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

• ClinicalTrials.gov Identifier: NCT02200042
• Recruitment Status: Terminated
• First Posted: July 25, 2014
• Results First Posted: August 28, 2019
• Last Update Posted: August 28, 2019
• Sponsor: NRG Oncology
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): NRG Oncology

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Stage III Intrahepatic Cholangiocarcinoma; Stage IVA Intrahepatic Cholangiocarcinoma	Radiation: Image Guided Radiation Therapy	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 1 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Randomization ratio (Experimental:Observation) = 2:1
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Randomized Phase III Study of Focal Radiation Therapy for Unresectable, Localized Intrahepatic Cholangiocarcinoma
• Actual Study Start Date: September 29, 2014
• Actual Primary Completion Date: July 2, 2018
• Actual Study Completion Date: July 2, 2018

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Overall Survival [ Time Frame: From randomization to last follow-up. Analysis occurs after all patients have been on study for at least two years. ]
   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.

Secondary Outcome Measures :

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

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, Alabama

University of Alabama at Birmingham Cancer Center

Birmingham, Alabama, United States, 35233

United States, Arkansas

University of Arkansas for Medical Sciences

Little Rock, Arkansas, United States, 72205

United States, California

Sutter Medical Center Sacramento

Sacramento, California, United States, 95816

United States, Georgia

Emory University Hospital Midtown

Atlanta, Georgia, United States, 30308

Piedmont Hospital

Atlanta, Georgia, United States, 30309

Emory University Hospital/Winship Cancer Institute

Atlanta, Georgia, United States, 30322

United States, Hawaii

Queen's Medical Center

Honolulu, Hawaii, United States, 96813

United States, Illinois

Northwestern University

Chicago, Illinois, United States, 60611

Decatur Memorial Hospital

Decatur, Illinois, United States, 62526

Loyola University Medical Center

Maywood, Illinois, United States, 60153

OSF Saint Francis Medical Center

Peoria, Illinois, United States, 61637

Northwestern Medicine Cancer Center Warrenville

Warrenville, Illinois, United States, 60555

United States, Indiana

Indiana University/Melvin and Bren Simon Cancer Center

Indianapolis, Indiana, United States, 46202

United States, Maryland

Maryland Proton Treatment Center

Baltimore, Maryland, United States, 21201

United States, Massachusetts

Massachusetts General Hospital Cancer Center

Boston, Massachusetts, United States, 02114

Boston Medical Center

Boston, Massachusetts, United States, 02118

Lahey Hospital and Medical Center

Burlington, Massachusetts, United States, 01805

United States, Missouri

Washington University School of Medicine

Saint Louis, Missouri, United States, 63110

Missouri Baptist Medical Center

Saint Louis, Missouri, United States, 63131

United States, New Hampshire

Dartmouth Hitchcock Medical Center

Lebanon, New Hampshire, United States, 03756

United States, New Mexico

University of New Mexico Cancer Center

Albuquerque, New Mexico, United States, 87102

United States, New York

Mount Sinai Hospital

New York, New York, United States, 10029

University of Rochester

Rochester, New York, United States, 14642

United States, Ohio

University of Cincinnati/Barrett Cancer Center

Cincinnati, Ohio, United States, 45219

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, United States, 43210

United States, Oregon

Legacy Good Samaritan Hospital and Medical Center

Portland, Oregon, United States, 97210

United States, Texas

M D Anderson Cancer Center

Houston, Texas, United States, 77030

United States, Utah

Huntsman Cancer Institute/University of Utah

Salt Lake City, Utah, United States, 84112

United States, Vermont

University of Vermont Medical Center

Burlington, Vermont, United States, 05401

United States, Washington

ProCure Proton Therapy Center-Seattle

Seattle, Washington, United States, 98133

University of Washington Medical Center

Seattle, Washington, United States, 98195

United States, West Virginia

West Virginia University Healthcare

Morgantown, West Virginia, United States, 26506

United States, Wisconsin

University of Wisconsin Hospital and Clinics

Madison, Wisconsin, United States, 53792

Canada, Quebec

The Research Institute of the McGill University Health Centre (MUHC)

Montreal, Quebec, Canada, H3H 2R9

Sponsors and Collaborators

NRG Oncology

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Theodore Hong; NRG Oncology

  Study Documents (Full-Text)

Documents provided by NRG Oncology:

Study Protocol and Statistical Analysis Plan  [PDF] March 20, 2017

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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. Erratum In: J Clin Oncol. 2019 Apr 10;37(11):942.

• Responsible Party: NRG Oncology
• ClinicalTrials.gov Identifier: NCT02200042
• Other Study ID Numbers: NRG-GI001; NCI-2014-00849 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); PNRG-GI001_A02PAMDREVW01; PNRG-GI001_A01PAMDREVW01; NRG-GI001 ( Other Identifier: NRG Oncology ); NRG-GI001 ( Other Identifier: CTEP ); U10CA180868 ( U.S. NIH Grant/Contract )
• First Posted: July 25, 2014
• Results First Posted: August 28, 2019
• Last Update Posted: August 28, 2019
• Last Verified: July 2019

Additional relevant MeSH terms:

Cholangiocarcinoma; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms