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Brief Summary
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Among biliary
tract cancers, Gall bladder cancer (GBC) is the commonest malignancy with
typical geographic distribution. GBC incidence is high in north and
north-eastern India. As per Delhi cancer registry, GBC is the third common
cancer in females with ASR of 10/100000 population. In India each year
>18,000 new gall bladder cancers are diagnosed. More than 80% present in
advanced/unresectable stage and median survival of untreated patient is 2-4
months.
It is highly
aggressive cancer having poor outcomes across the globe. It is the commonest
cause of cancer related death in
Chile and in
northern India (1). GBC has certain
peculiarities like anatomical location which makes the detection of cancer
difficult in early stages. It presents with obstructive jaundice which
precludes early start of chemotherapy and for many patients best supportive
care is the only treatment offered.
Atul Sharma et al first studied the role of
chemotherapy versus best supportive care in advanced gall bladder cancer (2) and established the role of chemotherapy. Genetically, majority of gall bladder cancers
are carrying p53 mutations which may lead to resistance to chemotherapy. Combination
of Gemcitabine and Platinum; Gemcitabine-Cisplatin (Gem-Cis) or modified
Gemcitabine-Oxaliplatin (mGemOx) are first line therapy for
metastatic/unresectable GBC based on randomized studies (3). Five-year survival rates of gall bladder cancers are 50% for stage
I, 28% for stage II, and less than 10% for inoperable stage III cancers. This
suggests that even curative surgery is not successful in majority of GBC
patients whose tumor has spread beyond muscle layer or has involved lymph nodes.
GBC has tendency for both
loco-regional and distant failures. It may involve surrounding adjacent
structures such as the liver, stomach, duodenum, pancreas, colon, omentum, or
abdominal wall. Recent publications have highlighted the importance of targeted
therapies in biliary tract cancers. Gall bladder cancer is enriched with
Her2neu amplification in 17-20% of cases, Her3neu amplification in 10 % of
cases. MET amplifications are seen in around 5% of cases (4–6). These targets have been
treated successfully in other malignancies and are routinely used in clinical
practice. At our institute, our data from departmental study has also revealed
similar findings in limited number of patients (3). This merits to take forward
this research, which will answer the long-awaited questions in advanced biliary
tract cancers.
Biliary tract
cancers (BTCs) have varied and unique incidence pattern and it has increasing
trend. In some part of the world, these are the commonest cancers.
Cholangiocarcinoma (CCA) is most common cancer in Thailand (north east region)
with age standardised rate (ASR) per 100,000 populations of 85 and it is least
common in Europe (ASR < 2) & United States (ASR 2.2) (7). Interestingly,
incidence varies in different parts of the county. In Thailand’s north east
region, it is the most common as mentioned, ASR is 14.5 and 5.7 in
North-central and South region respectively. Similarly, Gallbladder cancer
(GBC) has varied incidence pattern across in India. In northern states of India,
it is the most common and in southern states it is the least common (8,9).
Rarity in
western world, precluded BTCs from research in field of targeted and molecular
therapies. The prognosis of GBC has not changed in last 20 years (10).
Gemcitabine with Cisplatin or Oxaliplatin remained the standard of choice of
treatment in metastatic BTCs as first line setting and there is no established
second line therapy available till date(11,12). CCA
are classified as intra-hepatic (iCCA), perihilar (pCCA) and distal CCA (dCCA).
CCA and GBC are treated altogether in clinical trials considering their
anatomical location, physiological common functions and clinical presentations.
Rapid progress has been made as the next generation sequencing (NGS) reduce the
time and hundreds of genes analysed at one go (13).
References
1. Malhotra RK,
Manoharan N, Shukla NK, Rath GK. Gallbladder cancer incidence in Delhi urban: A
25-year trend analysis. Indian Journal of Cancer. 2017 Jan 10;54(4):673.
2. 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 Oct 20;28(30):4581–6.
3. Sharma
A, Shukla NK, Chaudhary SP, Sahoo R, Mohanti B, Deo SVS, et al. Final results
of a phase III randomized controlled trial comparing modified gemcitabine +
oxaliplatin (mGEMOX) to gemcitabine+ cisplatin in management of unresectable
gall bladder cancer (GBC). JCO. 2016 May 20;34(15_suppl):4077–4077.
4. Galdy
S, Lamarca A, McNamara MG, Hubner RA, Cella CA, Fazio N, et al. HER2/HER3
pathway in biliary tract malignancies; systematic review and meta-analysis: a
potential therapeutic target? Cancer Metastasis Rev. 2017;36(1):141–57.
5. Javle
M, Rashid A, Churi C, Kar S, Zuo M, Eterovic AK, et al. Molecular
Characterization of Gallbladder Cancer using Somatic Mutation Profiling. Hum
Pathol. 2014 Apr;45(4):701–8.
6. Javle
M, Churi C, Kang HC, Shroff R, Janku F, Surapaneni R, et al. HER2/neu-directed
therapy for biliary tract cancer. J Hematol Oncol. 2015 May 29;8:58.
7. Khan
SA, Tavolari S, Brandi G. Cholangiocarcinoma: Epidemiology and risk factors.
Liver Int. 2019;39 Suppl 1:19–31.
8. Shukla
HS, Sirohi B, Behari A, Sharma A, Majumdar J, Ganguly M, et al. Indian Council
of Medical Research consensus document for the management of gall bladder
cancer. Indian J Med Paediatr Oncol. 2015;36(2):79–84.
9. Unisa
S, Jagannath P, Dhir V, Khandelwal C, Sarangi L, Roy TK. Population-based study
to estimate prevalence and determine risk factors of gallbladder diseases in
the rural Gangetic basin of North India. HPB. 2011;13(2):117–25.
10. Lindnér
P, Holmberg E, Hafström L. Gallbladder cancer – no improvement in survival over
time in a Swedish population. Acta Oncologica. 2018 Nov 2;57(11):1482–9.
11. Valle
JW, Furuse J, Jitlal M, Beare S, Mizuno N, Wasan H, et al. Cisplatin and
gemcitabine for advanced biliary tract cancer: a meta-analysis of two
randomised trials. Ann Oncol. 2014 Feb;25(2):391–8.
12. Ying
J, Chen J. Combination versus mono-therapy as salvage treatment for advanced
biliary tract cancer: A comprehensive meta-analysis of published data. Critical
Reviews in Oncology/Hematology. 2019 Jul 1;139:134–42.
13. Lee
H, Ross JS. The potential role of comprehensive genomic profiling to guide
targeted therapy for patients with biliary cancer. Therap Adv Gastroenterol.
2017 Jun;10(6):507–20.
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