Drainage Alone or Combined with Anti-tumor Therapy for Treatment of Obstructive Jaundice Caused by Recurrence and Metastasis after Primary Tumor Resection

Obstructive jaundice is a cumbersome complication in patients with advanced solid malignancies. The primary tumors associated with obstructive jaundice include primary biliary tract tumors, pancreatic tumors, tumor of the ampulla of Vatter, and tumor of the duodenum. However, obstructive jaundice can be caused by metastasis to the porta hepatic from many different tumors such as gastric , colon, and breast cancer (Burke et al., 2003; Dambraukas et al., 2003). It may cause refractory symptoms and often impedes further use chemotherapy (Iruarrizaga et al., 2011). Drainage or stenting of an obstruction can relieve symptoms and restore serum biochemistry to normal. Improvement in liver function by biliary drainage may provide symptomatic relief and allow for antitumor therapies, including transhepatic chemoembolization (TACE) and chemotherapy (Cui et al., 2012; Li et al., 2012; Mao et al., 2012; Kong et al., 2012; Xiong et al.,


Introduction
Obstructive jaundice is a cumbersome complication in patients with advanced solid malignancies.The primary tumors associated with obstructive jaundice include primary biliary tract tumors, pancreatic tumors, tumor of the ampulla of Vatter, and tumor of the duodenum.However, obstructive jaundice can be caused by metastasis to the porta hepatic from many different tumors such as gastric , colon, and breast cancer (Burke et al., 2003;Dambraukas et al., 2003).It may cause refractory symptoms and often impedes further use chemotherapy (Iruarrizaga et al., 2011).
Drainage or stenting of an obstruction can relieve symptoms and restore serum biochemistry to normal.Improvement in liver function by biliary drainage may provide symptomatic relief and allow for antitumor therapies, including transhepatic chemoembolization (TACE) and chemotherapy (Cui et al., 2012;Li et al., 2012;Mao et al., 2012;Kong et al., 2012;Xiong et al., prognosis for patients with obstructive jaundice (Qian et al., 2006).But others think that anti-tumor treatment can reduce patients' resistance, especially the immune function after radiation and chemotherapy, which increases the chances of infection and other complications in patients with long-term prognosis (F.J. et al., 1997).Our study is comparing the drainage combined with anti-tumor therapy and only drainage to treat the obstructive jaundice caused by recurrence and metastasis after primary tumor resection.

Materials and Methods
We retrospectively analysis 42 patients (man 27; women 15; mean age 59±15) with obstructive jaundice caused by recurrence and metastasis after primary tumor resection in January 2008 and August 2012, all patients have the history of primary tumor surgical resection before intervational treatment.The patients' characteristics are summarized in table 1.All patients provided written, informed consent for the procedure, and our institutional review board approved the retrospective review of the patients' medical and imaging records.
PTBD and/or PTBS was performed in the Interventional diagnosis and treatment center, with the patient under local anesthesia by two interventional radiologist, using continuous fluoroscopy.Intravenous prophylactic antibiotic was given before all procedures using a secondgeneration cephalosporin or according to the oncologist's recommendation.Biliary puncture were carried out using a 21G Chiba needle through the ninth or tenth intercostal space at the right hemiclavicular line level for the right-lobe bile duct access or by the left anterior subxiphoideal access for left-lobe bile ducts.After bile duct contrastation, a coaxial system (NPAS-100; Cook, Bjaeverskov, Denmark) was introduced and a 0.035-in.angled-tip hydrophilic guidewire (Glidewire; Terumo, Tokyo, Japan) was used to cross the stenotic/obstructive area.During the procedure, if the guide wire could pass through the occlusion and into the duodenum, we prefer to use stent (according to patient's will and economy).External drainage was the first choice if the patient has infection before procudure, stent placement was chosen until infection under control in two weeks.When the occlusion was not crossed, external drainage biliary catheter was placed.
Patients received individualized treatment according to the different types of the tumor and the patient's physical condition, which reference to Antineoplastic Protocols.Anti-tumor treatment including systemic chemotherapy and local treatment.Local treatment including 125 iodine combined with stenting, radiofrequency ablation or TACE.TACE could received many times according to CT or MRI results after 1 to 2 months follow-up.
We defined obstructive time preprocedure for patients is from emerge jaundice to procedure date, and collect TBIL and ALT values last time preprocedure and one week after procedure.Overall survival was defined as the time from the transhepatic biliary drainage to death for any cause.Overall survival was estimated by Kaplan-Meier.Prognostic factors were evaluated by t test and

Results
The procedures were all successful in 42 patients, no major complications occured during procedure.The external drainage was done in 24 patients for the first time, primary stenting was done in 16 patients, stent combined with external drainage in 2 patients.We remove the drainage catheter in one week in 1 patient with stent combined with external drainage.1 patient's bilirubin level decline is not obvious in one week after procedure, we found that the proximal stent stenosis by cholangiography, hence the tube was indwelled.7 patients were chosen external drainage because of infection before procedure, 4 patients was under control in one week, and then peform stent placement.New infections occured after procedure in 5 cases (combined treatment group in 3 cases, only drainage group in 2 cases), blood culture of bacteriology examination, training result according to the regular inspection line before antibiotics, when the culture result with sensitive antibiotics, infection was under control in 4 patients, 1 patient was died because of sepsis.Blood culture of bacteriology examination is routing, we use antibiotics by experiences before bacterial culture results come out, and chose sensitive antibiotic to treat by the outcome of the bacterial culture.
Stenting combined with iodine insert during the procedure in 3 patients (2 of gastric cancer, 1 of colon cancer), After procedure, 18 patients were treated with systemic chemotherapy for primary tumor (1 of esophageal carcinoma, 10 of gastric cancer, 2 of colon cancer, 1of rectal cancer, 2 of breast cancer, 2 of ovarian cancer), 3 patients were treated with local chemoembolism (1 of gastric cancer, 2of colon cancer), radiofrequency ablation was performed in 1 patient (colon cancer).In Combination group, the TBIL level from 254.7 umol/L before procedure fell to 171.3 umol/L after procedure, only drainage group from 337.5 umol/L fell to 199.4 umol/L, both of the two groups have statistical significance (Table 1).In combination group, the ALT level from 159.1  1).But there is no statistical significance between the two groups of TBIL and ALT decreased (Table 2).
In the follow-up, the patients in combination group reobstruction is 125 days, significantly longer than only drainage group which is 89 days (p<0.05)(Table 2).There are 13 patients reobstruction in two groups after drainage to death or the end of follow-up (6 of combined group, 7 of only drainage group), all those patients received former procedure again.The mean survival time of combined group is 185 days, which is longer than only drainage group (p<0.05)(Table 2).4, 6, 8 month survival rates in Combined group and only drainage group were 72%, 52%, 32% and 72% , 18%, 0%, respectively (Figure 1). 2 patients were dead within 1 month after procedure.1 patient died of liver and kidney function failure, 1 patient died due to infection uncontrol.there is no statistical significance in the patients' age, gender, preprocedure infection, obstructive time, obstructive position, drainage type and tumor types between the two groups (Table 3).

Discussion
Because of the liver and lymph nodes around the bile duct are the main parts of tumor metastasis from other areas of the body, especially the gastrointestinal cancer (E. A. et al., 2013).Lymph nodes around of Hepatic hilar is rich, metastasis tumor can be easily cause hilus lymph node enlargement, which could oppress bile duct and cause obstructive jaundice.In our study, all patients with obstructive jaundice have the history of primary tumor resection.Obstructive jaundice caused by metastatic tumor not only yellowing of the skin and eyes (jaundice), itching and discomfort, but also cause liver cholestasis, which leading to liver cell ischemia, necrosis and aggravating liver damage (Hao et al., 2014).High blood bilirubin is contraindication for chemotherapy, so it is important to reduce the bilirubin level as soon as possible, which not only to alleviate the clinical symptoms of patients, but also to reduce liver function damage, promote the recovery of liver function, provide the opportunity for the subsequent treatment of primary tumor (Ho et al., 2013).
High bilirubin level for patients with obstructive jaundice not only damage the liver cells and reduce the liver synthetic ability, but also inhibit the cardiovascular system and lead to renal insufficiency, which could cause serious respiratory failure (Shin et al., 2013).There are 2 patients with liver and kidney function failure and death because of bilirubin did not decline.The TBIL and ALT which reflect the liver function recovery decreasing a lot in both groups have statistical significance, which indicate that botn groups could lowering bilirubin, promoting liver function recovery.The changes mean value of TBIL in combination group is -83.36 umol/L, lower than only drainage group which is -138.03umol/L; The changes mean value of ALT in combination group is -80.67 U/L, the dropping degree is small compared to only drainage group which is -109.47U/L.The changes of TBIL and ALT values in only drainage group were higher than the combinantion group.We consider that the antineoplastic drugs may have damage to liver cells, influence the synthesis and secretion of bilirubin in combination group.But there is no statistical significance between the two groups, the reason may be the anti-tumor treatment has not yet started after procedure in some patients and the follow-up time is short.
The main reason for drainage tube obstruction and stent blocking is tumor growth oppression by external drainage tube, tumour growth through stent mesh, tumor necrosis, biliary tract infection and so on (Westwood et al., 2010;Yu et al., 2010).Some researches has shown that peform PTBS for patients with malignant obstructive jaundice combined with anti-tumor treatment could significantly prolong stent patency and survival time (Qian et al., 2006).This study shows that the mean reobstructiive time in combination group is 125 days, significantly longer  (Todoroki T et al., 2000;Simmons et al., 2006;Zhu et al., 2012).
Interventional drainage in the treatment of the obstructive jaundice caused by recurrence and metastasis after tumor resection can decrease bilirubin level quickly in a short period and promote the liver function recovery.The united treatment in prolonging the survival time and reobstruction time more obvious than drainage only.There is no statistical significance regarding preprocedure infection, obstruction position and tumor type in our study, which is different from other literature.We consider that may related to the number of patient is few, the differences of treatment in different center, and need to be further study.

Table 1 . Indicators Changes Preoprocedure and Postprocedure
Tumor Therapy for Obstructive Jaundice Caused by Recurrence and Metastasis U/L dropped to 91.2 U/L after procedure, only drainage group from 177.1 U/L dropped to 67.6 U/L, both have statistical significance (Table

Figure 1. Cumulative Survival Rate in Patients of the Combined and Drainage Only Groups. Data
were obtained with the Kaplan Meier method than 89 days in only drainage group; the mean survival time in combination group is 185 days, whose long-term prognosis is better than 128 days in only drainage group.Table1shows that median survival time in combination group and only drainage drainage are 176 days and 135 days respectively, 4, 6, 8 month survival rates are 72%, 52%, 32% and 72% 18%, 0%, respectively.125 I seeds imbedding combined with PTBS, arterial perfusion embolism chemotherapy and systemic chemotherapy after PTBD/PTBS to treat local tumor could inhibit the growth of local tumor grow.It is important to use antibiotic to prevent and control infection