Study of losartan and SOC therapy in advanced biliary tract cancer

Among biliarytract cancers, Gall bladder cancer (GBC) is the commonest malignancy withtypical geographic distribution. GBC incidence is high in north andnorth-eastern India. As per Delhi cancer registry, GBC is the third commoncancer in females with ASR of 10/100000 population. In India each year>18,000 new gall bladder cancers are diagnosed.More than 80% present inadvanced/unresectable stage and median survival of untreated patient is 2-4months.

It is highlyaggressive cancer having poor outcomes across the globe. It is the commonestcause of cancer related death in

Chile and innorthern India (1).  GBC has certainpeculiarities like anatomical location which makes the detection of cancerdifficult in early stages. It presents with obstructive jaundice whichprecludes early start of chemotherapy and for many patients best supportivecare is the only treatment offered.

Atul Sharma et al first studied the role ofchemotherapy versus best supportive care in advanced gall bladder cancer (2) and established the role of chemotherapy.  Genetically, majority of gall bladder cancersare carrying p53 mutations which may lead to resistance to chemotherapy. Combinationof Gemcitabine and Platinum; Gemcitabine-Cisplatin (Gem-Cis) or modifiedGemcitabine-Oxaliplatin (mGemOx) are first line therapy formetastatic/unresectable GBC based on randomized studies (3). Five-year survival rates of gall bladder cancers are 50% for stageI, 28% for stage II, and less than 10% for inoperable stage III cancers. Thissuggests that even curative surgery is not successful in majority of GBCpatients whose tumor has spread beyond muscle layer or has involved lymph nodes.GBC has tendency for bothloco-regional and distant failures. It may involve surrounding adjacentstructures such as the liver, stomach, duodenum, pancreas, colon, omentum, orabdominal wall. Recent publications have highlighted the importance of targetedtherapies in biliary tract cancers. Gall bladder cancer is enriched withHer2neu amplification in 17-20% of cases, Her3neu amplification in 10 % ofcases. MET amplifications are seen in around 5% of cases (4–6). These targets have beentreated successfully in other malignancies and are routinely used in clinicalpractice. At our institute, our data from departmental study has also revealedsimilar findings in limited number of patients (3). This merits to take forwardthis research, which will answer the long-awaited questions in advanced biliarytract cancers.

  Biliary tractcancers (BTCs) have varied and unique incidence pattern and it has increasingtrend. 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 leastcommon in Europe (ASR < 2) & United States (ASR 2.2) (7). Interestingly,incidence varies in different parts of the county. In Thailand’s north eastregion, it is the most common as mentioned, ASR is 14.5 and 5.7 inNorth-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 inwestern world, precluded BTCs from research in field of targeted and moleculartherapies. The prognosis of GBC has not changed in last 20 years (10).Gemcitabine with Cisplatin or Oxaliplatin remained the standard of choice oftreatment in metastatic BTCs as first line setting and there is no establishedsecond line therapy available till date(11,12). CCAare classified as intra-hepatic (iCCA), perihilar (pCCA) and distal CCA (dCCA).CCA and GBC are treated altogether in clinical trials considering theiranatomical location, physiological common functions and clinical presentations.Rapid progress has been made as the next generation sequencing (NGS) reduce thetime 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: A25-year trend analysis. Indian Journal of Cancer. 2017 Jan 10;54(4):673.

2.         SharmaA, Dwary AD, Mohanti BK, Deo SV, Pal S, Sreenivas V, et al. Best supportivecare compared with chemotherapy for unresectable gall bladder cancer: arandomized controlled study. J Clin Oncol. 2010 Oct 20;28(30):4581–6.

3.         SharmaA, Shukla NK, Chaudhary SP, Sahoo R, Mohanti B, Deo SVS, et al. Final resultsof a phase III randomized controlled trial comparing modified gemcitabine +oxaliplatin (mGEMOX) to gemcitabine+ cisplatin in management of unresectablegall bladder cancer (GBC). JCO. 2016 May 20;34(15_suppl):4077–4077.

4.         GaldyS, Lamarca A, McNamara MG, Hubner RA, Cella CA, Fazio N, et al. HER2/HER3pathway in biliary tract malignancies; systematic review and meta-analysis: apotential therapeutic target? Cancer Metastasis Rev. 2017;36(1):141–57.

5.         JavleM, Rashid A, Churi C, Kar S, Zuo M, Eterovic AK, et al. MolecularCharacterization of Gallbladder Cancer using Somatic Mutation Profiling. HumPathol. 2014 Apr;45(4):701–8.

6.         JavleM, Churi C, Kang HC, Shroff R, Janku F, Surapaneni R, et al. HER2/neu-directedtherapy for biliary tract cancer. J Hematol Oncol. 2015 May 29;8:58.

7.         KhanSA, Tavolari S, Brandi G. Cholangiocarcinoma: Epidemiology and risk factors.Liver Int. 2019;39 Suppl 1:19–31.

8.         ShuklaHS, Sirohi B, Behari A, Sharma A, Majumdar J, Ganguly M, et al. Indian Councilof Medical Research consensus document for the management of gall bladdercancer. Indian J Med Paediatr Oncol. 2015;36(2):79–84.

9.         UnisaS, Jagannath P, Dhir V, Khandelwal C, Sarangi L, Roy TK. Population-based studyto estimate prevalence and determine risk factors of gallbladder diseases inthe rural Gangetic basin of North India. HPB. 2011;13(2):117–25.

10.       LindnérP, Holmberg E, Hafström L. Gallbladder cancer – no improvement in survival overtime in a Swedish population. Acta Oncologica. 2018 Nov 2;57(11):1482–9.

11.       ValleJW, Furuse J, Jitlal M, Beare S, Mizuno N, Wasan H, et al. Cisplatin andgemcitabine for advanced biliary tract cancer: a meta-analysis of tworandomised trials. Ann Oncol. 2014 Feb;25(2):391–8.

12.       YingJ, Chen J. Combination versus mono-therapy as salvage treatment for advancedbiliary tract cancer: A comprehensive meta-analysis of published data. CriticalReviews in Oncology/Hematology. 2019 Jul 1;139:134–42.

13.       LeeH, Ross JS. The potential role of comprehensive genomic profiling to guidetargeted therapy for patients with biliary cancer. Therap Adv Gastroenterol.2017 Jun;10(6):507–20.