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ORIGINAL ARTICLE
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A clinicoepidemiological and management profile of metastatic carcinoma gallbladder in the northeast part of Indian patients in a tertiary care center


1 Department of Medical Oncology, Army Hospital (Research and Referral), Delhi, India
2 Department of Medical Oncology, Command Hospital, Kolkata, India
3 Department of Medical Oncology, Command Hospital, Bangalore, India
4 Department of Radiation Oncology, Command Hospital, Kolkata, India
5 Department of Surgical oncology Oncology, Command Hospital, Kolkata, India
6 Basavatarakam Indo American Cancer Hospital and Research Institute, Hyderabad, India
7 Command Hospital, Pune, Maharashtra, India

Date of Submission22-Aug-2020
Date of Decision30-Sep-2020
Date of Acceptance29-Dec-2020
Date of Web Publication20-Aug-2021

Correspondence Address:
Abhishek Pathak,
MNAMS, Army Hospital (R&R), Kolkata, West Bengal
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_1213_20

 > Abstract 


Introduction: Metastatic gallbladder cancer (GBC) is a highly fatal malignancy and it is difficult to treat the advanced stage of GBC. In India, northern and northeastern states are the worst affected by this disease. We, hereby, report the clinicoepidemiological and management profile of 242 patients of metastatic carcinoma of GB.
Materials and Methods: In this study, a total of 242 cases of metastatic GBC (detected either on the first presentation or during follow-up) were managed at the Department of Medical Oncology tertiary care oncology center in the northeast part of India from May 2018 to September 2019. On presentation, all patients were subjected to detailed history and clinical examination, followed by requisite investigations and were treated as per the existent guidelines.
Results: One-hundred and forty-two patients were female, while 100 patients were male out of 242 patients. Female patients with metastatic GBC presented with the mean age of 54, while for males, 51.4 years. The most common presentation was pain abdomen (81.8%), while the second most common was anorexia (77.2%), followed by weight loss (62.8%) and mass per abdomen (60.7%). The most common site of metastasis recorded in our study was the liver (79.7%), followed by nonregional abdominal lymph node (69.4%) and ascites (64.4%). Out of the 242 patients, 24 patients had presented in poor Eastern Cooperative Oncology Group Performance Status (≥3) hence were deemed unfit for any oncological interventions. About 136 (56.1%) patients had presented with features of obstructive jaundice, however only 108 patients were subjected to biliary drainage procedure. After the biliary drainage procedures, only one-third (38 out of 136; 35.1%) of patients were finally able to receive chemotherapy.
Conclusion: In India, unfortunately, many patients present very late during the course of their illness. There is a need for the development of effective chemotherapy or targeted therapy and also there is an unmet need for patients' education. There has been an increase in the incidence of this malignancy, especially in the Northeast part of India; hence, it is the need of the hour to study various epidemiological and causative factors of the disease. Furthermore, the development of therapies for the effective management of this malignancy is really required.

Keywords: Metastatic carcinoma gallbladder, obstructive jaundice, percutaneous transhepatic biliary drainage



How to cite this URL:
Rathore A, Pathak A, Ranjan S, Sud R, Shivshankara M S, Pandaya T, Arvind P, Singh V P, Nikhil P, Guleria B. A clinicoepidemiological and management profile of metastatic carcinoma gallbladder in the northeast part of Indian patients in a tertiary care center. J Can Res Ther [Epub ahead of print] [cited 2021 Dec 5]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=324161




 > Introduction Top


Gallbladder cancer (GBC) is the most common biliary tract malignancy and it has been globally known to be a disease with high fatality rate. As per Globocan 2018 worldwide, it is considered to 21st most common cancer. Annually, 219,420 new cases have been detected with cumulative risk of 0.25. It has been ranked as the 18th leading cause of death due to cancer.[1]

In India, GBC is more common in the northern and northeastern states of India as compared to southern states. In India, women are affected twice more common in men and it is also the most common GI malignancy in women in northern India. Women with age more than 65 are the worst affected.[2]

As per the National Cancer Registry Program report 2020, GB ranks 3rd most common cancer in Tripura state and Kamrup urban PBCR among females. The male versus female age-adjusted rate (per 100,000) of various northeastern PBCR are Kamrup urban – 7.9 versus 16.2, Dibrugarh district – 4.4 versus 8.1, Aizawl district – 3.2 versus 6.1, Kolkata – 3.1 versus 6.5, Tripura – 3.0 versus 5.7, East Khasi Hill – 2.9 versus 6.1, Imphal west – 2.8 versus 7.4, Mizoram – 2.5 versus 4.3, Sikkim – 2.2 versus 5.8, Meghalaya – 2.1 versus 4.5, Manipur – 1.8 versus 4.0, and Nagaland – 1.7 versus 1.7, which is among the highest in India and also the females are much more commonly affected as compared to males.[3]

This cancer is usually diagnosed late due to its propensity to infiltrate the liver, other adjacent organs, and also the presenting symptoms are nonspecific, and it can mimic clinically as cholelithiasis and cholecystitis due to which this disease is usually diagnosed at an advanced stage. Advanced GBC continues to have a dismal survival rate, i.e., a 5-year survival rate of <5% in stage IV.

It is more common among females and has been strongly associated with cholelithiasis with chronic inflammation. Apart from that chronic typhoid infection, primary sclerosing cholangitis, anomalous pancreaticobiliary duct junction, and porcelain GB are the other risk factors.[4],[5]

In this study, we have studied the clinicoepidemiological profile of metastatic cancer of the GB and also the response to various therapeutic options for the patients. The metastatic cancer of GB continues to frustrate the treating oncologists around the world.


 > Materials And Methods Top


This study was an observational retrospective and prospective cohort study which was conducted at the Department of Medical Oncology, a tertiary care oncology center in the North-Eastern part of India. The study period of this study was from May 2018 to September 2019. Two-hundred and forty-two patients were included based on all those reporting to the outpatient department (OPD) or were getting admitted with the diagnosis of metastatic GBC (detected either on the first presentation or during follow-up in medical oncology OPD). On presentation, patients were evaluated by proper history taking, clinical examination, investigations, and they were treated as per the existent guidelines. All patients were diagnosed on the basis of biopsy or fine-needle aspiration cytology and were staged as metastatic disease on the basis of computed tomography (CT) scan of the chest, abdomen, and pelvis. All the patients were discussed in the multidisciplinary tumor board and all those labeled as metastatic disease were included in the study irrespective of whether they have presented initially or after previous history of GBC. Baseline characteristics of all the patients were recorded. The presenting symptoms leading to diagnosis were recorded and also the clinical signs were recorded. The data were collected retrospectively from patients' records as well as from hospital records and entered treating oncologists and were recorded on MS Excel. MS Excel was used for calculating various data results in percentages. Institutional Ethical Committee clearance was taken for conducting this study. Written informed consent of the patients was not taken in view of the retrospective nature of the study. The study is not registered with any clinical trials registry.

Inclusion criterion:

  1. All patients of metastatic GBC irrespective of Eastern Cooperative Oncology Group Performance Status (ECOG PS)
  2. Age >30 to <80 years
  3. All outdoor/admitted patients.


Exclusion criterion:

  1. Nonmetastatic GBC


Aim and objectives – The aim of this study was to study the clinicoepidemiological and management profile of patients with metastatic GBC.


 > Results Top


We had 242 patients of metastatic GB carcinoma in our institute from 2016 to 2019. Out of which, 100 (41.3%) were male and 142 (58.7%) were female. The mean age for males was 51.4 years and for females was 54 years. About 57% of the male were smokers, 34% were alcohol consumers, and 30% were tobacco chewer, while among females, 36%, 28%, and 45% were the respective figures. 25% of males and 58.7% of females had previous comorbidities. About 27% of the male patients had previous history of gall stones, while 23.1% of females had a similar history. Among all the patients, 24% of the male patients were obese (24 out of 100), while 47.1% of female patients were obese (67 out of 142) [Table 1].
Table 1: Patient's characteristics

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In our study, varied clinical manifestations were reported. The most common presentation was pain abdomen (81.8%), the second most common was anorexia (77.2%), followed by weight loss (62.8%) and mass per abdomen (60.7%). Few patients had rarer manifestation such as bony pain (1.2%), intestinal obstruction (12.3%), and altered sensorium (4.8%) [Table 2].
Table 2: Various clinical presentations

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Patients were diagnosed to have metastatic disease based on ultrasonography of the abdomen or CT scan of the abdomen, pelvis, and chest for staging. The most common site of metastasis recorded in our study was the liver (79.7%), followed by nonregional abdominal lymph node (69.4%) and ascites (64.4%). Among the lesser common sites of metastasis were pulmonary (11.5%), bone (1.2%), and brain (0.8%) [Table 3].
Table 3: Sites of metastasis

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Various histologies for metastatic GB carcinoma were recorded. The most common was adenocarcinoma (81.8%) out of which, the most common were poorly differentiated carcinoma (48.9%), followed by moderately differentiated carcinoma (26.7%) and well-differentiated carcinoma (24.2%). Among the less common histologies were squamous cell carcinoma (9.5%), adenosquamous carcinoma (6.6%), and sarcomatoid variant (2.0%) [Table 4].
Table 4: Various histologies

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Out of the 242 patients, 24 patients had presented in poor ECOG PS (≥3), hence were deemed unfit for any oncological interventions. These patients were treated with the best supportive care only. About 136 (56.1%) patients had presented with features of obstructive jaundice, however only 108 patients were subjected to biliary drainage procedure. After the biliary drainage procedures, only one-third (38 out of 136; 35.1%) of patients were finally able to receive chemotherapy. The rest of the patients had either progressed subsequent to the biliary drainage procedure or general condition of the patients had deteriorated so that they were unfit for chemotherapy [Figure 1].
Figure 1: Treatment algorithm

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Out of 242, only 148 patients could finally receive chemotherapy, and they received either gemcitabine or 5-FU based chemotherapy depending on the treating oncologist choice (89 and 59 respectively. Various chemotherapy protocols used were single-agent gemcitabine, gemcitabine with cisplatin, capecitabine single agent, or capecitabine with oxaliplatin [Figure 1].

Overall survival of the patients with metastatic carcinoma GB continues to be dismally low. Median overall survival was 6–8 months for the patients who could receive chemotherapy. However, this study was not powered enough to study the survival data.


 > Discussion Top


In this study, we have evaluated epidemiological, clinicopathological profile, and management related issues of the patient with metastatic GBC. We have studied 242 patients who have presented to tertiary care hospital in India. GB carcinoma is a less common disease in the western world, but in India, especially in the northern part of India, there has been a rising trend. The incidence of this disease in the northern and Northeast part of India is much more higher compared to South and West India.[6] Its incidence in North India is 10–22/100,000 population, which is the same as that of countries with higher incidence as in South America (Chile, Columbia).[7]

GBC affects females almost 2–6 times more than male patients, however in our study, females were around 1.4 times than that of male patients.[8],[9] The reason behind the female being more affected has been linked to the hormone estrogen. The estrogen and progesterone receptors are present on GB mucosa which increases GB stasis and stone formation which leads to increase in contact time of the mucosa with bacterial and chemical toxins. The other reasons which possibly could lead to more incidence of GBC in females are illiteracy, lesser access to economic resources, medical care, and micronutrient deficiencies.[10],[11]

In India, the mean age at which patients of GBC presents is similar to Latin American countries, but it is almost a decade earlier than in western countries. The average age of diagnosis in Indian is 51 ± 11 years, which is much less as contrast to 71.2 ± 12.5 years in the West.[7],[12] Increasing age is associated with increasing risk for GBC due to multiple risk factors acting tandemly which augment the pathogenesis of GBC.[13] GBC incidence is showing a steadily rising trend after the age of 30 years onward. In our study, the mean age of presentation for males was 51.4 years and 54 years for female patients which are the same as the national figures.

Gallstones are known risk factors associated with GBC and various Indian studies have shown that it is associated with the presence of gall stone in 70%–90% of patients.[14],[15] The age-adjusted risk for GBC in patients with gallstones was 4.5 and 11.5 in Swedish European origin, 16.2 and 46.4 in American Indians, 2.3 and 3 in American non European origin, respectively[16] These gallstones are known to cause the mechanical injury to the GB mucosa during GB contraction. These repeated injuries may promote GBC formation and this risk further increases if there are large irregular gall stones occupying a larger volume of the GB. The gall stone surface helps in the formation of biofilms allowing the growth of the bacteria. Helicobacter pylori and Salmonella typhi are known to initiate carcinogenesis.[17],[18] The deconjugated of bile acids and conjugated toxins alter the chemical composition of bile. The gall stones are accompanied with biliary stasis which causes the heavy metals and metabolites in the GB to accumulate. Hence, gallstones lead to the development of GBC in multiple ways. In our study, almost one-third of patients had history of having gall stones.

It has been seen that body mass index (BMI) >30 kg/m2 significantly increases the risk of GBC by almost two times. The relative risk of patients with BMI >30 kg/m2 is 1.88 (95% confidence interval [CI]: 1.66–2.13). Zatonski et al. in a large multicentric study showed that obesity increases the risk for GBC. The adjusted relative ratio was 2.1 (95% CI: 1.2–3.8) between the highest quartile and the lowest quartile for BMI.[19] However, many Indian studies have reported that patients with GBC were found to have lower BMI as compared to patients with gallstone disease. The reason behind this could be that the associated weight loss secondary to malignancy. However, it has also been noticed that most patients were not obese even in the beginning. However, a large population-based case–control study from India with 333 patients had shown that the BMI in fact had an inverse relationship with GBC.[19] However in our study 24%of male patients and 45% of female patients were obese.

In the early stage, GBC patients are usually asymptomatic, but in patients with metastatic disease, pain is the most common symptom, followed by anorexia, nausea, or vomiting. The symptoms of advanced GBC often differ from usual biliary colic and they are symptomatic with malaise, weight loss. Advanced GBC often presents with obstructive jaundice which is due to the invasion of the biliary tree or from metastatic deposit in the hepatoduodenal ligament.This diagnosis should be particularly suspected if a compression of the common hepatic duct by an impacted stone in the GB neck is identified (i.e., Mirizzi syndrome).[20]

On clinical examination a palpable gall bladder in a patient with jaundice is considered more to be due to an underlying malignancy. Courvoisier sign or Courvoisier Law was originally proposed to be a sign of malignancy (pancreatic, GB) rather than cholelithiasis. Patients may also present with hepatomegaly, a palpable mass, ascites, extraabdominal metastases (lung and pleura), or paraneoplastic syndromes (e.g., ectopic hormone secretion or acanthosis nigricans).[21]

Majority of GBC are usually detected accidentally in patients undergoing exploration for cholelithiasis. The poor prognosis is related to the advanced stage on upfront diagnosis due to vague and nonspecific symptoms and the anatomic position of the GB.

The only potentially curative modality for early-stage GBC is surgery. However, due to the extent of disease, minority of patients can actually undergo curative surgery, while for the rest of the patients, palliative treatment remains the only option. The goals of palliative treatment on are relief of jaundice pain, bowel obstruction, and prolongation of life. Jaundice is due to biliary obstruction (30%–60%); caused by the direct infiltration of the common hepatic duct by the tumor.[22] Although a biliary or intestinal bypass can be considered for palliation of obstructive jaundice, stenting through an endoscopic or percutaneous approach is generally preferred given that the majority of patients with advanced disease will have disseminated disease and the median survival is generally <6 months. At most institutions, an initial endoscopic attempt at drainage is usually preferred, as long as local endoscopic expertise is available.

Systemic chemotherapy provides only the modest benefit for advanced GBC. Most data are consisting of small and heterogeneous population of patients with GBC, cholangiocarcinoma, and occasionally some pancreatic and hepatic cancers that tend to respond differently to systemic therapy.[23],[24],[25]

The objective response rate with various chemotherapy regimens in patients with GBC varies from 10% to 60%. Data evaluating the role of treatment on survival are very limited. The only randomized trial which compared best supportive care versus chemotherapy with fluorouracil (FU) plus leucovorin (LV) or gemcitabine plus oxaliplatin (GEMOX) in 81 patients with unresectable GBC. The median overall survival was 4.5, 4.6, and 9.5 months in the basic supportive care, FU/LV, and GEMOX groups, respectively. The combination of gemcitabine plus cisplatin is a standard option for the treatment of advanced GBC, especially for patients without hyperbilirubinemia. Other options are single-agent capecitabine, immunotherapy for MSI-H patients.[26],[27],[28]

Kumar et al. had studied the disease in the northern part of India and observed that the risk of GBC is very high in North Indian females and mostly, the disease presents as LA or metastatic stage. The population of certain districts of the UK and Western UP have higher risk of development of GBC even without cholelithiasis.[29]

Limitations of the study

This study was a prospective as well as retrospective in nature with data limited to a single center. Our data are only from the northeast part of India and limited to the patents of particular subpopulation (army personnel, their dependents, and veterans). To study the epidemiology of this dreaded disease, long-term study is required which should involve the entire Indian subcontinent.


 > Conclusion Top


Metastatic GBC continues to be a disease with very high mortality and also there are very limited numbers of chemotherapy options. This disease has gradually become one of the top ten malignancies, especially in the northern part of India along the river gangetic belt. This study demonstrated the data related to the clinicoepidemiological and management profile of Northeast India for the first time. Our endeavor was to study various risk factors associated with the disease and their treatment profile. In our setting, most of our patients presented very late, mortality among our patients was also high due to no effective chemotherapy or targeted therapy.[30] GBC has been an orphan malignancy with steadily increasing incidence. Hence, it is recommended to do large randomized studies to develop effective therapy for this disease.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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