Patient case: 72-year-old male with Cholangiocarcinoma. Genetic variant: BRCA2. Other conditions: Diabetes.

Clinical trial: Gemcitabine Hydrochloride and Cisplatin With or Without Radiation Therapy in Treating Patients With Localized Liver Cancer That Cannot Be Removed by Surgery

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 hydrochloride and cisplatin is more effective with or without radiation therapy in treating patients with localized liver cancer that cannot be removed by surgery.

Detailed description: PRIMARY OBJECTIVES:
  I. To evaluate the addition of liver-directed radiation therapy to chemotherapy 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 to chemotherapy with respect to local control for patients with unresectable, localized intrahepatic cholangiocarcinoma.
  II. To evaluate the addition of liver-directed radiation therapy to chemotherapy with respect to adverse events for patients with unresectable, localized intrahepatic cholangiocarcinoma.
  III. To evaluate the addition of liver-directed radiation therapy to chemotherapy with respect to regional control for patients with unresectable, localized intrahepatic cholangiocarcinoma.
  IV. To evaluate the addition of liver-directed radiation therapy to chemotherapy with respect to distant metastases for patients with unresectable, localized intrahepatic cholangiocarcinoma.
  V. To evaluate the addition of liver-directed radiation therapy to chemotherapy with respect to progression-free survival for patients with unresectable, localized intrahepatic cholangiocarcinoma.
  OUTLINE:
  Patients receive gemcitabine hydrochloride intravenously (IV) over at least 30 minutes and cisplatin IV over 60 minutes on days 1 and 8. Treatment repeats every 21 days for 3 courses in the absence of disease progression or unacceptable toxicity. Patients without disease progression are randomized to 1 of 2 treatment arms.
  ARM I: Patients receive gemcitabine hydrochloride IV over 30 minutes and cisplatin IV over 60 minutes on days 1 and 8 for 1 course. Beginning 7-21 days from the last dose of chemotherapy, patients undergo 15 fractions of image-guided radiation therapy delivered over 19-26 or 27-34 days. Beginning 7 days after completion of radiation therapy, patients continue treatment with gemcitabine hydrochloride and cisplatin. Treatment repeats every 21 days for up to 5 courses in the absence of disease progression or unacceptable toxicity.
  ARM II: Patients receive gemcitabine hydrochloride IV and cisplatin IV as in Arm I. Treatment repeats every 21 days for up to 5 courses in the absence of disease progression or unacceptable toxicity. Patients may continue gemcitabine hydrochloride at the discretion of the treating physician.
  After completion of study treatment, patients are followed up every 3 months for 3 years then every 6 months for 5 years.

Eligibility: Inclusion Criteria:
  -  Pathologically (histologically or cytologically) proven diagnosis of intrahepatic cholangiocarcinoma (IHC) without distant extrahepatic metastasis within 90 days of registration; patients with an adenocarcinoma suggestive of a pancreaticobiliary primary with radiographic findings consistent with an intrahepatic cholangio-carcinoma are eligible
  -  Patient must have 1 lesion with a maximum AXIAL diameter of 12 cm; 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 (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. fludeoxyglucose F 18 [FDG] avid)
  -  Appropriate stage for protocol entry, including no distant metastases, based upon the following minimum diagnostic workup:
  -  History/physical examination within 30 days prior to registration
  -  Assessment by medical oncologist who specializes in treatment of IHC within 30 days of registration
  -  Pre-randomization scan (REQUIRED for all patients): computed tomography (CT) scan chest/abdomen/pelvis with multiphasic liver CT scan within 30 days prior to registration; if CT contrast is contraindicated, CT chest without contrast and magnetic resonance imaging (MRI) of abdomen and pelvis is permitted
  -  Zubrod performance status 0-1 within 30 days prior to registration
  -  Absolute neutrophil count (ANC) >= 1,500 cells/m^3
  -  Platelets >= 100,000 cells/mm^3
  -  Total bilirubin < 2.5 mg/dl
  -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 5.0 X institutional upper limit of normal
  -  Albumin >= 2.5 mg/dl
  -  Creatinine within normal institutional limits or creatinine clearance >= 60mL/min/1.73 m^2 for subject with creatinine levels above institutional normal
  -  Hemoglobin >= 9.0 g/dl; (note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 9.0 g/dl is acceptable)
  -  Patient must provide study specific informed consent prior to study entry
  -  Negative beta human chorionic gonadotropin (bHCG) within 14 days prior to study entry if patient is pre or perimenopausal
  Exclusion Criteria:
  -  Multiple lesions that don't meet the criteria as satellite lesions
  -  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
  -  Maximum diameter exceeding 12 cm (maximum diameter does not include satellite lesion)
  -  Hepatic insufficiency resulting in clinical jaundice, encephalopathy and/or variceal bleed within 60 days prior to study entry
  -  Prior radiotherapy to the region of the liver that would result in overlap of radiation therapy fields
  -  Prior selective internal radiotherapy/hepatic arterial yttrium therapy, at any time
  -  Direct tumor extension into the stomach, duodenum, small bowel or large bowel
  -  Prior invasive malignancy (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)
  -  Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable
  -  Currently receiving other anti-cancer agents
  -  Participants who require anticoagulation should receive low-molecular weight or standard heparin and not warfarin
  -  Prior surgery for the IHC; (liver resection is not allowed)
  -  Prior allergic reactions attributed to compounds of similar chemical or biologic composition to gemcitabine (gemcitabine hydrochloride) or cisplatin
  -  Severe, active co-morbidity, defined as follows:
  -  Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
  -  Transmural myocardial infarction within the last 6 months
  -  Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
  -  Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days before registration
  -  Human immunodeficiency virus (HIV) positive with cluster of differentiation (CD)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 within 30 days prior to registration; note also that HIV testing is not required for eligibility for this protocol
  -  End-stage renal disease (i.e., on dialysis or dialysis has been recommended)
  -  Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception
  -  Grade 3 or higher peripheral neuropathy

Relevance to patient case: not relevant