Neoplasms

All Conditions

Digestive System Diseases

Behaviors and Mental Disorders

Rare Diseases

Carcinoma

Gallbladder Neoplasms

Biliary Tract Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Biliary Tract Diseases

Gastrointestinal Diseases

Gallbladder Diseases

Quality of Life

Gallbladder Cancer

patients with biliary obstruction will undergo endoscopic stenting.

Biliary stenting

Pramod Garg, M.D, D.M.

Vikram Bhatia, M.D, D.M.

The purpose of the study is to determine whether palliative biliary stenting improves the quality of life, of gallblader cancer patients, who present with hilar block and obstructive jaundice.

For most patients with gallbladder cancer, cure is not possible and treatment should be therefore aimed at palliation of symptoms and maintaining quality of life (QOL) in the few months between diagnosis and death. Most of these patients suffer from intractable pruritis, pain, anorexia and general debility. Biliary stenting leads to a reduction in pruritis and jaundice, and is commonly offered to many unresectable patients. However stenting related complications like cholangitis, rescue percutaneous treatment and need for prolonged hospitalization often impair the remaining short survival of these patients. In these patients improving the QOL should be the primary focus, and survival a secondary end point in disease management. No study has addressed the issue of QOL of patients with gallbladder cancer, post stenting.

Three clinical studies have evaluated the change in the QOL of patients with malignant biliary obstruction after of endoscopic stenting. Ballinger et al evaluated 19 patients with unresectable pancreatic carcinoma before stenting and upto 12 weeks or death after stenting. The Rotterdam Symptom Checklist and the Hospital Anxiety and Depression Scale were used. Significant improvements were seen in the parameters of mood, indigestion, appetite and level of activity. Luman et al studied 47 inoperable patients with malignant biliary strictures. The European Organisation for Research and Treatment of Cancer QOL questionnaire (EORTC QLQ-C30) was used at baseline and 1 month after stenting. For patients successfully completing the follow up, significant improvement in emotional, cognitive , and global health scores was found after stenting. In addition to the expected improvement in pruritis and jaundice , anorexia, diarrhea and sleep pattern were also improved. Abraham et al studied 50 patients with malignant biliary obstruction without liver metastasis considered non surgical candidates, and undergoing palliative biliary stenting. The SF-36 Health Survey Questionnaire was used to quantify QOL at baseline and 1 month after stent insertion. Follow up data was available for only 26 patients. Among these patients a significant reduction in the bilirubin level was associated with improvement in the social function and mental health. A high baseline bilirubin (\> 14mg/dL) was associated with a lack of improvement at 1 month follow up.

Hence existing data regarding improvement in the QOL of patients undergoing palliative biliary stenting is sparce and incomplete. Gallbladder cancer presenting a hilar block is the most common biliary malignancy in India. Hilar tumors are associated with more technical failure of stenting, higher cholangitis rates, earlier stent blockage, and shorter survival as compared to distal biliary tumors. Only 6 patients with Klatskin tumors were included in one of the study.8 Patients with hilar block were either not included6, or were not specified7 in the other studies.

Health related quality of life (QOL) refers to the impact of a medical condition or its treatment on a person's expected physical, psychological and social well being.

Calman states that QOL evaluations measure the difference between the "hopes and expectations" of an individual and that individual's present experience.

The multidimensionality that is commonly assessed in QOL measures includes

1. Physical symptoms of the disease or its treatment or concurrent illness.
2. Functional capacity (ability and energy) for daily routine, social interactions, intellectual activity, emotional reactions and adjustments, economic independence.
3. Self-perception of wellness or its absence. There are two basic types of instruments for measuring the QOL: generic and disease specific. Generic instruments focus on the main components that constitute QOL, and are intended to be applied in a wide range of populations and health states across all diseases. There are many excellent validated self-completion questionnaires for cancer patients eg. EORTC QOL questionnaire, Functional assessment of Cancer Therapy (FACT), Rotterdam Symptom Checklist (RSCL), Functional Living Index Cancer (FLIC). All these questionnaires are multidimensional, and it is rarely required to develop a new instrument.

The EORTC QLQ-C30 has been developed in a multi-cultural setting, and translations are available in 43 languages. The instrument has been shown to be valid, reliable, and responsive to change. Disease specific modules are available to supplement the core questionnaire. Reference data is available for calculating sample size. The questionnaire is easily understood by most patients and is quick to complete (mean time 11 minutes).

The EORTC QLQ-C30 is a 30- item questionnaire composed of multi-item scales and single items that reflects the multidimensionality of the quality of life construct. It incorporates five functional scales (physical, role, cognitive, emotional, and social), three symptom scales (fatigue, pain, nausea and vomiting), and a global health and quality of life scale. The remaining single items assess additional symptoms commonly reported by cancer patients (dyspnea, appetite loss, sleep disturbance, constipation and diarrhea), as well as the perceived financial impact of the disease and its treatment. The functional scales have 16 questions, symptom scales have 6 questions, global quality of life has two questions, and there are six single item questions. For ease of interpretation, all scale and item scores are linearly transformed to a 0 to 100 scale. For the 5 functional scales and the global quality of life scale, a higher score represents a better level of functioning. For the symptom oriented scales and items, a higher score corresponds to a higher level of symptoms.

Hence we plan to prospectively study unresectable gallbladder cancer patients with hilar block to evaluate whether palliative stenting improves their quality of life, and whether the benefit afforded outweighs the early and late complications of stenting.

Palliative Biliary Stenting on the Quality of Life of Patients With Unresectable Carcinoma Gallbladder With Hiliar Block.

Effect of Palliative Biliary Stenting Versus Conservative Treatment on the Quality of Life (QOL) of Patients With Unresectable Carcinoma of the Gallbladder With Hiliar Block: A Randomised Controlled Trial

All India Institute of Medical Sciences, New Delhi

Additional Professor

Gland and Hormone Related Diseases

Pancreatic Neoplasms

Cholangiocarcinoma

Adenocarcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Endocrine Gland Neoplasms

Pancreatic Diseases

Endocrine System Diseases

Pancreatic Cancer

Bile Duct Cancer

Endoluminal radiofrequency ablation followed by biliary stenting

Radiofrequency ablation

Tomas Hucl, MD, PhD

Petra Truxova, Ing

Pancreatic cancer and cholangiocarcinoma are the most common causes of malignant biliary obstruction. They are diseases of increasing incidence and unfavorable prognosis. Only a minority of patients have a localized disease and are indicated for surgery with a chance of long-term survival. Locally advanced and metastatic tumors are treated with palliative chemotherapy or chemoradiotherapy; the results of such treatments are unsatisfactory. The average survival of patients with unresectable disease is 6 months and only 5 - 10 % of patients survive 5 years. Chemotherapy and radiotherapy can be used, however only with a palliative effect. Biliary drainage is an integral part of palliative treatment. Endoscopically or percutaneously placed stents improve quality of life, decrease cholestasis and pruritus, but do not significantly improve survival. Biliary stents get occluded over time, possibly resulting in acute cholangitis and require repeated replacement. Endoluminal biliary photodynamic therapy (PDT) and radiofrequency ablation (RFA), locally active endoscopic methods, have been increasingly used in recent years in palliative treatment of patients with malignant biliary obstruction. In photodynamic therapy, improved survival has been shown in two randomized controlled trials; however the technique suffers from technical complexity, high cost and low availability. In RFA, application of low voltage high frequency current during radiofrequency ablation results in tissue destruction by heat. Its antitumor effect may also be related to systemic changes in antitumor immunity. The use of endoluminal biliary RFA has so far been reported only in small retrospective cohorts of patients.

The aim of this randomized study is to compare efficacy of RFA plus stenting to stenting alone in palliative treatment of malignant biliary obstruction with survival as primary outcome. Secondary outcomes are stent patency, immediate and late complications, quality of life and effects on anti-tumor immunity in the RFA group.

Cholangiocarcinoma and pancreatic cancer are by far the two most common causes of malignant bile duct obstruction. Cholangiocarcinoma is an adenocarcinoma originating in the bile duct whereas pancreatic cancer is an adenocarcinoma derived from pancreatic ductal cells. The incidence rates of both diseases have been rising over the past decades. Both diseases still have a very unfavorable prognosis with 5 year survival rates as low as 5-10%. Surgery represents the only therapeutic modality with a curative potential, however most patients are non-eligible for surgical treatment at the time of diagnosis. Patients present with either distant metastases, have a locally advanced disease or are unfit for surgery because of advanced age and/or co-morbidities. The prognosis of patients with unresectable bile duct or pancreatic cancer is poor with a median survival time of about 6 months. Chemotherapy and radiotherapy provide only a slight survival benefit and thus have only palliative intent.

Most patients with cholangiocarcinoma and pancreatic cancer present with bile duct obstruction in the course of their disease. Bile duct obstruction relief is an important part of palliation therapy. Endoscopic retrograde cholangiography with bile duct stenting is the method of choice with a high rate of technical success and a lower complication rate compared to surgery. Biliary stents are either plastic or metal (self-expandable metal stents, SEMS). SEMS can be covered, uncovered or partially covered. Plastic stents are cheaper and easier to exchange but have a shorter patency compared to metal stents. Metal stents have been shown to improve survival of patients with proximal malignant biliary obstruction. Both plastic and metal become occluded in a significant proportion of patients, especially in those with a longer life expectancy. Stent occlusion is often an acute event leading to sepsis and a prompt intervention is required. Failure of achieving adequate drainage may result in severe cholangitis and death.

Photodynamic therapy has been used for bile duct tumor ablation for more than a decade. It is a two stage process in which a photosensitizing agent is taken by the tumor tissue and is than activated by light of a specific wave length. Two randomized trials showed improved survival of patients treated with PDT plus stenting compared to stenting alone. However, side effects of photodynamic therapy such as phototoxicity, high costs and limited availability restrict the use of PDT.

Radiofrequency ablation (RFA), by means of alternating high-frequency current, generates heat that results in coagulation necrosis of tissue. It is widely used to treat liver tumors or dysplastic Barrett's esophagus. Endoluminal biliary RFA has become possible upon availability of narrow ERCP RFA catheters and represents a new modality of intraductal tumor ablation. The probe can be introduced over a 0.035-inch wire through a standard endoscope, thus allowing endoscopic ablation of malignant bile duct obstruction. The bipolar catheter has multiple circumferential electrodes at the distal tip. The coagulative effect is delivered in the area between the two electrodes.

A few human non-randomized case series investigating the safety and efficiency of RFA were reported. Steel at al reported their results in 22 patients with malignant bile duct obstruction (16 patients with pancreatic cancer and 6 patients with cholangiocarcinoma). Immediate, 30 day complication rates and 90 day stent patency were evaluated as primary parameters. Intraductal RFA was followed by a SEMS placement. One patient developed asymptomatic elevation of amylase, one patients developed rigors and two patients developed cholecystitis requiring cholecystectomy. All except 3 patients achieved 90 day stent patency.

In a recent study of Sharaiha et al, 26 patients with pancreatic or bile duct cancer underwent RFA followed by plastic or metal stent placement. They were compared to 40 matched controls who underwent only stenting. Technical success rate was 100%. Multivariable Cox proportional regression analysis showed RFA to be an independent predictor of survival \[HR 0.29 (0.11-0.76), p = 0.012\] together with age and receipt of chemotherapy \[HR 1.04 (1.01-1.07), p = 0.011; HR 0.26 (0.10-0.70), p = 0.007\]. Surprisingly, SEMS patency rates were the same across all groups.

In an Austrian national retrospective study, 84 ablations were performed in 58 patients in 11 centers. Cholangiocarcinoma was present in 45 patients. Technical feasibility was 100%, however multiple complications occurred (1 liver infarct, 5 cholangitis, 3 hemobilia, 2 sepsis, 1 gall-bladder empyema, 1 liver coma).

RFA was also investigated in pancreatic cancers only. In a retrospective comparison of 23 patients and 46 controls, the median survival was better in the RFA group (226 vs. 123 days, p=0,01). The median stent patency was not different.

The safety profile of RFA seems to be acceptable, however severe complications have occured. In the study of Tal et al, 3 cases of bleeding were reported, two of them resulted in death. In all of these patients, plastic stents were used.

Increasing evidence indicates that RFA might stimulate anti-tumor immunity. Active anti-cancer immune responses depend on efficient presentation of tumor antigens and cytokine-mediated stimulatory signaling. Tumor cells are generally regarded as poor stimulators of T-cells. In contrast, antigen-presenting cells (APCs) are highly specialized in this function and are therefore important in the process of stimulation of T-cell responses to tumors. RFA has been shown to stimulate anti-tumor immunity through the induction of heat shock proteins, especially HSP 70. HSPs have the capacity to affect the immunogenicity of tumor cells, to chaperone antigenic peptides and deliver them into APCs, thus activate and regulate innate and adaptive immunity.

Based on the available evidence, RFA seems to be a technically feasible technique of malignant bile duct stricture ablation with a favorable safety profile. Retrospective case series have reported improved stent patency and survival in cholangiocarcinoma and pancreatic cancer patients following RFA. Thus, endoluminal RFA may represent a novel treatment modality in patients with malignant biliary obstruction. For this to happen, however, prospectively obtained comparative data with established treatment, i.e. biliary stenting, regarding safety and efficiency are necessary.

The investigators aim to compare endoscopic radiofrequency ablation plus stenting vs. stenting alone for malignant bile duct obstruction not eligible for surgical resection in a randomized controlled trial.

RFA for Malignant Biliary Obstruction

Radiofrequency Ablation Plus Stenting Versus Stenting Alone for Treatment of Malignant Biliary Obstruction

number of days/months of survival (being alive) post intervention

number of days/months of patent stent (not occluded) post intervention

number of complications related to procedure (bleeding, perforation, cholangitis will be combined to report as a complication)

validated questionnaire investigating quality of live post intervention

serum level of HSP 70 and selected cytokines will be measured from blood

Institute for Clinical and Experimental Medicine

Vice-chairman, Department of Gastroenterology and Hepatology

Symptoms and General Pathology

Recurrence

Bile Duct Neoplasms

Bile Duct Diseases

Antineoplastic Agents

Dermatologic Agents

All Drugs and Chemicals

Central Nervous System Depressants

Dihematoporphyrin Ether

Trioxsalen

Ether

Photosensitizing Agents

Photodynamic Therapy plus biliary stenting

porfimer sodium

biliary stenting

Stephen P. Pereira, MD

RATIONALE: Biliary stenting is the placement of a tube in the bile ducts to keep a blocked area open. Photodynamic therapy uses a drug, such as porfimer sodium, that is absorbed by tumor cells. The drug becomes active when it is exposed to light. When the drug is active, tumor cells are killed. It is not yet known whether biliary stenting is more effective with or without photodynamic therapy in treating patients with biliary tract tumors.

PURPOSE: This randomized phase III trial is studying biliary stenting to see how well it works compared with biliary stenting and photodynamic therapy using porfimer sodium in treating patients with locally advanced, recurrent, or metastatic cholangiocarcinoma or other biliary tract tumors that cannot be removed by surgery.

OBJECTIVES:

Primary

* To assess the efficacy, in terms of overall survival, of biliary stenting with vs without photodynamic therapy using porfimer sodium in advanced, recurrent, or metastatic biliary tract carcinoma.

Secondary

* To evaluate the two treatments arms with respect to progression-free survival, toxicity using NCI Common Toxicity Criteria (version 3.0), and quality of life.

OUTLINE: This is a multicenter study. Patients are stratified by participating center, primary site (gallbladder vs bile duct), disease stage (locally advanced vs metastatic), prior therapy (i.e., surgery, radiotherapy or chemotherapy) (yes vs no), performance score (0 vs 1 vs 2 vs 3), and prior treatment arm on UK chemotherapy trial ABC-02 (gemcitabine hydrochloride alone vs gemcitabine hydrochloride and cisplatin). Patients are randomized to 1 of 2 arms.

* Arm I: Patients undergo either endoscopic or percutaneous drainage and insertion of unilateral or bilateral plastic endoprostheses above the main strictures of the right and left hepatic bile ducts.
* Arm II: Patients undergo treatment as in arm I. Patients also receive porfimer sodium IV and then undergo laser activation 48 hours later.

After completion of study treatment, patients are followed every 3 months for at least 3 years.

Peer Reviewed and Funded or Endorsed by Cancer Research UK.

Biliary Stenting With or Without Photodynamic Therapy in Treating Patients With Locally Advanced, Recurrent, or Metastatic Cholangiocarcinoma or Other Biliary Tract Tumors That Cannot Be Removed by Surgery

Porfimer Sodium Photodynamic Therapy Plus Stenting Versus Stenting Alone in Patients With Advanced or Metastatic Cholangiocarcinomas and Other Biliary Tract Tumours: a Multicentre, Randomised, Phase Lll Study

University College, London

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Palliative Biliary Stenting on the Quality of Life of Patients With Unresectable Carcinoma Gallbladder With Hiliar Block.	NCT00391183	Gallbladder Can...	Biliary stentin...	18 Years - 90 Years	All India Institute of Medical Sciences, New Delhi
RFA for Malignant Biliary Obstruction	NCT03166436	Cholangiocarcin... Pancreas Cancer	Radiofrequency ... Biliary stentin...	18 Years -	Institute for Clinical and Experimental Medicine
Biliary Stenting With or Without Photodynamic Therapy in Treating Patients With Locally Advanced, Recurrent, or Metastatic Cholangiocarcinoma or Other Biliary Tract Tumors That Cannot Be Removed by Surgery	NCT00513539	Extrahepatic Bi... Gallbladder Can...	porfimer sodium biliary stentin...	18 Years -	University College, London
RFA for Malignant Biliary Obstruction	NCT03166436	Cholangiocarcin... Pancreas Cancer	Radiofrequency ... Biliary stentin...	18 Years -	Institute for Clinical and Experimental Medicine

Spots Global Cancer Trial Database for biliary stenting