Effect of external beam radiotherapy on patency of uncovered metallic stents in patients with inoperable bile duct cancer

Jun Kyu Lee, Won Kwon Kwack, Sang Hyub Lee, Jin Hee Jung, Jae Hyun Kwon, In Woong Han and Jin Ho Lee

Goyang and Seoul, Korea

Effect of external beam radiotherapy on patency of uncovered metallic stents in patients with inoperable bile duct cancer

Jun Kyu Lee, Won Kwon Kwack, Sang Hyub Lee, Jin Hee Jung, Jae Hyun Kwon, In Woong Han and Jin Ho Lee

Goyang and Seoul, Korea

BACKGROUND:Although biliary decompression with metallic stenting is the preferred treatment for inoperable bile duct cancer (BDC), maintenance of patency is still unsatisfactory. We tried to assess the effectiveness and safety of external beam radiotherapy (EBRT) for prolonging stent patency in patients having uncovered metallic stents.

METHOD:We retrospectively reviewed 50 patients who received endoscopic stenting, of whom 18 received EBRT (RT group) and 32 did not (non-RT group).

RESULTS:No difference was found in baseline characteristics between the two groups. Although stent patency was longer in the RT group than that in the non-RT group (140.7±51.3 vs 136.4±34.9 days,P=0.94), the difference was not statistically significant. There were a lower rate of stent occlusion (27.8% vs 50.0% of patients,P=0.12) and a longer overall survival (420.1± 73.2 vs 269.1±41.7 days,P=0.11) in the RT group than in the non-RT group, and the difference again was not statistically significant. The development of adverse reactions did not differ (55.6% vs 53.1% of patients,P=0.91). There was no serious adverse reaction in both groups (P=0.99).

CONCLUSIONS:EBRT did not significantly improve stent patency in patients with inoperable BDC having uncovered metallic stents. However, EBRT was safe. Future trials withrefined protocols for better efficacy are expected.

(Hepatobiliary Pancreat Dis Int 2014;13:423-427)

bile duct cancer;

radiotherapy;

survival;

self-expandable metallic stent;

patency

Introduction

Bile duct cancer (BDC) is one of the periampullary cancers and accounts for about 3% of gastrointestinal malignancies.[1]The peak age for patients with the disease is the seventh decade and the gender incidence shows a slight male preponderance.[2]Though complete resection is the only chance for cure, only 10%-20% of the patients are suitable for surgery.[2-5]Early invasion into adjacent organs is very frequent at the time of diagnosis. Also, many patients cannot undergo operation because of high surgical risks related with advanced age and accompanying co-morbidity. For non-surgical patients, biliary decompression by insertion of metallic stents, with proven effectiveness for improving quality of life, is the preferred treatment.[6-9]However, stent occlusion occurs in 19%-40% of patients because of the tumor growth and/or sludge formation before death.[10]It is not usually feasible to treat these patients with re-intervention because of rapidlyworsening course of the disease. Physicians tried several ways to prevent stent occlusion, such as a covered metallic stent, pharmacological treatments, etc.[11]However, nobody tried to prevent the stent occlusion via direct locoregional therapy which inhibits the growth of the tumor. The present study was to evaluate the effectiveness of prolonging stent patency and the safetyof external beam radiotherapy (EBRT) in patients with inoperable BDC treated with uncovered metallic stents.

Methods

Patients

The patients who underwent endoscopic metallic stenting due to inoperable BDC in Dongguk University Ilsan Hospital between July 2005 and March 2008 were reviewed retrospectively. A diagnosis of BDC was made from the integration of all the results of cytopathology, biopsy, imaging studies, or clinical observation. Inoperability was judged when curative resection was not possible anatomically or surgical risks outweighed potential benefits. Cases of unsuccessful stenting, defined as less than 50% reduction of serum bilirubin within 2 weeks after stent insertion, were excluded. All patients were followed monthly according to a unified protocol. EBRT was recommended for all of the patients and conducted with agreement. The patients who received a minimum dose of 50 Gy (28 fractions) of EBRT were categorized into RT group and those who did not into non-RT group. The patients who underwent more than a fraction of EBRT but dropped out before reaching 50 Gy were not included in the analyses. Systemic chemotherapy or a radiosensitizer was not used.

Procedures

Endoscopic retrograde cholangiopancreatography (ERCP) was performed with a side-viewing duodenoscope (TJF-260, Olympus Corporation, Tokyo, Japan) under appropriate sedation with meperidine and midazolam. Duodenal relaxation was obtained with scopolamine butylbromide. Continuous cardiopulmonary function was monitored for all patients. Under fluoroscopic guidance, operators chose devices and techniques for cannulation freely including the precut fistulotomy technique with a needle-type sphincterotome. After selective probing of the common bile duct, biliary sphincterotomy was performed with a pull-type sphincterotome. The length of a stricture was measured the duration from stent insertion to stent occlusion or death. The secondary outcomes were stent occlusion, overall survival and adverse reactions. Stent occlusion was defined as recurrence of clinical, laboratory or radiological features of obstructive jaundice. The causes of occlusion were also evaluated. The following adverse reactions which may be related possibly with EBRT and/ or stenting were monitored: nausea, vomiting, diarrhea, fatigue, fistula formation, pancreatitis and bleeding. Pancreatitis was defined as presence of abdominal pain lasting for more than 24 hours after the procedure with a more than 3-fold increase above the upper limit of normality in serum amylase or lipase. Bleeding was defined as the need for blood transfusion or a decrease in hemoglobin level of greater than 2 g/dL. An adverse reaction was defined as serious when an intervention resulted in any of the following outcomes according to the FDA guidance: death or a life-threatening event, hospitalization or prolongation of existing hospitalization, or a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions.

Statistical analysis

Data were analyzed using SPSS 20.0 for Windows (SPSS Inc., Chicago, IL, USA). The differences between the groups in categorical variables were analyzed using the Chi-square test with Yates' correction or Fisher's exact test, as applicable. Mean values were expressed as mean± standard error (SE) and compared using the Student'sttest. Overall survival and cumulative stent patency were calculated using the Kaplan-Meier method and compared using the log-rank test. Differences were considered statistically significant whenPvalues were ＜0.05.

Results

A total of 60 patients who received endoscopic metallic stenting because of inoperable BDC were analyzed and using Tandem RX cannulas (Boston Scientific, Natick, MA, USA) or Tracer Metro guidewires (Cook Endoscopy, Winston-Salem, NC, USA). After ensuring the passage of a guidewire through the stricture, a self-expandable uncovered metallic stent (Bonastent, Standard Sci-Tech, Seoul, Korea) was deployed. The diameter of stents was 10 mm and the lengths (40, 60 or 80 mm) were selected according to fluoroscopic findings.

Outcomes of interest

Fig. 1.Patient selection process. EBRT: external beam radiotherapy.

The primary outcome was stent patency, defined as10 of them were excluded (Fig. 1). Finally, 18 patients were included in the RT group and 32 in the non-RT group. Baseline characteristics did not differ between the two groups (Table 1). Although stent patency (140.7 ± 51.3 days vs 136.4±34.9 days,P=0.94) was longer in the RT group than in the non-RT group, it was statistically insignificant (Table 2 and Fig. 2).

There was a lower rate of stent occlusion (27.8% vs 50.0%,P=0.12) and a longer overall survival (420.1±73.2 days vs 269.1±41.7 days,P=0.11) in the RT group than in the non-RT group, the difference was not statistically significant. The adverse reactions were similar between the two groups (55.6% vs 53.1%,P=0.91, Table 2 and Fig. 3). There was no serious adverse reaction in both groups (P=0.99).

Table 1.Baseline characteristics (n, %)

Table 2.Comparison of RT and non-RT groups (n, %)

Fig. 2.Kaplan-Meier graph showing stent patency (P=0.90).

Fig. 3.Kaplan-Meier graph showing overall survival (P=0.11).

Discussion

BDC is one of the most aggressive malignant tumors with a 5-year survival rate of less than 5%.[2]The number of surgical candidates is limited at the time of diagnosis and non-surgical modality with proven efficacy for survival benefit is not established. Metallic stenting is an option for jaundiced patients since it improves the quality of life. However, placement of a stent is not associated with the prolongation of survival.

Previous studies[12,13]reported beneficial effects of systemic chemotherapy in patients with inoperable BDC. However, survival gain was minimal although only patients who could endure toxicity were enrolled selectively in most trials.[12,14]Systemic chemotherapy cannot be performed feasibly in an ordinary patient with BDC since the general condition tends to be poor. In contrast, EBRT may be tolerated well in most of patients with BDC because of the advanced techniques, such as intensity-modulated or image-guided radiotherapy and breathing management, which decreased the toxicities.[15,16]However, the data of the effects of EBRT on patients with BDC treated with metallic stents are paucity and we therefore conducted this study.

There were a number of earlier studies which reported the benefits of radiotherapy in patients withBDC.[17-21]However, EBRT has not been conducted as actively as before since metallic stenting became the mainstay of palliative therapy in patients with BDC. There might be a concern that radiation may interfere with the physical properties of metallic stents or cause unexpected side effects. When radiation is applied for cancer tissue in which a metallic stent is incorporated, secondary electron beams and scatter induced by the inserted stent may cause dose perturbation at the interface between the stent and surrounding tissue, suggesting the possibility of an over and under dose.[22]Tsuji et al[22]reported a 9% increase in the absorption dose of scatter around the biliary metallic stent in dogs. There was 0 to 7.3% radiation dose enhancement due to backscatter in a dosimetric film model of 16 different esophageal stents.[23]Chen et al[24]concluded that the net impact of dose enhancement is negligible and dose reduction is unnecessary as long as multiple fields are used in a solid water phantoms experiment with various esophageal stents. Few standardized modified protocols, however, were suggested from human studies, especially for BDC. In the only relevant modern study, Park et al[25]reported that the patency of biliary metal stents in pancreaticobiliary cancer patients who received chemoradiation therapy was significantly longer than that in those who did not. However, out of 40 patients, 29 had pancreatic cancer and only one had BDC in this study. Also, because EBRT was performed concurrently with chemotherapy, the exact role of EBRT could not be estimated. To the best of our knowledge, this is the first study which assessed the role of EBRT on patency of uncovered metallic stents in patients with BDC.

The life quality of a patient with inoperable BDC is closely related to the relief of obstructive jaundice. Currently, endoscopic or percutaneous biliary stenting, preferentially with a metallic stent, has replaced surgical bypass. However, as maintenance of stent patency is still unsatisfactory, there are ongoing efforts to prevent occlusion. Besides a covered metallic stent and pharmacological treatment, placement of a stent which elutes a drug or with an antireflux valve was attempted.[26,27]EBRT is a rational approach for this purpose since it can inhibit the growth of a tumor directly. The present study showed that the stent occlusion rate in the EBRT group was lower, although it did not reach to the significant level. The present study also confirmed the safety of EBRT in BDC treatment. Future trials for improving stent patency or overall survival with refined protocols are expected. Recently, photodynamic therapy and radiofrequency ablation have been introduced for treating malignant biliary obstruction. Though they can be used safely and feasibly in patients having metallic stents, anti-tumor effects cannot be expected outside bile ducts. Therefore, the combinations of these modalities with EBRT may be good challenges.[28,29]

This study has a few limitations in addition to the retrospective design and small sample size. Firstly, there might be a selection bias since the number of patients was smaller in the RT group than in the non-RT group. It is admitted that advanced age (the mean ages were 69.3 years in the RT group and 71.7 years in the non-RT group) and accompanying co-morbidity might have contributed to the uneven distribution of patients. However, previous studies[30,31]showed that the influences were not great because both of them were not associated with stent patency. Secondly, EBRT was used without radiosensitizer. The beneficial effects of concurrent chemo-radiation therapy are established in many gastrointestinal malignancies. However, data are lacking in the results in patients with BDC, especially having metallic stents. Since EBRT and chemotherapy, even radiosensitizer, might have synergic or added effects on tumor treatment and thus, complicates the role of EBRT in the treatment of BDC, we therefore did not use chemotherapeutic agents or radiosensitizer. Our purpose was to evaluate the safety of EBRT per se since safety is as important as the effectiveness.

In conclusion, the stent patency of uncovered metallic stents was not significantly improved with EBRT in patients with inoperable BDC. However, EBRT is safe in the treatment of BDC with uncovered metallic stents, future trials with refined protocols for better efficacy are expected.

Contributors:LSH proposed the study. LJK and KWK were involved in study design, wrote the first draft, and contributed equally to the article. JJH and KJH collected data. HIW and LJH provided study materials. LSH is the guarantor.

Funding:None.

Ethical approval:This study was approved by the institutional review board of the Dongguk University Ilsan Hospital.

Competing interest:No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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Received January 17, 2014

Accepted after revision May 20, 2014

Author Affiliations: Departments of Internal Medicine (Lee JK, Kwack WK and Lee JH), Radiology (Jung JH and Kwon JH) and Surgery (Han IW), Dongguk University Ilsan Hospital, College of Medicine, Dongguk University, Goyang 410-773, Korea; Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, College of Medicine, Seoul National University, Seoul 110-744, Korea (Lee SH)

Sang Hyub Lee, MD, PhD, Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, College of Medicine, Seoul National University, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea (Tel/Fax: +82-2-760-8112; Email: gidoctor@ snu.ac.kr)

? 2014, Hepatobiliary Pancreat Dis Int. All rights reserved.

10.1016/S1499-3872(14)60282-4

Published online July 17, 2014.