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Perioperative Therapy Preoperative Chemotherapy Versus Chemoradiotherapy in Locally Advanced Gall Bladder Cancers (POLCAGB)

Primary Purpose

Gall Bladder Cancers

Status
Recruiting
Phase
Phase 2
Locations
India
Study Type
Interventional
Intervention
Gemcitabine
Cisplatin
Chemoradiation
PETCECT
Laparoscopy
Sponsored by
Tata Memorial Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Gall Bladder Cancers

Eligibility Criteria

19 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Locally advanced T3 or T4 tumors with one or more of the following:

-> 2 cm but < 5 cm liver invasion

  • Radiological involvement of antropyloric region of stomach, duodenum, hepatic flexure of colon or small intestine, but without infiltration of the mucosa on endoscopy.
  • Type I/II invasion -Involvement of bile duct (common hepatic duct or proximal 1/3 of the common bile duct) causing obstructive jaundice
  • Radiological suspicion of lymph node involvement N1 {stations 8, 12, 13) Hepatic artery (Station 8), hepatoduodenal ligament (Station 12), retropancreatic/retroduodenal (Station 13) i.e. size>1cm in short axis, round in shape, and heterogenous enhancement on PET scan.
  • Vascular involvement : impingement/ involvement (<180 degree angle) of one or more of the following blood vessels common hepatic artery/ right hepatic artery/main portal vein/right portal vein (stage III disease)
  • Patient who have undergone prior cholecystectomy having residual disease with at least one of the above features.
  • Biopsy/ cytology proven adenocarcinoma
  • More than 18 years of age
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 Normal hematological and renal and hepatic functions (serum bilirubin < 3mg/dl)

Exclusion Criteria:

  • Resectable disease
  • Evidence of distant metastasis (Liver, Lung, peritoneum, port site etc)
  • Involving major part of the liver precluding restriction of full RT doses
  • Received any prior radiation or chemotherapy.

Sites / Locations

  • Tata Memorial CentreRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Chemotherapy arm

Chemoradiation arm

Arm Description

Post staging laparoscopy, all patients will receive chemotherapy using Injection Gemcitabine 1000 mg/m2 delivered day 1 and 8 every 3 weeks. In addition, Injection Cisplatin 25 mg/m2 for and 4 cycles week 1 to week 11.

Post staging laparoscopy in Experimental arm The radiation dose will be 50-55 Gy/ 25 fractions to the gross disease and 45 Gy/ 25 fractions to suspected microscopic disease along with weekly gemcitabine (300 mg/ m2). Radiotherapy will be for 5 weeks which will be followed by 2 cycles of chemotherapy with Injection Gemcitabine (Gemcite,Gemzar) 1000 mg/m2 delivered day 1 and 8 every 3 weeks and cisplatin (Cisplat, Cytoplatin) 25 mg/m2from week 7 to week 11. During week 12-13 patients will undergo repeat PETCECT scan. If the scan shows partial or good response then patients will be evaluated for surgery. Surgery if possible will be done between weeks 13-15. In case of inoperable disease patients will receive further chemotherapy

Outcomes

Primary Outcome Measures

Overall Survival
To compare the Overall survival between the patients treated with neoadjuvant chemotherapy alone vs. patients treated with neoadjuvant chemoradiation. Overall survival will be calculated from the date of randomization to the date of death

Secondary Outcome Measures

Surgical resection rate
R0 surgical resection rate would be compared in patients who undergo complete resection.
Progression free survival
Progression free survival between the two groups. survival will be calculated from the date of randomization to the date of progression whether local or distal.
Number of participants with treatment related serious adverse events
Adverse events are assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Adverse events are considered to be related to treatment if the Investigator deems them to be either possibly, probably, or definitely related to treatment Acute toxicities will be measured within 12 weeks of completeion of neoadjuvant Radiotherapy or Chemotherapy
Deterioration free rate of quality of life (QOL) scores at baseline and three monthly
QOL questionnaires will be applied to patients at baseline and every 12 weeks for a maximum of 12 months. The secondary endpoint will be analysed at the end of the study. FACT (Functional Assessment of Cancer Therapy) -Hep (Hepatic) version 4 will be used to assess quality of life for all patients. It will be assessed at baseline then at the completion of neoadjuvant treatment thereafter 3 monthly at every follow up

Full Information

First Posted
July 29, 2016
Last Updated
July 4, 2022
Sponsor
Tata Memorial Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT02867865
Brief Title
Perioperative Therapy Preoperative Chemotherapy Versus Chemoradiotherapy in Locally Advanced Gall Bladder Cancers
Acronym
POLCAGB
Official Title
Perioperative Therapy Preoperative Chemotherapy Versus Chemoradiotherapy in Locally Advanced Gall Bladder Cancers
Study Type
Interventional

2. Study Status

Record Verification Date
November 2018
Overall Recruitment Status
Recruiting
Study Start Date
September 6, 2016 (Actual)
Primary Completion Date
September 10, 2025 (Anticipated)
Study Completion Date
September 10, 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Tata Memorial Hospital

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Locally advanced Gall bladders cancers not amenable for curative resection are often treated with chemotherapy alone which is the current standard of care. Randomized trials have shown survival benefit with combination chemotherapy in gallbladder cancers. Gallbladder cancer is not common western world and thus there is lack of evidence regarding the impact of neoadjuvant or concurrent chemo-radiation in this cancer.Use of neoadjuvant treatment with chemotherapy alone or chemoradiotherapy has shown to downsize these tumors to safely undergo R0 resection in few published studies. Also if the patients develop distant metastasis during this neoadjuvant therapy they can be spared of unnecessary surgery. In a pilot study of 28 patients by Engineer et al conducted at Tata Memorial centre treated with neoadjuvant concurrent chemoradiation the investigators could achieve R0 resectability rate 0f 47% with a median overall survival (OAS) and progression free survival (PFS) of 35 and 20 months for the patients undergoing R0 resection. In this study the investigators intend to compare the effects of using neoadjuvant chemotherapy alone vs. neoadjuvant chemoradiation and chemotherapy for locally advanced gall bladder cancers in terms of down staging and overall survival.
Detailed Description
Introduction: Adenocarcinoma of the gallbladder (GBCA) is the most common malignancy of the biliary tract and its incidence is alarmingly high in the Indian subcontinent. Complete surgical excision is the standard of care for both gallbladder and pancreatic cancers. Unfortunately, majority of these cancers are diagnosed at an advanced, inoperable stage and only 10-30% of the patient present with resectable disease. Gall bladder cancers which are T3/T4 with liver infiltration, with or without visceral/vascular infiltration or having large local lymph node metastases; in the absence of distant metastases are generally considered as locally advanced. There prognosis in terms of resectability and survival remains dismal in most of the reports. Even with aggressive surgery like extrahepatic bile duct resection or pancreaticoduodenectomy the 5 year survival rate for stage III disease ranges 30% to 42% in best of the reports. But these results are often not reproducible. Locally advanced Gall bladders cancers not amenable for curative resection are often treated with chemotherapy alone which is the current standard of care. Randomized trials have shown survival benefit with combination chemotherapy in gallbladder cancers. In a randomized trial combination chemotherapy of Gemcitabine and cisplatin was superior to Gemcitabine chemotherapy alone and local tumor response in terms of partial downsizing or stable disease was achieved in 81% of cases. With Gemcitabine and Cisplatin based Neoadjuvant chemotherapy (NACT) some locally advanced GB cancers do get downstaged to undergo resection. Recent publication from Tata Memorial Centre, where NACT alone was given which resulted in surgical resection rate of 43% median OAS and PFS being 13 months and 8 months. Study methodology: All patients with diagnosis of non metastatic locally advanced Gall bladder cancers who fulfill the study eligibility criteria will be evaluated for study participation and will undergo Positron emission tomography and contrast enhanced computerized tomography (PETCECT) scan and staging laparoscopy to rule out metastatic disease. Patients will undergo upfront randomization into one of the study arms. A proportion of patients are expected to have jaundice or cholangitis at presentation. At study inclusion there should be no clinical evidence of active cholangitis or unresolved biliary obstruction. Liver Function Tests, Renal Function Tests and CA 19-9 within 4 weeks of treatment initiation. Systemic Chemotherapy arm (Standard Arm or Arm A) Those randomized to NACT will proceed to receive systemic gemcitabine 1000 mg/m2delivered day 1 and 8 every 3 weeks and cisplatin 25 mg/m2 for and 4 cycles (week 1- week 11). Chemoradiation arm (Study Arm or Arm B) The radiation dose will be 50-55 Gy/ 25 fractions to the gross disease and 45 Gy/ 25 fractions to suspected microscopic disease along with weekly gemcitabine (300 mg/ m2). Radiotherapy will be for 5 weeks which will be followed by 2 cycles of chemotherapy (week 7 to week 11) These radiotherapy (RT) doses have found to be safe in the investigators pilot study. During week 12-13 patients will undergo repeat PETCECT scan. If the scan shows partial or good response then patients will be evaluated for surgery. Surgery if possible will be done between weeks 13-15. In case of inoperable disease patients will receive further chemotherapy. With locally progressive/systemic disease on chemotherapy patients may be considered for second line palliative chemotherapy or best supportive care. The use of radical dose chemoradiation is not allowed on disease progression in the systemic chemotherapy arm. However palliative radiation may be used. Surgery Surgical procedure will be en-bloc resection including cholecystectomy with a liver wedge excision and periportal lymph node clearance. Nodal clearance from station number 8, 12, 13 with sampling of inter aortocaval node will be done. Extrahepatic biliary excision or additional organ excision will be done as per the discretion of operating surgeon. Post Surgery all patients will receive additional adjuvant chemotherapy Number of patients enrolled: Screened 350 Enrolled 314

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Gall Bladder Cancers

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
314 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Chemotherapy arm
Arm Type
Active Comparator
Arm Description
Post staging laparoscopy, all patients will receive chemotherapy using Injection Gemcitabine 1000 mg/m2 delivered day 1 and 8 every 3 weeks. In addition, Injection Cisplatin 25 mg/m2 for and 4 cycles week 1 to week 11.
Arm Title
Chemoradiation arm
Arm Type
Experimental
Arm Description
Post staging laparoscopy in Experimental arm The radiation dose will be 50-55 Gy/ 25 fractions to the gross disease and 45 Gy/ 25 fractions to suspected microscopic disease along with weekly gemcitabine (300 mg/ m2). Radiotherapy will be for 5 weeks which will be followed by 2 cycles of chemotherapy with Injection Gemcitabine (Gemcite,Gemzar) 1000 mg/m2 delivered day 1 and 8 every 3 weeks and cisplatin (Cisplat, Cytoplatin) 25 mg/m2from week 7 to week 11. During week 12-13 patients will undergo repeat PETCECT scan. If the scan shows partial or good response then patients will be evaluated for surgery. Surgery if possible will be done between weeks 13-15. In case of inoperable disease patients will receive further chemotherapy
Intervention Type
Drug
Intervention Name(s)
Gemcitabine
Other Intervention Name(s)
Gemcite, Gemzar
Intervention Description
Those randomized to systemic chemotherapy alone will proceed to receive Chemotherapy Gemcitabine gemcitabine 1000 mg/m2delivered day 1 and 8 every 3 weeks for 4 cycles
Intervention Type
Drug
Intervention Name(s)
Cisplatin
Other Intervention Name(s)
Cytoplat
Intervention Description
Inj. cisplatin 25 mg/m2 delivered. day 1 and 8 every 3 weeks for 4 cycles
Intervention Type
Radiation
Intervention Name(s)
Chemoradiation
Other Intervention Name(s)
Intensity modulated radiotherapy
Intervention Description
Radiotherapy will be for 5 weeks and will be given only in the study arm. The radiation dose will be 50-55 Gy/ 25 fractions to the gross disease and 45 Gy/ 25 fractions to suspected microscopic disease along with weekly gemcitabine (300 mg/ m2).
Intervention Type
Procedure
Intervention Name(s)
PETCECT
Other Intervention Name(s)
PET scan
Intervention Description
All the patients will undergo PETCECT to rule out metastatic disease
Intervention Type
Procedure
Intervention Name(s)
Laparoscopy
Other Intervention Name(s)
Diagnostic laparoscopy
Intervention Description
Patients will be subjected to staging laparoscopy with 16b1 lymph node biopsy to rule out metastatic disease.
Primary Outcome Measure Information:
Title
Overall Survival
Description
To compare the Overall survival between the patients treated with neoadjuvant chemotherapy alone vs. patients treated with neoadjuvant chemoradiation. Overall survival will be calculated from the date of randomization to the date of death
Time Frame
6 years
Secondary Outcome Measure Information:
Title
Surgical resection rate
Description
R0 surgical resection rate would be compared in patients who undergo complete resection.
Time Frame
6 years
Title
Progression free survival
Description
Progression free survival between the two groups. survival will be calculated from the date of randomization to the date of progression whether local or distal.
Time Frame
6 years
Title
Number of participants with treatment related serious adverse events
Description
Adverse events are assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Adverse events are considered to be related to treatment if the Investigator deems them to be either possibly, probably, or definitely related to treatment Acute toxicities will be measured within 12 weeks of completeion of neoadjuvant Radiotherapy or Chemotherapy
Time Frame
From the start of treatment until 30 days after the end of treatment, up to approximately 14 months
Title
Deterioration free rate of quality of life (QOL) scores at baseline and three monthly
Description
QOL questionnaires will be applied to patients at baseline and every 12 weeks for a maximum of 12 months. The secondary endpoint will be analysed at the end of the study. FACT (Functional Assessment of Cancer Therapy) -Hep (Hepatic) version 4 will be used to assess quality of life for all patients. It will be assessed at baseline then at the completion of neoadjuvant treatment thereafter 3 monthly at every follow up
Time Frame
Upto 2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
19 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Locally advanced T3 or T4 tumors with one or more of the following: -> 2 cm but < 5 cm liver invasion Radiological involvement of antropyloric region of stomach, duodenum, hepatic flexure of colon or small intestine, but without infiltration of the mucosa on endoscopy. Type I/II invasion -Involvement of bile duct (common hepatic duct or proximal 1/3 of the common bile duct) causing obstructive jaundice Radiological suspicion of lymph node involvement N1 {stations 8, 12, 13) Hepatic artery (Station 8), hepatoduodenal ligament (Station 12), retropancreatic/retroduodenal (Station 13) i.e. size>1cm in short axis, round in shape, and heterogenous enhancement on PET scan. Vascular involvement : impingement/ involvement (<180 degree angle) of one or more of the following blood vessels common hepatic artery/ right hepatic artery/main portal vein/right portal vein (stage III disease) Patient who have undergone prior cholecystectomy having residual disease with at least one of the above features. Biopsy/ cytology proven adenocarcinoma More than 18 years of age Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 Normal hematological and renal and hepatic functions (serum bilirubin < 3mg/dl) Exclusion Criteria: Resectable disease Evidence of distant metastasis (Liver, Lung, peritoneum, port site etc) Involving major part of the liver precluding restriction of full RT doses Received any prior radiation or chemotherapy.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Reena Engineer, MBBS MD
Phone
+91 22 2417 7000
Ext
7165
Email
reena_engineer@rediffmail.com
First Name & Middle Initial & Last Name or Official Title & Degree
Mahesh Goel, MBBS MS
Phone
+91 22 2417 7000
Ext
7172
Email
drmaheshgoel@gmail.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Reena Engineer, MBBS MD
Organizational Affiliation
Professor and Radiation oncologist
Official's Role
Principal Investigator
Facility Information:
Facility Name
Tata Memorial Centre
City
Mumbai
State/Province
Maharashtra
ZIP/Postal Code
400012
Country
India
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Reena Engineer, MD
Phone
+912224177165
Email
reena_engineer@rediffmail.com
First Name & Middle Initial & Last Name & Degree
ShyamKishore Shrivastava, MD
Phone
+912224177163
Email
shrivastavask@tmc.gov.in
First Name & Middle Initial & Last Name & Degree
Reena Engineer, MD

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
31253621
Citation
Engineer R, Patkar S, Lewis SC, Sharma AD, Shetty N, Ostwal V, Ramaswamy A, Chopra S, Agrawal A, Patil P, Mehta S, Goel M. A phase III randomised clinical trial of perioperative therapy (neoadjuvant chemotherapy versus chemoradiotherapy) in locally advanced gallbladder cancers (POLCAGB): study protocol. BMJ Open. 2019 Jun 27;9(6):e028147. doi: 10.1136/bmjopen-2018-028147.
Results Reference
derived

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Perioperative Therapy Preoperative Chemotherapy Versus Chemoradiotherapy in Locally Advanced Gall Bladder Cancers

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