|Year : 2020 | Volume
| Issue : 3 | Page : 128-132
A study on the clinical profile and treatment outcomes in gallbladder carcinoma from Northern India
Amit Sreen1, Ravi K Anadure1, HP Singh2, Rohit Sharma3, Anurag Garg4
1 Department of Medicine, Army Hospital Research and Referral, New Delhi, India
2 Department of Oncology, Army Hospital Research and Referral, New Delhi, India
3 Department of Oncosurgery, Army Hospital Research and Referral, New Delhi, India
4 Department of Anaesthesia, Army Hospital Research and Referral, New Delhi, India
|Date of Submission||09-Aug-2020|
|Date of Decision||19-Sep-2020|
|Date of Acceptance||27-Oct-2020|
|Date of Web Publication||26-Nov-2020|
Ravi K Anadure
Department of Medicine, Army Hospital Research and Referral, New Delhi - 110 001
Source of Support: None, Conflict of Interest: None
Aim: Gallbladder carcinoma (GBC) is a common cancer in women in North India. This prospective observational study aimed at systematically studying the clinical features, treatment response, and survival pattern of GBC patients, in a North Indian population. Materials and Methods: The clinical profile, staging of disease, and treatment outcomes of 116 consecutive patients with histologically confirmed GBC, presenting to a tertiary care hospital in Lucknow from June 2013 to August 2015, with a follow-up period of 2 years till August 2017, were studied. Data were captured on a predesigned study proforma and analyzed with appropriate statistical tools. Results: The median age at presentation was 60 years and 67 patients had coexisting gall stones. Patients were divided into three treatment groups for the analysis. Group A comprised patients who underwent radical cholecystectomy followed by adjuvant chemotherapy. Group B included patients who received the best supportive care and Group C consisted of patients who received palliative chemotherapy. The median overall survival (mOS) was 16, 2, and 9 months for Group A, B, and C patients, respectively. The mOS was 8 months for all patients, irrespective of treatment groups. On univariate analysis, factors having an adverse impact on mOS included obstructive jaundice, elevated liver enzymes, treatment groups, and advanced stage of disease. On multivariate analysis, only factor found significantly associated with mOS was treatment group (P < 0.05). Conclusions: GBC was found to be the second most common malignancy among females in our hospital registry with a uniformly poor prognosis. Patients receiving radical surgery and adjuvant chemotherapy were the longest survivors in this study. Better screening and early diagnosis are the cornerstones of improving outcomes in this aggressive malignancy.
Keywords: Chemotherapy, gallbladder carcinoma, supportive care, surgery, survival
|How to cite this article:|
Sreen A, Anadure RK, Singh H P, Sharma R, Garg A. A study on the clinical profile and treatment outcomes in gallbladder carcinoma from Northern India. Oncol J India 2020;4:128-32
|How to cite this URL:|
Sreen A, Anadure RK, Singh H P, Sharma R, Garg A. A study on the clinical profile and treatment outcomes in gallbladder carcinoma from Northern India. Oncol J India [serial online] 2020 [cited 2021 Jan 20];4:128-32. Available from: https://www.ojionline.org/text.asp?2020/4/3/128/301584
| Introduction|| |
Gallbladder carcinoma (GBC) is a common gastrointestinal malignancy seen in North India. It has a high prevalence, mainly along the Indo Gangetic plains of Uttar Pradesh (UP) and Bihar. The reasons for high incidence in this population are presently not well understood. There are several postulated etiologies for GBC, which include cholelithaisis, typhoid carrier state, obesity, genetic predisposition, estrogens, chemical carcinogens, and diet. GBC is an aggressive malignancy with a median overall survival (mOS) of <1 year and a 5-year survival rate of <5% for patients not eligible for radical cholecystectomy., The tumor commonly presents in Stage IV and is usually inoperable. Only 10%–30% of patients are found suitable for surgery. Adjuvant chemotherapy may be beneficial among patients with locally advanced GBC (T3 or T4), hepatic-sided T2 tumors, node positivity, or R1 resection. A large number of patients have locally advanced unresectable cancer that may mandate neoadjuvant chemotherapy. Prognosis of GBC is poor, even in the setting of attempted curative resection. Therefore, the majority of GBC patients receive palliative systemic chemotherapy. The aim of this study was to look at the clinical profile and prognostic markers of GBC in Indian patients and assess the mOS offered by currently available treatment regimens.
| Materials and Methods|| |
This was a prospective observational study of 116 consecutive GBC patients, presenting to a tertiary care hospital in Lucknow, from June 2013 to August 2015, with a follow-up period of 2 years till August 2017. This Armed Forces Hospital serves as a tertiary care hospital for the states of UP, Uttarakhand, and Bihar. The study was approved by the Institutional Ethics Committee (IEC letter number: CHCC/IEC/126/2013), and all participants gave written informed consent for the study.
Patients were included in the study only if they had a confirmed tissue diagnosis of GBC. Pertinent investigations included complete blood counts, liver function tests, kidney function tests, ultrasound of the abdomen, computed tomography, or magnetic resonance imaging scan of the abdomen. Patients with obstructive jaundice underwent magnetic resonance cholangiopancreatography. Tumor marker (CA 19.9) was done in all the cases. Clinical and pathologic staging was achieved with TNM system, supported by a whole-body positron-emission tomography which was done in all the cases. Data were captured on a predesigned pro forma, which included the clinical profile, laboratory, and radiology investigations, staging of tumor using the American Joint Committee on Cancer 7th ed.ition, the treatment group to which the patient belonged and their survival.
Patients undergoing chemotherapy had to be in Eastern Cooperative Oncology Group performance status 0, 1, or 2 and have an estimated life expectancy of more than 2 months. In GBC patients found to have a resectable tumor, radical cholecystectomy was performed, which included cholecystectomy with en block hepatic resection and lymphadenectomy (porta hepatis, gastrohepatic ligament, and retrodudoneal).
All the patients were grouped into three broad treatment categories such as:
- Group A: These patients underwent radical cholecystectomy followed by adjuvant chemotherapy with modified gemcitabine plus oxaliplatin (mGEMOX)-based regimen. In mGEMOX protocol, gemcitabine 900 mg/m2 and oxaliplatin 80 mg/m2 intravenous infusion was given on days 1 and 8 of each cycle at three weekly intervals for six cycles
- Group B: Patients who were found unfit to undergo surgery or chemotherapy were offered the best supportive care (BSC)
- Group C: Patients with inoperable or metastatic disease were offered palliative chemotherapy with single-agent, oral tablet capecitabine at a dose schedule of 850 mg/m2 body surface area twice daily for 14 days every 3 weeks.
All patients were seen at every chemotherapy cycle, and drug side effects were categorized according to the National Cancer Institute's Common Toxicity Criteria for Adverse Events (Version 3). In patients with Grade 3 or 4 toxicity, the therapy was deferred till resolution of side effects. After the end of treatment, patients were seen every 3 months for tumor progression and survival with monitoring of blood counts and liver and renal functions, as per the National Comprehensive Cancer Network guidelines, Version 3.
All statistical analyses were performed using the SPSS Version 20.0 proprietary software package, developed by IBM, Armonk, New York, USA. The Chi-square test (χ2 test) was used for comparison of baseline characteristics among the three treatment groups. mOS was calculated from the date of diagnosis until the date of death. Survival curves were calculated by the Kaplan–Meier method. Univariate analysis evaluated the effect of various prognostic factors on the survival of the patients and a log–rank test compared survival in different groups. Multivariate analysis by Cox proportional hazards regression modeling assessed the effect that independent covariates had on survival. Probability P < 0.05 was considered significant.
| Results|| |
GBC was the second most common malignancy in females presenting to this hospital after breast cancer. In the 2-year study period, a total of 116 patients were diagnosed with GBC. The median age of presentation was 60 ± 11.4 years. There was a female predominance with a female-to-male ratio of 3:1.
A family history of cancer was present in 8 (6.9%) cases. This included uterine cancer (3 cases), gastrointestinal cancer (2 cases), and leukemia, brain, and hepatocellular malignancy (1 case each). Co-existing gallstones were noted in 67 (57.8%) patients. The size of stone varied from 1 to 3 cm and number of stones was single in 19 patients and multiple in 48 patients. The common presenting symptoms included pain abdomen in 62 (53.4%), dyspepsia in 56 (48.3%), anorexia in 34 (29.3%), and weight loss in 12 (10.3%) cases. Obstructive jaundice was the presenting feature in 28 cases (24.1%). The majority of patients presented at Stage IVB consisting of 73 cases (62.9%). The details of demographics and clinical profile are summarized in [Table 1].
The 116 patients were grouped in one of the three treatment modalities. For treatment, 30, 31, and 55 number of patients were assigned to Group A, B, and C, respectively. The chemotherapy protocols used were mGEMOX in 30 (25.9%) cases and tablet capecitabine in 55 (47.4%) patients.
The mOS for all 116 patients as a cohort was 8 months at a median follow-up of 24 months. On univariate survival analysis for biochemical markers, the mOS was significantly higher among the patients having aspartate aminotransferase (AST) ≤40 IU versus >40 IU (P = 0.0049) and alkaline Phosphatase ≤175 IU versus >175 IU (P = 0.0010). Furthermore, better mOS was found on univariate analysis among the patients having no obstructive jaundice versus having obstructive jaundice (P = 0.0008) and the patients under group A treatment modality versus other treatment groups (P = 0.0000). A poor mOS was seen in Stage IVB patients versus patients with other stages of GBC (P = 0.0315). The age at presentation and gender of the patients did not have an impact on mOS in this study. The details of univariate analysis are summarized in [Table 2]. On further multivariate analysis only factor found significantly associated with mOS was treatment group (P <0.05). Sixty-seven of the 116 patients studied (57.8%) had died at 2-year follow-up.
|Table 2: Factors influencing median overall survival (univariate analysis)|
Click here to view
The adverse effects of chemotherapy drugs noted in the study population were generally mild and manageable with supportive therapies and drug holidays. One patient had Grade 1 neutropenia and two patients had Grade 1 neuropathy. Diarrhea occurred in eight patients and was Grade 1 in three patients, Grade 2 in four patients, and Grade 3 in one patient.
| Discussion|| |
GBC is the second most common malignancy in females after breast cancer presenting to our hospital. The mean age of presentation of 60 years in our study is similar to that reported by other authors. GBC usually affects younger populations of India in fifth and sixth decades of life in comparison to the west. A higher incidence of GBC among females (female-to-male ratio of 3:1) in our analysis has been observed by several authors. Gallstones were detected in 67 out of 116 cases (57.8%) of our study population. This has varied in different series from 54% to 86%., Obstructive jaundice as initial presentation was found in 24.1% of our cases and this has varied from 20% to 75% in different series. The stage of GBC at the presentation in this study is comparable to other studies.,,
Chemotherapy of GBC and biliary tract cancer (BTC) has evolved from 5-fluorouracil-based regimes to gemcitabine-based therapies. The advantages of systemic chemotherapy over BSC in improving survival were suggested in an evaluation of mGEMOX versus BSC. A prospective study on 40 patients of intermediate and advanced GBC who underwent surgery followed by chemotherapy with 5-FU plus leucovorin demonstrated mOS time of 5.5 months for T4 patients to 81 months for T1 patients. Combination therapy with cisplatin consistently yields higher response rates and mOS.
Single-agent gemcitabine has mOS times ranging from 6 to 16 months with relative risks varying from 0% to 30%. A systematic review on the role and rationale of gemcitabine in the treatment of cholangiocarcinoma and GBC was done in a 13 single-arm phase II trial report. It pointed toward gemcitabine as the most active agent. New studies have focused on improving efficacy by combining gemcitabine with other agents while maintaining a tolerable toxicity profile. Gemcitabine has been combined with 5 Fu, cisplatin, oxaliplatin capecitabine, irinotecan, bevacizumab, and cetuximab., The combination demonstrates mOS of 7–16 months. A movement toward molecularly based targeted therapy has occurred in recent years, with several pathways emerging as putative therapeutic targets.,
Gemcitabine-cisplatin (GC) combination chemotherapy is the standard of care today for patients with BTCs. Two randomized trials have shown the superiority of combination of GC over single-agent gemcitabine. The UK ABC-02 study showed a benefit for the GC combination. The mOS in the GC group was 11.7 months compared with 8.1 months for gemcitabine-only group (P <0.001). BT22 a Japanese study on BTC demonstrated that gemcitabine monotherapy gave mOS of 7.7 months, as opposed to GC which is 11.2 months. In our study, patients in Group A who received adjuvant chemotherapy with gemcitabine and oxaliplatin had mOS of 16 months. The benefit with gemcitabine and oxaliplatin combinations has been reported in several trials., Sharma et al. in their study on unresectable GBC patients found a higher mOS of 9.5 months for mGEMOX chemotherapy group in comparison to fluorouracil–folinic acid chemotherapy group and BSC groups (P = 0.039).
Unresected GBC is a rapidly fatal disease. Most of the reports of cure of GBC occurred “by accident” after complete excision of early stage disease by simple cholecystectomy for gallstones. The surgical treatment of GBC has traditionally resulted in poor survival. This is due to the advanced stage at presentation and the aggressive nature of these tumors. Five-year survival for GBC in different series ranges between 5% and 12%., In 1978, a review of 6222 cases revealed a 4.1% 5-year survival rate. These results were echoed by various studies and have not changed much over the years. These globally dismal results reinforce the nihilism that surrounds this disease.
Treatment with radical cholecystectomy is potentially curative although this procedure is possible only in 10%–38% of patients., Even after resection, the rate of recurrence is approximately 60%. Recent 5-year survival rates in patients undergoing “radical” resection have improved to as high as 36%., The present study suggests that with optimal surgical management, recurrence may be reduced. Fong and Malhotra have reported mOS for resected patients to be 26 months and 5-year survival of 38%. For patients not offered surgery, mOS was 5.4 months and 5 year survival was 4% (P <0.001). These studies demonstrated that an important factor in determining long-term survival is the performance of a margin negative R0 resection. Investigators also demonstrated that R1, or debulking operations, does not improve survival. Surgery with radical cholecystectomy was feasible in our study in 30 (25.8%) cases. Theoretically, if all 38% of the 30 patients who underwent radical cholecystectomy (Group A) in this study were to survive, then the anticipated 5-year survival among 116 GBC patients would only be 12 patients (10.1%). This indicates the poor prognosis of this cancer. In our study, the patients undergoing radical cholecystectomy (Group A) had maximum survival. This is borne out by the fact that surgery for GBC is the only curative modality [Figure 1].
|Figure 1: Type of treatment group and its impact on median overall survival. (Cum Survival: Cumulative survival, OSMONTH: Median overall survival in months, TOTALRX: Total treatment given)|
Click here to view
Obstructive jaundice at presentation adversely impacts survival and has been reported by other authors. Elevated alkaline phosphatase also adversely impacted survival. This could be due to the fact it is elevated in patients with obstructive jaundice which is a known poor prognostic factor. Elevated AST too had an adverse impact on survival. This could be due to it being elevated in patients with metastatic disease which is another known poor prognostic factor.
On multivariate analysis, the treatment group was the only factor found significant for mOS. This is because Group “A” patients underwent radical surgery, which is the only accepted curative option for GBC patients.
| Conclusions|| |
GBC is a common cancer among Indian women and seems to be associated with gallstone disease. It usually presents in an advanced stage (Stage IV) in majority of the cases, which poses serious challenges in effective management strategies. Radical cholecystectomy followed by adjuvant chemotherapy leads to the best survival in this cancer. The rather poor mOS of only 8 months in this study, and other similar Indian studies, calls for better screening methods and early detection of this aggressive malignancy to improve the survival rates and long-term outcomes.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Acharya MR, Patkar S, Parray A, Goel M. Management of gallbladder cancer in India. Chin Clin Oncol 2019;8:35.
Marcano-Bonilla L, Mohamed EA, Mounajjed T, Roberts LR. Biliary tract cancers: Epidemiology, molecular pathogenesis and genetic risk associations. Chin Clin Oncol 2016;5:61.
Batra Y, Pal S, Dutta U, Desai P, Garg PK, Makharia G, et al
. Gallbladder cancer in India: A dismal picture. J Gastroenterol Hepatol 2005;20:309-14.
Pandey M, Pathak AK, Gautam A, Aryya NC, Shukla VK. Carcinoma of the gallbladder: A retrospective review of 99 cases. Dig Dis Sci 2001;46:1145-51.
Hickman L, Contreras C. Gallbladder cancer: Diagnosis, surgical management, and adjuvant therapies. Surg Clin North Am 2019;99:337-55.
Dutta U, Bush N, Kalsi D, Popli P, Kapoor VK. Epidemiology of gallbladder cancer in India. Chin Clin Oncol 2019;8:33.
Mehrotra R, Tulsyan S, Hussain S, Mittal B, Singh Saluja S, Singh S, et al
. Genetic landscape of gallbladder cancer: Global overview. Mutat Res 2018;778:61-71.
Singh SK, Talwar R, Kannan N, Tyagi AK, Jaiswal P, Kumar A. Patterns of presentation, treatment, and survival rates of gallbladder cancer: A prospective study at a tertiary care centre. J Gastrointest Cancer 2018;49:268-74.
Duffy A, Capanu M, Abou-Alfa GK, Huitzil D, Jarnagin W, Fong Y, et al
. Gallbladder cancer (GBC): 10-year experience at memorial sloan-kettering cancer centre (MSKCC). J Surg Oncol 2008;98:485-9.
Ostwal V, Swami R, Patkar S, Majumdar S, Goel M, Mehta S, et al
. Gemcitabine-cisplatin (GC) as adjuvant chemotherapy in resected stage II and stage III gallbladder cancers (GBC): A potential way forward. Med Oncol 2018;35:57.
Sharma A, Dwary AD, Mohanti BK, Deo SV, Pal S, Sreenivas V, et al
. Best supportive care compared with chemotherapy for unresectable gall bladder cancer: A randomized controlled study. J Clin Oncol 2010;28:4581-6.
Manterola C, Vial M, Roa JC. Survival of a cohort of patients with intermediate and advanced gall bladder cancer treated with a prospective therapeutic protocol. Acta Cir Bras 2010;25:225-30.
Dingle BH, Rumble RB, Brouwers MC, Cancer Care Ontario's Program in Evidence-Based Care's Gastrointestinal Cancer Disease Site Group. The role of gemcitabine in the treatment of cholangiocarcinoma and gallbladder cancer: A systematic review. Can J Gastroenterol 2005;19:711-6.
Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, et al
. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N
Engl J Med 2010;362:1273-81.
Okusaka T, Nakachi K, Fukutomi A, Mizuno N, Ohkawa S, Funakoshi A, et al
. Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: A comparative multicentre study in Japan. Br J Cancer 2010;103:469-74.
Geynisman DM. Toward Personalized Treatment of Advanced Biliary Tract Cancers. Discov Med 2012;14:41-57.
Patkar S, Ostwal V, Ramaswamy A, Engineer R, Chopra S, Shetty N, et al
. Emerging role of multimodality treatment in gall bladder cancer: Outcomes following 510 consecutive resections in a tertiary referral center. J Surg Oncol 2018;117:372-9.
Fong Y, Malhotra S. Gallbladder cancer: Recent advances and current guidelines for surgical therapy. Adv Surg 2001;35:1-20.
Piehler JM, Crichlow RW. Primary carcinoma of the gallbladder. Surg Gynecol Obstet 1978;147:929-42.
Zaidi MY, Maithel SK. Updates on gallbladder cancer management. Curr Oncol Rep 2018;20:21.
He C, Cai Z, Zhang Y, Lin X. Prognostic model to predict cancer-specific survival for patients with gallbladder carcinoma after surgery: A population-based analysis. Front Oncol 2019;9:1329.
Dasari BV, Ionescu MI, Pawlik TM, Hodson J, Sutcliffe RP, Roberts KJ, et al
. Outcomes of surgical resection of gallbladder cancer in patients presenting with jaundice: A systematic review and meta-analysis. J Surg Oncol 2018;118:477-85.
[Table 1], [Table 2]