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Table of Contents
REVIEW ARTICLE
Year : 2018  |  Volume : 1  |  Issue : 1  |  Page : 2-9

Current management strategies in gallbladder cancers


1 Department of Medical Oncology, TMH, Mumbai, Maharashtra, India
2 Department of Surgical Oncology, TMH, Mumbai, Maharashtra, India
3 Department of Radiation Oncology, TMH, Mumbai, Maharashtra, India

Date of Web Publication12-Dec-2018

Correspondence Address:
Dr. Anant Ramaswamy
Department of Medical Oncology, Tata Memorial Centre, E. Borges Road, Parel, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CRST.CRST_4_18

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  Abstract 


Gallbladder cancers (GBC) are common in the Indo-Gangetic belt of India. Most consensus guidelines in the West have considered GBC as part of the biliary tract cancer spectrum; however, considering the markedly higher burden of GBC in India, there is a need to have specific management treatment strategies in the Indian scenario. The extent of surgical resections, the use of staging laparoscopies, the optimum adjuvant therapy for resected high-risk GBC (T3 or T4 disease and node-positive disease), as well as the preferred second-line chemotherapeutic regimens for advanced GBC are questions that remain incompletely defined and answered. The current review presents a synopsis of currently available evidence and emerging approaches in the treatment of GBC.

Keywords: Current, gallbladder, gallbladder cancer, Indian, management, review


How to cite this article:
Ostwal V, Dsouza S, Patkar S, Lewis S, Goel M, Khobragade K, Ramaswamy A. Current management strategies in gallbladder cancers. Cancer Res Stat Treat 2018;1:2-9

How to cite this URL:
Ostwal V, Dsouza S, Patkar S, Lewis S, Goel M, Khobragade K, Ramaswamy A. Current management strategies in gallbladder cancers. Cancer Res Stat Treat [serial online] 2018 [cited 2019 Jul 17];1:2-9. Available from: http://www.crstonline.com/text.asp?2018/1/1/2/247329




  Introduction Top


Gallbladder cancers (GBC) are some of the most common biliary tract cancers in certain parts of the world with an incidence and prevalence that varies distinctly with region and ethnicity. Certain regions in India have a very high incidence, e.g. Kamrup, New Delhi, with some evidence to suggest that there is a rising incidence of GBC across the country. Multiple international consensus guidelines have been formulated across the globe; however, they generally consider GBC as part of the biliary tract spectrum as opposed to considering it as a separate entity. There is increasing research to suggest that cholangiocarcinomas and GBC have a differing genetic and molecular landscape.[1],[2] This fact coupled with the higher prevalence of GBC in India suggests that these cancers require individual and specific attention to management in the Indian setup.[3] The current document encompasses various aspects of the current standards of management of GBC as well as certain approaches that are being evaluated in the Indian context.


  Epidemiological Context of Gallbladder Cancer in India Top


India has one of the highest incidence and prevalence rates for GBC across the world, though there are widespread differences in incidences across the country.[3] This geographical variation in the country has been suggested as a causal factor for GBC, beyond the known risk factors (gallstones, chronic inflammation, and infections). Data extracted from population-based cancer registries were used as a basis for a hospital-based case–control study of GBC at Tata Memorial Hospital (Mumbai, Maharashtra, India). In this study, the researchers clearly identified marked variation in incidence with the risk highest in certain districts in the North East (Kamrup) as compared to regions in South India. An odds ratio of 4.82 (95% confidence interval [CI], 3.87–5.99) was observed for developing GBC for individuals born in a high-risk region compared to those born in a low-risk region. There was also an increased risk with increased length of residence in a high-risk region for GBC. Besides geographical factors, genome-wide association studies have also recently identified specific genetic variations in the BCB1 and ABCB4 genes (associated hepatobiliary phospholipid transport) in Indian patients with GBC.[4]


  Initial Diagnosis and Staging Top


GBC is commonly diagnosed at an advanced stage though it may also be diagnosed incidentally after simple cholecystectomy for presumed benign disease (incidental GBC [IGBC]) as well. Other clinical presentations may include a suspicious mass detected on ultrasonography during evaluation for other conditions or on evaluation for jaundice. The initial workup should include a detailed history and physical examination, liver function tests, and directed imaging. Although ultrasonography of the abdomen has a relatively high sensitivity for the detection of tumor at advanced stages, it is limited in the diagnosis of early lesions and is unreliable for staging.[5] Gallbladder masses are best evaluated by contrast-enhanced computed tomography (CECT) of the abdomen with predominant advantages being the detection of portal nodes, peritoneal implants, and vascular invasion.[6] CECT scan can be augmented with magnetic resonance imaging (MRI) for further evaluation of hepatic or biliary tract infiltration.[7] In patients with known or suspected GBC, 18-fluorodeoxyglucose (FDG) positron-emission tomography (PET) with simultaneous CT scan has demonstrated the ability to detect occult peritoneal, omental, and/or lymph node metastases with a sensitivity of 56%.[8],[9]

Elevated serum carcinoembryonic antigen (CEA) levels (higher than 4.0 ng/ml) or CA19-9 levels (higher than 20 units/ml) could be suggestive of GBC. However, these markers are not specific for GBC and hence must be done as part of the baseline assessment and not for diagnostic purposes. Baseline CA19-9 is best used to guide treatment and follow-up; it may have a prognostic value in the absence of biliary obstruction.[10]

Histopathologic diagnosis should be established before any nonsurgical treatment modality; however, this is not essential in patients planned for curative surgery with characteristic radiological features of GBC.[10]

The American Joint Committee on Cancer (AJCC) staging systems for GBC are shown in [Table 1] (AJCC 7th Edition) and [Table 2] (AJCC 8th Edition), with the major changes being the division of T2 disease to T2a and T2b stages and the change in methodology of reporting nodal status (shifted from location to number of nodes).[11]
Table 1: Definitions of American Joint Committee on Cancer tumor, node, and metastasis staging (7th edition and 8th edition)

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Table 2: American Joint Committee on Cancer prognostic stage groups (7th edition and 8th edition)

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  Incidental Gallbladder Cancers Top


IGBC at cholecystectomy is found in approximately 0.2%–1.1% of all laparoscopic cholecystectomies. The incidence of finding residual disease at any site can be as high as 37.5% in T1 tumors, 56.7% in T2 tumors, and 77.3% in T3 tumors. IGBCs have a potentially better prognosis as compared to nonincidental disease when managed with R0 resection; however, if GBC is suspected during laparoscopic surgery, the procedure should be aborted, and the patient referred to a specialized hepatobiliary center.[12],[13]

Preoperative workup and surgical restaging

A review of precholecystectomy imaging should be done to determine the location of the tumor in addition to discussing the intraoperative findings with the referring surgeon. Both CECT and MRI provide critical information in restaging the patient. FDG PET-CT scans done 4 to 6 weeks after initial surgery can occasionally be useful to stratify patients with IGBC for further effective systemic treatment.[9]

A staging laparoscopy has been shown to upstage patients and avoid unnecessary laparotomy in approximately 20% to 36% of patients.[14] Limited data suggest that increasing the time interval between the initial simple cholecystectomy and radical re-resection may not have a significant impact on the incidence of recurrences.[14],[15],[16]

Surgical treatment of T1 and T2 incidental gallbladder cancer

For T1a disease, simple cholecystectomy with negative cystic duct margin is considered sufficient with a cure rate of 85% to 100% and no additional resection is warranted.[17] T1b tumors are associated with an incidence of residual disease of up to 10% and lymph node involvement ranging from 10% to 20%.[18] Therefore, additional radical resection which includes hepatic bed resection (segment IV B and V) and portal lymphadenectomy (stations 8, 12, and 13) are indicated. A similar radical resection is recommended for patients with T2 disease as well.[19]

Surgical treatment of T3 and T4 incidental gallbladder cancer

T3 disease has a high incidence of residual disease and metastatic nodes, approximating 36% and 46%, respectively.[12] Management includes radical resection of the gallbladder fossa with portal nodal lymphadenectomy. There is often a need for more extensive hepatic and bile duct resection for the attainment of negative surgical margins. In the case of T4 disease, the role of extensive vascular reconstructions in the treatment of GBC has not been shown to provide a durable survival benefit, and these patients can be enrolled in clinical trials evaluating the role of neoadjuvant therapy.[19]

Besides the extent of resection, the importance of avoiding perforations and biliary spillage is emphasized, considering the higher recurrence rates with such complications.[20],[21]

Extent of liver and extrahepatic bile duct (and other organ) resection in incidental gallbladder cancer

The size of the wedge liver resection depends on the pathologic depth of the tumor and stage of disease, ranging from limited segment IVB and V wedge resections to formal anatomic resections. The routine performance of a major hepatectomy compared with a partial hepatectomy (non-anatomic resection of the gallbladder bed) or a formal segment IVB/ V resection has not been associated with improved survival.[22],[23] A right hepatectomy may occasionally be required to ensureadequate tumor clearance and an R0 resection in tumors involving hepatic inflow vascular structures.

Extrahepatic biliary tree invasion can be divided into four types, namely:

  • Type I: direct extramural spread
  • Type II: continuous intramural spread
  • Type III: distant spread separated from the primary tumor
  • Type IV: spread of cancer cells from metastatic lymph nodes.


Routine bile duct resection has no impact on survival and is not associated with higher lymph node yield.[12] Unless there is a positive cystic duct margin to warrant additional re-excision, bile duct resection can be avoided. In cases when there is concern, intraoperative frozen section of the cystic duct stump margin can help determine the need for extended duct resection. Extrahepatic biliary tract excision is reserved for patients in the above scenarios or for microscopic involvement of cystic duct margin on intraoperative frozen section evaluation. Routine extended resections in GBC patients are associated with higher morbidity rates.[24] In well-selected patients, the resection of other organs, including the stomach, colon, and duodenum, in the absence of distant metastatic disease, may be resected to ensure R0 resection.


  Extent of Lymph Node Dissection in Gallbladder Cancer Top


The incidence of LN involvement varies by T-stage, approximating 12%, 31%, and 45% in patients with T1b, T2, and T3 tumors, respectively.[12] The presence of N1 nodal disease is not considered an absolute contraindication to surgical resection. At least six lymph nodes should be removed during surgery for accurate staging.[25] The highest peripancreatic lymph node marks the transition between the N1 and N2 fields and has been found to be prognostic. A standard portal lymphadenectomy for gallbladder cancer beyond T1a includes nodes in the porta hepatis, gastrohepatic ligament, and retroduodenal space (stations 8, 12, and 13).


  Evaluation and Management of Suspected Gallbladder Carcinoma Top


Patients may present with symptoms of indigestion, pain, weight loss, jaundice, presence of a palpable mass, as well as nonspecific symptoms such as weight loss, lethargy, and loss of appetite. Patients may also present with signs of migratory thrombophlebitis or with signs of lung/ bone metastases.

Preoperative workup

Patients without tissue diagnosis

Pathologic diagnosis in non-incidental disease is considered unnecessary for patients who are potentially resectable. Xanthogranulomatous cholecystitis associated with large gallstones and extensive inflammation remains a diagnostic dilemma and limits the ability to perform simple cholecystectomy. Few authors recommend extensive intraoperative core-needle biopsies with immediate frozen section analysis before committing to radical resection.[10],[26],[27]

Role of staging laparoscopy

GBC has a propensity to involve regional nodes and peritoneal surfaces, therefore, staging laparoscopy is recommended in all patients with suspected GBC. This can prevent futile laparotomy in 38% to 62% of patients with additional detection of N2 disease with the help of intraoperative ultrasound.[14],[16]

Liver resection in suspected gallbladder cancer

Tumors limited to the wall of the gallbladder (T1b to T3) are recommended to undergo radical resection, which includes hepatic resection, portal lymphadenectomy with or without extrahepatic biliary tree excision. The goal of the liver resection is to ensure a margin of resection of approximately 1 to 2 cm because there is no serosal surface on the liver side of the gallbladder. The size of the segment IVB/ V resection should be adjusted depending on the pathologic depth and imaging characteristics of the tumor. The standard resection is an anatomic resection of segments IVB and V; however, it is possible to do a smaller wedge resection for early-stage cancers with no radiographic disease in the liver. If a segment IVB/ V resection would result in an inadequate margin, an extended right hepatectomy may be required.[28]

Surgical principles regarding lymph node dissection and biliary tract excision in suspected GBC remain the same as described for IGBC.


  Obstructive Jaundice and Management Top


The presence of jaundice suggests malignant invasion of the biliary tree and a majority will have disseminated disease even if it is not detectable on preoperative workup or operative exploration. These patients, therefore, require meticulous preoperative evaluation. The median disease-specific survival among jaundiced patients is only 6 months.[29] These patients usually require en bloc resection of the common hepatic duct/common bile duct and are associated with positive margins in 40%.[30] Although biliary or intestinal bypass can be considered for palliation of obstructive jaundice, stenting through a percutaneous or endoscopic approach is generally preferred as the median survival for these patients is less than 6 months.[31] Drainage of as little as 30% of the liver parenchyma may be sufficient to adequately palliate jaundice and relieve pruritus. Success rates for endoscopic stenting are similar to percutaneous technique but are associated with higher complication rates particularly cholangitis.[32] As a result, in most institutions, an initial endoscopic attempt at drainage is made only if local endoscopic expertise is available.


  Neoadjuvant Approaches in Gallbladder Cancer Top


The neoadjuvant approach to initially unresectable GBC is a concept that is gaining ground. Since surgical resection is the only curative treatment available in GBC, there is a suggestion that downstaging initially unresectable tumors after neoadjuvant chemotherapy or neoadjuvant CRT may enable increased numbers of patients to undergo surgery and potential cure. Whereas a number of small prospective and retrospective studies have shown promising outcomes with such an approach regarding increasing resectability, further prospective studies are required to ensure uniform selection criteria for such patients as well as to evaluate actual improvement in survival.[47],[48],[49] Investigators at Tata Memorial Hospital (Mumbai, Maharashtra, India) are conducting one such prospective trial, POLCA-GB, with precisely such a mandate.[50] The trial aims to compare chemotherapy alone (four cycles of gemcitabine-cisplatin or gemcitabine-oxaliplatin) versus CRT (RT concurrent with gemcitabine) followed by chemotherapy (two cycles of gemcitabine-cisplatin or gemcitabine-oxaliplatin) with the goal being to downstage initially unresectable GBC and permit potentially curative resection.


  Adjuvant Treatment of Resected Gallbladder Cancer Top


The role of adjuvant chemotherapy

The decision for adjuvant chemotherapy (and treatment) in the current era should be based on recent evidence as opposed to the data collected over multiple treatment periods. The single randomized control trial by Takada et al., published in 2002, while comprising the entire cohort of biliary tract cancers showed a significant survival benefit for the GBC subset with adjuvant chemotherapy as opposed to observation. However, the regimen used (5-fluorouracil [5-FU] plus mitomycin C) would be considered potentially outdated by current standards.[33] Whereas there was a surfeit of RCTs over the last decade addressing adjuvant chemotherapy for operated GBC, two studies in quick succession with contrasting results over the last two years have helped enunciate management strategies.

The randomized phase III trial PRODIGE 12-ACCORD 18 (UNICANCER GI) evaluated adjuvant gemcitabine and oxaliplatin versus surveillance in 196 patients with resected localized biliary tract cancer. Patients were randomized within 3 months of R0 (85%) or R1 resection, lymph node involvement was seen in 36%, and median follow-up was 44 months. Median recurrence-free survival (RFS) was 30.4 months (95% CI, 15.4–45.8) versus 22 months (95% CI, 13.6–38.3) (P = 0.31) suggesting no benefit of adjuvant chemotherapy.[34] In sharp contrast to the negative results of the PRODIGE 12-ACCORD 18 trial, the results of the BILCAP trial evaluating adjuvant single-agent capecitabine versus observation in operated biliary tract cancers (BTC) showed a significantly improved survival with adjuvant chemotherapy (per protocol analysis – 53 vs. 36 months; P = 0.028). The BILCAP study comprised 18% of patients with GBC.[35] While the results of these two large trials are potentially contradictory, current recommendations for adjuvant chemotherapy also take into account the results of the meta-analyses by Horgan et al., Ma et al., and Ghidini et al.[36],[37],[38] The meta-analyses specifically suggest a benefit for adjuvant chemotherapy, maximally in patients with R + resections, lymph node positivity, and Stage II and above disease. The meta-analysis by Ghidini et al. clearly identified a weighted mean overall survival (OS) difference between adjuvant chemotherapy and control arms of 4.3 months (95% CI, 0.88–7.79, P = 0.014), with adjuvant chemotherapy reducing the risk of death by 41% (hazard ratio = 0.59, 95% CI, 0.49–0.71; P < 0.001).

Suggestions based on the current evidence for adjuvant chemotherapy in resected GBC include the following:

  • Adjuvant chemotherapy for patients with T1b and above disease
  • Adjuvant chemotherapy for patients with node-positive disease
  • A specific recommended regimen for adjuvant chemotherapy to be used is yet undecided; however, acceptable regimens would be single-agent capecitabine and gemcitabine-based regimens (single-agent gemcitabine and gemcitabine-cisplatin).



  The Role of Adjuvant Chemoradiotherapy in Resected Gallbladder Cancer Top


Adjuvant chemoradiotherapy is one of the recommended practices in major guidelines.[10],[39] There are no randomized studies establishing the role of adjuvant radiotherapy (RT)/concurrent chemoradiation (CRT) in resected GBC. Data are limited to retrospective series from single institutions and large national databases, with heterogeneity regarding patients with different types of biliary tract cancers (including intrahepatic and extrahepatic cholangiocarcinomas), older RT techniques, nonstandard treatment, and incomplete surgery.

Mitin et al. evaluated the outcomes of 5029 patients with T1-T3 N0-1 GBC treated with surgery followed by adjuvant therapy using data from the National Cancer Database of the USA. Adjuvant CRT as compared to observation alone significantly improved the 3-year OS with a hazard ratio of 0.47 (95% CI, 0.39–0.58) in a majority of tumor stages, excepting T1N0M0 tumors.[40] Whereas the extent of locoregional as opposed to systemic relapses in GBC recurrences may be debated, combining chemotherapy with CRT may maximize local control, and reduce distant recurrence.[41]

Whereas no randomized Phase III data exist that compare adjuvant chemotherapy with adjuvant CRT, Horgan's meta-analysis identified a benefit for CRT as an adjuvant strategy.[36] Most of this benefit was in patients who had R + resections and node-positive disease. The single-arm SWOG S0809 phase II trial, which evaluated the role of chemotherapy (gemcitabine-capecitabine) and CRT (RT concurrent with capecitabine) in patients with resected BTC (24% GBC; n = 79) is one of the major trials in the modern era which has shown good outcomes with adjuvant CRT (Median OS-35 months).[42] Adjuvant RT has shown improvement in survival compared to surgery alone in studies extracted from the SEER database.[43] High stage (T2 and above) and node-positive patients derived maximum benefit from adjuvant RT, while data exist for adjuvant radiation alone in resected BTC/ GBC, it would be difficult to offer adjuvant radiotherapy alone in the current era, considering the benefits of adjuvant chemotherapy, and CRT seen in recent trials.[41],[44]

Radiation volume and dose

The treatment volume encompasses the tumor bed (porta and resected margins) and the regional nodes such as porta hepatis, peripancreatic, celiac, and paraaortic. The preferred radiation dose schedule is 45 Gy in 25 fractions over 5 weeks (1.8 Gy per fraction) along with concurrent chemotherapy. A boost of 5 to 9 Gy should be given to the region of positive margins while 15 Gy may be given in cases of the gross residual lesion based on normal tissue tolerance.[41],[45] Three-dimensional conformal radiotherapy/intensity-modulated radiotherapy is the preferred radiation technique for reducing normal tissue toxicity. Key concerns while offering radiotherapy to the patients with GBC would be the toxicity to the liver, right kidney, and duodenum/ stomach/ small bowel. The dose constraints to organs at risk are as follows: Duodenum: volume (V) receiving 50 Gy < 10% and volume receiving 40 Gy < 35%, small bowel: mean dose of < 45 Gy, kidney: mean dose < 18 Gy to both kidneys, and liver: V35 Gy < 35%.

Suggested indications regarding adjuvant CRT in resected GBC include

  • For patients with T stage T2 and above disease
  • For patients with node-positive disease
  • For patients with R + resection status
  • Either gemcitabine or capecitabine can be combined with radiotherapy.[10],[39]



  Follow-Up Guidelines for Resected gallbladder Cancer Top


There are no data to support a single standard follow-up schedule. Follow-up visits may include clinical examination, blood tests (including tumor markers CA19-9 and CEA) and CT scan of chest, abdomen, and pelvis. There must be a physician–patient discussion regarding appropriate follow-up scheduling and imaging. After potentially curative treatment, follow-up should consist of 3-monthly visits during the first 2 years after therapy, followed by 6-monthly visits until 5 years, and annual visits after 5 years of follow-up.[10] The National Comprehensive Cancer Network guidelines recommend imaging every 6 months for 2 years if clinically indicated, then annually up to 5 years.[46]

During treatment for advanced disease, follow-up should be conducted at a frequency of 2 to 3 months to allow the best assessment of treatment efficacy or as required for disease-related complications.


  Management of Metastatic/unresectable Gallbladder Cancer Top


Most patients with GBC present with unresectable or metastatic disease (70% to 90%). The current standard of care for advanced GBC is palliative chemotherapy using a gemcitabine-based doublet, with cisplatin or oxaliplatin commonly being the accompanying drug. This is based on the seminal ABC-02 and BT-22 trials which compared gemcitabine-cisplatin to gemcitabine, and the trial from All India Institute of Medical Sciences (AIIMS), New Delhi, India, which compared gemcitabine-oxaliplatin to 5-fluorouracil and best supportive care.[51],[52],[53] The ABC-02 trial comparing gemcitabine-cisplatin to gemcitabine found an OS benefit for the doublet regimen (11.7 vs. 8.1 months; P < 0.001). The study from AIIMS also showed an OS benefit for the gemcitabine-oxaliplatin compared to single-agent 5-fluorouracil and best supportive care (9.5 vs. 4.6 vs. 4.5 months; P = 0.039). There are no comparative published trials comparing the regimens; usage is essentially individual or institution-based.[54],[55] Patients with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 to 2 may be considered for single-agent gemcitabine, while patients with ECOG PS 3 or 4 may be considered for palliative care alone. It may also be added that patients with ECOG PS 3 to 4 have not been included in the major trials for advanced BTC/ GBC, and the benefit or lack of benefit with palliative chemotherapy in such patients has not been systematically addressed. Besides gemcitabine-based regimens, 5–fluorouracil-based regimens can also be considered in case gemcitabine-based regimens are not feasible. All patients with metastatic or unresectable disease should have access to palliative care concurrent with ongoing chemotherapy.

A majority of patients with advanced GBC progress on first-line chemotherapy within approximately 8 months of therapy. Postprogression outcomes remain guarded; however, there appears to be a role for second-line chemotherapy in a select group of patients with well-maintained ECOG PS.[56] In an ideal scenario, such patients should be enrolled in clinical trials evaluating the role of chemotherapy in such a setting. Commonly used regimens include 5-FU or capecitabine monotherapy, or combination of capecitabine/ 5–FU with oxaliplatin and irinotecan.[56],[57]

Studies examining chemotherapy with monoclonal antibody combinations have been evaluated with disappointing results and are not recommended outside of a clinical trial. Suggested first-line regimens for advanced GBC, besides enrolment in a clinical trial are:

  • Gemcitabine-cisplatin
  • Gemcitabine–oxaliplatin
  • Gemcitabine–capecitabine[58],[59]
  • Single-agent gemcitabine.



  Conclusions Top


GBCs are a component of the biliary tract cancer spectrum that require specific management in the Indian scenario, considering their high incidence and prevalence. Good quality optimal surgery, avoidance of unnecessarily morbid surgeries, the use of radical cholecystectomy in patients with disease beyond T1a stage, and correct selection of adjuvant therapy are paramount to maximize outcomes in resected GBC. Patients, who have unresectable but non-metastatic cancers, should be enrolled in clinical trials evaluating downstaging approaches with neoadjuvant chemotherapy or chemoradiation. Patients with unresectable and metastatic disease should be treated with palliative first-line chemotherapy with ongoing supportive care concurrently.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  In this article
Abstract
Introduction
Epidemiological ...
Initial Diagnosi...
Incidental Gallb...
Extent of Lymph ...
Evaluation and M...
Obstructive Jaun...
Neoadjuvant Appr...
Adjuvant Treatme...
The Role of Adju...
Follow-Up Guidel...
Management of Me...
Conclusions
References
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