Radiation Therapy in Unresectable Gall Bladder Cancer

Official title

Systemic Therapy With or Without Radiation Therapy in Unresectable Nonmetastatic Gall Bladder Carcinoma: Open Label, Parallel Arm, Phase 2/3 Integrated Randomized Clinical Trial

Overview

The goal of this clinical trial is to compare two treatment regimes, namely, systemic therapy (chemotherapy and/or immunotherapy) alone vs. systemic therapy and radiation therapy in patients with inoperable but localized gallbladder cancer. The main questions it aims to answer are: * Whether adding radiation therapy to systemic therapy improves overall survival? * What are the effects on other endpoints like cancer-free intervals, side effects, and quality of life? Participants will be randomly assigned to one of the two treatment regimes mentioned earlier by a computer-based program. Researchers will compare survival and quality of life outcomes between the two groups.

Detailed description

Gallbladder cancer (GBC) incidence is exceptionally high in India and most patients present with an unresectable or advanced disease. There is limited clinical evidence on optimal therapy of biliary tract cancers in general and more so for gall bladder cancers which are relatively rare in the Western world.

As per current clinical practice, Surgery remains the mainstay of curative treatment for resectable GBC, and systemic therapy with or without radiotherapy is offered for unresectable GBC. The current standard of systemic therapy is to administer 6 months of Gemcitabine-based regimen and the median overall survival of these patients is about 10-12 months. The national and Institutional guidelines suggest the use of radiation in unresectable GBC. The role of radiation therapy in this setting has not been evaluated in phase 3 randomized clinical trials although it is being offered routinely at our Centre if the patients remain nonmetastatic after initial systemic therapy. We propose a phase 2/3 integrated randomized clinical trial evaluating the role of adding radiotherapy to chemotherapy in improving survival outcomes in patients with unresectable GBC based on nonrandomized data from our institution suggesting a benefit with the addition of radiation therapy in this setting.

Patients with histologically verified, unresectable GBC who do not progress (RECIST 1.1) after an initial 3 months of Gemcitabine-based systemic therapy are invited to participate in this open-label, parallel arm, superiority design randomized controlled trial. Patients randomized to the 'RT arm' will receive hypo fractionated conformal image-guided radiotherapy to a dose of 40-55Gy in 10 (up to 15) fractions to the primary and regional lymph node basins delivered over 2-3 weeks. Systemic therapy is resumed after completion of radiotherapy for 3 more months. The patients in the 'Chemo alone arm' or 'Systemic therapy alone' arm will complete 3 more months of systemic therapy as per the current institutional standard. All patients will be considered for further systemic therapy (either as maintenance therapy or at the time of relapse) at the discretion of the treating medical oncologist.

The primary outcomes of the Phase 2 and Phase 3 components are progression-free survival and Overall survival respectively with an interim analysis planned at 36 months to evaluate futility. Secondary outcomes include local control, toxicity, and quality of life measures. The estimated sample size 249 is and the expected duration of the study is 67 months including the follow-up period.

Interventions

• Drug Systemic therapy (Gemcitabine plus Cisplatin)
  Participants will receive one of the following Gemcitabine-based systemic therapy alone: Gemcitabine 1000mg/m2 and Cisplatin 25 mg/m2, each administered on Days 1 and 8 every 3 weeks (q3w) Duration: 3 months (in addition to 3 months previously received)
• Radiation RT
  Participants will receive radiation therapy in addition to systemic therapy Hypofractionated external image guided radiation to a dose of 40-55Gy in 10 sessions (up to 60Gy in 15 sessions) over 2-3 weeks. This is followed by systemic therapy as in the Systemic therapy alone arm.
• Drug Systemic therapy (Gemcitabine plus oxaliplatin)
  Gemcitabine 1000 mg/m2 and oxaliplatin 100 mg/m2 IV infusion on days 1 and 8 q2w. Duration: 3 months
• Drug Systemic therapy (Gemcitabine plus Cisplatin plus Durvalumab)
  Durvalumab 1500 mg via intravenous (IV) infusion q4w, starting on Cycle 1 in combination with cisplatin 25 mg/m2 and gemcitabine 1000 mg/m2 each administered on Days 1 and 8, q3w. Duration 3 months Durvalumab (12 months)
• Drug Systemic therapy (Gemcitabine plus cisplatin plus nab-paclitaxel)
  Gemcitabine 800 mg/m2, cisplatin, 25 mg/m2, and nab-paclitaxel 100 mg/m2, on days 1 and 8, q3w Duration: 3 months

Primary outcome measures

• Median overall survival [Time frame: 2 years]

Secondary outcome measures (9)

• Progression free survival [Time frame: 2 years]
• Locoregional progression free survival [Time frame: 2 years]
• Response rate [Time frame: 6 months]
• Acute toxicities [Time frame: 3 years]
• Late toxicities [Time frame: 3 years]
• Acute toxicities [Time frame: 3 years]
• Late toxicities [Time frame: 3 years]
• Quality of life assessment (Gen) [Time frame: 2 years]
• Quality of life assessment (Liver specific) [Time frame: 2 years]

Eligibility criteria

Inclusion criteria

• Histologically proven (biopsy/cytology) adenocarcinoma of gall bladder. Gall bladder neck primaries with hilar block mimicking hilar cholangiocarcinoma will also be included.
• Non metastatic at presentation as determined using cross sectional imaging and diagnostic laparoscopy if done as a part of standard work up recommended in the joint clinic.
• Locally advanced disease with one or more of the following
• Extensive liver infiltration not amenable for surgery but feasible for safe radiation delivery (Liver minus gross tumor volume at least 700cc)
• Vascular involvement: encasement (>180-degree angle) of one of the vessels: Hepatic artery, main portal vein, right or left portal vein
• Obstructive jaundice with hilar involvement (type 2 non communicating block and higher blocks as per Bismuth-Corlette classification)
• Stable disease or partial response (RECIST 1.1) after initial 3 months of Gemcitabine based chemotherapy
• More than 18 years of age
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 fit for chemotherapy
• Normal hematological and renal and hepatic functions allowing safe delivery of chemotherapy
• Hematological- Hb> 80 g/L, ANC ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L.
• Liver functions- bilirubin ≤ 2 x upper limit normal (ULN), AST/ALT ≤ 5 x ULN, alkaline phosphatase ≤ 6 x upper limit normal (ULN) S. albumin ≥ 30 g/L
• Renal function- Creatinine ≤ 1.5 ULN, Creatinine clearance >= 50 mL/min

Exclusion criteria

• Patients with distant metastasis (including nonregional lymph nodes metastasis) will be excluded.
• Prior abdominal therapeutic radiation
• Past or current history of other malignancies not curatively treated and without evidence of disease for more than 5 years, except for curatively treated basal cell carcinoma of the skin and in situ carcinoma of the cervix
• Pregnancy/Lactating women

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

India · 1 center

• Tata Memorial Centre — Mumbai

Publications

• Verma V, Surkar SM, Brooks ED, Simone CB 2nd, Lin C. Chemoradiotherapy Versus Chemotherapy Alone for Unresected Nonmetastatic Gallbladder Cancer: National Practice Patterns and Outcomes. J Natl Compr Canc Netw. 2018 Jan;16(1):59-65. doi: 10.6004/jnccn.2017.7067. PMID 29295882
• Sinha S, Engineer R, Ostwal V, Ramaswamy A, Chopra S, Shetty N. Radiotherapy for locally advanced unresectable gallbladder cancer - A way forward: Comparative study of chemotherapy versus chemoradiotherapy. J Cancer Res Ther. 2022 Jan-Mar;18(1):147-151. doi: 10.4103/jcrt.JCRT_1568_20. PMID 35381776

Identifiers

NCT: NCT06214572 · 4145

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗