Chemo Alone or in Combination With Radiation in Unresectable Cholangiocarcinoma

Study Overview
=================
Brief Summary
-----------------
The study evaluates impact of high dose radiation on overall survival in patients with unresectable nonmetastatic cholangiocarcinoma. The study randomizes patient between systemic chemotherapy alone and systemic chemotherapy and high dose radiation

Detailed Description
-----------------
Currently the standard of care of unresectable non-metastatic cholangiocarcinoma is chemotherapy which has a median survival of 11.7 months (ABC-02 study). While this study included almost 60% of patients with cholangiocarcinomas (intrahepatic, extra hepatic and hilar), almost 73-76% of patients in each arm had metastases to begin with. And while the overall survival of the entire cohort was significantly improved by gemcitabine plus cisplatin compared to cisplatin alone, the hazard ratios for intrahepatic {0.57 (0.34-0.94)}, extra hepatic {0.73 (0.43-1.23)} and hilar cholangiocarcinomas {0.59 (0.32-1.09)} were all insignificant. Even though concurrent chemoradiation+/= brachytherapy has been used for management of cholangiocarcinomas for more than 3 decades the lack of level I evidence prevents from it being recommended as the first line management across multidisciplinary clinics. While either modality alone rarely yields survival of more than 12 months, recent reports of improved median survival with combination of high dose radiation and systemic chemotherapy necessitates investigation into role of combination of high dose (chemo) radiation and systemic chemotherapy. All patients with diagnosis of nonmetastatic unresectable cholangiocarcinoma who fulfill the study eligibility criteria will be evaluated for study participation. Patients will undergo upfront randomization into one of the study arms (systemic chemotherapy alone vs Systemic chemotherapy+ High dose radiation) The study stratification criteria will be done according the primary site i.e. Intrahepatic vs Extrahepatic.

Official Title
-----------------
Phase III Randomized Trial of High Dose Chemoradiation and Systemic Chemotherapy vs Systemic Chemotherapy Alone in Patients With Unresectable Nonmetastatic Cholangiocarcinoma

Conditions
-----------------
Cholangiocarcinoma

Intervention / Treatment
-----------------
* Radiation: High Dose Radiation
* Drug: Systemic chemotherapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age >18 years Performance Status 0-2 Tissue diagnosis of adenocarcinoma of the biliary tract. Wherever tissue diagnosis is not feasible in spite of repeated attempts a multidisciplinary consensus on clinicoradiological diagnosis of cholangiocarcinoma (CA 19-9= 100mg/ml with a radiological evidence of malignant stricture) should be made and patients consent should be available for treatment without tissue diagnosis. Unresectable disease as determined by hepatobiliary surgical team. No evidence of peritoneal or distant metastasis. No radiological evidence of paraaortic nodal disease. Child A or Child B (score 7) Ability to tolerate radical treatment. Exclusion Criteria: Multicentric intrahepatic cholangiocarcinoma (however adjacent satellite lesions are permitted) Inability to deliver safe radiation due to high tumor/ liver ratio. Active cholangitis. Expected Survival<6 months. Unresolved biliary tract obstruction. Inability in deliver systemic chemotherapy (persistent bilirubin>3)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Systemic Chemotherapy<br>Irrespective of arm allocation Baseline Positron Emission Tomography(PET) scan and hepatic function assessment will be done. Those randomized to this arm will receive systemic chemotherapy delivered on day 1 and 8 every 3 weekly, with gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2. After first 4 cycles patients will undergo repeat Contrast Enhanced Computed Tomography(CECT)/PET scan. If CECT/PET scan shows stable/ responding disease then patients will continue to receive the same chemotherapy. In case of locally progressive/ systemic disease on chemotherapy patients may be considered for second line palliative chemotherapy or best supportive care. The use of radical chemoradiation is not allowed on disease progression in this arm. However palliative radiation may be used. | Drug: Systemic chemotherapy<br>* This arm will receive maximum 8 cycles of gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 delivered on day 1 and 8 every 3 weekly.<br>* Other names: Gemcitabine and Cisplatin regimen;|
| Experimental: Chemotherapy and radiation<br>In those randomized to radiation arm with receive high dose radiation with Intensity Modulated Radiation Therapy in addition to systemic and concurrent chemotherapy. The gross tumor will comprise the high dose volume. The adjacent areas of suspected microscopic disease will form the low dose volume. When only external radiation is used the aim will be to deliver 52.5-60 Gy/ 25 fractions to the gross disease and 45 Gy/ 25 fractions to suspected microscopic disease along with weekly gemcitabine (300 mg/ m2) . | Radiation: High Dose Radiation<br>* The aim will be to deliver 52.5-60 Gy/ 25 fractions to the gross disease and 45 Gy/ 25 fractions to suspected microscopic disease along with weekly gemcitabine (300 mg/ m2) .<br>* Other names: Radiation;Drug: Systemic chemotherapy<br>* This arm will receive maximum 8 cycles of gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 delivered on day 1 and 8 every 3 weekly.<br>* Other names: Gemcitabine and Cisplatin regimen;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | The trial is designed to assess a 36 month benefit overall survival | 3 years from completion of study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| loco-regional progression free survival | Will compare the loco-regional progression free survival between both the arms | 3 years from completion of accrual | 
| Toxicity Assessment | Assessment will be done according to CTCAE v4.0 | upto 3 years | 
| Quality of Life Assessment of patients over a period of time | Assessment will be done according to Fact-Hep(version 4) | 3 years from completion of accrual | 
| Surgical Resectability Rates | To assess the number of patient who can be taken for surgery in view of good response after treatment | 6 weeks from completion of primary treatment | 
| cause specific survival | Will compare the cause specific survival between both the arms | 3 years from completion of accrual |