptist Medical Center
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • University of New Mexico Cancer Center
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai Hospital
    • Rochester, New York, United States, 14642
      • University of Rochester
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati Cancer Center-UC Medical Center
    • Columbus, Ohio, United States, 43210
      • Ohio State University Comprehensive Cancer Center
  • Oregon
    • Portland, Oregon, United States, 97210
      • Legacy Good Samaritan Hospital and Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute/University of Utah
  • Vermont
    • Burlington, Vermont, United States, 05401
      • University of Vermont Medical Center
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington Medical Center - Montlake
    • Seattle, Washington, United States, 98133
      • FHCC Proton Therapy Center
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • West Virginia University Healthcare
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Carbone Cancer Center - University Hospital

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Pathologically (histologically or cytologically) proven diagnosis of intrahepatic cholangiocarcinoma (IHC) without distant extrahepatic metastasis prior to study entry. Patients with an adenocarcinoma suggestive of a pancreaticobiliary primary with radiographic findings consistent with an intrahepatic cholangio-carcinoma are eligible.
2. Patient must have 1 lesion with a maximum AXIAL diameter of 12cm at the time of study entry. Up to 3 satellite lesions are permitted. Satellite lesions, are defined as lesions less than 2 cm that are within 1 cm of the periphery of the dominant lesion (gross tumor volume [GTV]) are permitted. The satellite lesions are NOT included in the AXIAL diameter measurement. Regional Lymph Node involvement within the porta hepatis (as medial as superior mesenteric vein [SMV] portal vein confluence) is permitted if nodes are deemed clinically positive (i.e. FDG [Fluorine 18 fluorodeoxyglucose] avid);

3. Appropriate stage for protocol entry, including no distant metastases, based upon the following minimum diagnostic workup:

   • Pre-study entry Scan (REQUIRED for All Patients to confirm no progression): computed tomography (CT) scan chest/abdomen/pelvis with multiphasic liver CT scan within 30 days prior to study entry. If CT contrast is contraindicated, CT chest without contrast and MRI of abdomen and pelvis is permitted;

4. Zubrod Performance Status 0-1 at the time of study entry;
5. Age ≥ 18;

6. Complete blood count (CBC) / differential obtained within 21 days prior to study entry, with adequate bone marrow function defined as follows:

   • Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3;
   • Platelets ≥ 75,000 cells/mm3;
   • Total bilirubin < 2.5 mg/dl;
   • Aspartate Aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (Serum glutamic pyruvic transaminase [SGPT]) < 5.0 X institutional upper limit of normal;
   • Albumin ≥ 2.5mg/dl;
   • Creatinine within normal institutional limits or creatinine clearance ≥ 60 mL/min/1.73 m2 for subject with creatinine levels above institutional normal;
   • Hemoglobin(Hgb) ≥ 9.0 g/dl. (Note: The use of transfusion or other intervention to achieve Hgb ≥ 9.0 g/dl is acceptable.)
7. Patient must provide study specific informed consent prior to study entry;
8. Negative Beta-Human Chorionic Gonadotropin (bHCG) prior to study entry if patient is pre or peri-menopausal.
9. Must have received 6 months of Gemcitabine/Cisplatin chemotherapy without progression. Disease response to chemotherapy is also permitted. If toxicity precludes 6 months of chemotherapy at least 4 months of Gemcitabine/Cisplatin must have been administered.

Exclusion Criteria:

1. Multiple lesions that don't meet the criteria as satellite lesions as defined in protocol;
2. Extrahepatic metastases or malignant nodes beyond the periportal region. Celiac, pancreaticoduodenal and para-aortic nodes> 2 cm are ineligible. Note that benign non-enhancing periportal lymphadenopathy is not unusual in the presence of hepatitis and is permitted, even if the sum of enlarged nodes is > 2.0 cm;
3. Hepatic insufficiency resulting in clinical jaundice, encephalopathy and/or variceal bleed at the time of study entry;
4. Prior radiotherapy to the region of the liver that would result in overlap of radiation therapy fields;
5. Prior selective internal radiotherapy/hepatic arterial Yttrium therapy, at any time;
6. Direct tumor extension into the stomach, duodenum, small bowel or large bowel;
7. Prior invasive malignancy, excluding the current diagnosis, (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years. (Note: carcinoma in situ of the breast, oral cavity, or cervix is all permissible);
8. Prior systemic chemotherapy for the study cancer other than gemcitabine/cisplatin; note that prior chemotherapy for a different cancer is allowable;
9. Currently receiving other anti-cancer agents;
10. Participants who require anticoagulation should receive low-molecular weight or standard heparin and not warfarin;
11. Prior surgery for the IHC. (Liver resection is not allowed);

12. Severe, active co-morbidity, defined as follows:

    • Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months of study entry;
    • Transmural myocardial infarction within the last 6 months of study entry;
    • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of study entry;
    • Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days prior to study entry;
    • HIV positive with CD4 (cluster of differentiation 4) count < 200 cells/microliter. Note that patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count ≥ 200 cells/microliter at the time of study entry. Note also that HIV testing is not required for eligibility for this protocol;
    • End-stage renal disease (ie, on dialysis or dialysis has been recommended).
13. Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic;
14. Grade 3 or higher peripheral neuropathy at the time of study entry.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Radiation therapy; Liver-directed radiation therapy	Radiation: Image Guided Radiation Therapy; Patients undergo 15 fractions of image-guided radiation therapy delivered over 19-26 or 27-34 days.; Other Names: IGRT; image-guided radiation therapy
No Intervention: Observation; No radiation therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Overall survival time is defined as time from randomization to the date of death from any cause. Overall survival rates are estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact.	From randomization to last follow-up. Analysis occurs after all patients have been on study for at least two years.

Secondary Outcome Measures

Outcome Measure	Time Frame
Distant Metastases	From randomization to last follow-up. Analysis occurs after all patients have been on study for at least two years.
Incidence of Adverse Events Evaluated Using National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0	From randomization to last follow-up. Analysis occurs after all patients have been on study for at least two years.
Local Progression	From randomization to last follow-up. Analysis occurs after all patients have been on study for at least two years.
Progression-free Survival (PFS)	From randomization to last follow-up. Analysis occurs after all patients have been on study for at least two years.
Regional Progression Defined as Progression or Existing or Appearance of New Nodal Disease	From randomization to last follow-up. Analysis occurs after all patients have been on study for at least two years.

Collaborators and Investigators

• Sponsor: NRG Oncology
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Theodore Hong, NRG Oncology

Publications and helpful links

General Publications

• Tao R, Krishnan S, Bhosale PR, Javle MM, Aloia TA, Shroff RT, Kaseb AO, Bishop AJ, Swanick CW, Koay EJ, Thames HD, Hong TS, Das P, Crane CH. Ablative Radiotherapy Doses Lead to a Substantial Prolongation of Survival in Patients With Inoperable Intrahepatic Cholangiocarcinoma: A Retrospective Dose Response Analysis. J Clin Oncol. 2016 Jan 20;34(3):219-26. doi: 10.1200/JCO.2015.61.3778. Epub 2015 Oct 26.

Study record dates

Study Major Dates

• Study Start (Actual): September 29, 2014
• Primary Completion (Actual): July 2, 2018
• Study Completion (Actual): July 2, 2018

Study Registration Dates

• First Submitted: July 8, 2014
• First Submitted That Met QC Criteria: July 23, 2014
• First Posted (Estimated): July 25, 2014

Study Record Updates

• Last Update Posted (Actual): May 19, 2026
• Last Update Submitted That Met QC Criteria: April 28, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Carcinoma; Cholangiocarcinoma; Therapeutics; Radiotherapy; Radiotherapy, Image-Guided
• Other Study ID Numbers: NRG-GI001 (Other Identifier: CTEP); U10CA180868 (U.S. NIH Grant/Contract); NCI-2014-00849 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); PNRG-GI001_A02PAMDREVW01; PNRG-GI001_A01PAMDREVW01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.