Radiation Therapy vs. Observation Following Gemcitabine and Cisplatin for Inoperable Localized Liver Cancer
Condition: Stage III Intrahepatic Cholangiocarcinoma; Stage IVA Intrahepatic Cholangiocarcinoma
MeSH terms: Cholangiocarcinoma
Intervention: Image Guided Radiation Therapy
Intervention description: Patients undergo 15 fractions of image-guided radiation therapy delivered over 19-26 or 27-34 days.
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Randomization ratio (Experimental:Observation) = 2:1
Masking: None (Open Label)
Enrollment: 1.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

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.
    

Eligibility 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.