Neoplasms

All Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Symptoms and General Pathology

Digestive System Diseases

Behaviors and Mental Disorders

Rare Diseases

Carcinoma

Urinary Bladder Neoplasms

Jaundice

Jaundice, Obstructive

Gallbladder Neoplasms

Biliary Tract Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Biliary Tract Diseases

Gastrointestinal Diseases

Gallbladder Diseases

Hyperbilirubinemia

Skin Manifestations

Quality of Life

Gallbladder Cancer

percutaneous 10 F stent, endoscopic 10 F stent insertion

Endoscopic biliary stenting, Percutaneous biliary stenting

Peush Sahni, MS, PhD

Sundeep Saluja, MS, MCh

Cancer of the gallbladder (CaGB) is one of the most common causes of malignant obstructive jaundice. Jaundice is the second most common presentation and occurs in 30-60% of patients with CaGB. It is obstructive in nature and frequently associated with pruritus, which is very disturbing for the patients. The usual mechanism of obstruction is direct infiltration of the bile duct by the tumour. Most patients with CaGB with obstructive jaundice are not amenable to a curative surgical resection and hence effective palliation is the goal of treatment. Although surgical bypass has been the traditional palliative approach, it is associated with substantial morbidity and mortality. Non-operative alternatives in the form of percutaneous and endoscopic drainage are available. A few trials have shown that endoscopic drainage is better than percutaneous drainage in patients with lower end bile duct obstruction due to pancreatic and peri-ampullary cancer. However, the scenario is quite different in patients with upper end of bile duct obstruction as occurs due to CaGB. Endoscopic drainage is associated with a higher incidence of cholangitis in patients with a block at the upper end of the bile duct and the success rate varies from 40% to 80%, while percutaneous drainage may be associated with complications such as biliary leak and bleeding. There has been no randomized trial comparing endoscopic and percutaneous drainage in patients with malignant obstruction due to CaGB. The objective of the present study is to carry out a randomized prospective trial comparing percutaneous and endoscopic biliary drainage in patients with CaGB with obstructive jaundice and to assess their quality of life.

Hypothesis: Percutaneous biliary stenting is superior to endoscopic stenting in providing successful biliary drainage by 20% in patients with unresectable malignant hilar block due to carcinoma of gall bladder.

Background: Malignant biliary obstruction at the liver hilum is caused by a heterogeneous group of tumours that include cholangiocarcinoma, gallbladder cancer (CaGB) and metastatic cancer. CaGB is the commonest cause of malignant hilar obstruction in India (1). Jaundice is the second most common presentation and occurs in 30-60% of patients with CaGB (2-5). It is obstructive in nature and frequently associated with pruritis, which is very disturbing for the patients. Most patients with CaGB with surgical obstructive jaundice are not amenable to a curative surgical resection (5) and hence effective palliation is the goal of treatment. Although surgical bilioenteric bypass has been the traditional palliative approach (6), it is associated with substantial morbidity and mortality. Non-operative alternatives in the form of percutaneous and endoscopic drainage are available (7-8). Unilateral drainage of single liver lobe may be sufficient to palliate the jaundice and, pruritis and improve the quality of life (9-15). A few trials have shown that endoscopic drainage is better than percutaneous drainage in patients with lower end bile duct obstruction due to pancreatic and periampullary cancer. However, the scenario is quite different in patients with hilar malignant obstruction. Endoscopic drainage is associated with a higher incidence of cholangitis in patients with a block at the confluence (Bismuth types 2 and 3) and the success rate varies from 40% to 80%, while percutaneous drainage may be associated with complications such as biliary leak and bleeding. There has been no randomized trial comparing endoscopic and percutaneous drainage in patients with malignant hilar obstruction alone.

Objective: To compare unilateral PTBD and endoscopic stenting in patients with CaGB with hilar block in terms of Successful drainage and Quality of life Patients and Methods Consecutive patients with CaGB and jaundice will be enrolled in the study. The diagnosis of CaGB and biliary obstruction will be established on the basis of an ultrasound of the abdomen and a dual phase CT scan. Histological and/or cytological confirmation of the malignancy will be established wherever possible by doing a FNAC/trucut biopsy. Hilar block will be classified according to the Bismuth Corlette classification based on the preprocedural investigations (16). Final differentiation between type 2 and 3 blocks will be based on findings noted during intervention.

Inclusion criteria CaGB with hilar block not suitable for curative resection with one or more of the following criteria: (i) Jaundice with serum bilirubin \>10 mg/dl, (ii) Pruritus, (iii) Cholangitis Exclusion criteria: Poor performance status: Karnofsky index \< 60, Type 1 and 4 hilar block, Uncontrolled ascites, Duodenal obstruction, Patients who opted for insertion of a metallic stent.

Sample size calculation: The number of patients to be included was calculated to be 91 patients in each group based on the assumption that percutaneous drainage will be better than endoscopic drainage by 20 %. The sample size was calculated by the formula for a power of 80% and alpha error of 0.05.

The patients will be randomly divided into two groups using random blocks generated by a computer.

Group A - percutaneous biliary drainage (PTBD) Group B - Endoscopic stenting (ES) Pre-procedural preparation(17) Patients will undergo detailed investigations and an informed consent will be obtained.

The procedure will be performed under conscious sedation (midazolam and pentozocine) with a liberal infiltration of local anesthetic at the site and the capsule of the liver for PTBD.

1. PTBD procedure (17) Either a right or left sided approach will be used for PTBD. Once entry will be gained to a suitable duct the standard Seldinger technique will be used to place a guidewire in the biliary system. The tract will be dilated and after crossing the obstruction with a hydrophilic guidewire, a ring biliary catheter will be placed to provide internal-external drainage. In a subsequent session, a 10 F, straight plastic stent (polyurethane) will be placed into the system across the obstruction to provide internal drainage.
2. Endoscopic stenting (18) A therapeutic duodenoscope and a standard sphincterotome will be used for cannulation of the bile duct. A hydrophilic guidewire will be used to cross the malignant stricture. After the stricture is crossed a guide catheter will be passed over the guidewire and then a 10 F straight plastic stent will be inserted across the stricture over the guidewire.

Primary outcome measures:

1. Successful drainage: A decrease in bilirubin to less than 75% of the pretreatment value within 7 days
2. Early cholangitis: Occurring within 48 hours to 7 days of the procedure as evidenced by fever, leukocytosis and worsening LFTs.
3. Quality of life

Secondary outcome measures:

1. Complications
2. Procedure-related and 30-day mortality
3. Stent patency time will be defined by time to stent occlusion.

Hematological and biochemical parameters will be assessed at days 2 and 7, 1 month after stent placement and every 3 months thereafter. Patients will be re-evaluated 7 days, 1 month after stent placement and 3 months thereafter.

Quality of life will be assessed using the WHO-QOL BREF26 and EORTC QLQ-30 questionnaires pre-procedure, at 1 month and at 3 months.

World Health Organization-QOL BREF-26 (19) This has 26 items, which cover physical, psychological, social and environmental domains. The daily activity is graded in accordance with the 5 grade scale of performance status recommended by the WHO. WHO-QOL domain scores will be calculated using the guidelines given in the WHO-QOL scoring manual. A high score represents a high level of QOL.

EORTC QLQ-30 (20) The EORTC QLQ-30 consists of 30 generally applicable items. It incorporates a functional scale (items 1-5), a role functioning scale (item 6,7), a general symptom scale (item 8-19), scales on cognitive (item 20-25), emotional (items 21-24) and social (items 26-27) functioning, financial strain scale (item 28) and global health status scale (item 29,30). Scoring will be done using the EORTC scoring manual.

A high score for a functional scale will represent a high/healthy level of functioning, a high score for global health status/QOL will represent high QOL but a high score for symptom scale/item will represent a higher level of symptomatology/ problem.

All patients will be instructed to contact the department, if any symptom suggestive of a complication appeared. Additional information regarding current status or death will be obtained by direct contact with the referring physician or the patient by telephone/letter.

Statistical analysis Data will be analyzed according to both the intention-to-treat (ITT) and per protocol (PP) methods. The baseline characteristics will be expressed in mean (SD). The Pearson chi -square test and Fischer exact test will be used for comparison of categorical data as appropriate. The t-test will be used for comparison of continuous variables. Cumulative survival will be estimated using Kaplan-Meier life table analysis, and the groups will be compared by log rank chi-square test.

The QOL score analysis will be done using Paired 't' test for comparison between baseline and 1 month and baseline and 3 months within the groups. MANOVA will be used to assess the trend of the scores.

References

1. Malkan G, Mohandas KM. Epidemiology of digestive cancers in India. I. General principles and esophageal cancer. Indian J Gastroenterol 1997;16(3):98-102
2. Wanebo HJ, Castle WN, Fechner RE. Is carcinoma of the gall bladder a curable lesion? Ann Surg 1982;195:624-31.
3. Kelly TR, Chamberlain TR. Carcinoma of the gall bladder. Am J Surg 1982; 143:737-41
4. Morrow CF, Sutherland DE, Florack G, Eisenberg MM, Grage TB. Primary carcinoma gall bladder: Significance of subserosal lesions and results of aggressive surgical treatment and adjuvant chemotherapy. Surgery 1983;94:709-14
5. Kumaran V, Gulati MS, Paul SB, Pande GK, Sahni P, Chattopadhyay TK. The role of dual phase helical CT in assessing respectability of carinoma of the gall bladder. Eur Radiol 2002;12:1993-99.
6. Bismuth H, Castaing D, Traynor O. Resection or palliation; priority of surgery in the treatment of hilar cancer. World J Surg 1988; 12:39-47.
7. Huibregtse K, Tytgat GNJ. Palliative treatment of jaundice by transpapillary introduction of biliary endoprosthesis. Gut 1982; 23:371-5.
8. Cotton PB. Endoscopic methods for relief of malignant obstructive jaundice. World J Surg 1984;8:854-61.
9. Dowsett JF, Vaira D, Hatfield AR, Cairns SR, Polydorou AA, Frost R, et al. Endoscopic biliary therapy using the combined percutaneous and endosopic route. Gastroenterology 1989;96:1180-6.
10. Polydorou AA, Cairns SR, Dowsett JF, Hatfield AR, Salmon PR, Cotton PB, et al. Palliation of proximal malignant biliary obstruction by endoscopic endoprosthesis insertion. Gut 1991;32:685-9.
11. De Palma GD, Galloro G, Sicilliano S, Ivonini P, Catanzano C. Unilateral versus bilateral endoscopic hepatic duct drainage in patients with malignant hilar biliary obstruction: results of a prospective, randomized and controlled study. Gastrointest Endosc 2001;53:547-53
12. Sherman S. Endoscopic drainage of malignant hilar obstruction: is one biliary stent enough or should we place two? Gastrointest Endosc 2001;53:681-4.
13. Chang WH, Kortan P, Haber GB. Outcome in patients with bifurcation tumors who undergo unilateral versus bilateral hepatic duct drainage. Gastrointest Endosc 1998;47:354-62
14. Mehta S, Ozden ZS, Dhanireddy S, Pleskow DP, Chutanni R. Endoscopic single versus double (bilateral) Wallstents for palliation of malignant Bismuth type III/IV hilar strictures: comparison of clinical outcomes and costs (abstract). Gastrointest Endosc 1999;49:AB234.
15. De Palma, Angelo Pezzullo, Maria Rega, Unilateral placement of metallic stents for malignant hilar obstruction: a prospective study. Gastrointest Endosc 2003;55:50-5.
16. Bismuth H, Castaing D, Traynor O. Resection or palliation :priority of surgery in the treatment of hilar cancer. World j Surg 1988;12:39-47.
17. Gulati MS, Srinivasan A, Agarwal PP. Percutaneous Management of Malignant Biliary Obstruction: The Indian Perspective. Tropical Gastroenterology 2003;24:47-58.
18. Ahuja V, Garg PK, Kumar D, Goindi G, Tandon RK. Presence of white bile associated with lower survival in malignant biliary obstruction. Gastrointest Endosc 2002;55:186-91.
19. World Health Organization Handbook for Reporting Results of cancer Treatment. World Health Organization Publication No .48 Geneva World Health Organization 1979.
20. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993;85:365-76.

Endoscopic Versus Percutaneous Drainage For Hilar Block in Gall Bladder Cancer

Endoscopic Versus Percutaneous Biliary Drainage For Hilar Block Due to Carcinoma Gall Bladder: A Randomized Prospective Trial and Quality Of Life Assessment

All India Institute of Medical Sciences, New Delhi

VP Gupta

Inflammation

Gallstones

Cholelithiasis

Cholecystolithiasis

Women from the cohort with gallbladder cancer

Women from Chile screened for gallbladder cancer with and without gallstones

Jill E. Koshiol, M.D.

Background:

- Chile has the highest diagnosis and death rates of gallbladder cancer in the world. Gallbladder cancer is also the leading cause of cancer death in Chilean women. High rates of gallstones and obesity, as well as genetic concerns, may explain these high rates. Researchers want to study gallbladder cancer in more depth in Chile. A small study must be done to see if a full-scale study is feasible.

Objectives:

- To test the methods and procedures of a small-scale study of gallbladder cancer in Chile.

Eligibility:

* Individuals at least 18 years of age who have gallbladder cancer or gallstones, or are healthy control volunteers.
* Participants will be recruited from four clinical centers in Chile.

Design:

* Participants will be screened with a physical exam and medical history. Because gallbladder cancer has a high fatality rate, family members may be asked to provide additional medical history information if study participants die or become too ill to provide this information.
* Participants will provide blood, urine, stool, hair, fingernail, and saliva samples.
* Gallstones, bile, and tissue samples will be collected from those who have gallbladder removal surgery. Normal and tumor tissue samples will be collected as needed.
* Treatment will not be provided as part of this protocol. This is a data collection study only.

Gallbladder cancer is a leading cause of cancer death among women in Chile, which has among the highest reported gallbladder cancer incidence and mortality rates in the world. Gallbladder cancer provides a particularly good model for understanding the role of inflammation in carcinogenesis since the major risk factor, gallstones, causes substantial inflammation in the gallbladder. Chile also has a high prevalence of obesity, diabetes, and metabolic syndrome, which are increasingly understood as inflammatory disorders, but the extent to which their carcinogenic effects are mediated through inflammatory pathways is unknown.

While the vast majority of gallbladder cancer cases have gallstones, only a small fraction of

gallstone patients ever develop gallbladder cancer. Since there is no way to identify this small

proportion at risk, gallstone cases are cholecystectomized, which, given large absolute numbers of individuals with gallstones, results in overtreatment of some and under-treatment of others in a high-risk area like Chile. While cholecystectomy is standard treatment for symptomatic relief, there are more people who need surgery than there are surgeons to perform them, and individuals aged 34-49 are prioritized for treatment, regardless of symptoms. This practice may lead to overtreatment among 34-49-year-olds and under treatment of individuals aged 50 and above since they have to wait longer for surgery. At the same time, about 30% of patients with a biliary colic attack will never have another attack, and cholecystectomy does not always lead to the cessation of symptoms. In addition, cholecystectomy has been associated with an increased risk of other digestive diseases. Thus, cholecystectomy may not be needed in all gallstone patients and may in fact increase the risk of cancer in some. Better predictors of risk are clearly needed.

As with other cancers, dysplasia is an important epidemiologic endpoint as the immediate precursor to cancer since the vast majority of gallbladder cancers develop through a histologic continuum of chronic cholecystitis, pseudopyloric metaplasia, incomplete intestinal metaplasia, dysplasia, and cancer. Thus, our aim is to identify risk factors for gallbladder dysplasia and cancer (GDC) and potential non-invasive risk stratification methods, such as ultrasound characteristics alone or in combination with inflammatory markers and patient characteristics, to better understand the etiology and natural history of GDC and to help inform strategies for GDC prevention.

Together with collaborators at Pontifica Universidad Catolica (PUC), we successfully completed a pilot study in Chile that was previously reviewed and approved by SAG and provided baseline data for the proposed study. Our pilot demonstrated high recruitment rates in the target enrollment area (80%) and high rates of questionnaire completion (100%), blood collection (78% population-based controls), and participant retention (93% of eligible completed a follow-up visit). Information from the pilot was used to optimize procedures for the longitudinal study. We also found that both gallstones and gallbladder cancer were associated with systemic immune alterations, which as we previously demonstrated, reflect inflammatory changes in the gallbladder detectable in bile. The next step is to demonstrate that these markers precedeGDC by longitudinally measuring their levels among gallstone patients.

We propose to prospectively assess risk factors and early detection markers for GDC by conducting the Chile Biliary Longitudinal Study (BiLS), a cohort study of 6250 individuals with gallstones from the high- risk southern-central region of Chile. Because women are twice as likely to have gallstones and twice as likely to have gallbladder cancer as men, we plan to maximize our screening efficiency and number of outcomes by screening and enrolling women only. Since Chile is conducting a general population cohort in a small town in the high-risk area, will we benefit from the infrastructure that is already in place and be able to compare the women in our study to a set of men with gallstones enrolled by the Chilean study. We plan to enroll women with gallstones over 2 years and follow them for 6 years, conducting visits every other year to collect data on the primary exposures of interest, inflammatory markers and ultrasound characteristics, as well as additional exposures of interest, such as infections, genetics, and environmental exposures (e.g., aflatoxin, pesticides). The cohort will be complemented by an incident case-control study of 300 women with gallbladder cancer and 600 controls with and without gallstones obtained from the cohort participants.

Initial Study of Gallbladder Cancer in Chile

A Pilot Study of Gallbladder Cancer in Chile

Pontificia Universidad Catolica de Chile

National Cancer Institute (NCI)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Endoscopic Versus Percutaneous Drainage For Hilar Block in Gall Bladder Cancer	NCT00409864	Gallbladder Can... Obstructive Jau...	Endoscopic bili...	18 Years - 80 Years	All India Institute of Medical Sciences, New Delhi
Initial Study of Gallbladder Cancer in Chile	NCT01520259	Gallbaldder Can...		18 Years - 100 Years	National Institutes of Health Clinical Center (CC)
Endoscopic Versus Percutaneous Drainage For Hilar Block in Gall Bladder Cancer	NCT00409864	Gallbladder Can... Obstructive Jau...	Endoscopic bili...	18 Years - 80 Years	All India Institute of Medical Sciences, New Delhi
Initial Study of Gallbladder Cancer in Chile	NCT01520259	Gallbaldder Can...		18 Years - 100 Years	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for gallbaldder cancer