Role of intraluminal brachytherapy in palliation of biliary obstruction in cholangiocarcinoma:A brief review

lNTRODUCTlON

Biliary tract carcinomas,also known as cholangiocarcinomas,may be intrahepatic or extrahepatic.Intrahepatic cholangiocarcinomas arise from the biliary duct epithelium within the liver parenchyma.Extrahepatic cholangiocarcinomas include hilar and distal cholangiocarcinomas.Among these variants,the hilar variety,also known as Klatskin tumor,is the most common.It arises at the junction of the right and the left hepatic ducts.

If a sailor unties4 one knot, he has a fair wind; when he unties the second, it blows hard; but if the third and fourth are loosened, then comes a storm, which will root up whole forests

The Asian population is more susceptible to developing bile duct carcinomas.The disease is more frequently seen in Thailand,India,Japan,and Korea.The incidence varies from 0.3 to 6

lakh population[1].Surgery is the only curative treatment.However,the disease is resectable only in a minority of the cases.Biliary obstruction is common and results in symptoms such as jaundice,intense pruritis,or pain abdomen.The various means of palliation include biliary drainage procedures,which may be endoscopic or percutaneous,external beam radiation therapy (EBRT),palliative chemotherapy,and intraluminal brachytherapy (ILBT) with or without EBRT.

CLlNlCAL FEATURES AND PATHOLOGY

Cholangiocarcinoma is a disease of the elderly,mostly affecting those more than 60 years of age.It is seen more commonly in males as compared to females.The risk factors include parasitic infection by organisms such as

and

,biliary stones,and smoking.Primary sclerosing cholangitis and hepatitis C are the other risk factors.Primary sclerosing cholangitis with or without cholangitis is the commonest risk factor in Western countries[2].

In the early stages,the patient is usually asymptomatic.The signs and symptoms are non-specific.These may include pain abdomen,fever,jaundice,loss of weight,loss of appetite,generalized itching,and other features of biliary obstruction.Distant metastasis is fairly common[3].Most of the patients present with either locally advanced or metastatic disease.

Deufel

[41] have described the HDR brachytherapy in patients with cholangiocarcinoma

a nasobiliary route[41].They did the procedure using an 8.5 Fr or 10 Fr nasobiliary catheter inserted

ERCP technique.This was followed by insertion of a 4.7 Fr treatment catheter into the nasobiliary catheter.The dose schedules described are a single fraction of 9.3 Gy or fractionated regime using four fractions of 4 Gy delivered twice a day.For patients who are suitable for liver transplantation after neoadjuvant chemoradiation,the minimally invasive nasobiliary approach may be preferred as there is a higher risk of tumor seeding with transhepatic technique[42].However,the nasobiliary route is technically more difficult and may not be preferred in the palliative setting.

Sahai

[22] reviewed the literature on the role of radiation in adjuvant,neoadjuvant,definitive,and palliative settings.They concluded that stenting with palliative radiotherapy,either external or brachytherapy,improves the stent patency rates and survival in unresectable cholangiocarcinoma[22].

DlAGNOSTlC WORK-UP

Ultrasonography (USG) is the baseline investigation done whenever a biliary obstruction is suspected.It may reveal dilated biliary channels,any mass,or the presence of gallstones.Contrast-enhanced computed tomography (CECT) is the standard imaging tool,especially for staging and preoperative assessment.The delayed scans are useful for diagnosing intrahepatic cholangiocarcinomas which may show contrast enhancement on delayed scans due to abundant fibrous stroma[5-7].However,CECT may not show the true longitudinal extent of perihilar cholangiocarcinoma[8].Magnetic resonance imaging (MRI) with magnetic resonance cholangiopancreatography (MRCP) is considered the imaging modality of choice.It allows the assessment of the entire biliary tree as well as the vascular anatomy[9].

Cancer antigen (CA) 19-9,carcinoembryonic antigen (CEA),and CA-125 are the non-specific tumor markers,which may help in establishing the diagnosis[10].Tissue diagnosis is essential before a patient can be given chemotherapy or radiotherapy.This may be quite challenging,especially if the patient has primary sclerosing cholangitis or biliary strictures.The biopsy samples,collected by endoscopic imaging and tissue sampling,are usually inadequate for molecular typing.In this setting,liquid biopsy holds promise.It is mainly based on circulating free DNA and circulating tumour DNA[11].Cholangiocarciomas exhibit specific RNA profiles in extra-cellular vesicles in a patient’s serum and urine.It is one of the promising liquid biopsy markers[12].

MANAGEMENT

The most frequent complication of ILBT is cholangitis[45].Other side effects of PTBD combined with ILBT include nausea,vomiting,and gastroduodenal ulceration[34].

Bonet Beltrán

[21] did a systematic review and meta-analysis in patients with extrahepatic bile duct cancer.The authors reported a significant benefit of adjuvant radiation,especially in patients with extrahepatic cholangiocarcinoma.This benefit was seen in terms of improved overall survival[21].

Cholangiocarcinomas are histologically adenocarcinomas in 95% of cases[2].These can be well-differentiated,moderately differentiated,or poorly differentiated[4].

The tears flowed freely when I entered the dining room. The clock stood forlornly quiet. As quiet as the funeral parlor6 had been. Hushed. The clock even seemed smaller. Not quite as magnificent without my grandfather s special touch. I couldn t bear to look at it.

There is no definite consensus on the role of adjuvant chemotherapy.The studies have reported variable results.A retrospective study on patients with hilar cholangiocarcinoma showed a significant improvement in survival in those who received adjuvant chemotherapy[23].The greatest benefit of adjuvant chemotherapy is seen in those with lymph node positive or resection margin positive status[24].After the BILCAP study,capecitabine is considered to be the standard treatment for biliary tract cancers in the adjuvant setting[25].

Neoadjuvant therapy has been explored in cholangiocarcinoma with the aim to achieve negative surgical margins and improve survival rates.Nelson

[26] conducted a study in patients diagnosed with extra-hepatic cholangiocarcinoma.These patients received neoadjuvant chemo-radiotherapy with 5-flourouracil and EBRT with or without brachytherapy.They reported a R0 resection rate of 91.7%[26].Similar results have been reported by Jung

[27] and Sumiyoshi

[28].

Novel treatment options are opening the doors of a new world.There is increasing interest in the use of targeted therapy and immunotherapy.Targeted therapies have demonstrated a role in mainly intrahepatic cholangiocarcinoma[29].Fibroblast growth factor receptor (FGFR) aberrations and isocitrate dehydrogenase (IDH) mutations based therapy hold promise[30,31].

There are several ongoing trials on immunotherapy in advanced biliary tract cancers.Although monotherapy with immune check-point inhibitors or their combination with other anti-cancer agents shows only modest survival advantages and efficacy,there is a need to test these patients for deficiency in mismatch repair proteins (dMMR),high microsatellite instability (MSI-H),increased tumor mutational burden (TMB),and programmed death-ligand 1 (PD-L1) expression[32,33].

Due to low resectability,the goal of treatment is palliation in most of the patients.Endoscopic retrograde cholangiopancreaticography (ERCP) or percutaneous transhepatic biliary drainage (PTBD) are the initial procedures that may be used to relieve biliary obstruction resulting from cholangiocarcinoma.These procedures are only palliative with a median survival of around 6 mo[34].This article provides a concise overview of the role of ILBT in the palliation of biliary obstruction.Biliary drainage,which is done either endoscopically or percutaneously,can palliate symptoms,but ILBT can decrease the tumor size and delay the tumor ingrowth.

ILBT offers an effective means of palliating biliary obstruction in patients with cholangiocarcinoma.The article focuses mainly on the role of ILBT in the palliation of malignant biliary obstruction.ILBT delivers a high dose of radiation to the tumor with sparing of surrounding normal tissues,thus avoiding many of the side effects seen with external beam radiation.The high dose

fraction in ILBT can have an ablative effect on the tumor and can lead to better symptom control and quality of life.The transhepatic approach is preferred over the endoscopic technique as ILBT is easier to perform when combined with PTBD as compared to ERCP.ILBT,when combined with these drainage procedures,improves the stent patency rates by inhibiting tumor ingrowth.There is a need for prospective studies to compare the quality of life and outcome in such patients using ILBT.

ROLE OF BRACHYTHERAPY

ILBT can be used in cholangiocarcinomas with both palliative and curative intent.With curative intent,it can be used following chemoradiotherapy to escalate the tumor dose and thus increase the local control[35].The main indication in the palliative setting is to relieve the biliary obstruction.The mechanism may be

preventing stent re-occlusion,which may occur due to tumor ingrowth[36,37].

In the same manner he was respectfully given to understand that he must wait, and after several hours the sixty hooded55 and shrouded56 figures re-appeared, and conducted him with great ceremony, and also very very slowly, to a banqueting hall, where they all placed themselves at a long table

When ILBT is combined with EBRT,usually 30-40 Gy are delivered

EBRT and 15-20 Gy in 2-3 fractions

high dose rate (HDR) brachytherapy.When pulsed dose rate brachytherapy (PDR) is used in the combined modality setting,a single course of 20 Gy is usually prescribed[3].In the palliative setting,the HDR ILBT dose is usually 15-20 Gy in 3-4 Gy/fraction.When PDR brachytherapy is used,1 or 2 fractions of 20-40 Gy may be prescribed[3].

ILBT techniques,dose,and response

ILBT can be performed using ERCP or PTBD.Whenever possible,percutaneous transhepatic technique is preferred.It is reported that when PTBD is combined with ILBT,the median survival time increases[38,39].The feasibility of ILBT is better with PTBD.Lesions in the right and left hepatic duct,as well as the common bile duct,can be easily assessed.Before PTBD,imaging is done to know the exact site and extent of the obstruction.It can be assessed

USG,CT,or MRI.First,percutaneous transhepatic cholangiography is performed followed by biliary decompression.ILBT catheters are inserted when serum bilirubin levels decrease and the patient stabilizes.Jain

[40] performed ILBT when the serum bilirubin levels decreased to 2 mg% or fell to 50% of the baseline.Other inclusion criteria reported by them included Eastern Cooperative Oncology Group (ECOG) performance status 0-2;absence of fever,signs of cholangitis,or any evidence of distant metastasis[40].Aggarwal

[34] did ILBT after biliary drainage

PTBD when the serum bilirubin levels were below 5 mg%[34].They did PTBD under USG and fluoroscopic guidance.After biliary decompression,an internal-external drainage tube was inserted and left in place for 7-10 d to allow bilirubin levels to fall and the patient’s general condition to improve.When ILBT was performed,the external-internal catheter was replaced with brachytherapy catheter.Its tip was placed 1.5-2 cm beyond the distal end of the stricture.These patients received a dose of 8 Gy in 2 fractions at an interval of 1 wk

HDR brachytherapy.Various brachytherapy doses and schedules are described in the literature.Jain

[40] used a dose of 10-14 Gy at 1 cm from the central axis of the source,which was delivered

HDR microselectron[40].

Long ago there lived two brothers, both of them very handsome, and both so very poor that they seldom had anything to eat but the fish which they caught

On the third31 morning after they had left their father s house they set about their wandering again, but only got deeper and deeper into the wood, and now they felt that if help did not come to them soon they must perish

Bruha

[37] in their study on cholangiocarcinoma patients with malignant obstructive jaundice treated by HDR ILBT,showed that the mean stent patency was 418 d[37].Jain

[40] reported a mean stent patency duration of 9.4 mo in patients with cholangiocarcinoma treated by PTBD and ILBT[40].

Chen

[43] showed a similar trend in their study.The stent patency rate in patients who underwent ILBT with PTBD was 45%.However,this rate was just 21%in the group of patients who had only stent placement.The dose of ILBT used was 14-21 Gy in 3-4 fractions.The duration of stent patency was also significantly greater in the ILBT group[43].

Aggarwal

[34] reported an improvement in symptoms such as fatiguability,nausea,vomiting,pain,icterus,pruritis,dyspnea,insomnia,and loss of appetite after palliation with PTBD combined with ILBT[34].Mayer

[44] reported symptomatic improvement in pruritis and jaundice in all their patients with unresectable bile duct malignancy after biliary decompression with PTBD followed by ILBT.The dose of brachytherapy in their study was 2.5 Gy in 2 fractions

day for a total dose of 10 Gy.However,five of their patients also received EBRT[44].Few of the studies in which brachytherapy has been used with palliative intent,mainly to relieve biliary obstruction,are presented in Table 1.

Complications

Surgery is the only curative treatment for cholangiocarcinomas.The disease is resectable in only 10%-15% of the patients[13,14].The low resection rates may be due to invasion of the hepatic artery or portal vein,lymph node involvement,or the invasion of the adjacent structures.Some patients may present with peritoneal or distant metastasis,so are inoperable,and need to be managed with palliative intent.Operative mortality has been reported to be 5%-10% in some studies[14-16].The 5-year survival rates after surgery are 9%-18% for proximal bile duct lesions and 20%-30% for distal bile duct lesions[2].Although phase 2 studies and some retrospective studies suggest the advantage of adding adjuvant therapy,there are no phase 3 studies to support this[17-20].

Limitations

ILBT is not used frequently due to the lack of availability and expertise and patient’s moribund condition due to disease.Also,there is paucity of literature,and a lack of survival benefit.But in patients with malignant biliary obstruction,it can be used as an adjunct to systemic therapies.It can be used as an adjunct to biliary drainage in the palliative setting.

CONCLUSlON

Elizabeth and I are 18 now, and about to graduate. I think about our elementary-school friendship, but some memories have blurred. What happened that day in fifth grade when Beth suddenly stopped speaking to me? Does she know that I ve been thinking about her for seven years? If only we could go back, discover what ended our relationship.

However, it was not long after our honeymoon1 when my husband climbed into the tomb called the office and wrapped his mind in a shroud2 of paperwork and buried himself in clients, and I said nothing for fear of turning into a nagging3 wife. It seemed as if overnight an invisible wall had been erected4 between us.

Khosla D contributed to conceptualization and manuscript preparation,writing,and editing and was responsible for the integrity of the article;Zaheer S and Gupta R contributed to literature search and manuscript writing and editing;Madan R contributed to literature search;Goyal S contributed to manuscript editing;Kumar N and Kapoor R reviewed and approved the manuscript.

The authors declare no conflicts of interest in the preparation of the manuscript.

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers.It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BYNC 4.0) license,which permits others to distribute,remix,adapt,build upon this work non-commercially,and license their derivative works on different terms,provided the original work is properly cited and the use is noncommercial.See:https://creativecommons.org/Licenses/by-nc/4.0/

India

Divya Khosla 0000-0002-7912-115X;Samreen Zaheer 0000-0002-9769-8593;Rahul Gupta 0000-0002-5775-0959;Renu Madan 0000-0002-6649-4328;Shikha Goyal 0000-0002-9972-6682;Narendra Kumar 0000-0002-3755-8900;Rakesh Kapoor 0000-0003-3789-1591.

Fan JR

What a torment57 her stout58 old attendants and servants sometime thought her when she insisted on staying awake, and making them chatter52 or do something, when they could hardly keep their eyes open! Sometimes, however, the princess would pretend to go to sleep, and then, after all her women had gladly followed her example, she would get up and go out by herself, her veil hanging loosely about her

When my friend asked me What will make this love last? I ran through all the obvious reasons: commitment, shared interests, unselfishness, physical attraction, communication. Yet there s more. We still have fun. Spontaneous good times. Yesterday, after slipping the rubber band off the rolled up newspaper, Scott flipped4 it playfully at me: this led to an all-out war. Last Saturday at the grocery, we split the list and raced each other to see who could make it to the checkout5 first. Even washing dishes can be a blast. We enjoy simply being together.

Wang TQ

Fan JR

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