Demographic data and progression-free survival of the patients with biliary cancers receiving palliative chemotherapy in India

Received 09 July 2018 Revised 01 October 2018 Accepted 20 October 2018 Early online 02 January 2019 Print 31 January 2019 Biliary tract cancers are among the sixth most commonly diagnosed alimentary tract cancers. The incidence of this disease is higher among Indians in comparison to other countries. Due to lack of any definitive treatment palliative chemotherapy usually adopted particularly for advanced unresectable gallbladder cancers. The purpose of this study is to gather the demographical data and the various treatment modalities in place in the clinical practice for patients presented with gallbladder complications. Progression-free survival following the palliative chemotherapy was also assessed and presented as mean and 95% CI. Results from this study gathered clinically relevant and important data on the patients presented with gall bladder complications starting from the diagnosis of the disease, treatments implicated, response to the treatment and progression-free survival of the patients on palliative chemotherapy. Corresponding author

Biliary tract cancers are among the sixth most commonly diagnosed alimentary tract cancers. The incidence of this disease is higher among Indians in comparison to other countries. Due to lack of any definitive treatment palliative chemotherapy usually adopted particularly for advanced unresectable gallbladder cancers. The purpose of this study is to gather the demographical data and the various treatment modalities in place in the clinical practice for patients presented with gallbladder complications. Progression-free survival following the palliative chemotherapy was also assessed and presented as mean and 95% CI. Results from this study gathered clinically relevant and important data on the patients presented with gall bladder complications starting from the diagnosis of the disease, treatments implicated, response to the treatment and progression-free survival of the patients on palliative chemotherapy. 1 , however among Indians incidence is reported to vary with the geography and overall incidence of BTC among Indians is more than other countries 2 . Among North Indians incidence reported to be more compared to south Indians 2 and the places near the Gangetic belt have higher incidence of gallbladder cancer. Also, incidence in females reported being almost double in comparison to males 1 . BTC can be Gallbladder cancers (GBC), or bile duct cancer also known as cholangiocarcinomas (CC). Gallbladder cancer (GBC) is the most common BTC and the fifth most common gastrointestinal cancer 3 . Most biliary tract cancers present in the advanced stage where palliative chemotherapy is the only an option which is basically to improve the symptoms of the disease and to improve the quality of life of the patient. Only in the small proportion of patients who present in early stage, curative surgery can be offered. Most cancers present in the advanced stage where palliative chemotherapy is the only option. Although BTC are common in India, there is a scarcity of Indian data. The purpose of the present study is to assess the pattern of care of gallbladder and biliary tract cancers in a community care setting. This study will help us know the profile of GBC in India and inform us the treatment modalities for GBC in real time clinical settings in hospitals outside of clinical trials. This study also states the metrics of the treatment-related toxicity and outcomes.

Materials and methods
A retrospective observational study was conducted by recruiting patients with confirmed diagnosis of gallbladder cancer or cholangiocarcinoma from NRI General Hospital and American Oncology Hospital between March 2016 and March 2018. Patients were recruited following inclusion and exclusion criteria and were then followed for another 19 months to capture demographic data on percentage of the patients experiencing the different types of the GBC, symptoms represented with, treatment modalities implicated and response to palliative chemotherapy with different treatment modalities they have undergone following the standard protocols at the discretion of the specialists, researcher had not influenced or had no role in deciding the treatment for the patient. Ethical clearance for the study was obtained from the NRI general hospital and as the nature of the study was a retrospective observational study, consent waiver was obtained. Required data for the study was obtained from the medical records either from hospitals online databases or from the written notes from the patients files. All patients considered for the study had a case record form (CRF), where patients data relevant to the study was captured. A detailed history including symptoms, co-morbid conditions, performance status, blood investigations, imaging study reports, histology of biliary tract cancer were documented. Joint clinic decisions, treatment details and their outcomes including response rates, progression of tumor, survival status and toxicity to chemotherapy were noted.

Statistical analysis
Statistical analysis was performed in SPSS version 24. Depending on the type of the data variables were either categorical or metric. For categorical variables summary data was calculated and presented as percentages and for metric variables as arithmetic mean.
Profession free survival (PFS) will be defined as the time from registration until tumour progression or death or last follow up occurred. All time-toevent curves for PFS were estimated according to the Kaplan-Meier method. A p-value less than 0.05 is statistically significant, where applicable. Majority of the patients were diagnosed with gallbladder cancers (92%) and the adenocarcinoma (96%) was the main histological outcome for the patients. Fine needle aspiration cytology (FNAC) was the most used technique to study the histology of the tissues and CT scan (66%) followed by PET CT scan (32%) were the popular imaging techniques used for diagnosis whereas MRI (2.7%) was least preferred.
After the initial assessment of the symptoms and confirmed diagnosis for GBC, treatment modalities implemented were variable. Majority of the patients started with palliative chemotherapy (70%) and about 12% of the patients underwent surgical procedures. Table 2 presents the various treatment modalities implemented for the patients diagnosed with GBC.
Response to the treatment with some clinical benefit was noted in about half of the patients (46%), however only two patients (2%) achieved complete response. Table 3 presents the Response to treatment with first-line palliative chemotherapy.
Out of 219 patients, 154 received palliative chemotherapy, patients who were lost to follow-up or who didn't proceeded for chemotherapy after initiation were excluded from the study. After a median follow up of 19 months mean progression-free survival (PFS) in all the patients (including gallbladder & cholangiocarcinoma) was 5.5 months (95% CI 4.5 -6.5 months) (Fig 1).

Discussion
The purpose of this study is to gather the demographical data and the various treatment modalities in place in the clinical practice for patients presented with gallbladder complications. Progression-free survival following the palliative chemotherapy was also assessed and presented as mean and 95% CI.
Results from this study gathered clinically relevant and important data on the patients presented with gall bladder complications starting from the diagnosis of the disease, treatments implicated, response to the treatment and progression-free survival of the patients on palliative chemotherapy.   Number of females with the gallbladder complications where almost doubled that of the males in this study which implicates the higher incidence among females and is in coincidence with other reported studies 1,[5][6][7][8][9] . In our present study majority number of patients were from Uttar Pradesh (20.1 %), Bihar (19 %), West Bengal (18.8 %) and Maharashtra (13.3%).This study also demonstrates the higher incidence of GBC in Gangetic belt as it was reported in various Indian studies 7,10 .
Most of histological types of gallbladder cancers were adenocarcinomas (95.3 %) similar to what has been reported in other studies 11,12 . The common symptoms at presentation were pain (79.5%) and jaundice (21.5%). These presenting symptoms is similar to that reported from other countries 11,13 and as well as from India 14 . Metastasis at different sites was found in 67 % of patients, however majority of patients (43%) had metastasis at single site and lymph node metastasis followed by liver metastasis were the mostly noted metastasis sites 15 . Clinicians found to relay more on Fine needle aspiration cytology (FNAC) to study the histology of the tissues and CT scan (66%) followed by PET CT scan (32%) were the popular imaging techniques for diagnosis whereas MRI (2.7%) was least preferred.
The number of patients with GBC in our study having associated with gallstones on imaging was 32 %. This is a lower than that reported by Pandey et al 16 as 63.6% and Batra et al 14 as 54% from India. However, this discrepancy was also noted with other reports where a lack of correlation between gallstones and GBC reported [17][18][19] .
Following confirmed diagnosis for GBC majority of patients (70%) were started on palliative chemotherapy. Combination chemotherapy was preferred to single drug treatment in 88% of the patients who underwent palliative chemotherapy. Mostly preferred combination chemotherapy used by clinicians were Gemcitabine and Cisplatin (in 48% of patients on palliative chemotherapy) followed by Gemcitabine and Oxaliplatin which was used in about 40% of cases. On the other hand, surgery was opted only for about 12% of the patients for the treatment of GBC. These findings are in accordance with the previous reports 20 .

Metastatic
gall bladder cancer and cholangiocarcinomas (biliary tract cancers-BTC) are managed either with systemic chemotherapy or offered best supportive care (BSC). Most of the studies done in this setting were small and had a mixture of gall bladder and cholangiocarcinoma. Various combination chemotherapy regimens used in phase 2 clinical trials in the treatment of metastatic cholangiocarcinomas have shown median survival ranging from 6 months to 15.2 months 21,22 . Only two phase 3 trials have been conducted till date in the setting of metastatic BTC, both of which have shown Gemcitabine-Cisplatin combination compared to Gemcitabine alone to be associated with a significantly greater median overall survival and median progression free survival 23,24 . In ABC02 trial of Gemcitabine/ cisplatin vs. Gemcitabine alone in 410 patients with advanced/metastatic biliary tract cancers showed a 3 month OS and PFS benefit of combination arm. Hence gemcitabine/cisplatin is considered as standard option for advanced biliary cancer. Majority of patients on first-line palliative chemotherapy responded to the treatment and had either clinical benefit or stable disease or complete or partial or objective response to the treatment, however about 32% of the patients showed progression of the disease. Among the patients with gall bladder cancer who underwent upfront surgical resection, 11 of 23 patients had relapse of the disease within a median of 9 months (5.7 to 12.2 months). These are similar to the rates reported by Jarnagin et al 25 .
Among patients who were treated with first-line palliative chemotherapy, the objective response rates (ORR) in our study was 15.1 % and in addition 25.8 % had stable disease. This was lower compared to GERCOR study (ORR=36%) and the study from India by Sharma et al (ORR=30.8%) 4,22 . Our median progression-free survival (PFS) of 5.5 months was lesser than other studies (Sharma et al-PFS=8.5, GERCOR-PFS =5.7), while ABC02, a large phase 3 trial with gemcitabine and cisplatin reported objective response of 38% with survival of 11.7 months 24 .
Overall survival was not calculated in our study group since a large number of patients were lost to follow up. The patients were not contacted to inquire about their disease or death status as it is a retrospective study. In our study there were no statistically significant differences in the rate of response between the gallbladder and cholangiocarcinoma subgroups (results not reported), the similar results were demonstrated in ABC02 trial 24 .