Phase II SBRT & Chemo for Unresectable Cholangiocarcinoma Followed by Liver Transplantation

Study Overview
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Brief Summary
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The purpose of this study is to determine progression-free survival at 12 months for stereotactic body radiotherapy (SBRT) and chemotherapy for unresectable hilar cholangiocarcinoma (CCA).

Detailed Description
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Investigators hope to learn more about neoadjuvant SBRT and chemotherapy for unresectable CCA, and if SBRT followed by chemotherapy can lead to successful liver transplantation. This knowledge is important for this patient group as this disease is a highly lethal malignancy that often presents as unresectable, however surgery or transplantation are the only curative options.

Official Title
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Phase II Study of Stereotactic Body Radiotherapy (SBRT) and Chemotherapy for Unresectable Cholangiocarcinoma Followed by Liver Transplantation

Conditions
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Cholangiocarcinoma, Hepatobiliary Neoplasm, Liver Cancer, Bile Duct Cancer, Cancer of Gallbladder

Intervention / Treatment
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* Procedure: Stereotactic Body Radiotherapy
* Drug: Gemcitabine
* Drug: Cisplatin
* Drug: Carboplatin
* Drug: Capecitabine
* Drug: 5FU
* Procedure: Liver transplantation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of cholangiocarcinoma by any of the below: Positive transcatheter biopsy or brush cytology CA 19-9 &#8805; 100mg/mL with a malignant-appearing stricture on cholangiography Biliary ploidy by fluorescent in situ hybridization with a malignant stricture on cholangiography Liver tumors not to exceed 8 cm in greatest axial dimension (800 cc of uninvolved liver) Unresectable tumor above cystic duct Hepatic lesion in patients for whom surgical resection is not possible or would not result in an opportunity for cure by any of the below: Bilateral segmental ductal extension Encasement of the main portal vein Unilateral segmental ductal extension with contralateral vascular encasement Unilateral atrophy with either contralateral segmental ductal or vascular (hepatic artery, portal vein) involvement Ascites is allowed if the Model for End-Stage Liver Disease (MELD) score is <15[1] Age > 18 years old Eastern Clinical Oncology Group performance status 0, 1 or 2 (Appendix 1) Lab values within 2 wks prior to randomization: See STUDY SCHEMA for specific blood count inclusion criteria: ANC &#8805; 500 x 109/L (&#8805; 1500/mm3), Platelets &#8805; 5 x 109/L (&#8805; 50,000/mm3), Hgb &#8805; 9g/dL Adequate liver function: Total bilirubin &#8804;1.5 x upper limit of normal (ULN); ALT and/or AST & alkaline phosphatase &#8804; 5 x ULN. Adequate biliary drainage, with no evidence of active uncontrolled infection (patients on antibiotics are eligible). See STUDY SCHEMA for specific renal function inclusion criteria: Adequate renal function with a calculated GFR &#8805; 40 ml/min. If the calculated GFR is below 40 ml/min a 24 hour urine creatinine clearance can be used. Albumin > 2.5 mg/dL INR &#8804; 1.5 Life expectancy > 6 months Capable of giving written informed consent Exclusion Criteria: Prior radiotherapy to the upper abdomen Contraindication to receiving radiotherapy Prior chemotherapy Prior biliary resection or attempted resection Prior transperitoneal biopsy Large esophageal varices without band ligation Active GI bleed or within 2 weeks of study enrollment Ascites refractory to medical therapy or shunting Active/unresolved biliary tract obstruction Presence of multifocal, lymphatic, or extrahepatic metastases Participation in another concurrent treatment protocol If history of other primary cancer, subject eligible only if she or he has: Curatively resected non-melanomatous skin cancer Curatively treated cervical carcinoma in situ Other primary solid tumor curatively treated with no known active disease present and no treatment administered for the last 3 years Any evidence of severe or uncontrolled systemic diseases or laboratory finding that in the view of the investigator makes it undesirable for the patient to participate in the trial Any psychiatric or other disorder (eg brain metastases) likely to impact on informed consent Pregnancy or breast-feeding While not excluded, patients with significant impaired hearing must be made aware of potential ototoxicity and may choose not to be included. If included, baseline audiograms are recommended and, in those given cisplatin, should be followed by repeat audiograms prior to cycle 2.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SBRT, Chemo and Liver Transplantation<br>The patients received Stereotactic Body Radiotherapy and Chemotherapy followed by a liver transplantation. The chemo could be any combination of the following: Gemcitabine, Cisplatin, Carboplatin, Capecitabine and 5FU | Procedure: Stereotactic Body Radiotherapy<br>* Standard of care<br>* Other names: External photon radiation;Drug: Gemcitabine<br>* 100 mg/m2, IV<br>* Other names: Gemzar;Drug: Cisplatin<br>* 25 mg/m2, IV<br>* Other names: Platinol-AQ;Drug: Carboplatin<br>* AUC 2, based on Calvert formula, IV<br>* Other names: Paraplatin-AQ;Drug: Capecitabine<br>* 1000 mg/m2, PO<br>* Other names: Xeloda;Drug: 5FU<br>* 200 mg/m2<br>* Other names: Fluoroplex;Procedure: Liver transplantation<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival at 12 Months | Progression free survival is defined to be the time to progression of disease or death. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic Complete Response Rate | Pathologic complete response will be defined as no residual tumor cells seen on the explanted liver specimen. | 12 months | 
| Serum CA 19-9 Levels | Initial level of Cancer antigen 19-9 | 12 months | 
| Overall Survival at 12 Months | the estimated probability for the percentage of participants with overall survival at 12 months. | 12 months | 
| Liver Transplant Rate | The number of patients receiving liver transplant among patients who initially have tumors ≤3 cm | 12 months | 
| Freedom From Local Progression at 12 Months | the proportion of patients who experienced a local recurrence at 12 months with death as a competing risk | 12 months | 
| Liver Transplant Conversion Rate | The ability to successfully perform liver transplant among patients who initially have tumor >3 cm | 12 months | 
| Median Time to Overall Survival | The time to overall survival is defined as the time to death from any cause. The median was determined via Kaplan Meier methodology. | 18 months |